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Prescribing

Outlook

New Medicines

September 2013

A resource for the NHS to

help with budget setting,

prescribing planning and

medicines management.

Contents

Foreword ...... 1 Abbreviations ...... 3 Key ...... 4 Summary of predicted launch dates ...... 5 Highlights ...... 8 Table 1. Pipeline drugs ...... 11 BNF 1. Gastrointestinal system ...... 11 BNF 2. Cardiovascular system ...... 13 BNF 3. Respiratory system ...... 18 BNF 4. Central nervous system ...... 20 BNF 5. Infections ...... 22 BNF 6. Endocrine system ...... 26 BNF 7. Obstetrics, gynaecology, and urinary-tract disorders ...... 29 BNF 8. Malignant disease and immunosuppression ...... 30 BNF 9. Nutrition and blood ...... 51 BNF 10. Musculoskeletal and joint diseases ...... 53 BNF 11. Eye ...... 56 BNF 13. Skin ...... 57 BNF 14. Vaccines ...... 59 Table 2. Drugs in Prescribing Outlook 2012 - development delayed ...... 60 Table 3. Recent UK drug launches or licence extensions ...... 61 BNF 1. Gastrointestinal system ...... 61 BNF 2. Cardiovascular system ...... 61 BNF 3. Respiratory system ...... 61 BNF 4. Central nervous system ...... 62 BNF 5. Infections ...... 62 BNF 6. Endocrine system ...... 63 BNF 7. Obstetrics, gynaecology, and urinary-tract disorders ...... 63 BNF 8. Malignant disease and immunosuppression ...... 64 BNF 9. Nutrition and blood ...... 66 BNF 10. Musculoskeletal and joint diseases ...... 66 BNF 11. Eye ...... 66 BNF 12. Ear, nose and oropharynx ...... 67 BNF 13. Skin ...... 67 Patent expiries 2013 - 2015 ...... 68 Biosimilar developments ...... 69 Index ...... 71 Acknowledgements ...... 73

Foreword

Managing new medicines the option to submit a proposal for a Patient Access Schemes (PAS). This allows NICE to recommend Underpinning the strategic direction for managing new treatments that it might otherwise not have been found to be medicines is the Department of Health's report Innovation cost effective. PAS are either cost (discounts, free stock Health and Wealth, Accelerating Adoption and Diffusion in etc) or outcome (price variation linked to patient outcomes) the NHS document (2011, updated 2012) . It sets out the based. A list of NICE technologies with an approved PAS Government’s support for the NHS to embrace innovation can be viewed on the NICE website. In Prescribing Outlook to meet current and future healthcare challenges and current PAS schemes are highlighted if they are relevant to outlines the importance of early adoption and diffusion of a new medicine in the same therapeutic area, and, although clinically and cost effective innovative practices, including this will not give an indication of the likely cost of the new medicines. Horizon scanning is essential at many medicine, it suggests that subsequent treatment options will organisational levels so that new medicines that improve have to be competitive. patient outcomes can be planned for and adopted. The role of NICE is expanding to include support for Since April 2013, NHS England Area Teams have a implementation of NICE guidance. Where relevant, links strategic medicines management role and are responsible are provided in Prescribing Outlook to NICE pathways, for commissioning the majority of high cost drugs as well commissioning guidance and quality standards. Quality as all . The detail of the operational standards are designed to drive and measure quality mechanisms underpinning these responsibilities is yet to improvements within a particular area of care and be be fully outlined although a number of interim reflected in commissioning frameworks. NICE commissioning documents relevant to medicines have implementation tools for launched drugs include costing been published including: templates and these may provide relevant information for Individual funding requests (IFRs) – for when drugs are drugs yet to be launched. The NICE Medicines and not routinely commissioned. Prescribing Centre (MPC) has produced good practice Implementation and funding of NICE guidance guidance on developing and updating local formularies in Experimental and unproven treatments response to Innovation Health and Wealth, Accelerating On-going treatment following a NHS England funded Adoption and Diffusion in the NHS. It advises that local trial systems and processes for accessing medicines support On-going treatment following non-commercially funded innovation where appropriate and recommends horizon clinical trials scanning is included as a standing agenda item in local On-going access to treatment following a trial of formulary decision-making meetings. treatment It is estimated more than 70% of the secondary care drugs On-going access to treatment following industry bill can be accounted for by ‘high cost’ drugs excluded from sponsored clinical trials or funding the Payment by Results (PbR) tariff, the national system for Specialised Services Commissioning Innovation Fund paying trusts for activity. Standard tariff prices do not (SSCIF) always allow fair reimbursement of some interventions so a

list of drugs and services excluded from the tariff has been The cancer drug fund (CDF), set up to facilitate patient developed. The majority of drugs appearing on this list access to cancer treatments that fail to get NICE approval, (previously known as ‘PbR exclusions’, now referred to as is being managed by NHS England until the end of 2013. ‘Specified high cost drugs’) are likely to be commissioned The most recent list of drugs funded by the CDF can be by NHS England via specialised commissioning systems accessed via the NHS England website. The intention is but the detail of exactly which drugs and how the funding that the CDF will cease as value based pricing (VBP) is streams operate is awaited. The Manual outlining which implemented in January 2014. Under VBP, different pricing services (and treatments) are commissioned by NHS strategies will apply to different indications for drugs based England has been published but will be updated shortly. on the assessed ‘value’ for each indication. The mechanism for VBP is still to be decided but NICE will have As of April 2013 the Department of Health is no longer a central role in the process and be responsible for the full responsible for managing PbR; Monitor has been charged value assessment of medicines (see terms of reference). with this and is currently consulting on the future direction There are already situations where the same medicine has of the Tariff. There are few changes for the 2013/14 PbR a different price for different indications. This is especially tariff (see tab 19 for high cost drugs detailed list) but true for medicines that have an orphan designation. In this payment mechanisms for high cost drugs in 2014/15 could case, the medicine will have a different brand name for be influenced by the outcome of the consultation. In non-orphan and orphan indications. previous editions of Prescribing Outlook an ‘educated guess’ as to the potential tariff positioning of each new The majority of new medicines highlighted in this document medicine has been made. Current uncertainty now makes are due to be launched in 2014 or beyond. Their launch will this difficult. In the absence of additional guidance for be affected by VBP reimbursement negotiations, but exactly 2014/15, estimates of tariff positioning in this document are how is currently uncertain. For high cost new medicines based on historical assumptions. An ‘educated guess’ is that are in the NICE work programme manufacturers have also made on the likely commissioning route for individual

UKMi September 2013 Solely for use within the NHS and not for commercial use. page 1 No responsibility is accepted for the content of documents derived from this original publication. medicines to take into account new commissioning About Prescribing Outlook arrangements outlined above. The aim of the annually published Prescribing Outlook series produced by UK Medicines Information (UKMi) is to For the pharmaceutical industry, the cost of bringing a new assist NHS organisations in planning, implementing and drug to the market is high. It is inevitable that more effort is budgeting for new medicines or licence extensions and being put into looking for new uses for, or new formulations national guidance. It provides support to commissioners of, currently licensed products. Applications for licence and providers by highlighting new medicines and service extensions are processed through licensing systems faster developments that may require dialogue about financial than those for new drugs as less safety and technical data and operational resource implications. The Prescribing are required. Data collection of pipeline licence extensions Outlook series is produced for primary and secondary care and new formulations has also improved over recent years. NHS organisations and has a national perspective. This As a result an increased number of potential licence document is the first in the series that comprises extensions appear in this document. This year, to manage Prescribing Outlook - New Medicines and Prescribing this, there are two types of monograph; a full monograph Outlook - National Developments, and is supported by an with all the information previously included and an electronic Cost Calculator. These are all available at abbreviated entry (highlighted in blue) containing basic www.ukmi.nhs.uk. The component documents of the information for those drugs with an anticipated launch date Prescribing Outlook series are published each autumn in in 2015 or beyond. This enables us to highlight drugs near line with annual budget planning timeframes and key and slightly further away from launch in the same outputs from NICE. Updates on the progress of individual therapeutic area. medicines at other times throughout the year can be found As in previous editions of Prescribing Outlook, drugs with on the UKMi New Drugs Online database. patents due to expire in the near future are highlighted as The content and presentation of the Prescribing Outlook they are then open to generic competition. It is important series has evolved following consultation with users. These that the possibility of generic options is considered as part documents they are all now only published electronically of the wider medicines management agenda, hence their but are formatted to make them suitable for printing. inclusion in this document together with an ‘educated Further specialist medicines information not included in the guess’ as to which have the potential for generic series can also be obtained from local and regional competition and an indication whether generic product medicines information centres. See www.ukmi.nhs.uk. licence applications are currently in progress in the EU. For the first time we have included a separate section on Prescribing Outlook – New Medicines. It aims to provide biosimilar drugs. Although there are a small number of advance information about new medicines (and new biosimilar drugs already on the market there are many licensed indications or formulations) with anticipated more in the pipeline that could have a potentially cost market launches in the next 18 to 24 months. In addition, saving impact on medicines budgets. It is estimated about brief details of drugs launched in the last 12 months are 50% of the current UK market for biological medicines included as this is often useful for local planning purposes. spend may be subject to biosimilar competition by 2019.1 The content is not comprehensive but focuses on medicines with the potential for significant clinical or There are a number of regulatory schemes that impact on financial impact on the NHS. Estimates of potential uptake, the availability of new medicines. Those that allow earlier patient, service and financial implications are included access to medicines in the EU and UK include ‘individual where possible. Reference is made to relevant national patient supply’ and ‘conditional approval’. Where relevant, guidance and links to in-depth independent reviews are and if known, details of these are included in this included, where available. document. Details of a scheme which would allow patients access to new medicines prior to licensing were put out for How is the content decided? consultation by the Medicines and Healthcare products Various criteria are applied to prioritise those medicines in Regulatory Agency (MHRA) in July 2012. The intention of the pipeline likely to have the largest impact. These the scheme is to widen access to "promising new include considering whether: medicines that will treat, diagnose or prevent life threatening, chronic or seriously debilitating conditions the medicine is expected to provide a significant without adequate treatment options". The outcome of the improvement in disease management, consultation is awaited. the medicine is first-in-class or has a major new indication,

there are limited alternatives, 1. Anon. What are biosimilars and are they important? Drug and the medicine cost will be high, Therapeutics Bulletin 2013; 51(5): 57-60. the target population is large, there is likely to be a significant effect on service implications e.g. route/ formulation/ method of delivery, the medicine or disease area is an NHS priority, the medicine has significant additional indications in the advanced pipeline stage, the medicine is in the EU licensing process, there is likely to be significant media interest.

UKMi September 2013 Solely for use within the NHS and not for commercial use. page 2 No responsibility is accepted for the content of documents derived from this original publication. There will be additional, unquantifiable, factors that have Foundation Trust. [email protected], implications for the NHS such as local demographics and [email protected] prescribing preferences which cannot be accommodated in New Drugs Online (NDO) database includes information a national document. on medicines in clinical development from phase II trials to More detailed information on the medicines listed can be product launch and includes links to evaluated information obtained from the UKMi New Drugs Online (NDO) on medicines up to one year post launch. This database is database which can be accessed directly from the generic maintained by UKMi and forms the basis of the content of name hyperlink in this document. Prescribing Outlook – New Medicines. This dynamic horizon scanning tool is updated daily and can be used to Please direct comments on Prescribing Outlook – New produce reports based on a number of criteria including Medicines to the editor: Helen Davis, North West possible launch date, stage of clinical development or Medicines Information Centre, Pharmacy Practice Unit. pharmaceutical company. Access is free to all with an NHS [email protected]. email address via www.ukmi.nhs.uk but requires individual registration. Access is. Limited access is also freely available to non-NHS users via Evidence search Other UKMi horizon scanning resources (www.evidence.nhs.uk). Prescribing Outlook – National Developments estimates Please direct comments and enquiries on New Drugs the impact on clinical practice and prescribing budgets of Online to: Alexandra Denby, London Medicines Information national guidance, mainly that issued by NICE. It is Service-Northwick Park, Northwick Park & St Mark's intended to inform discussions between commissioners Hospitals. [email protected] and providers, and highlight issues around implementation of guidance. Access is via www.ukmi.nhs.uk. Prescribing Outlook – Cost Calculator is an Excel Horizon scanning and new medicines support spreadsheet tool to facilitate estimates of potential materials are available via www.ukmi.nhs.uk prescribing changes for a local population. Access is via www.ukmi.nhs.uk. The information in these resources is the best available at the time of publication but Please direct comments on Prescribing Outlook – National Developments and the Cost Calculator to: Devika Sennik is subject to significant change with time. or David Erskine, London and South East Medicines Information Centre, Guy’s and St. Thomas’ NHS

Abbreviations

AWMSG All Wales Medicines Strategy Group NICE-MPC NICE Medicines and Prescribing Centre BNF British National Formulary NNH Number needed to harm CCG Clinical Commissioning Group NNT Number needed to treat DH Department of Health NPC National Prescribing Centre (now the NICE Medicines and Prescribing Centre – MPC) EMA European Medicines Agency ns Not significant EU European Union PAS Patient Access Scheme HR Hazard ratio PbR Payment by Results HRG Healthcare Resource Group (definition) RDTC Regional Drug & Therapeutics Centre, i.m. Intramuscular Newcastle i.v. Intravenous s.c. Subcutaneous L(C)NDG London (Cancer) New Drugs Group SIGN Scottish Intercollegiate Guidelines Network. MHRA Medicines and Healthcare products SMC Scottish Medicines Consortium Regulatory agency SmPC Summary of Product Characteristics MTRAC Midland Therapeutics Review & Advisory Committee TBC To be confirmed NDO New Drugs Online UKMi United Kingdom Medicines Information NETAG North East Treatment Advisory Group US United States NHSE NHS England NIHR-HSC National Institute for Health Research Horizon Scanning Centre NICE National Institute for Health and Care Excellence

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Key

Generic Indication Current status Predicted UK National guidance: Relevant name and The PII/III – in phase two/three trials. launch or publications (funding source). formulation indication licence NICE - National Institute for Health and Filed – licence application has extension Brand name for the been submitted. Care Excellence: www.nice.org.uk (DH). Company product. An informed SIGN - Scottish Intercollegiate Guidelines Recommended for approval – estimate based The closer opinion of the advisory committee Network. www.sign.ac.uk (NHS the drug is on knowledge of Scotland). Medicines of the licensing authority to launch processes and SMC - Scottish Medicines Consortium. are listed by suggests the medicine should be the more timescales www.scottishmedicines.org.uk (NHS BNF licensed. In the EU a full licence involved in specific this is likely within three months. Scotland). category can be. licensing and linked Relevant links are included. systems. AWMSG - All Wales Medicines Strategy Licensed – the product has been Group. www.wales.nhs.uk/awmsg (NHS). to relevant It is easier to Reviews: Independent reviews and publicly Included in granted a marketing licence. The predict when a regional guidance that is accessible available abbreviated company determines launch product will be to all NHS sectors published pages of the entries. date. available once it between 2011 and 2013. Included in NDO Launched – the medicine is is has entered abbreviated entries. database. marketed in the EU. If launched the licensing The elsewhere in the world, but not process as NICE-MPC: NICE Medicines and company the UK, there are links to known time Prescribing centre (DH). that holds prescribing data. frames apply. NIHR-HSC - NIHR Horizon Scanning the Orphan status – If a medicine has However, once Centre. www.nhsc-healthhorizons.org.uk. marketing a designated orphan status this is a licence has (NIHR). rights in the indicated (see definition page 7). been granted NPC - National Prescribing Centre (now EU is listed the company The following apply to US the NICE-MPC. www.npc.co.uk. (Legacy together decides when expediated programmes for site for reviews prior to May 2012). with a co- and where to serious or life-threatening UKMi - United Kingdom Medicines promoter launch the conditions and suggest the drug Information. www.ukmi.nhs.uk (NHS). company if product. relevant. will pass through licensing L(C)NDG - London (Cancer) New Drugs systems faster: Included in Group (NHS organisations in Greater abbreviated Breakthough therapy status – London). entries. Included in preliminary evidence indicates MTRAC - Midlands Therapeutics Review abbreviated substantial improvement over & Advisory Committee. www.mtrac.co.uk. entries. existing therapies on clinically (Primary Care NHS organisations in the significant outcomes. Midlands). Fast-track status –potential to NETAG - North East Treatment Advisory address unmet needs. Group. www.netag.nhs.uk (legacy site of Priority review – provides sub-group of North East Specialised significant improvement in safety Commissioning Group). or effectiveness. RDTC - Regional Drug & Therapeutics Centre. rdtc.nhs.uk. (NHS organisations Included in abbreviated entries. in the North East of England). Target population: Data Implications: Factors highlighted include patient options, monitoring or testing requirements on prevalence (number and service implications related to medicine delivery. with the disease) and Financial implications: Cost implications are assessed based on a number of assumptions incidence (number of new such as whether the medicine is added to existing therapy or is a competitor in areas where cases each year) are budgets are established. Factors that are difficult to quantify include likely uptake of the reported for a 100,000 medicine within the target population. For launched products, costs are taken from the latest population, if possible. published NHS costs, or, for generic prices, from the Drug Tariff. Where a patient access Sector: An indication of scheme (PAS) may apply this is indicated. Unless stated, costs do not include VAT. which sector in the NHS Likely commissioning route: An estimate of the potential commissioning route based on the medicine is likely to NHS structures implemented since Apr 2013 i.e. CCG or NHS England (NHSE). Included in impact, at least initially, in abbreviated entries. terms of service provision. Payment by Results (PbR): The actual or anticipated tariff position based on historical assumptions. For drugs not yet launched this becomes an educated guess. Drugs previously referred to as ‘PbR exclusions’ are now known as ‘Specified high cost drugs’. If a drug is not likely to be a specified high cost drug it is therefore, by default, likely to be included within tariff and will be listed as ‘HRG included’. Included in abbreviated entries. Pharmacology: Therapeutic class and/or mode of action and administration details. Included in abbreviated entries. Efficacy: Key studies with a link to trial details, especially when relevant for licence application. Primary outcome data and patient, rather than disease, orientated outcomes are preferentially included where available. Safety: For medicines already marketed for other indications a link to the product information is included. For new medicines, information is included where it is thought adverse effects reported to date may influence licensing requirements e.g. increased monitoring or where they differ significantly from those associated with current treatments.

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Summary of predicted launch dates

This list summarises the earliest predicted UK launch date for pipeline drugs listed in Table 1 – Pipeline drugs. Refer to the index for a full list of generic and proprietary names. *Indicates which drugs have been assigned orphan status in the EU (see page 7 for more details).

BNF Drug Indication Page BNF Drug Indication Page Late 2013 9 Alipogene Lipoprotein lipase 52 tiparvovec* deficiancy 1 Golimumab Ulcerative colitis 11 10 Canakinumab* Juvenile idiopathic 53 2 Lomitapide Hypercholesterolaemia- 16 arthritis familial 10 Ustekinumab Psoriatic arthritis 54 2 Defibrotide* Hepatic veno-occlusive 17 10 Ataluren* Duchenne muscular 55 disease dystrophy 3 Indacaterol/ Chronic obstructive 18 10 Pegloticase Gout prophylaxis 55 glycopyrronium pulmonary disease 11 Macular oedema 56 3 Nalfurafine* Dialysis-related pruritus 19 13 Afamelanotide* Erythropoietic 58 4 Lurasidone Schizophrenia 20 protoporphyria 5 Tobramycin* Cystic fibrosis 22 14 Meningococcal Meninitis B 59 5 Bedaquiline Tuberculosis 22 group-B vaccine 5 Cobicistat HIV infection (booster) 23 2014 5 Dolutegravir HIV infection 23 1 Vedolizumab Ulcerative colitis 11 6 Alogliptin Type 2 diabetes mellitus 26 1 Teduglutide* Short bowel syndrome 12 6 Canagliflozin Type 2 diabetes mellitus 26 1 Vedolizumab Crohn's disease 12 6 Dapagliflozin/ Type 2 diabetes 27 2 Apixaban Venous 13 metformin mellitus thromboembolism 6 Follitropin alfa Biosimilar 70 treatment 7 Botulinum A Overactive bladder 29 2 Dabigatran Venous 13 toxin thromboembolism treatment and 8 * Thyroid cancer 31 secondary prevention 8 Non-small cell lung 31 2 Rivaroxaban Secondary prevention of 14 cancer atherothrombotic events 8 33 in acute coronary emtansine syndrome 8 Trastuzumab/ Breast cancer 34 2 Rivaroxaban Acute coronary 14 hyaluronidase syndrome- prevention of stent thrombosis 8 Masitinib* 36 2 Cangrelor Acute coronary 15 8 Colorectal cancer 37 syndrome – thrombosis 8 Sipuleucel-T 39 prevention 8 Radium-223 Prostate cancer 40 2 Vorapaxar Secondary prevention of 15 chloride cardiovascular events 8 Malignant 43 2 Riociguat Pulmonary arterial 16 8 Non-Hodgkin’s 45 hypertension 2 Clevidipine Hypertension, 17 8 Non-Hodgkin’s 45 perioperative lymphoma 3 Umeclidinium Chronic obstructive 18 8 46 pulmonary disease 8 48 3 Umeclidinium Chronic obstructive 18 /vilanterol pulmonary disease 8 Laquinimod Multiple sclerosis 49 3 Budesonide/ Asthma 19 8 Dimethyl Multiple sclerosis 50 formoterol fumarate (Bufomix) 8 Teriflunomide Multiple sclerosis 50 3 Omalizumab Urticaria 19 9 Eltrombopag Thrombocytopenia 51 4 Loxapine Agitation associated 20 9 Sodium Urea cycle disorders 52 with schizophrenia and phenylbutyrate bipolar disorder

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BNF Drug Indication Page BNF Drug Indication Page 4 Dextrometh- Pseudobulbar affect 21 9 Elosulfase alfa* Mucopolysaccharidosis 51 orphan/quinidine IVA 4 Liraglutide Obesity 21 10 Golimumab Juvenile idiopathic 53 arthritis 5 Simeprevir Hepatitis C 24 10 Apremilast Psoriatic arthritis 54 5 Sofosbuvir Hepatitis C 24 10 Idebenone* Duchenne muscular 56 6 Bazedoxifene/ Postmenopausal 28 dystrophy conjugated osteoporosis and estrogens menopausal symptoms 11 Aflibercept Diabetic macular 56 oedema 6 degludec Type 1 and 2 diabetes 27 /insulin aspart mellitus 13 Apremilast Psoriasis 57 6 Pasireotide* Acromegaly 28 13 Tofacitinib Psoriasis 57 6 Tolvaptan Polycystic kidney 29 13 Secukinumab Psoriasis 58 disease 13 Propranolol Infantile haemangioma 58 6 Follitropin alfa Biosimilar 70 2015 or 2016 7 Collagenase Peyronie's disease 30 clostridium 1 Obeticholic acid Cirrhosis 12 histolyticum 1 Infliximab Biosimilar 70 8 Thyroid cancer 30 2 Desmoteplase Stroke 15 8 * Thyroid cancer 31 2 Evolcumab Hyperlipidaemia 16 8 Enobosarm Non-small cell lung 33 2 Alirocumab Hypercholesterolaemia 16 cancer 3 Masitinib Asthma 19 8 Trastuzumab Breast cancer 34 emtansine 3 Ataluren* Cystic fibrosis 20 8 Breast cancer 34 3 Lumacaftor Cystic fibrosis 20 8 Breast cancer 35 5 ABT450/ Hepatitis C 25 ritonavir / ABT- 8 Regorafenib Gastrointestinal stromal 36 267/ ABT333 tumours 5 Asunaprevir/ Hepatitis C 25 8 Hepatocellular 37 daclatasvir heat-sensitive* carcinoma 5 Sofosbuvir/ Hepatitis C 25 8 Sorafenib Renal cell carcinoma 38 ledipasvir 8 Apaziquone 38 5 Actoxumab/ Clostridium difficile 25 8 Prostate cancer - 39 bezlotoxumab infection treatment 6 Insulin inhaled Type 1 and 2 diabetes 27 8 Ovarian cancer 40 mellitus 8 Bevacizumab Ovarian cancer 41 6 Exenatide Type 2 diabetes 27 implant mellitus 8 * Ovarian cancer 41 6 Insulin glargine Biosimilar 70 8 * Ovarian cancer 41 8 Brain cancer Glioblastoma 30 8 Ipilimumab Malignant melanoma 42 vaccine* 8 Ipilimumab Malignant melanoma 43 8 Afatinib 30 8 Malignant melanoma 44 8 Afatinib Non-small cell lung 32 8 Dasiprotimut-T* Non Hodgkin’s 45 cancer lymphoma 8 Belagen- Non-small cell lung 32 8 * Multiple myeloma 46 pumatucel-L cancer 8 * Chronic lymphocytic 47 8 LDK378 Non-small cell lung 32 leukaemia cancer 8 * Chronic lymphocytic 47 8 Non- small cell lung 32 leukaemia cancer 8 * Cutaneous T cell 48 8 Non-small cell lung 32 lymphoma cancer 8 Peginterferon Multiple sclerosis 49 8 Ganetespib Non-small cell lung 32 beta 1a cancer 8 Teriflunomide Multiple sclerosis 51 8 Anamorelin Cancer cachexia 33 8 Trastuzumab Biosimilar 70 8 Sorafenib Breast cancer 35 8 Breast cancer 35

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BNF Drug Indication Page BNF Drug Indication Page 8 * Hepatocellular 37 8 Rigosertib* Myelodysplastic 48 carcinoma syndromes 8 Sorafenib* Hepatocellular 37 8 Daclizumab Multiple sclerosis 50 carcinoma 8 Fingolimod Multiple sclerosis 50 8 Custirsen Prostate cancer 39 9 Sebelipase alfa* Liposomal acid lipase 52 8 Cabozantinib Prostate cancer 40 deficiency 8 Trebananib Ovarian cancer etc. 42 10 Masitinib 53 8 * Ovarian cancer 42 10 Secukinumab Rheumatoid arthritis 53 8 Eribulin* Sarcoma 42 10 Secukinumab Ankylosing spondylitis 54 8 Talimogene Malignant melanoma 44 10 Secukinumab Psoriatic arthritis 54 laherparepvec 10 Lesinurad Gout 55 8 Cobimetanib Malignant melanoma 44 10 Odanacatib Osteoporosis in men 55 8 Erismodegib Basal cell carcinoma 44 10 Infliximab Biosimilar 70 8 Multiple myeloma 46 11 Aflibercept Macular oedema 57 8 * Mantle cell lymphoma 47 Uncertain 8 Chronic lymphocytic 47 leukaemia 2 Serelaxin Heart failure 17 8 Vosaroxin* Acute myeloid 47 8 Omacetaxine* Chronic myelogenous 46 leukaemia meppesuccinate leukaemia

8 Ibrutinib Chronic lymphocytic 48 leukaemia

*Indicates which drugs have been assigned orphan status in the EU. To qualify for orphan designation, a medicine must meet one of these criteria: It is intended for a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 (50 in 100,000) people in the EU; It is intended for a life-threatening, seriously debilitating or serious and chronic condition and without incentives it is unlikely that the revenue after marketing would cover the investment in its development. In both cases, there must also be either no satisfactory method of diagnosis, prevention or treatment of the condition concerned authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition. Manufacturers of drugs that have received orphan designation benefit from incentives to support development of medicines to treat rare diseases. The US definition of an orphan drug is different. It is defined as a rare disease occurring in less than 200,000 individuals. Assuming a US population of about 311 million this translates to a prevalence of about 65 in 100,000. The definition of an ultra orphan condition used by NICE is a UK prevalence of less than 1 in 50,000.

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Highlights

The drugs listed below have been selected from table 1 (drugs not yet marketed) as warranting special consideration due to their expected overall NHS impact taking account of financial implications, service provisions, place in therapy and target population. Such data are limited so the list is for guidance only and will not take account of local factors or perspective which will vary by sector, geography and speciality. You may also want to refer to table 3 (recently launched drugs) to identify those requiring active management locally.

Drug Indication Reasons for highlighting

Defibrotide Hepatic In haematopoietic stem-cell transplant VOD is a leading cause of morbidity and mortality. page 17 veno- Supportive care is the current treatment option. Defibrotide will be the first specific therapy occlusive for VOD. It is likely to be expensive; based on a dose of 25mg/kg/day, current named disease patient cost is around £40,000 for 21 days treatment. (VOD). Likely commissioning route: NHSE. PbR: Specified high cost drug.

Rivaroxaban Acute Rivaroxaban 2.5mg twice daily will be used for prevention of atherosclerotic events in page 14 coronary patients with elevated cardiac biomarkers in combination with one or more antiplatelets. syndrome However, bleeding risks may be a concern, especially in older patients. Cost will be in (ACS). addition to existing therapy; price is currently uncertain. Likely commissioning route: CCG. PbR: HRG included.

Dextro- Pseudo- PBA can develop in several neurological diseases such as multiple sclerosis, or following methorphan/ bulbar brain injury. The estimated prevalence of PBA is up to 500 per 100,000 people. This is the quinidine affect first drug licensed for PBA. Diagnosis needs confirmation before treatment and may page 21 (PBA). increase referrals to specialist neurosciences. It is likely to be considerably more expensive than unlicensed alternatives. Likely commissioning route: NHSE. PbR: Likely HRG included.

Insulin Type 1 and Estimated UK prevalence of diagnosed diabetes was 2.9 million people in 2011and a degludec/ type 2 further 850,000 are undiagnosed. Prevalence is projected to increase to 5 million by 2025. insulin aspart diabetes Spending on analogue insulin is increasing and combination use of analogues is likely to page 27 mellitus. increase. Likely commissioning route: CCG. PbR: HRG included.

Tolvaptan Autosomal- ADPKD has a prevalence of 100-1,300 per 100,000 people. In 2007 polycystic kidney page 29 dominant disease accounted for 12.7% of patients receiving renal transplants. There are currently no polycystic therapies that modify disease course and slow decline in renal function. Current options kidney include anti-hypertensives, dialysis and renal transplant. Tolvaptan 60mg/day costs over disease £4,100/month. (ADPKD) Likely commissioning route: Uncertain -depending on statge of renal failure. PbR: Specified high cost drug.

Everolimus Breast The incidence of metastatic BC in the UK is about 32 per 100,000 people. 25% are HER2- cancer positive with a worse prognosis. About 70% of patients do not respond to first-line (BC), trastuzumab and the rest develop resistance within the first year. Trastuzumab advanced emtansine Adding everolimus first-line may improve response rates and delay need for second-line HER2- chemotherapy; it will compete with i.v. and costs will be additive. Used second pages 34,35 positive – or third-line everolimus is an alternative to for overcoming trastuzumab resistance. first-, Current monthly cost of everolimus is £2,250 to £2,970. second- or First-in-class is an antibody conjugate of trastuzumab and an anti- third-line. mitotic agent, maytansinoid DM1. Used first-line in combination with pertuzumab it would prevent the need for first-line chemotherapy and could result in a delay in disease progression and improved quality of life. Cost is unknown but it would displace trastuzumab plus taxane therapy. US cost is $9,800 a month. When used second or third- line trastuzumab emtansine will compete with other second-line options including biological therapies, and hormonal therapies. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

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Trastuzumab/ Breast Trastuzumab is co-formulated with recombinant human hyaluronidase to facilitate hyaluronidase cancer - s.c. absorption of trastuzumab through subcutaneous tissue. Compared to the i.v. formulation page 34 formulation. which is given as a 30 minute infusion, s.c. trastuzumab will reduce preparation and administration time. Cost is currently unknown.

Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

Masitinib Pancreatic UK incidence of pancreatic cancer is 13 per 100,000 people; 90% have advanced disease page 36 cancer, at diagnosis and 3% survive 5 years. Masitinib may extend life in patients with few options. advanced – It will be given in addition to , which is recommended by NICE for patients with

first-line. a Karnofsky score of ≥50. A test for the prognostic genetic biomarker is being developed. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

Regorafenib Colorectal UK incidence of CRC is 67 per 100,000 people; 20-55% of patients present with metastatic page 37 cancer disease. Management is mainly palliative with surgery and chemo/radiotherapy. For (CRC), patients with no further treatment options, regorafenib may delay disease progression and metastatic – improve quality of life. Regorafenib will be additive to other therapies. UK cost is unknown third- or but US cost is $9,350 per month. fourth-line. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

Pazopanib Ovarian UK incidence of OC is 21 per 100,000 people. 75% receive first-line platinum cancer chemotherapy; between 70 and 80% respond. Of these 55-75% relapse within 2 years and (OC). most receive platinum chemotherapy a second or third time before developing resistance. Bevacizumab Pazopanib will be used as maintenance after first-line chemotherapy in addition to current

therapies, and may delay need for second-line chemotherapy. Monthly cost of 800mg daily Vintafolide is £2,200. pages 40, 41 Bevacizumab will be used in addition to chemotherapy in advanced platinum-resistant disease. Current cost of 10 doses (15mg/kg) for a 65kg woman is £23,000. Vintafolide will be used in advanced platinum-resistant, folate receptor (FR)-positive disease and a radiopharmaceutical diagnostic test is needed to identify FR-positive tumours (90% of patients). Vintafolide will be used in addition to doxorubicin. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

Ipilimumab Malignant UK incidence of malignant melanoma is about 21 per 100,000 people, and is doubling melanoma. every 10-20 years. 7% of 15-64 year olds present with advanced (III/IV) disease compared with 20% aged ≥65 years. Median survival is 6-9 months, with 40-50% of stage III patients Trametinib surviving 5 years.

Ipilimumab will be used in resected high-risk stage III disease (first-line adjuvant therapy) to Dabrafenib delay or prevent recurrence, and in unresectable or metastatic disease (first-line with pages 42, 43, ). There is currently no standard adjuvant therapy. In combination with first-line 44 standard of care dacarbazine, ipilimumab will be an option for patients whose tumours do not have BRAF mutations. Ipilimumab costs £52,500 per dose for a 70kg person. Oral trametinib will be used in unresectable or metastatic BRAF-positive disease (first-or second-line monotherapy and first-line in combination with dabrafenib). Trametinib, like dabrafenib and , are alternatives to i.v. dacarbazine. A test is needed to identify BRAF-positive patients. Combination therapy offers the possibility of improved survival and better tolerability. US cost of trametinib is $8,700 for a 30-day supply. Dabrafenib, used alone for first-line therapy, is likely to be similarly priced to vemurafenib (£7,000 per month). Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

Rituximab Non- Rituximab s.c. will be an option for all patients with NHL for whom i.v. rituximab is currently page 45 Hodgkin's indicated. Those with poor venous access may be initial candidates. It could reduce lymphoma outpatient preparation and administration time. Rituximab s.c. is likely to cost the same as (NHL) - s.c. the current i.v. formulation but future availability of biosimilar i.v. formulations may affect formulation. pricing strategy. Likely commissioning route: NHSE. PbR: Specified high cost drug.

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Obinutuzu- Chronic UK annual incidence of CLL is 4.2 per 100,000 people, increasing to over 30 per 100,000 mab lymphocytic in those over 80 years of age. leukaemia Obinutuzumab and ofatumumab are humanised anti-CD20 monoclonal antibodies and (CLL). Ofatumumab alternatives for patients with co-morbidities who cannot have FCR (, , rituximab). Current options for these patients include or page 47 bendamustine (both with/ without rituximab) or reduced dose FCR. Ofatumumab 100mg costs £1,820 per month. Alternative costs are chlorambucil £56, bendamustine £966, rituximab £1,572. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

Alemtuzumab Multiple In a population of 100,000, 39 will have relapsing-remitting disease (RRMS). 31% of these sclerosis - receive, disease modifying agents; 74% interferons and 26% glatiramer. The availability of relapsing- more convenient and acceptable oral preparations could increase the proportion of patients Laquinimod remitting treated. NICE estimated that fingolimod, the first licensed oral preparation for RRMS, could (RRMS). take up to 15% of the interferon market share. There may be price competition as more Dimethyl oral agents become available. fumarate Alemtuzumab will be for active RRMS defined by clinical or imaging features. As a single annual i.v. treatment it may be attractive. Use is likely to be in the second-line setting. Teriflunomide Acquisition cost may be similar to other options but there may be additional monitoring costs. Oral laquinimoddimethyl fumarate and teriflunomide will compete with fingolimod pages 48, 49, which costs about £19,500/year although there is a PAS in place. 50 Likely commissioning route: NHSE. PbR: Specified high cost drugs.

Eltrombopag Thrombo- About 216,000 people in the UK are infected with hepatitis C (340 per 100,000); estimates page 51 cytopenia of the prevalence of HepC-associated TCP ranges from 0.16 - 45.4%. TCP may interfere (TCP) with diagnostic procedures, such as liver biopsy, and may exclude patients from antiviral associated treatment. Eltrombopag will be used where TCP prevents starting, or limits the ability to with maintain, optimal interferon-based therapy. Eltrombopag costs between £770 and £3,080 hepatitis C for 28 days treatment. (HepC). Likely commissioning route: Uncertain – depending on complexity of patient. PbR: Specified high cost drug.

Elosulfase Mucopoly- Mucopolysaccharidosis type IVA affects less than 15 in 100,000 people in the EU and there alfa saccharid- are currently no licensed treatments. Elosulfase is likely to be expensive and similar to page 51 osis IVA. other treatments for mucopolysaccharidosis diseases (galsulfase, idursulfase, laronidase). Likely commissioning route: NHSE. PbR: Likely specified high cost drug.

Apremilast Plaque Estimated prevalence of psoriasis in England is 1.63%; about 20 per 100,000 people have page 54 psoriasis, moderate to severe disease. Plaque psoriasis is the most common form, affecting 80-90% moderate to of people; about 1.1% are eligible for biological treatment. Apremilast is likely to be severe. licensed for use after conventional systemic therapies, but as an oral preparation may be considered preferable to parenteral biological therapies. Acquisition and administration cost may be lower than for biologicals. Likely commissioning route: CCG. PbR: Likely specified high cost drug.

Ataluren Duchenne DMD affects 1 in 3,600 to 6,000 male births in the UK; about 100 boys are diagnosed page 55 muscular annually and prevalence is about 1,500. 10-15% have a nonsense mutation (150-195 dystrophy, patients in the UK). Current options (corticosteroids) can delay but not prevent loss of nonsense- walking ability. Ataluren is the first therapy to target the underlying defect in nmDMD. It is mutation likely to be additional to current therapy in ambulant patients but could prolong (nmDMD). independence and delay complications. Likely to be expensive. Likely commissioning route: NHSE. PbR: Likely specified high cost drug.

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Table 1. Pipeline drugs BNF 1. Gastrointestinal system

Golimumab Indication: Current status: Predicted National guidance: injection Ulcerative colitis (UC), Recommended for UK licence NICE: UC - management, infliximab - UC Simponi moderate to severe – approval in EU Jul extension: subacute manifestations, acute second-line if inadequate 2013. MSD 2013 exacerbations. Biologic drugs response/ intolerance/ Licensed in US - commissioning guide. contra-indication to see prescribing Reviews: NIHR HSC Sep 2011. conventional therapy. information. Target population: The incidence and Implications: Golimumab will be a second-line option with the advantage of prevalence of UC in the UK is about 10 and s.c. administration vs. i.v. administration for infliximab. However, monthly 240 per 100,000 people, respectively. 30– administration is required vs. every 6-8 weeks for infliximab. 60% of people will have at least one relapse Financial: As a further treatment option it will be additional to current costs. per year. About 80% of these are mild to moderate and about 20% are severe. Likely commissioning route: CCG. PbR: Specified high cost drug. Sector: Secondary care. Pharmacology: Anti-TNF monoclonal antibody given by monthly s.c. injection. Efficacy: The published PURSUIT-SC study (n=774) compared induction treatment with golimumab (either 200mg or 400mg at week 0 and 100mg or 200mg at week 2) with placebo. The primary outcome of clinical response (defined as Mayo score of ≥30% and 3 points vs. baseline score, with a decrease in rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 6 was met by 52%, 55% and 30% of patients, respectively (p<0.01, NNT=4). In the published PURSUIT-M study 464 patients who had responded to induction therapy in PURSUIT-SC were randomised to golimumab 50mg, 100mg or placebo every 4 weeks to week 52. Clinical response was maintained through to week 54 in 47% (p=0.01, NNT=6), 50.6% (p<0.001, NNT=5) vs. 31.4%, respectively. Safety: See medicines.org.uk.

Vedolizumab Indication: Current status: Predicted National guidance: injection Ulcerative colitis (UC), Filed in EU Mar UK As for golimumab above. launch: Takeda moderate to severe - 2013. Reviews: NIHR HSC Mar 2013. second-line when 2014 resistant/ intolerant to conventional therapy and to TNF-alpha antagonists. Target population: As for golimumab Implications: As first in a new class this could be an attractive option for above. patients with limited alternatives. It could compete with golimumab above as Sector: Secondary care. a second-line option but has the disadvantage of being an i.v. infusion. Financial: As a further treatment option it will be additional to current costs. Likely commissioning route: CCG. PbR: Likely specified high cost drug. Pharmacology: Monoclonal-antibody, alpha4-beta7 antagonist (first-in-class), given as a 30 minute i.v. infusion. Efficacy: In the published PIII GEMINI I study, patients were randomised to vedolizumab or placebo at weeks 0, 2, 6 and then at 4- or 8-week intervals for up to one year. The primary outcome was the proportion of patients with clinical response at week 6 (induction period) and clinical remission at week 52. At week 6, response rates were 47.1% with vedolizumab vs. 25.5% with placebo (p<0.01, NNT=5). Among initial responders re-randomised at 6 weeks, 52-week remission rates were 44.8% with 4 weekly vs. 41.8% with 8 weekly vedolizumab vs. 15.9% for placebo (p<0.001 for both, NNT=3 and 4). Safety: Frequency of adverse events in trials was comparable to placebo.

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Vedolizumab Indication: Current status: Predicted National guidance: injection Crohn’s disease, moderate Filed in EU Mar UK NICE: Crohn’s disease: pathway, clinical Takeda to severe - second-line 2013. launch: guideline; infliximab and adalimumab; when resistant/ intolerant 2014 Biologic drugs commissioning guide. to conventional therapy Reviews: NIHR HSC Mar 2013. and to TNF-alpha antagonists. Target population: Estimates of UK Implications: As first in a new class vedolizumab could be an attractive prevalence of Crohn’s disease range from 50 option for patients with limited alternatives. to 150 per 100,000 people; 20% may have Financial: As a further treatment option it will be additional to current costs. severe active disease and up to 50% may be resistant to, or intolerant of, existing therapy, Likely commissioning route: CCG. PbR: Likely specified high cost drug. including TNF inhibitors. Sector: Secondary care. Pharmacology: Monoclonal-antibody, alpha4-beta7 integrin antagonist (first-in-class), given as a 30 minute i.v. infusion. Efficacy: In the published PIII GEMINI II study, patients were randomised to vedolizumab or placebo at weeks 0, 2, 6 and then at 4- or 8-week intervals for up to one year. The primary outcome was the proportion of patients in clinical remission at week 6 (induction period) and week 52. At week 6, remission rates were 14.5% with vedolizumab vs. 6.8% with placebo (p<0.03, NNT=13). Among initial responders re-randomised at 6 weeks, remission rates at 52 weeks were 36.4% with vedolizumab every 4 weeks vs. 39.0% for vedolizumab every 8 weeks vs. 21.6% for placebo (p<0.01 for both, NNT=7 and 6). In GEMINI III in 315 patients who failed anti-TNF therapy remission rates at week 6 were 15.2% vs. 12.1% for vedolizumab and placebo, respectively (p=ns). Safety: Frequency of adverse events in trials was comparable to placebo.

Teduglutide Indication: Current status: Predicted National guidance: injection Short bowel syndrome Licensed in EU UK NICE: Nutrition support in adults: clinical Revestive (SBS). Sep 2012 with launch: guideline. NPS Pharma- orphan status – 2014 Reviews: No recent reviews. ceuticals see prescribing information. Target population: The UK estimated Implications: Teduglutide would be the first drug specifically licensed for incidence of short bowel syndrome is 2 to 5 SBS, the most common indication for home parenteral nutrition (PN). It may cases per million people. reduce PN volume requirements. Sector: Severe intestinal failure treatment is Financial: Likely to be expensive and additive to current options. The cost of a specialised service. teduglutide in the US is $295,000 a year. EU launch has been delayed by returning rights from Takeda to NPS Pharmaceuticals who recently established an office in Dublin in preparation for EU pricing negotiations. Teduglutide may initially be available on a named patient basis. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Glucagon-like peptide-2 (GLP-2) analogue given by daily s.c injection. Efficacy: In a published PIII study (n=86) teduglutide 0.05mg/kg was compared with placebo. Reduction in PN of ≥20% at weeks 20 to 24 was achieved by 63% vs. 30%, respectively (p=0.002, NNT=3). Patients completing this study were eligible to enter a 2-year follow-up study where all received teduglutide 0.05mg/kg. At a 6-month interim review, continued reductions in PN had been achieved and 3 patients no longer required PN. Another published PIII study (n=83) compared teduglutide to placebo. Teduglutide 0.10mg/kg did not meet the primary outcome of reduction of ≥20% in PN in weeks 16-24 (25% vs. 6%, p=ns). However, a post-hoc analysis of patients on teduglutide 0.05mg/kg did meet the primary outcome (46% vs. 6%, p<0.01, NNT=3). In a continuation study, of those who achieved ≥20% reduction of PN at week 20 and 24 in the initial study, 75% sustained this response after up to one year of continuous treatment.

Obeticholic Indication: Current status: Predicted Reviews: None. acid Cirrhosis, primary biliary - PIII. UK Likely commissioning route: NHSE. oral launch: second line. PbR: Likely HRG included. Intercept Pharmacology: 2015 Modified bile acid; farnesoid X receptor agonist - first-in-class.

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BNF 2. Cardiovascular system

Dabigatran Indication: Current status: Predicted National guidance: oral Venous thromboembolism Filed in EU Jun UK licence NICE: VTE pathway, quality standard, Pradaxa (VTE) - treatment and 2013. extension: anticoagulation commissioning guide, Boehringer secondary prevention 2014 guideline - thromboembolic diseases; Ingelheim (long-term). VTE treatment and prevention: dabigatran due Oct 2014, rivaroxaban. SIGN: VTE. Reviews: No recent reviews. Target population: Annual incidence of Implications: Dabigatran will compete with rivaroxaban currently licensed for pulmonary embolism (PE) and deep vein treatment and prevention of recurrent DVT and PE and with apixaban thrombosis (DVT) is about 40 and 100 per currently in PIII studies for this indication (see below). Differences in dosing 100,000 people, respectively. frequency may be important for compliance. Sector: Initiated in secondary care. Financial: Competition will continue to influence pricing strategies. Likely commissioning route: CCG. PbR: HRG included. Pharmacology: Direct thrombin inhibitor. Efficacy: Treatment. The published RE-COVER non-inferiority study (n=2,539) compared dabigatran (150mg twice daily) to warfarin (INR 2.0-3.0) for acute symptomatic VTE. The primary outcome was a composite of recurrent symptomatic VTE and deaths related to VTE, which was confirmed in 2.4% of patients on dabigatran and 2.1% of patients on warfarin (p<0.001 for non-inferiority). Major bleeding did not differ between the groups at 1.6% vs. 1.9%, respectively. Secondary prevention. Two published PIII trials have compared dabigatran (150 mg twice daily) with warfarin (RE-MEDY, n=2,866) or placebo (RE-SONATE, n=1,353) in patients who had completed at least 3 months of treatment for VTE. In RE- MEDY, after a mean of 68 weeks treatment dabigatran was found to be non-inferior to warfarin for prevention of the primary outcome of recurrent symptomatic VTE or death associated with VTE (1.8% vs. 1.3%, p=0.01 for non-inferiority). Major bleeding was less common with dabigatran than warfarin (0.9% vs. 1.8%, p=0.06). In RE-SONATE, after a mean of 24 weeks treatment, recurrent VTE occurred in 0.4% vs. 5.6% of patients, respectively (p<0.001). Major or clinically relevant non-major bleeding was more common with dabigatran than placebo (5.3% vs. 1.8%, p=0.001, NNH=29). Safety: See medicines.org.uk.

Apixaban Indication: Current status: Predicted National guidance: oral Venous thromboembolism PIII. UK licence As for dabigatran above. extension: Eliquis (VTE) treatment - extended Reviews: None. Pfizer use. 2014 Target population: Annual incidence of Implications: Rivaroxaban is now licensed for treatment and prevention of pulmonary embolism (PE) and deep vein recurrent DVT and PE and dabigatran could have a similar licence soon (see thrombosis (DVT) is about 40 and 100 per above). Apixaban will be a competitor; differences in dosing frequency may 100,000 people, respectively. be important for compliance. Sector: Initiated in secondary care. Financial: Competition will influence pricing strategies. Likely commissioning route: CCG. PbR: HRG included. Pharmacology: Factor Xa inhibitor. Efficacy: The published PIII AMPLIFY trial (n=5,395) compared apixaban (10mg twice daily for 7 days, then 5mg twice daily for 6 months) with standard care (enoxaparin and warfarin). Apixaban was non-inferior to standard care for the primary outcome recurrent symptomatic VTE or death related to VTE (2.3% vs. 2.7%, p<0.001 for non-inferiority). In the published PIII AMPLIFY-EXT trial (n=2,486) apixaban was compared with placebo for 12 months. Recurrent VTE or death was more common with placebo (8.8%) than apixaban 2.5mg twice daily (1.7%) or apixaban 5.0mg twice daily (1.7%, p<0.001, NNT=14 for both comparisons). Safety: See medicines.org.uk.

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Rivaroxaban Indication: Current status: Predicted National guidance: oral Acute coronary syndrome Licensed in the UK NICE: ACS: Ticagrelor , unstable angina Xarelto (ACS) - prevention of EU May 2013 – launch: and NSTEMI, secondary prevention post Bayer atherothrombotic events in see prescribing 2014 MI, prasugrel with percutaneous patients with elevated information. coronary intervention, rivaroxaban due cardiac biomarkers Mar 2015. (combination with SIGN: ACS antiplatelet drugs). Reviews: NPC Mar 2012, NIHR HSC Apr 2011. Target population: ACS refers to a group of Implications: Long term management of ACS includes the use of aspirin conditions including ST segment elevation and another antiplatelet agent (clopidogrel, prasugrel or ticagrelor). myocardial infarction (STEMI), non-STEMI Rivaroxaban 2.5mg twice daily is licensed for use in combination with aspirin and unstable angina. In England during alone or with aspirin plus clopidogrel or ticlopidine. Few patients over 75 2011/12, there were 72,400 hospital years of age were included in the ATLAS study. admissions for angina and 50,708 for Financial: Cost will be in addition to existing therapy; price of 2.5mg tablets myocardial infarction. is currently uncertain. Sector: Initiated in secondary care. Likely commissioning route: CCG. PbR: HRG included. Pharmacology: Factor Xa inhibitor. Efficacy: The published PIII ATLAS ACS 2 TIMI 51 trial (n=15,526) compared rivaroxaban with placebo in patients hospitalised with ACS, who were also receiving aspirin and a thienopyridine (clopidogrel or ticlodipine). The 2-year event rate for the primary outcome, a composite of death from cardiovascular (CV) causes, myocardial infarction or stroke, was reduced in patients on rivaroxaban 2.5mg or 5mg twice daily vs. placebo (8.9% vs.10.7%, HR 0.84, p=0.008). Rivaroxaban 2.5mg reduced CV death rate (p=0.002) and death from any cause (p=0.002); a survival benefit was not seen with 5mg. Safety: See prescribing information. The rate of major bleeding unrelated to CABG was increased with rivaroxaban compared to placebo in the above trial (2.1% vs. 0.6%, p<0.001), but the risk of fatal bleeding was similar.

Rivaroxaban Indication: Current status: Predicted National guidance: oral Prevention of stent PIII in EU. UK licence NICE: ACS pathway, unstable angina & extension: Xarelto thrombosis in acute Not approved in NSTEMI, myocardial infarction with ST- Bayer coronary syndrome (ACS). US Jun 2013. 2014 segment elevation. SIGN: ACS. Reviews: None. Target population: In 2011-12 there were Implications: First of the new oral anticoagulants to seek a licence for this 53,567 admissions in England for balloon indication. Familiarity with the drug may increase willingness to use. angioplasty and insertion of stent into a Financial: Rivaroxaban is added to standard therapy for ACS, so cost will coronary artery. also be additive. Sector: Initiated in secondary care. Likely commissioning route: CCG. PbR: HRG included. Pharmacology: Factor Xa inhibitor. Efficacy: A published, pre-specified sub-group analysis of a PIII trial (sub-group n=9,631) compared twice daily rivaroxaban (2.5mg or 5.0mg) with standard care (aspirin with or without a thienopyridine) in patients with ACS who had at least one stent inserted. There was no difference in the rate of definite stent thrombosis (1.0% vs.1.3%, p=ns). The pooled rate of definite or probable stent thrombosis was lower with rivaroxaban (1.5% vs. 1.9%, p=0.017). Safety: See medicines.org.uk.

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Cangrelor Indication: Current status: Predicted National guidance: injection Thrombosis prevention PIII in EU. UK None relevant. launch: The Medicines (coronary) in percutaneous Filed in US Jul Reviews: NIHR HSC Nov 2012. Company coronary intervention (PCI). 2013. 2014 Target population: 88,692 PCIs were Implications: For patients undergoing PCI, current guidelines recommend carried out in the UK in 2011. antiplatelet therapy and antithrombin co-therapies. Cangrelor may be Sector: Secondary care. suitable for patients unable to take oral therapy or for those who require a rapidly reversible therapy. Financial: Likely to displace current options but as an i.v. infusion is likely to be more expensive. Likely commissioning route: NHSE. PbR: Likely HRG included. Pharmacology: Antiplatelet (P2Y12 antagonist) given by i.v. infusion. Half life 3-6 minutes; platelet function restored in less than 60 minutes. Efficacy: A published pooled analysis of two PIII trials (n=13,049) compared cangrelor with clopidogrel in patients with non- ST-elevation acute coronary syndromes who underwent PCI. There was no difference in the primary outcome of death, MI or ischaemia-driven revascularisation (7.3% vs. 7.5%). A published PIII trial (n=11,145) compared cangrelor to clopidogrel alone. The primary outcome (a composite of death, myocardial infarction, ischaemia-driven revascularisation or stent thrombosis at 48 hours) occurred in 4.7% vs. 5.9%, of patients, respectively (p=0.005, NNT=84) Safety: There was no difference between groups in the rates of severe bleeding.

Vorapaxar Indication: Current status: Predicted National guidance: oral Secondary prevention of PIII with plans to UK NICE: Myocardial infarction (MI) - MSD cardiovascular (CV) events file in EU in 2013. launch: secondary prevention; Vascular disease in patients with a history of Filed in US Jul 2014 – clopidogrel and dipyridamole MI and no history of TIA or 2013. SIGN: Prevention of CV disease update stroke. in progress. Reviews: No recent reviews. Target population: Around 1.5 million Implications: Likely to be added to existing therapies but the associated people in the UK have had an MI (about bleeding risk could make it difficult to establish a place in therapy. 2,380 per 100,000). Financial: Likely to be considerably more expensive than current options. Sector: Initiated in secondary care. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: Thrombin receptor antagonist (PAR-1 inhibitor). Efficacy: In a published PIII study 26,449 patients with prior MI, stroke or peripheral artery disease were randomised to vorapaxar or placebo in addition to standard treatment, including antiplatelet drugs. At 3 years, the primary outcome (death from CV causes, MI or stroke) occurred in 9.3% of the vorapaxar vs.10.5% of the placebo group (HR 0.87, p<0.01). In a published pre-specified analysis of the subgroup with prior MI (n=17,779) the primary outcome occurred in 8.1% vs. 9.7%, respectively (3 year estimates; HR 0.80, p<0.01). Safety: Moderate/severe bleeding occurred in 4.2% vs. 2.5% of patients, respectively (p<0.001) and an increased risk of intracerebral haemorrhage in 1.0% vs. 0.5%, respectively (p<0.01). In the MI subgroup, 3 year estimates for moderate/severe bleeding were 3.4% vs. 2.1%, respectively (HR 1.61, p<0.01).

Des- Indication: Current status: Predicted Reviews: NIHR HSC Sep 2011. moteplase Stroke, acute ischaemic, PIII. UK Likely commissioning route: CCG. injection launch: within 9 hours of symptom PbR: Likely specialist top-up as for Lundbeck onset. 2015 alteplase. Pharmacology: Plasminogen activator.

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Lomitapide Indication: Current status: Predicted National guidance: oral Hypercholesterolaemia, Licensed in EU UK NICE: Familial hypercholesterolaemia: Lojuxta homozygous familial Aug 2013. launch: guideline; Cardiovascular disease Aegerion (HoFH). 2013 prevention: commissioning guide. Pharma- SIGN: Prevention of cardiovascular ceuticals disease - update in progress. Reviews: No recent reviews. Target population: HoFH is rare, with an Implications: Lomitapide may be an option for patients with HoFH with an incidence of about one case per million inadequate response to current therapy. Genetic confirmation of HoFH people. should be obtained prior to starting therapy. Treatment may reduce the Sector: Secondary care. requirement for LDL apheresis in some patients. Financial: Likely to be very expensive, but may reduce need for LDL apheresis. US price is around $25,000/month. Likely commissioning route: CCG. PbR: Likely specified high cost drug. Pharmacology: Microsomal triglyceride transfer protein inhibitor (first-in-class) given orally once daily. Efficacy: In a published PIII open-label study (n=29) lomitapide combined with a low-fat diet was added to standard therapy, with or without apheresis. The mean reduction in LDL cholesterol (LDL-C) from baseline was 50% at 26 weeks (primary outcome), 44% at 56-weeks and 38% at 78-weeks (p<0.01 for all comparisons vs. baseline). Some patients were able to reduce or discontinue LDL apheresis. Safety: Hepatotoxicity has been reported and regular liver function testing is advised. Gastrointestinal adverse effects are common.

Evolcumab Indication: Current status: Predicted Reviews: NIHR HSC Mar 2013. injection Hyperlipidaemia. PIII. launch: Likely commissioning route: CCG. Amgen Pharmacology: 2015 PbR: Likely specified high cost drug. Monoclonal antibody - PCSK9 inhibitor.

Alirocumab Indication: Current status: Predicted Reviews: NIHR HSC Dec 2012. injection Hypercholesterolaemia – PIII. UK Likely commissioning route: CCG. launch: Sanofi third line. PbR: Likely specified high cost drug. Pharmacology: 2016 Monoclonal antibody - PCSK9 inhibitor.

Riociguat Indication: Current status: Predicted National guidance: oral Pulmonary arterial Filed in EU Feb UK None relevant. launch: Adempas hypertension (PAH) and 2013. Reviews: No recent reviews. Bayer chronic thromboembolic Recommended for 2014 pulmonary hypertension approval in the US (CTEPH) Aug 2013. Target population: 7,000 patients attended Implications: Riociguat will be an additional option for PAH and CTEPH. specialist PH centres in the UK in 2012, of Current options include prostacyclins, endothelin antagonists and whom 88% had a final diagnosis. Among phosphodiesterase inhibitors. Riociguat will be the first treatment specifically those with a diagnosis 47% had PAH and licensed for CTEPH. 19% CTEPH, equating to 2,895 and 1,170 Financial: Likely to be expensive and as a further treatment option will be patients, respectively. additive to current costs. Sector: National Pulmonary Hypertension Likely commissioning route: NHSE. PbR: Specified high cost drug. Service (see commissioning policy statement). Pharmacology: Guanylate cyclase stimulant (first-in-class). Efficacy: PAH. The published 12-week, PIII PATENT-1 study compared individually titrated riociguat with placebo in 443 patients with symptomatic PAH. Riociguat improved the primary outcome of 6-minute walking distance (6-MWD) by 36 meters (p<0.01) vs. placebo. In patients that reached one year of treatment in the long-term extension trial PATENT-2 the improvement in 6-MWD was 48 meters. CTEPH. The 16-week, published PIII CHEST-1 study compared individually titrated riociguat with placebo in 261 patients with CTEPH or persistent/recurrent PH after surgery. Riociguat improved the primary outcome of 6-minute walking distance by 46 meters (p<0.01) vs. placebo. After one year of treatment in the CHEST-2 extension trial the improvement in 6-MWD was 48 meters. Safety: To date no serious adverse effects have been reported.

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Serelaxin Indication: Current status: Predicted Reviews: NIHR HSC Jul 2012. injection Acute heart failure (AHF) – Filed in EU Dec launch: Likely commissioning route: CCG. Novartis decompensated. 2012. Uncertain. PbR: Likely HRG included. Pharmacology: Recombinant human relaxin-2, a peptide hormone.

Defibrotide Indication: Current status: Predicted National guidance: injection Hepatic veno-occlusive Recommended for UK None relevant. launch: Defitelio disease (VOD) - treatment approval in EU Jul Reviews: NIHR HSC Aug 2011, LNDG Gentium in haematopoietic stem-cell 2013 with orphan 2013 due TBC. transplant (HSCT). status. Target population: VOD is a leading cause Implications: Supportive care is the current treatment option. Defibrotide will of morbidity and mortality after HSCT. be the first specific therapy for VOD. Without treatment 85% of those with severe Financial: Likely to be expensive. Based on a dose of 25mg/kg/day, current VOD die within 100 days of HSCT. named patient cost is around £40,000 for 21 days treatment. Sector: Secondary or tertiary care. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Cytokine modulator given every 6 hours for at least 21 days. Efficacy: In a PIII trial (n=134) in patients with severe VOD and multi-organ failure, 24% in the defibrotide group achieved a complete response at 100 days (primary outcome) vs. 9% in the historical control group (p<0.02, NNT=7). Mortality rate at day 100 (secondary outcome) was 62% vs. 75%, respectively, (p>0.05). An EMA analysis of US patient registry data showed that patients with severe VOD who received defibrotide plus standard care had better outcomes, including a higher survival rate after 100 days following transplantation, than those given standard care alone. Safety: No safety concerns have been reported to date, with the frequency of adverse events comparable to control.

Clevidipine Indication: Current status: Predicted National guidance: oral Hypertension, Licensed in UK UK None relevant. launch: Cleviprex perioperative. Nov 2011 – see Reviews: No recent reviews. The Medicines prescribing 2014 Company information. Target population: Perioperative Implications: Clevidipine is one of only two drugs (the other being esmolol) hypertension may affect 25% of hypertensive specifically licensed for the management of perioperative hypertension. patients undergoing surgery. Financial: Likely to be more expensive than available generic options. Sector: Secondary care. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: Ultra short-acting dihydropyridine calcium channel antagonist given by i.v. infusion. Efficacy: Pooled results from three open-label PIII studies (ECLIPSE 1, 2 & 3) are published. Among patients undergoing cardiac surgery randomised to clevidipine, glyceryl trinitrate, sodium nitroprusside or nicardipine (n=1,512), there was no difference in primary outcome events (death, MI, stroke or renal dysfunction at 30 days) between the clevidipine group and the pooled comparator group. Safety: See medicines.org.uk.

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BNF 3. Respiratory system

Indacaterol/ Indication: Current status: Predicted National guidance: glycopyrron- Chronic obstructive Recommended for UK NICE: COPD – clinical guideline, ium inhaler pulmonary disease approval in EU Jul launch: commissioning guide, quality standard. Ultibro (COPD). 2013. 2013 Reviews: NIHR HSC Aug 2011. Breezhaler Novartis Target population: An estimated 3 million Implications: The first combination inhaler to contain a long-acting people in the UK are affected by COPD. The muscarinic antagonist (LAMA) for use when maintenance long-acting beta rate of COPD in the population is estimated agonist (LABA) is insufficient and an inhaled corticosteroid is not suitable. at between 2% and 4%; the diagnosed Financial: Likely to be similar to other combination products. prevalence is 1.5%. Likely commissioning route: CCG. PbR: Likely HRG included. Sector: Secondary and primary care. Pharmacology: Once daily LABA and LAMA combination as a capsule for inhalation. Efficacy: In the published PIII SHINE trial 2,144 patients were randomised to indacaterol/glycopyrronium, indacaterol, glycopyrronium, tiotropium or placebo. For the primary outcome of trough FEV1 at week 26, the difference between the combination and indacaterol alone was 0.07L, (p<0.01) and 0.09L vs. glycopyrronium (p<0.01). In the published PIII ILLUMINATE trial (n=523) indacaterol/ glycopyrronium was compared to salmeterol/fluticasone combination. At week 26, FEV1 (area under curve) at 12 hours was higher with indacaterol/glycopyrronium (difference 0.138L, p<0.0001). Safety: In a 52-week safety study, ENLIGHTEN (n=339) the most frequent adverse event was COPD exacerbation (28.0% vs. 25.7% in placebo group).

Umeclidinium Indication: Current status: Predicted National guidance: inhaler Chronic obstructive Filed in EU Apr UK NICE: As for indacaterol/ Espanda pulmonary disease 2013. launch: glycopyronnium above. GlaxoSmith- (COPD). 2014 Reviews: None. Kline Target population: As for Indacaterol/ Implications: Umeclidinium will complete with aclidinium, glycopyrronium glycopyronnium above. and tiotropium. The place of long-acting muscarinic antagonists (LAMAs) is Sector: Secondary and primary care. described in the NICE COPD guideline. Financial: Likely to be similar to other long-acting bronchodilators. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: A once-daily LAMA formulated as a dry powder inhaler administered once daily. Efficacy: Two on-going PIII trials of 600 patients each (one and two) involve the addition of once daily umeclidinium (62.5mcg or 125mcg) or placebo to twice daily fluticasone/salmeterol (250/50mcg) over 12 weeks. The primary outcome is change from baseline in trough FEV1 at day 85. A 12-week PIII trial with the same outcome has compared umeclidinium 62.5mcg or 125mcg to placebo in 206 patients. Significant improvements were shown in mean change from baseline in trough FEV1 for 62.5mcg (127ml) and 125mcg (152ml) vs. placebo. Safety: A PIII 52-week study is evaluating safety and tolerability.

Umeclidinium Indication: Current status: Predicted National guidance: /vilanterol Chronic obstructive Filed in EU Jan UK As for indacaterol/ glycopyronnium inhaler pulmonary disease 2013. launch: above. GlaxoSmith- (COPD). 2014 Reviews: NIHR HSC Feb 2012. Kline Target population: As for indacaterol/ Implications: A long-acting muscarinic antagonist (LAMA) and long-acting glycopyronnium above. beta agonist (LABA) combination is not yet available in a single inhaler. Sector: Secondary and primary care. Financial: Likely to be similar to other combination products. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: A once-daily dry powder inhaler containing a LAMA and a LABA. Efficacy: In four 24-week studies the primary outcome was trough FEV1 at day 169. In a PIII study (n=871) the difference between tiotropium and umeclidinium/vilanterol (UMEC/VI) 125/25mcg was 74ml (p<0.01) and 60ml vs. UMEC/VI 62.5/25mcg (p=0.02). In another PIII study (n=846), both doses of UMEC/VI were more effective than tiotropium by 88 to 90ml (p<0.01). In a third PIII study (n=1,537) UMEC/VI 62.5/25mcg was more effective than placebo by 167ml (p<0.01) and in a fourth PIII study (n=1,493) UMEC/VI 125/25mcg was better than placebo by 238ml (p<0.01). Safety: In the above studies, cardiovascular adverse events were seen in 6 to 11% of patients on UMEC/VI.

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Budesonide/ Indication: Current status: Predicted National guidance: formoterol Asthma. Filed in the EU UK NICE: Quality standard. inhaler launch: Apr 2013. SIGN: British guideline on the Bufomix 2014 management of asthma. Easyhaler Reviews: None. Orion Pharma Target population: At least 1 in 10 children Implications: Bufomix will compete with Seretide and Symbicort. and 1 in 12 adults have asthma in the UK. Financial: Likely to be similar to other dry powder inhalers (DPIs). Sector: Secondary and primary care. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: Dry powder inhaler (DPI) containing a corticosteroid and long-acting beta agonist (LABA). Efficacy: A PI/II study (n=87), has evaluated the bioequivalence of the Easyhaler to Symbicort Turbohaler. Safety: For adverse effects of budesonide/formoterol DPI, see medicines.org.uk.

Masitinib Indication: Current status: Predicted Reviews: NIHR HSC Sep 2012. oral Asthma, severe persistent. PIII. UK Likely commissioning route: NHSE. launch: AB Science Pharmacology: PbR: Likely specified high cost drug. 2015 inhibitor.

Nalfurafine Indication: Current status: Predicted National guidance: injection Pruritus, uraemic dialysis- Filed in EU Aug UK None relevant. launch: Winfuran related. 2012 with orphan Reviews: None. 2013 Fresenius status. Medical Care Target population: In the EU uraemic Implications: No other treatments are specifically licensed for uraemic pruritus affects about 3.5 per million people. pruritus. Options include gabapentin and UVB phototherapy. Data from 2003-2004 indicates about 50% of Financial: Likely to be more expensive than off-label use of oral agents. patients on haemodialysis in the UK have moderate to extreme pruritus. Likely commissioning route: NHSE. PbR: Likely HRG included. Sector: Renal services are a specialised service. Pharmacology: Kappa opioid agonist. Efficacy: A published meta-analysis reviewed data from 144 patients on haemodialysis with severe, uncontrolled pruritus. Patients received nalfurafine or placebo by i.v. infusion 3 times a week after haemodialysis. A 100-mm visual analogue scale was used to measure the “worst itching” during the previous 12 hours. At week 2, a mean difference of 9.53mm was found between nalfurafine and placebo (p<0.03). 36% on nalfurafine achieved ≥50% decrease from baseline in worst itching vs. 14% on placebo (p<0.03). Safety: The meta-analysis found adverse events to be similar to placebo.

Omalizumab Indication: Current status: Predicted National guidance: injection Urticaria, chronic idiopathic PIII. UK licence None relevant. extension: Xolair or spontaneous (CIU/CSU) Reviews: NIHR HSC Sep 2012. Novartis - second line. 2014 Target population: In the UK, the point Implications: Omalizumab will be a second-line option for CIU/CSU prevalence of chronic urticaria is 0.1-0.51%, refractory to H1-antihistamines. It will provide an alternative option to off-label of which up to 50% of cases are idiopathic leukotriene receptor- and H2-receptor antagonists. (50-250 per 100,000 people). First-line Financial: Current cost of omalizumab is £256 for 150mg; there will be therapy is effective in <50% of patients. additional administration costs. Sector: Secondary care. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Monoclonal antibody – IgE receptor antagonist given by s.c injection every four weeks. Efficacy: A published PIII trial (n=323) compared omalizumab 75mg, 150mg, or 300mg (every 4 weeks for 12 weeks) with placebo in symptomatic patients with CIU despite H1-antihistamine therapy. The primary outcome was change from baseline to week 12 in a weekly itch-severity score (ranging from 0 to 21). At week 12, the mean reduction from baseline was 5.9 in the 75mg group (p=0.46), 8.1 for 150mg (p=0.01) and 9.8 for 300mg (p<0.01) vs. 5.1 for placebo. In a published PIII trial in 336 patients with CIU/CSU the mean reduction in itch-severity score from baseline at week 12 was 8.6 in the 300mg group vs. 4.0 for placebo (p<0.01). Safety: See medicines.org.uk.

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Ataluren Indication: Current status: Predicted Reviews: None. oral Cystic fibrosis (CF), PIII in EU with UK Likely commissioning route: NHSE. launch: Genzyme patients with nonsense orphan status. PbR: Likely specified high cost drug. mutation (nmCF). 2015 Pharmacology: CF transmembrane conductance regulator stimulant.

Lumacaftor Indication: Current status: Predicted Reviews: None. oral Cystic fibrosis, in PIII in EU, fixed UK Likely commissioning route: NHSE. launch: Vertex combination with ivacaftor dose combination PbR: Likely specified high cost drug. in homozygous F508del product also in PIII 2015 patients. trials. Pharmacology: Breakthrough CF transmembrane therapy and conductance regulator orphan drug status stimulant. in US. BNF 4. Central nervous system

Loxapine Indication: Current status: Predicted National guidance: inhalation Acute agitation associated Licensed in EU UK NICE: Clinical guidelines: schizophrenia, Adasuve with schizophrenia or Feb 2013 – see launch: bipolar disorder. Commissioning guide: Grupo Ferrer bipolar disorder. prescribing 2014 schizophrenia. information. SIGN: Schizophrenia, bipolar disorder. Reviews: RDTC Jun 2013, LNDG Feb 2013. Target population: In England there are Implications: Inhaled administration is less invasive than i.m. injection and about 755 people with schizophrenia and may be preferred by some patients. 865 with bipolar disorder per 100,000 people. Financial: Likely to be more expensive than oral and i.m. alternatives. More than 90% of people with either condition will experience agitation in their Likely commissioning route: CCG. PbR: Likely HRG included. lifetime, with an average of 11 to 12 episodes of acute agitation each year. Sector: Secondary care. Pharmacology: Dopamine D2 and serotonin 5-HT2A antagonist given by single-dose inhaler. Efficacy: Schizophrenia. A published PIII trial (n=344) compared up to 3 doses of loxapine 4.5 or 9.1mg with placebo in agitated in-patients with schizophrenia. At 2-hours post first dose the change from baseline in Positive and Negative Syndrome Scale–Excited Component (PANSS-EC) was -8.1, -8.6 and -5.5, respectively (both p<0.01 vs. placebo). Bipolar. In a published PIII trial in in-patients with bipolar I associated agitation (n=314), change from baseline in PANSS-EC score 2 hours after the first dose was -8.1 with 4.5mg, -9.0 with 9.1mg and -4.9 with placebo (both p<0.01 vs. placebo). Safety: See prescribing information. Severe respiratory effects (bronchospasm) are possible.

Lurasidone Indication: Current status: Predicted National guidance: oral Schizophrenia. Filed in the EU UK NICE: Schizophrenia - Clinical guideline, Latuda Oct 2012. launch: commissioning guide. Takeda Launched in US 2013 SIGN: Schizophrenia. see prescribing Reviews: NICE Evidence summary Apr information. 2013. Target population: In England there are Implications: Lurasidone will be an additional treatment option alongside about 800 per 100,000 people with existing antipsychotics. A lower incidence of weight gain may be attractive. schizophrenia. Financial: Likely to be more costly than existing atypical antipsychotics. Sector: Initiated in secondary care. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: Dopamine and serotonin receptor antagonist. Efficacy: In a published PIII trial, 478 hospitalised patients received lurasidone (40mg or 120mg), olanzapine or placebo. Improvement in the primary outcome of change from baseline to week 6 in the Positive and Negative Syndrome Scale (PANSS) total score was greater with lurasidone 40mg (-25.7, p=0.002), lurasidone 120mg (-23.6, p=0.022) and olanzapine (-28.7, p<0.001) vs. placebo (-16.0). Lurasidone and olanzapine were not directly compared. Safety: In a published safety trial (n=621) the frequency of adverse events with lurasidone was similar to risperidone, but fewer patients experienced increased weight (9.3% vs. 19.8%).

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Liraglutide Indication: Current status: Predicted National guidance: injection Obesity. PIII. UK licence NICE: Obesity guidelines. extension: Victoza SIGN: Obesity. 2014 Novo Nordisk Reviews: No recent reviews. Target population: In 2011, 24% of men Implications: It is likely liraglutide injection will be preferentially used in and 26% of women (>16 years) were classed overweight patients with diabetes. It will have the advantage over exenatide obese (BMI ≥30kg/m2); 41% of men and 33% which, although causes weight loss, is not specifically licensed for obesity. of women were overweight (BMI 25 to The liraglutide dose for obesity is much higher than for diabetes. 2 <30kg/m ). Financial: Based on a 3mg daily dose current cost of liraglutide is about Sector: Initiated in secondary care with £183/month vs. £32/month for orlistat 120mg 3 times a day. continued use in primary care. Likely commissioning route: CCG. PbR: HRG included. Pharmacology: Glucagon-like peptide analogue given by daily s.c. injection. Efficacy: A published PIII study (n=422) compared liraglutide 3mg with placebo over 56 weeks following a 12-week low- calorie dietary run-in. Mean reduction in body weight was -6.2% for liraglutide vs. -0.2% for placebo (p<0.01). A ≥5% reduction in body weight was achieved by 50.5% vs. 21.8% of patients, respectively (p<0.01). A 20-week published PII study (n=564) compared liraglutide 1.2, 1.8, 2.4 or 3mg with placebo and orlistat 360mg/day. Mean weight loss with liraglutide ranged from 4.8 - 7.2kg vs. 2.8kg with placebo and 4.1kg with orlistat (p=0.003 for liraglutide 2.4 mg vs. orlistat and p<0.0001 for liraglutide 3.0 mg vs. orlistat). In a published extension of this study, patients receiving liraglutide (2.4mg or 3mg pooled) for two years lost 3.0kg more than those on orlistat (p<0.01). Safety: See medicines.org.uk.

Dextro- Indication: Current status: Predicted National guidance: methorphan/ Pseudobulbar affect Licensed in EU UK NICE: Pathways: stroke, dementia; quinidine (PBA). Jun 2013 – see launch: Clinical guidelines: multiple sclerosis, oral prescribing 2014 stroke rehabilitation, dementia, Nuedexta information. Parkinson’s disease; Quality standard: Jenson dementia Reviews: None. Target population: PBA can develop in Implications: First drug licensed for this indication. Confirmation of several neurological diseases or following diagnosis is required before treatment as use in other emotional lability brain injury. The estimated prevalence of conditions would be off-label. This may increase referrals to specialist PBA is up to 500 per 100,000 people, of neurosciences. Although the indication is for treatment of PBA due to any whom about 14 per 100,000 will have cause efficacy has only been studied in those with ALS or MS. amyotrophic lateral sclerosis (ALS) or Financial: Likely to be considerably more expensive than unlicensed multiple sclerosis (MS). alternatives (SSRIs, TCAs, levodopa, amantadine and thyrotropin-releasing Sector: Adult specialist neurosciences are a hormone). specialised service. Likely commissioning route: NHSE. PbR: Likely HRG included. Pharmacology: Dextromethorphan is a sigma-1 receptor agonist and NMDA antagonist. Quinidine is a CYP2D6 inhibitor, which increases plasma levels of dextromethorphan. Efficacy: A published 12-week PIII trial (n=326) compared dextromethorphan plus quinidine (30/10mg (DMq-30) or 20/10mg (DMq-20) twice daily) with placebo in ALS and MS patients with clinically significant PBA. The primary outcome of PBA- episode daily rate was 46.9% lower for DMq-30 and 49.0% lower for DMq-20 vs. placebo (p<0.01 for both). Safety: No safety concerns are reported to date, but patients with cardiovascular disorders were excluded from studies.

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BNF 5. Infections

Tobramycin Indication: Current status: Predicted National guidance: solution for Cystic fibrosis (CF) Filed in EU Nov UK NICE: CF (pseudomonas lung infection). inhalation launch: associated respiratory tract 2012 with orphan Reviews: None. Vantobra infections. status. 2013 Pari Pharma Target population: CF affects over 8,500 Implications: The eFlow nebuliser system allows delivery of high people in the UK. In 2008, 39.4% were found concentration/low volume with shorter nebulisation time. to be chronically infected with P. aeruginosa; Financial: The current cost of 28-days therapy with Bramitob or TOBI 19.6% of these used nebulised tobramycin. nebuliser solutions is £1,187. Vantobra is likely to be competitive. Sector: Secondary care, adult and paediatric Likely commissioning route: NHSE. PbR: Specified high cost drug. specialist service. Pharmacology: Aminoglycoside antibiotic administered via the eFlow nebuliser delivery system. Efficacy: A 28-day, PII study (n=78), compared Vantobra 100 (150mg/1.5mL) administered twice daily via an investigational eFlow nebuliser system with TOBI (tobramycin 300mg/5mL) delivered via the PARI LC PLUS nebuliser. The primary outcome was tobramycin serum level as a surrogate safety measure. However, inhalation time was also assessed with the average inhalation time being 4-4.5 minutes for Vantobra vs. 16-17 minutes for TOBI. Safety: Maximum tobramycin serum levels were lower than recommended safety thresholds.

Bedaquiline Indication: Current status: Predicted National guidance: oral Tuberculosis (TB), multi- Filed in EU Aug UK NICE: Tuberculosis pathway. launch: Situro drug resistant (MDR). 2012. WHO interim guidance on the use of Janssen-Cilag Licensed in US - 2013 bedaquiline Jun 2013. see prescribing Reviews: None. information. Target population: Around 9,000 cases of Implications: Bedaquiline will be used in addition to second-line options. In TB are reported each year in the UK. Most the US it is only indicated when other options are not available. WHO occur in major cities, particularly London. In recommend it should only be used when an effective regimen with four 2011, there were 431 reports of MDR-TB, a second-line drugs plus pyrazinamide is not possible or when there is 26% increase from 2010. evidence of resistance to any fluoroquinolone in addition to MDR-TB. Sector: Secondary care. Financial: As add on therapy cost will be additional and is likely to be expensive. WHO conclude it would be cost effective in most settings. Likely commissioning route: NHSE. PbR: Likely HRG included. Pharmacology: Oral diarylquinoline ATPase inhibitor, first-in-class. Administered by directly observed therapy for 24 weeks. Efficacy: In a published PII study (n=47), bedaquiline (400mg daily for 2 weeks then 200mg 3 times a week for 6 weeks) added to background second-line therapy reduced the time to conversion to a negative sputum culture (primary outcome) vs. placebo (p=0.003), and increased the number of patients with conversion (secondary outcome) at week 8 (48% vs. 9%, respectively, NNT=3). In a subsequent PII study (n=160) bedaquiline (24 weeks treatment) decreased time to culture conversion vs. placebo (83 vs. 125 days, respectively, HR 2.44, p<0.0001) and improved culture conversion rates at week 24 vs. placebo (79% vs. 58%, respectively, p=0.008, NNT=5). Using WHO-recommended treatment outcome definitions applied to final 120-week data, 58% vs. 32%, respectively, were defined as cured (p=0.003, NNT=4). Safety: In the US there are warnings that an increased risk of death (NNH=11) was seen in one study. WHO recommend testing and monitoring for QT prolongation as well as strict conditions for use pending further data to assess risk vs. benefit.

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Cobicistat Indication: Current status: Predicted National guidance: oral HIV infection, enhancer of Recommended for UK British HIV Association (BHIVA) 2012. launch: Tybost the protease inhibitors approval in EU Jul Reviews: None. Gilead atazanavir and darunavir. 2013. 2013 Target population: In 2012, about 6,000 Implications: Cobicistat will be the second enhancer available in the UK, patients were diagnosed with HIV and about ritonavir being the first. However, unlike ritonavir, cobicistat has no inherent 96,000 were living with HIV with around 25% antiretroviral activity. being undiagnosed. Financial: Ritonavir cost ranges from about £20 to £78/month. Cost of Sector: Secondary care. cobicistat is likely to be competitive. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Specific inhibitor of CYP3A without antiretroviral activity. Efficacy: In a published PII study, 79 patients received cobicistat or ritonavir as enhancers for atazanavir in combination with emtricitabine plus tenofovir. The primary outcome of HIV-1 RNA <50 copies/mL at week 24 was achieved by 84% on atazanavir/cobicistat vs. 86% on atazanavir/ritonavir, and was sustained to week 48 (82% vs. 86%, respectively). Pharmacokinetic analyses showed comparable cobicistat- and ritonavir-boosted atazanavir exposures. An ongoing non- inferiority PIII study (n=692) is assessing cobicistat vs. ritonavir in combination with atazanavir plus tenofovir plus emtricitabine. The primary outcome was achieved in 85% on atazanavir/cobicistat vs. 87% on atazanavir/ritonavir. Safety: In patents on cobicistat, changes in e-GFR occurred, remained stable through to week 48 and were similar to that seen in patients receiving ritonavir.

Dolutegravir Indication: Current status: Predicted National guidance: oral HIV infection, in Filed in the EU UK As for cobicistat above. launch: ViiV healthcare combination with other Dec 2012 and in Reviews: None. UK antiretroviral agents. US with priority 2013 review status. Target population: As for cobicistat above. Implications: BHIVA guidelines suggest therapy-naïve patients start with Sector: Secondary care. two nucleoside reverse transcriptase inhibitors (NRTIs) plus one of the following: a ritonavir-boosted protease inhibitor (PI/r), an NNRTI (non-NRTI) or an integrase inhibitor. BHIVA do not recommend switching to an integrase inhibitor in patients with previous NRTI resistance mutations, historical/ existing mutations associated with NRTI resistance or past virological failure on NRTIs. Once daily dosing with dolutegravir may be an advantage over raltegravir twice daily. Financial: Cost of raltegravir is £616/month. Elvitegravir is only available in a combination tablet (Stribald). Dolutegravir is likely to be competitive. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Integrase inhibitor taken once daily. Efficacy: The primary outcome in various PIII non-inferiority studies assessing dolutegravir plus optimised background regimen (OBR) was the proportion of patients achieving HIV-1 RNA <50 copies/mL (virological suppression). In the published SPRING-2 study, 822 treatment-naïve patients received daily dolutegravir or twice daily raltegravir, plus OBR. At 48 weeks, 88% vs. 85%, respectively, achieved virological suppression, demonstrating non-inferiority. In the SINGLE study, 833 treatment-naïve patients received dolutegravir plus Kivexa, or Atripla. At 48 weeks, virological suppression was achieved by 88% vs. 81%, respectively (p=0.003). In the SAILING study in 715 treatment-experienced, integrase-inhibitor naive patients interim 24-week data show virological suppression was achieved in 79% on dolutegravir vs. 70% on raltegravir (p=0.003). Virologic non-response was seen in 15% and 24%, respectively. In the open-label VIKING-3 study in183 treatment-experienced patients with resistance to raltegravir and/or elvitegravir, dolutegravir plus OBR led to a fall in mean HIV-RNA levels by 1.4 log10 copies/mL after 7 days and 63% of patients had virological suppression at 24 weeks. Safety: Dolutegravir has a similar safety profile to raltegravir.

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Sofosbuvir Indication: Current status: Predicted National guidance: oral Hepatitis C viral infection Filed in EU Apr UK NICE: HCV- PEG/RBV, HCV genotype 1 Gilead (HCV), genotype 1 to 6 2013 and in US launch: - telapravir, boceprevir. infection. with accelerated 2014 SIGN: Hepatitis C. approval and priority review Reviews: NIHR HSC Sep 2012. status. Target population: There are an estimated Implications: HCV is a major cause of liver transplantation. Patients with 173,000 chronically infected HCV patients in genotype 1 are treated with triple therapy. Sofosbuvir is another option with England and Wales; only 91,000 of these are efficacy shown in HCV genotypes 1-6. It could reduce treatment duration diagnosed. Chronic HCV was the primary with the advantage of reduced dosing frequency vs. available options. cause of 2,967 hospital admissions in Financial: Monthly cost of boceprevir is £2,800 and telaprevir is £7,466. England in 2010/11, with 2,688 bed days. Sofosbuvir is likely to be competitive. Sector: Secondary care. Likely commissioning route: NHSE. PbR: Likely specified high cost drug. Pharmacology: Once daily nucleotide NS5B inhibitor. Efficacy: The primary outcome of all PIII studies is the proportion of patients achieving a sustained virologic response at 12 weeks (SVR12) after the end of therapy. In the published open-label NEUTRINO study, 90% of 327 treatment-naïve patients with HCV genotypes 1, 4, 5 or 6 treated with sofosbuvir plus peginterferon alfa 2a plus ribavirin (PEG/RBV) achieved a SVR12. In the published FISSION non-inferiority study, 499 patients with genotype 2 or 3 were treated with either sofosbuvir/RBV given for 12 weeks or PEG/RBV given for 24 weeks. SVR12 was 67% in both groups. In the sofosbuvir/RBV group, response rates in patients with genotype 3 were lower than in those with genotype 2 (56% vs. 97%, respectively). In the published PIII POSITRON study in 278 patients with genotypes 2 or 3 for whom treatment with peginterferon was not an option, the SVR12 was 78% in the sofosbuvir/RBV group vs. 0% for placebo (p<0.001). In the published PIII FUSION study in 201 patients who had not had a response to prior interferon treatment, patients received sofosbuvir/RBV for 12 or 16 weeks. The SVR12 was 50% and 73% (p<0.001), respectively. In both studies, response rates were lower in patients with genotype 3 than genotype 2. Sofosbuvir is also in PIII trials in patients co-infected with HIV. Safety: Adverse events were less frequent with sofosbuvir than with peginterferon. Common adverse effects include headache, fatigue, nausea, and insomnia.

Simeprevir Indication: Current status: Predicted National guidance: oral Hepatitis C virus infection Filed in EU Apr UK As for sofosbuvir above. launch: Janssen-Cilag (HCV), genotype 1 or 4 in 2013. Reviews: NIHR HSC - treatment naïve adults with compensated 2014 Sep 2012, failed interferon Sep 2012. liver disease who are treatment naïve or have failed interferon. Target population: As for sofosbuvir above. Implications: Other oral protease inhibitors for genotype 1 infection are Sector: Secondary care initiated. taken twice or three times a day. Financial: As for sofosbuvir above. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Once daily NS3/4A protease inhibitor. Efficacy: The primary outcome of all the following PIII studies is the number of patients achieving a sustained virologic response at 12 weeks (SVR12) after the end of therapy. Treatment naïve: In CONCERTO-1, 183 patients received peginterferon alfa-2a plus ribavirin (PEG/RBV) for up to 24 or 48 weeks plus simeprevir or placebo for 12 weeks. SVR12 was achieved by 89% vs. 62%, respectively. In CONCERTO-4, 79 patients received PEG/RBV plus simeprevir for 12 weeks followed by response-guided treatment. SVR12 was 92%. In QUEST-1 (n=394) and QUEST-2 (n=391) patients received simeprevir or placebo for 12 weeks plus interferon-based therapy for 24 or 48 weeks. 80% and 81% of those on simeprevir achieved SVR12, respectively. Failed interferon: In CONCERTO-2,106 previous non-responders received simeprevir plus PEG/RBV for 12 or 24 weeks, followed by response-guided treatment. SVR12 was achieved by 53 vs. 36% of patients after 12 or 24 weeks. In CONCERTO-3, 49 relapsed patients received simeprevir plus PEG/RBV for 12 weeks, plus PEG/RBV for up to 36 weeks. SVR12 was achieved by 96% of patients. In CONCERTO-4, 79 patients received simeprevir plus PEG/RBV for 12 weeks followed by response-guided treatment. SVR12 in patients who had previously relapsed on interferon-based treatment was 100% and 39% in prior non-responders. In PROMISE, 393 previously relapsed patients received simeprevir or placebo with PEG/RBV for 12 weeks then PEG or RBV for 12 or 36 weeks. 79% of the simeprevir group achieved SVR12. On-going trials include a PIII trial in patients with concomitant HIV-1 infection and the RESTORE trial in those with genotype 4 infection. Safety: In the PROMISE study, simeprevir was associated with influenza-like illness, rash and itching.

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Sofosbuvir/ Indication: Current status: Predicted Reviews: None. ledipasvir Hepatitis C viral infection, PIII. UK Likely commissioning route: NHSE. oral launch: genotype 1. PbR: Likely specified high cost drug. Gilead Pharmacology: 2015 Ledipasvir is a NS5A protein inhibitor and sofosbuvir is a nucleotide NS5B inhibitor.

Asunaprevir/ Indication: Current status: Predicted Reviews: None. daclatasvir Hepatitis C virus infection, PIII. UK Likely commissioning route: NHSE. oral launch: genotype 1. PbR: Likely specified high cost drug. Bristol Myers Pharmacology: 2015 Squibb Asunaprevir is a NS3 protease inhibitor and daclatasvir is a NS5A inhibitor.

ABT450/ Indication: Current status: Predicted Reviews: None. ritonavir/ Hepatitis C virus infection, PIII. UK Likely commissioning route: NHSE. ABT267/ launch: genotype 1. PbR: Likely specified high cost drug. ABT333 2015 oral Pharmacology: AbbVie Ltd ABT 450 is a NS3/4A inhibitor, ABT 267 is a NS5A inhibitor, ABT 333 is a non-nucleoside inhibitor.

Actoxumab/ Indication: Current status: Predicted Reviews: None. bezlo- Clostridium difficile PIII. UK Likely commissioning route: NHSE. toxumab infections, prevention of launch: (children and young people) or CCG injection recurrence. 2016 (adults). MSD Pharmacology: PbR: Likely HRG included. Monoclonal antibodies against C difficile- producing toxin A (actoxumab) and toxin B (bezlotoxumab).

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BNF 6. Endocrine system

Alogliptin Indication: Current status: Predicted National guidance: oral Diabetes, type 2 (T2DM). Recommended for UK NICE: Diabetes: pathway, quality Vipidia approval in EU Jul launch: standard. Alogliptin/ 2013. 2013 SIGN: Management of diabetes. metformin Launched in US - Reviews: NICE-MPC May 2013. Vipdomet see prescribing oral information. Takeda Target population: Estimated UK Implications: Vipdomet will be the fifth DPP-4 inhibitor/metformin prevalence of diagnosed diabetes was 2.9 combination available in the UK. million people in 2011; 85% have T2DM and Financial: The 28-day cost for other DPP-4 inhibitors alone and in about 72% are receiving . It is combination is £30-35. Alogliptin combinations will have to be competitive. thought a further 850,000 are undiagnosed. Likely commissioning route: CCG. PbR: Likely HRG included. Sector: Primary care. Pharmacology: Oral dipeptidyl peptidase-4 (DPP-4) inhibitor. Efficacy: Unless stated otherwise, the primary outcome for all trials is mean change in HbA1c from baseline to week 26. Adding alogliptin 12.5mg or 25mg to metformin (n=527) resulted in changes in HbA1c of -0.6% (both doses) vs. -0.1% with placebo (p<0.001). In a PIII study patients received either alogliptin 25mg daily, 12.5mg twice daily, metformin 500mg or 1g twice daily, or a combination of both. Change in HbA1c was greater with combination (p<0.001) than with either monotherapy. Results from the 2-year ENDURE study (n>2,600) with alogliptin or glipizide plus metformin showed HbA1c reductions at week 104 were -0.68% and -0.72% for alogliptin 12.5 and 25mg, respectively, vs. glipizide (-0.59%). In a study (n=390) alogliptin 12.5mg or 25mg (added to insulin therapy ± metformin) was compared with placebo. HbA1c reductions were -0.63%, -0.71% and -0.13%, respectively (p<0.001). In a 52-week study (n=803) alogliptin 25mg or pioglitazone 15mg were added to metformin (≥1500mg) plus pioglitazone 30mg therapy. HbA1c change from baseline was -0.7% vs. 0.29%, respectively (p<0.001). In 441 elderly patients alogliptin was compared with glipizide in patients who were treatment-naïve or only taking one antidiabetic medication. The mean change in HbA1c at week 52 was -0.14% vs. -0.095%, respectively. The EXAMINE study (n=5,400) will assess cardiovascular outcomes of alogliptin vs. placebo, in addition to standard of care, in subjects with T2DM and acute coronary syndrome. Final results are expected in 2014. Alogliptin may also be available in combination with pioglitazone although this is a little used treatment option in the UK. Safety: Incidence of hypoglycaemia with alogliptin was similar to that seen with other therapies, but lower than that seen with sulphonylureas in elderly patients (5.4% vs. 26%). There have been reports of pancreatitis in patients taking alogliptin.

Canagliflozin Indication: Current status: Predicted National guidance: oral Diabetes, type 2. Filed in EU Jun UK As for alogliptin above, canagliflozin due launch: Invokana 2012 and Mar Jun 2014, dapagliflozin. Canagliflozin/ 2013 (combination 2013 and Reviews: NIHR HSC Apr 2011. metformin with metformin). 2014 oral Launched in US – (comb- ination) Janssen-Cilag see prescribing information. Target population: As for alogliptin above. Implications: NICE have approved dapagliflozin for dual therapy with Sector: Primary care. metformin in certain circumstances but not as triple therapy with metformin and sulphonylureas. Canagliflozin is another option. Financial: Canagliflozin will compete with dapagliflozin at £37 per month. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: Sodium-glucose co-transporter 2 (SGLT2) inhibitor. Efficacy: In the published CANTATA-M monotherapy study (n=584), HbA1c changes at week 26 with canagliflozin 100mg and 300mg were -0.77% and -1.03%, and were sustained to week 52 (-0.81% and -1.1%, respectively). Dual therapy regimens: In the published CANTATA-SU study (n=1,450), for lowering of HbA1c at 52 weeks, canagliflozin 100mg was non- inferior to glimepiride; canagliflozin 300 mg was superior (difference -0.12%). In CANTATA-D (n=1,284) canagliflozin, placebo or sitagliptin were added to metformin for 26 weeks, then all patients on placebo were switched to sitagliptin for a further 26 weeks. At week 52, both doses of canagliflozin were non-inferior to sitagliptin at lowering HbA1c, and canagliflozin 300mg was superior. Triple therapy regimens: In the 26-week PIII CANTATA-MSU (n=469) study HbA1c changes were -0.13% with placebo, -0.85% with canagliflozin 100mg and -1.06% with 300mg (p<0.001). In the published CANTATA-D2 study (n=755) canagliflozin showed a greater reduction in HbA1c at week 52 vs. sitagliptin (-1.03 vs. -0.66%). Canagliflozin also showed improvement in weight reduction and blood pressure vs. sitagliptin (p<0.001). In the CANTATA-MP study (n=340), canagliflozin was added to metformin and pioglitazone. The 26-week HbA1c changes were -0.89% (100mg) and -1.03% (300mg) (p<0.001), which were sustained to week 52 (-0.98% and -1.07% respectively). In CANVAS, which is due to complete in 2018, the effects of canagliflozin on cardiovascular events are being compared with placebo (n=4,330). Canagliflozin has been used with metformin in a number of the above studies, this data plus bioequivalence studies will be used in the licence application for the canagliflozin/metformin combination. Safety: Higher rates of genital and urinary tract infections with canagliflozin reflect increases in urinary glucose excretion.

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Dapagliflozin/ Indication: Current status: Predicted National guidance: metformin Diabetes, type 2. Filed in EU Dec UK NICE: As for alogliptin above, oral 2012. launch: dapagliflozin. AstraZeneca/ 2013 Reviews: NIHR HSC May 2011. Bristol Myers Squibb Target population: As for alogliptin above. Implications: NICE has approved use of dapagliflozin as dual therapy with Sector: Primary care. metformin in certain circumstances. The combination product may be more convenient for patients stabilised on the two drugs taken separately. Financial: Currently UK cost for 28 days treatment with various metformin formulations ranges from around £1.50 to £12; dapagliflozin costs about £37/month. The combination product will have to compete with this. Likely commissioning route: CCG. PbR: HRG included. Pharmacology: SGLT2-inhibitor with a biguanide in a once daily formulation. Efficacy: Dapagliflozin is licensed for use in combination with other glucose-lowering medicines, such as metformin, when these, together with diet and exercise, do not provide adequate glycaemic control. Bioequivalence studies comparing fixed- dose combination products with individual components have been undertaken. Safety: See medicines.org.uk.

Exenatide Indication: Current status: Predicted Reviews: None. implant Diabetes, type 2. PIII trials in EU UK Likely commissioning route: CCG. launch: Intarcia Pharmacology: and US. PbR: HRG included. therapeutics 2016 Long-acting analogue of glucagon-like peptide 1 (GLP-1) delivered via DUROS device over 3-12 months.

Insulin Indication: Current status: Predicted National guidance: degludec/ Diabetes, type 1 (T1DM) Licensed in EU UK As for alogliptin above. insulin aspart and type 2 (T2DM). Jan 2013. launch: injection Reviews: NIHR HSC - T1DM, T2DM, Company plan to 2014 Jan 2011. Ryzodeg launch early 2014. Novo Nordisk Target population: As for alogliptin above. Implications: In T2DM NICE recommends insulin (starting with human NPH About 15% of adults and children with insulin or a long-acting insulin analogue) for patients with HbA1c not diabetes have T1DM. controlled with metformin plus sulfonylurea. Ryzodeg will be another option Sector: Primary and secondary care. for those not controlled on oral therapy or basal insulin regimens. Financial: Cost of 1,500 units of NovoMix 30 is about £30 and of Humulin M3 £15-22. Cost of 1,500 units insulin degludec is £72. Ryzodeg is likely to be more expensive than currently available insulin combinations. Likely commissioning route: CCG. PbR: HRG included. Pharmacology: Long-acting basal insulin [degludec, 70%] plus short-acting bolus insulin [aspart, 30%] (IDegAsp). Efficacy: Unless stated otherwise, in all studies, the primary outcome was HBA1c change at 26 weeks. T1DM. In the published BOOST-T1 study (n=548) IDegAsp given once-daily with any meal with insulin aspart (IAsp) at remaining meals was non-inferior to once-daily insulin detemir with IAsp at all meals. T2DM. In BOOST-START 1 (n=530) and BOOST-INTESIFY-BASAL (n=465) IDegAsp demonstrated non-inferiority vs. insulin glargine (IGlar). In the published BOOST: Intensify All trial (n=296), at 26 weeks, mean HbA1c was 7% with IDegAsp vs. 7.3% with IGlar (difference -0.28%, p<0.01). Safety: See medicines.org.uk. This has not been approved in the US pending further cardiovascular outcomes data.

Insulin Indication: Current status: Predicted Reviews: No recent reviews. inhalation Diabetes, types 1 and 2. PIII trials in EU UK Likely commissioning route: CCG. launch: Afrezza Pharmacology: and US. PbR: Likely HRG Included. 2015 MannKind Dry-powder formulation of Corporation insulin, rapid acting.

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Bazedoxifene/ Indication: Current status: Predicted National guidance: conjugated Postmenopausal Filed in EU Jul UK NICE: Osteoporosis pathway. estrogens launch: osteoporosis and 2012. SIGN: Management of osteoporosis. oral menopausal symptoms. 2014 Duavive Reviews: None. Pfizer Target population: It is estimated that more Implications: NICE suggests first-line treatment for primary prevention of than 2 million women have osteoporosis in postmenopausal osteoporosis is a bisphosphonate. Raloxifene (a SERM) is England and Wales. After the menopause, not recommended for primary prevention of osteoporotic fractures but can be the prevalence of osteoporosis increases used for secondary prevention. Many preparations are available for markedly with age, from about 2% at 50 menopausal symptoms. Bazedoxifene plus conjugated oestrogens (BZA/CE) years of age rising to more than 25% at 80 is another option and, as a single tablet, could be attractive. years. Financial: Current 28-day treatment costs range from £1.10 (alendronate Sector: Primary care. 70mg/week) to £17.06 (raloxifene 60mg/day) and £25.60 (strontium ranelate 2g/day). Conjugated oestrogens for HRT cost around £3-6 for 3 months treatment. BZA/CE is likely to be competitive. Likely commissioning route: CCG. PbR: Likely HRG included. Pharmacology: Selective oestrogen receptor modulators (SERM) plus oestrogen receptor agonist. Efficacy: Five PIII Selective Estrogen Menopause and Response to Therapy (SMART) studies have been undertaken, the results of four are fully published. Endometrial safety and changes in bone mineral density (BMD) are assessed in SMART-1 (n=3,397), SMART-4 (n=1,061) and SMART-5 (n=1,843). In SMART-1, over 24 months, BZA/CE was associated with low rates (<1%) of endometrial hyperplasia and endometrial thicknesses that were similar to placebo. BMD increases seen in all three studies were significantly greater with BZA/CE vs. placebo and in SMART-1, were greater with most doses of BZA/CE vs. raloxifene. In SMART-1 and SMART-2 (n=332) studies, the incidence of hot flushes by week 12 was reduced by 50-85% with BZE/CE vs. 17-50% with placebo (p<0.01). BZA/CE was used in SMART 3 (n=664) to treat vulvar/vaginal atrophy. BZA/CE increased superficial, and decreased parabasal, cells vs. placebo (p<0.01). Vaginal pH and dryness improved with BZA/CE vs. placebo (p≤0.05). Safety: BZA/CE is associated with low rates (<1%) of endometrial hyperplasia and endometrial thicknesses.

Pasireotide Indication: Current status: Predicted National guidance: None. LAR Acromegaly. PIII in EU with UK Reviews: No recent reviews. injection orphan status. launch: Signifor 2014 Novartis Target population: The UK incidence of Implications: Pasireotide will compete with other somatostatin analogues, acromegaly is about 3 per million; about pegvisomant and dopamine agonists. 3,000 have the condition. Financial: Current depot therapy includes lanreotide 30mg (£645/month) or Sector: Secondary care. octreotide 20mg (£776/ month) for initial therapy, dose and/or frequency adjusted according to response. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Somatostatin analogue in a long-acting release (LAR) i.m. injection given every 4 weeks. Efficacy: In the PIII PASPORT-ACROMEGALY study (n=358), pasireotide LAR was compared with octreotide LAR both given by monthly i.m. injection. At 12 months, 31.3% on pasireotide LAR vs. 19.2% on octreotide LAR (p=0.007) achieved a biochemical response (growth hormone level <2.5mcg/L and normal insulin like growth factor-1). Those who did not initially achieve biochemical control could switch to the other treatment in a 6-month extension phase; 81 switched to pasireotide LAR and 38 to octreotide LAR. A biochemical response was achieved by 21.0% and 2.6%, respectively. A PIII study assessing pasireotide vs. octreotide or lanreotide is ongoing. Safety: See medicines.org.uk for short-acting formulation. Hyperglycaemia is more common with pasireotide than octreotide.

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Tolvaptan Indication: Current status: Predicted National guidance: oral Autosomal-dominant PIII in EU. UK licence NICE: Chronic kidney disease pathway. extension: Samsca polycystic kidney disease Not recommended SIGN: Diagnosis and management of Otsuka (ADPKD) for approval in US 2014 chronic kidney disease. Pharma- Aug 2013. Reviews: NIHR HSC Apr 2012. ceuticals Target population: ADPKD has a Implications: There are currently no therapies that modify the disease prevalence of 100-1,300 per 100,000 people course and slow the rate of decline in renal function. Current management (at least 60,000 in the UK). In 2007 options include anti-hypertensives, dialysis and renal transplantation. polycystic kidney disease accounted for Financial: Based on current prices, tolvaptan 60mg/day will cost over 12.7% of patients receiving renal transplants. £4,100/month. Sector: Secondary care initiated. Likely commissioning route: Uncertain -depending on statge of renal failure. PbR: Specified high cost drug. Pharmacology: Selective vasopressin V2-receptor antagonist. Efficacy: In the published PIII TEMPO 3:4 trial (n=1,445) patients received tolvaptan at the highest of three dose regimens tolerated or placebo. At 3 years, the increase in total kidney volume in the tolvaptan group was 2.8% per year vs. 5.5% per year for placebo (p<0.001). Secondary outcome measures including a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline favoured tolvaptan (p=0.01 and p<0.001, respectively). Safety: See medicines.org.uk. In the TEMPO 3:4 trial more patients on tolvaptan had raised liver enzymes. The MHRA has issued a safety warning. BNF 7. Obstetrics, gynaecology, and urinary-tract disorders

Botulinum A Indication: Current status: Predicted National guidance: toxin Overactive bladder (OAB), Filed in UK, date UK licence NICE: Lower urinary tract symptoms in (onabotulinu idiopathic in adults who uncertain. extension: men - pathway, quality standard due Sep m-toxin A) have an inadequate Recommended for 2013 2013; Urinary incontinence in women – injection response/are intolerant of approval in EU guideline, update due Sep 2013, Botox antimuscarinic medication. (but not UK) Dec commissioning guide. Allergan 2012. SIGN: Urinary incontinence. Launched in US - Reviews: NICE-MPC Sep 2012. see prescribing information. Target population: The estimated Implications: NICE guidance suggests that botulinum toxin is an option in population with OAB for whom patients able and willing to self-catheterise, for whom standard therapy with antimuscarinic treatment does not give an lifestyle changes, bladder retraining and anticholinergic drugs has failed and adequate response is around 0.265%, who might otherwise have been considered for surgical intervention or equating to around 106,000 adults in neuromodulation. England. Financial: The current NHS cost of Botox is £138.20 for a 100-unit vial; the Sector: Secondary care. cost per patient will be £276.40/year if given twice. This does not include the cost of the procedure. Likely commissioning route: CCG. PbR: Specified high cost drug. Pharmacology: Purified neurotoxin complex presented as a single 1,000 unit injection administered as 20 individual 5 unit injections into the detrusor muscle. The effects of a single injection can last for between 3-10 months. Efficacy: In a published 12-week PIII trial (n=557) in the EMBARK programme, botulinum A toxin 100 units reduced the primary outcome of daily urinary incontinence episodes vs. placebo (-2.65 vs. -0.87, p<0.001) and 22.9% vs. 6.5% of patients became completely continent (NNT=6). More patients on botulinum A toxin reported a positive response on the treatment benefit scale (primary outcome) vs. placebo (60.8% vs. 29.2%, respectively, p<0.001). Similar results have been noted in another PIII study (n=548) in the EMBARK programme. An on-going, long-term follow-up study (n=750) has completed enrolment. The published UK RELAX study (n=240) reported that 31% of women were continent at 6 months after one botulinum 200 unit injection vs. 12% on placebo (NNT= 5). Safety: In the PIII trials, 18% of patients had urinary tract infections, 9% had dysuria and 6.5% had urinary retention. NNH (urinary tract infection/ requirement for self catheterisation) was 5 for botulinum and 8 for placebo.

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Collagenase Indication: Current status: Predicted National guidance: clostridium Peyronie’s disease (PsD). PIII in EU. UK licence NICE: Extracorporeal shock waves for histolyticum extension: PsD. injection Filed in US in Nov 2012. 2014 EAU Guidelines on Penile Curvature Xiapex 2012. Auxilium Reviews: None. Target population: PsD affects around 1% Implications: Current therapy incudes oral potassium para-aminobenzoate, of men; it will improve or resolve intralesional interferon-alpha or verapamil, and surgery. spontaneously in about 13%. The average Financial: Xiapex 900 microgram currently costs £650; much more than age of onset is in the fifth decade with many interferon-alpha. cases undiagnosed. Likely commissioning route: CCG. PbR: Specified high cost drug. Sector: Secondary care. Pharmacology: Collagenase stimulant injected into penile plaque twice weekly every 6 weeks for up to 4 treatment cycles, each injection accompanied by penile modelling. Efficacy: A post-hoc meta-analysis of two identical 52-week PIII studies IMPRESS I and II has been published, each enrolling over 400 men. Those treated with collagenase had a 34% mean improvement in penile curvature vs. 18% in those on placebo (representing a mean change -17.0 vs. -9.3 degrees, respectively). The mean change in Peyronie’s disease symptom bother score was improved with collagenase treatment (-2.8 vs. -1.8, p=0.004). Safety: Local treatment site reactions are common and include injection site haematoma, pain and swelling. Across IMPRESS I and II, 3 cases of corporal rupture and 3 serious penile haematomas occurred. BNF 8. Malignant disease and immunosuppression

Brain cancer Indication: Current status: Predicted Reviews: No recent reviews. vaccine Glioblastoma multiforme, PIII with orphan UK Likely commissioning route: NHSE. injection launch: first-line adjuvant therapy. status. PbR: Chemotherapy is locally DCVax-L Pharmacology: 2015 negotiated. Northwest Bio- Immunostimulant vaccine therapeutics manufactured using the patient’s dendritic cells and resected tumour tissue.

Afatinib Indication: Current status: Predicted Reviews: NIHR HSC Mar 2013. oral Head and neck cancer, PIII. UK licence Likely commissioning route: NHSE. extension: Giotrif squamous cell – locally PbR: Chemotherapy is locally Boehringer advanced, recurrent or 2015 negotiated. Ingelheim metastatic - second-line. Pharmacology: Tyrosine kinase inhibitor blocking EGFR and HER2.

Sorafenib Indication: Current status: Predicted National guidance: oral Thyroid cancer, Filed in EU and UK licence None relevant. extension: Nexavar differentiated (DTC) – US Jul 2013 with Reviews: No recent reviews. Bayer advanced, radioactive- priority review in 2014 iodine refractory. the US. Target population: UK incidence of thyroid Implications: Options for recurrent or metastatic disease include surgery, cancer is 3.5 per 100,000; DTC (papillary radioactive iodine and radiotherapy. Sorafenib will be the first drug licensed and follicular) accounts for 80%. 5-20% of for progressive disease. patients develop local or regional Financial: This is additional therapy that currently costs £2,980 a month. recurrences and 10-15% have distant Median treatment duration in a PII trial was 16.5 months. metastases. Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary or tertiary care. negotiated. Pharmacology: Blocks Raf and tyrosine kinases, vascular endothelial and platelet derived receptors. Efficacy: In the published PIII DECISION study (n=417), median PFS was 10.8 months with sorafenib vs. 5.8 months with placebo (HR 0.58, p<0.0001). Median overall survival (OS) had not been reached in either arm. A partial response (PR) was seen in 12.2% and 0.5% of sorafenib and placebo patients, respectively (p<0.0001); 42% and 33% had stable disease (SD) lasting at least 6 months, respectively. In a published PII study (n=31), 59% had a clinical response (25% a PR and 34% SD); 22% had progressive disease. In published long-term results, median PFS was 18 months and median OS was 34.5 months. In a published PII study (n=19), the radiological response rate was 18% and OS 79% at 12 months. Safety: See medicines.org.uk.

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Lenvatinib Indication: Current status: Predicted National guidance: oral Thyroid cancer, PIII with orphan UK As for sorafenib above. launch: Eisai differentiated (DTC) – status. Reviews: None. advanced, radioactive- 2014 iodine refractory. Target population: As for sorafenib above. Implications: Options for recurrent or metastatic disease include surgery, Sector: Secondary or tertiary care. radioactive iodine and radiotherapy. A competitor to twice-daily sorafenib. Financial: Likely to be similarly priced to sorafenib (£2,980/month). Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: A once-daily, multi-targeted kinase inhibitor of VEGFR1-3, FGFR1-4 and RET tyrosine kinases. Efficacy: Data from a PII trial (n=58) show an objective clinical response rate of 50%; the rate in patients who received prior VEGFR-directed treatment (n=17) was 41%, in those with no prior VEGFR-directed treatment it was 54%. Median PFS was 12.6 months after a minimum follow-up of 8 months. Results from the placebo-controlled PIII SELECT trial (n=360) are expected in 2013. A PII trial enrolling 104 patients with DTC and medullary TC is expected to complete in Oct 2013. Safety: In a PII trial, 10% of patients experienced grade 3 diarrhoea, hypertension and proteinuria. Toxicities were manageable by dose reduction in 35% of patients. 23% withdrew from the study due to adverse events.

Cabozantinib Indication: Current status: Predicted National guidance: oral Thyroid cancer, medullary Filed in EU Dec UK None relevant. launch: Cometriq (MTC). 2012 with orphan Reviews: NIHR HSC Feb 2012. Exelixis status. 2013 Launched in US - see prescribing information. Target population: MTC is rare, accounting Implications: First-line therapy is thyroidectomy. Cabozantinib may slow for 5-8% of all thyroid (about 0.2 per disease progression in patients who cannot be managed by surgery alone 100,000 people). and will be an alternative to . Sector: Secondary or tertiary care. Financial: Likely to be expensive but may offset other treatment costs. An alternative to vandetanib which costs £5,000 per month. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Tyrosine kinase inhibitor that blocks RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL and TIE-2. Efficacy: In the published PIII EXAM trial (n=330) progression-free survival (PFS) was 11.2 months with cabozantinib vs. 4.0 months with placebo (HR 0.28, p<0.0001). One-year PFS was 47.3% and 7.2%, respectively; overall response rates were 28% and 0%, respectively (p<0.0001). In a published PI study (n=35), 29% had a partial response to cabozantinib, and 49% had tumour shrinkage of 30% or more. At two years, 30% were progression-free. Safety: Cabozantinib has been associated with perforations, fistulas, haemoptysis and gastrointestinal haemorrhage.

Afatinib Indication: Current status: Predicted National guidance: oral Non-small cell lung cancer Recommended for UK NICE: Lung cancer - pathway, quality Giotrif (NSCLC), advanced with approval in EU Jul launch: standard; NSCLC - afatinib due May Boehringer EGFR mutation. 2013. 2013 2014. Ingelheim Licensed in US - SIGN: Lung cancer, update due 2013. see prescribing Reviews: No recent reviews. information. Target population: UK incidence of Implications: Afatinib will compete with first generation EGFR inhibitors, advanced NSCLC is 45 per 100,000 people; and . It is a less complicated and less toxic alternative to i.v. 25% are able to have first-line therapy. chemotherapy in selected patients. Epidermal (EGFR) is Financial: PASs are in place for erlotinib and gefitinib for NSCLC. Monthly overexpressed in 10-15% of tumours. list price is £1,600 and £2,000, respectively. Sector: Secondary care. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Tyrosine kinase inhibitor irreversibly blocking receptors, including HER2. Efficacy: In the published global PIII LUX-Lung 3 trial (n=345) comparing first-line afatinib with and , median progression-free survival (PFS) was 11.1 vs. 6.9 months, respectively (HR 0.58, p=0.001). In 308 patients with EGFR mutation, median PFS was 13.6 months for afatinib vs. 6.9 months for chemotherapy (0.47, p=0.001). The objective response rate was 56% for afatinib vs. 23% in the control group (p<0.0001). Afatinib also delayed time to deterioration of cancer-related symptoms of cough (0.6, p=0.007) and dyspnoea (0.68, p<0.01). The PIII LUX-Lung 6 trial compared afatinib with cisplatin and gemcitabine in 364 Asian patients; median PFS was 11.0 vs. 5.6 months, respectively (0.28, p<0.0001). Safety: Common adverse effects are diarrhoea, rash, mucositis and paronychia.

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Belagenpu- Indication: Current status: Predicted Reviews: None. matucel-L Non-small cell lung cancer PIII. UK Likely commissioning route: NHSE. injection launch: – second-line. Granted fast track PbR: Chemotherapy is locally Lucanix Pharmacology: status in US. 2015 negotiated. NovaRx Antisense-DNA vaccine. Corporation

Afatinib Indication: Current status: Predicted Reviews: None. oral Non-small cell lung cancer PIII. UK licence Likely commissioning route: NHSE. extension: Giotrif – second-line plus. PbR: Chemotherapy is locally Boehringer Pharmacology: 2015 negotiated. Ingelheim Tyrosine kinase inhibitor blocking EGFR and HER2. Dacomitinib Indication: Current status: Predicted Reviews: NIHR HSC Nov 2012. oral Non-small cell lung cancer, PIII. UK Likely commissioning route: NHSE. launch: Pfizer advanced – second-line PbR: Chemotherapy is locally plus. 2015 negotiated. Pharmacology: Pan-HER tyrosine kinase inhibitor.

Ganetespib Indication: Current status: Predicted Reviews: None. injection Non-small cell lung cancer PIII. UK Likely commissioning route: NHSE. launch: Synta (NSCLC), advanced – PbR: Chemotherapy is locally second-line plus. 2015 negotiated. Pharmacology: A second-generation heat shock protein-90 inhibitor.

Eribulin Indication: Current status: Predicted Reviews: NIHR HSC May 2013. injection Non-small cell lung cancer, PIII. UK licence Likely commissioning route: NHSE. extension: Halaven advanced – third-line. PbR: Chemotherapy is locally Eisai Pharmacology: 2015 negotiated. Synthetic analogue of halichondrin B, with tubulin-based antimitotic activity.

LDK378 Indication: Current status: Predicted Reviews: NIHR HSC Mar 2013. oral Non-small cell lung cancer, PII. UK Likely commissioning route: NHSE. launch: Novartis ALK-positive, locally Granted PbR: Chemotherapy is locally advanced or metastatic – breakthrough 2015 negotiated. second-line. therapy status in Pharmacology: US. ALK inhibitor.

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Enobosarm Indication: Current status: Predicted National guidance: oral Non-small cell lung cancer PIII in EU. UK NICE: Lung cancer pathway, quality launch: Ostarine (NSCLC), advanced – PIII in US with fast standard. GTXi prevention and treatment track status. 2014 SIGN: Lung cancer, update due 2013. of cachexia. Reviews: NIHR HSC Nov 2012. Target population: Cancer-related cachexia Implications: Therapeutic options are limited for patients with cachexia, but (loss of skeletal muscle mass and include nutritional support, short-term corticosteroids and progestogens. progressive functional impairment) occurs in Enobosarm is intended to be given to patients receiving first-line 50% of cancer patients and causes at least chemotherapy and may improve quality of life. 20% of deaths. The UK incidence of Financial: Costs will be additive to current therapy. advanced NSCLC is 45 per 100,000 people; 25% receive first-line chemotherapy. Likely commissioning route: NHSE. PbR: Likely HRG included. Sector: Secondary care. Pharmacology: A first-in-class, non-steroidal selective androgen receptor modulator (SARM). Efficacy: In a published PII trial (n=100; 31 with NSCLC), median total lean body mass (LBM) at 4 months increased from baseline with enobosarm 1mg and 3mg (1.5kg and 1.0kg, respectively; both p<0.05) but not with placebo (0.02kg; p=0.88). Absolute changes from baseline in mean stair climb power (SCP) with enobosarm 1mg, 3mg and placebo were 18.0%, 21.7% and 4.8%, respectively. Although not designed to assess survival, the survival hazard ratios for patients on enobosarm 1mg or 3mg vs. placebo were 0.80 and 0.70, respectively. Initial data from two PIII trials (both n=325) show enobosarm failed to meet criteria for the co-primary outcome of LBM and SCP; POWER1 involves patients on first-line platinum plus taxane chemotherapy, and POWER2 involves patients on first-line platinum plus non-taxane chemotherapy. Although the effect of enobosarm vs. placebo on SCP was inconsistent, LBM was significantly increased at all assessment times (p=0.0003 and p=0.0227 at day 84 for POWER1 and POWER2, respectively). Survival and quality of life results are awaited. Safety: Transient changes in liver function tests have been reported.

Anamorelin Indication: Current status: Predicted Reviews: None. oral Anorexia/cachexia PIII. UK Likely commissioning route: NHSE. launch: Helsinn associated with non-small PbR: Likely HRG included. cell lung cancer. 2015 Pharmacology: Ghrelin receptor agonist.

Trastuzumab Indication: Current status: Predicted National guidance: emtansine Breast cancer (BC), Filed in EU Sep UK NICE: BC pathways - early/locally injection advanced, HER2-positive 2012. launch: advanced, advanced and familial, BC Kadcyla – second/ third-line. Launched in US - 2013 quality standard; trastuzumab emtansine Roche see prescribing due Aug 2014. information. SIGN: Breast cancer. Reviews: NIHR HSC Jan 2011. Target population: The incidence of BC in Implications: This will compete with other second-line options including the UK is about 80 per 100,000 people. biological therapies, chemotherapies and hormonal therapies. About 40% develop metastatic disease; 25% Financial: Cost unknown but will displace other expensive treatments. US of these are HER2-positive which has a cost is $9,800 a month. worse prognosis. About 70% of patients do not respond to first-line trastuzumab and the Likely commissioning route: NHSE. PbR: Chemotherapy is locally rest develop resistance within the first year. negotiated. Sector: Secondary care. Pharmacology: First-in-class trastuzumab emtasine (T-DM1) is an antibody conjugate of trastuzumab and an anti-mitotic agent, maytansinoid DM1. Given by 3-weekly i.v. infusion. Efficacy: The published EMILIA study enrolled 991 patients with BC that progressed after first-line trastuzumab and a taxane. Median progression-free survival (PFS) was 9.6 months for T-DM1 vs. 6.4 months for lapatinib and (LC) (HR 0.65, p<0.001). Median overall survival at the second interim analysis was 30.9 months vs. 25.1 months, respectively (0.68, p<0.001). Objective response rates were 43.6% for T-DM1 and 30.8% for LC. 1-year and 2-year survival rates with T- DM1 were 85% and 65%; with LC they were 78% and 52%, respectively. The PIII TH3RESA study is comparing T-DM1 with treatment of choice in 606 women who have received at least 2 prior HER2 regimens. Results are due in 2015. Safety: Compared with LC, T-DM1 more commonly causes thrombocytopenia and raised liver enzymes, but less often causes diarrhoea, vomiting and hand-foot syndrome. Liver function and left ventricular ejection fraction require monitoring.

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Trastuzumab Indication: Current status: Predicted National guidance: emtansine Breast cancer (BC), PIII. UK licence As for trastuzumab emtansine above. injection extension: advanced, HER2-positive Reviews: NIHR HSC Jun 2012. Kadcyla – first-line in combination 2014 Roche with pertuzumab. Target population: As for trastuzumab Implications: This could prevent the need for first-line chemotherapy and emtansine above. could result in a delay in disease progression and improved quality of life. Sector: Secondary care. Financial: Cost unknown but would displace trastuzumab plus taxane therapy. US cost is $9,800 a month. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: As above. Efficacy: The PIII MARIANNE study is assessing progression-free survival (PFS) in 1,092 patients given first-line trastuzumab emtansine, either alone or in combination with pertuzumab vs. trastuzumab plus taxane. Results are expected in 2014. In a published PII trial (n=137), the objective response rate with T-DM1 was 64.2% vs. 58.0% with trastuzumab plus . Compared with the control group, there was a 41% reduction in risk of disease progression or death with T-DM1, with median PFS of 9.2 months vs.14.2 months, respectively (HR 0.59). Safety: T-DM1 caused fewer grade ≥3 adverse effects (46% vs. 91%) and adverse effects leading to discontinuations (7% vs. 41%) than trastuzumab plus taxane. Liver function and left ventricular ejection fraction require monitoring.

Trastuzumab/ Indication: Current status: Predicted National guidance: hyaluronidase Breast cancer (BC), early Licensed in EU UK As for trastuzumab emtansine above. injection launch: and metastatic HER2- Sep 2013. Reviews: NIHR HSC Jan 2011, NICE- Herceptin SC positive (all BC indications 2013 MPC Mar 2013. Roche for which trastuzumab is currently indicated). Target population: As for trastuzumab Implications: Compared to the i.v. formulation, s.c. trastuzumab will reduce emtansine above. preparation and administration time and would facilitate homecare delivery. Sector: Secondary care. This s.c. formulation is presented as a fixed dose formulation unlike the i.v. formulation that is dosed according to body weight. Biosimilar formulations of i.v. trastuzumab are in development (see page 70). Financial: Cost unknown but may reduce overall costs and clinic time. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Anti-HER2 monoclonal antibody co-formulated with recombinant human hyaluronidase to facilitate absorption of trastuzumab through subcutaneous tissue. Given by s.c. injection every 3 weeks. Efficacy: The published PIII HannaH study compared the pharmacokinetics and efficacy of s.c and i.v. trastuzumab in 596 women with early HER2-postive BC. The s.c. formulation was non-inferior to the i.v. formulation; serum trough plasma concentrations before surgery were at least as high (69.0 and 51.8 microgram/mL, respectively) and efficacy as determined by pathological complete response was similar in both groups (45.4% and 40.7%, respectively). Safety: Adverse effects are consistent with those of i.v. trastuzumab. See medicines.org.uk.

Bevacizumab Indication: Current status: Predicted National guidance: injection Breast cancer (BC), early PIII. UK licence As for trastuzumab emtansine above. extension: Avastin HER2-positive – adjuvant Reviews: NIHR HSC Apr 2012. Roche therapy. 2014 Target population: As for trastuzumab Implications: Despite treatment with trastuzumab, many women develop emtansine above. Around 95% of patients recurrent or metastatic disease. The addition of bevacizumab may improve present with localised disease and are response rates and delay progression. eligible for surgery. 15-20% are HER2- Financial: Costs will be additive to chemotherapy and trastuzumab. Current positive and have a worse prognosis; nearly cost of one year’s treatment with bevacizumab for a 65kg woman is about all require adjuvant treatment with £40,000. trastuzumab, which lowers risk of recurrence by 25-50% and risk of death by 17-33%. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Sector: Secondary care. Pharmacology: Vascular endothelial growth factor antagonist, given by i.v. infusion every 3 weeks. Efficacy: The PIII BETH study is investigating whether giving bevacizumab for one year in addition to chemotherapy (docetaxel/ or 5-, and cyclophosphamide) plus trastuzumab improves invasive disease-free survival in 3,509 women who have undergone surgery. Interim results are expected in 2013. Safety: See medicines.org.uk.

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Everolimus Indication: Current status: Predicted National guidance: oral Breast cancer (BC), PIII. UK licence As for trastuzumab emtansine above. extension: Afinitor advanced HER2-positive – Reviews: NIHR HSC Apr 2012. Novartis first-line. 2014/2015 Target population: As for trastuzumab Implications: About 70% of patients are resistant to trastuzumab. Adding emtansine above. everolimus may improve response rates and delay need for second-line Sector: Secondary care. chemotherapy. Oral everolimus will compete with i.v. pertuzumab. Financial: Costs will be additive to trastuzumab and chemotherapy. Current cost of everolimus 10mg daily is £2,970 per month, and the costs of a 420mg dose of pertuzumab given three-weekly is £2,400 (excluding loading dose and administration costs). Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: mTOR inhibitor. Efficacy: The PIII BOLERO-1 trial (n=717) is assessing addition of first-line everolimus to trastuzumab and paclitaxel. Results are imminent. This study was initiated following published PI trial results. Disease was controlled for more than 6 months in 74% of 27 women with prior resistance to trastuzumab given everolimus in addition to paclitaxel and trastuzumab. Overall response rate was 44% and progression-free survival (PFS) was 8.5 months. A pooled analysis of PII data from 47 women with trastuzumab resistance showed adding everolimus to trastuzumab produced partial responses in 7 patients and persistent stable disease (lasting 6 months or longer) in 9 patients. Median PFS was 4.1 months. Safety: See medicines.org.uk.

Everolimus Indication: Current status: Predicted National guidance: oral Breast cancer (BC), PIII. UK licence As for trastuzumab emtansine above. extension: Afinitor advanced HER2-positive – Reviews: NIHR HSC Feb 2012. Novartis second- or third-line with 2014 trastuzumab. Target population: As for trastuzumab Implications: Current options for patients resistant to trastuzumab produce emtansine above. low response rates and short durations of response. Everolimus is an Sector: Secondary care. alternative to lapatinib for overcoming trastuzumab resistance. Financial: Costs will be additive to trastuzumab and chemotherapy. Current cost of everolimus 5mg daily is £2,250/month, and lapatinib1g daily is £1,300/ month. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: mTOR inhibitor. Efficacy: Final results of the placebo-controlled PIII BOLERO-3 trial (n=569) showed that adding everolimus 5mg daily to trastuzumab and reduced risk of disease progression by 22% (HR 0.78, p<0.01). Median time to progression was 7.0 months in the everolimus group and 5.8 months in the placebo group. All patients were resistant to trastuzumab- containing regimens and 27% were pre-treated with a lapatinib-containing regimen. Overall survival data are not yet mature. Safety: See medicines.org.uk.

Sorafenib Indication: Current status: Predicted Reviews: NIHR HSC Aug 2011. oral Breast cancer, locally PIII. UK licence Likely commissioning route: NHSE. extension: Nexavar advanced metastatic PbR: Chemotherapy is locally Bayer HER2 negative, with 2015 negotiated. capecitabine – second- line. Pharmacology: VEGFR, PDGFR and RAF inhibitor.

Palbociclib Indication: Current status: Predicted Reviews: None. oral Breast cancer, advanced PII. UK Likely commissioning route: NHSE. launch: Pfizer or metastatic – first-line. Granted PbR: Chemotherapy is locally Pharmacology: breakthrough 2015 negotiated. Cyclin-dependent kinase therapy status in inhibitor. US.

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Regorafenib Indication: Current status: Predicted National guidance: oral Gastrointestinal stromal PIII. UK NICE: GIST - , ; not launch: Stivarga tumours (GIST), metastatic Launched in US - recommended – higher-dose imatinib Bayer – third-line. see prescribing 2014 (after imatinib 400mg failure). information. Reviews: None. Target population: The incidence of Implications: Regorafenib will provide another option for patients who have metastatic GIST is 4 per million people. failed imatinib and sunitinib. About two thirds of patients do not respond, Financial: It will be additive to other therapies. UK cost unknown but is or develop resistance, to first-line imatinib. $9,350/month in the US. A PAS is in place in the UK for sunitinib in GIST. Sunitinib is a second-line option. Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary care. negotiated. Pharmacology: Multi-targeted inhibitor of angiogenic, stromal and oncogenic kinase receptors, taken once daily for 3 weeks of every 4-week cycle. Efficacy: In the published PIII GRID study 199 patients whose disease progressed despite at least 2 prior treatments received regorafenib or placebo, in addition to best supportive care. Median progression-free survival (PFS) was 4.8 months for regorafenib vs. 0.9 months for placebo (HR 0.27, p<0.0001). PFS rates at 3 and 6 months were 60% and 38% with regorafenib vs. 11% and 0% with placebo. The disease control rate (defined as the rate of partial response (PR) plus stable disease (SD) lasting for ≥12 weeks) was 53% vs. 9%, respectively (p<0.0001). In a published PII study (n=33), the clinical benefit rate (defined as complete or PR, and SD ≥16 weeks) was 79%. Four patients achieved PR, and 22 exhibited SD ≥16 weeks. Median PFS was 10.0 months. Safety: Severe and sometimes fatal hepatotoxicity has been reported.

Masitinib Indication: Current status: Predicted National guidance: oral Pancreatic cancer, Filed in EU Oct UK licence NICE: Pancreatic cancer – gemcitabine; Kinaction advanced – first-line in 2012 with orphan extension: masitinib due TBC. AB Science combination with status. 2013 Reviews: NIHR HSC Dec 2011. chemotherapy. Target population: UK incidence of Implications: Masitinib may extend life in patients with a bleak prognosis pancreatic cancer is 13 per 100,000 people; and few therapeutic options. It will be given in addition to gemcitabine, which 90% have advanced disease at diagnosis is recommended by NICE for patients with a Karnofsky score of ≥50. and 3% survive 5 years. Financial: Cost of masitinib will be additive to current therapies. A test for Sector: Secondary care. the prognostic genetic biomarker is being developed. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Tyrosine kinase inhibitor which targets c-, platelet-derived growth factor receptors and receptor 3. Efficacy: In a PIII trial (n=348), the primary outcome of improved overall survival (OS) was not met in patients given masitinib vs. placebo, both in combination with gemcitabine (p=ns). However, masitinib increased median OS in two subgroups. In patients with a genetic biomarker (GBM) indicative of aggressive disease, median OS was 11.0 with masitinib vs. 5.0 months with placebo (0.29, p=0.00004); OS rates at 12 and 18 months were respectively, 41.4% and 18.5% for masitinib vs. 11.1% and 4.2% for placebo. In patients without the GBM, median OS in the placebo arm was 14.3 months. In patients with pain at baseline (VAS score >20mm on a 100mm scale) median OS was 8.1 months with masitinib vs. 5.4 months with placebo (0.61, p=0.01); OS rates at 12 and 18 months were respectively, 32.2% and 18.2% for masitinib vs. 17.8% and 7.8% for placebo. In patients without pain, median OS was 15.4 months for placebo. Safety: Common adverse events in a published trial include nausea, vomiting, rash, oedema, and haematological effects.

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Doxorubicin Indication: Current status: Predicted National guidance: heat-sensitive Hepatocellular carcinoma PIII in EU with UK NICE: HCC - radiofrequency ablation, liposomes (HCC), inoperable – first- orphan status. launch: microwave ablation, sorafenib not injection line. PIII in US with 2014 recommended. ThermoDox orphan and fast Reviews: NIHR HSC Dec 2011. Celsion track status. Target population: UK incidence of HCC is Implications: For patients with limited treatment options, ThermoDox offers 6 per 100,000 people. Potentially curative the possibility of greater efficacy and fewer systemic adverse effects than options are surgery (suitable for <25%) and standard chemotherapy because of the combined effects of targeted microwave or radiofrequency ablation (RFA). cytotoxicity and ablation. Sorafenib is licensed for advanced HCC but not 90% present with unresectable disease and recommended by NICE. Mitozantrone is also used in the palliation of non- 2-year survival rates are 8-50%; chemo- resectable primary hepatocellular carcinoma. embolisation (chemotherapy delivered via Financial: Likely to be more expensive than standard options. the hepatic artery) is an option for some but systemic chemotherapy has limited benefits. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Sector: Secondary care. Pharmacology: A heat-activated liposomal formulation of doxorubicin, which is released when the tumour site is heated by microwave or radiofrequency ablation (RFA) to 39-42oC. Given by 30 minute infusion, started 15 minutes prior to ablation. Efficacy: In the PIII HEAT trial (n=700), ThermoDox in combination with RFA vs. RFA alone did not improve progression-free survival (PFS). However, post-hoc analysis showed ThermoDox improved PFS and overall survival in 300 patients who had optimal RFA lasting ≥45 minutes, regardless of HCC lesion size. Safety: Pre-medication is required to minimise infusion-related reactions.

Ramucirumab Indication: Current status: Predicted Reviews: None. injection Hepatocellular carcinoma PIII in EU with UK Likely commissioning route: NHSE. launch: Eli Lilly (HCC), advanced – orphan status. PbR: Chemotherapy is locally second-line. 2015 negotiated. Pharmacology: Vascular endothelial growth factor receptor-2 antagonist.

Sorafenib Indication: Current status: Predicted Reviews: NIHR HSC Aug 2011. oral Hepatocellular carcinoma - PIII with orphan UK licence Likely commissioning route: NHSE. extension: Nexavar adjuvant therapy. status in EU and PbR: Chemotherapy is locally Bayer Pharmacology: US and fast track 2015 negotiated. in US. VEGFR, PDGFR and RAF inhibitor.

Regorafenib Indication: Current status: Predicted National guidance: oral Colorectal cancer (CRC), Recommended for UK NICE: CRC: pathway, quality standard; Stivarga metastatic disease – third- approval in EU launch: regorafenib (suspended); not Bayer or fourth-line. Jun 2013. 2013 recommended - bevacizumab, Launched in US - , . see prescribing SIGN: CRC. information. Reviews: NIHR HSC Aug 2011. Target population: UK incidence of CRC is Implications: For patients with no further treatment options, regorafenib may 67 per 100,000 people. 20-55% of patients delay disease progression and improve quality of life. present with metastatic disease. Financial: Regorafenib will be additive to other therapies. UK cost is Management is mainly palliative with surgery unknown but US cost is $9,350/month. A PAS is in place for cetuximab as and chemo/radiotherapy for symptom first-line therapy for CRC in the UK. control. Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary care. negotiated. Pharmacology: Multi-targeted inhibitor of angiogenic, stromal and oncogenic kinase receptors, taken once daily for 3 weeks of every 4-week cycle. Efficacy: The published PIII CORRECT study, in 753 adults with metastatic CRC that had progressed after receiving all approved drugs for CRC, was stopped early after meeting its primary outcome. Median overall survival was 6.4 months in patients randomised to regorafenib plus best supportive care (BSC) vs. 5.0 months for placebo plus BSC (HR 0.77, p=0.0052). Median progression-free survival was 1.9 vs. 1.7 months, respectively (0.49, p<0.0001). The on-going expanded- access PIII CONSIGN study is designed to collect safety data. Safety: Severe and sometimes fatal hepatotoxicity has been reported.

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Sorafenib Indication: Current status: Predicted National guidance: oral Renal cell carcinoma PIII with orphan UK licence NICE: Urological cancer; pazopanib, Nexavar (RCC) - adjuvant therapy. status. extension: sunitinib (first-line advanced); not Bayer 2014/2015 recommended – bevacizumab, sorafenib, sunitinib (second-line) and . Reviews: None. Target population: UK incidence of RCC is Implications: RCC recurs in 30% of patients undergoing nephrectomy for 12 per 100,000 people. Patients with stage 1 localised disease. Sorafenib may delay development of metastatic disease, (39%) and 2 (16%) RCC, and some with which responds to targeted therapies, such as sorafenib and sunitinib, but stage 3 (26%), are candidates for surgery. not to chemotherapy. Five-year survival ranges from 40-90% in Financial: Cost of sorafenib 400mg twice daily is £2,980/month. stage 1-3 disease, and 10% in stage 4. Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary care. negotiated. Pharmacology: Blocks Raf and tyrosine kinases, vascular endothelial and platelet derived growth factor receptors. Efficacy: Adjuvant sorafenib in patients who have undergone partial or radical nephrectomy, at high or intermediate risk of relapse, is being studied in two PIII trials. SORCE is a placebo-controlled trial in 1,656 patients treated for 1 or 3 years; ASSURE (n=1,923) will compare sorafenib with sunitinib or placebo for 1 year. Results are expected in 2013 and 2016, respectively. In a published trial, overall recurrence rate was 15.0% in patients receiving sorafenib (n=20), 17.4% in patients given sunitinib (n=23) and 38.7% in those receiving no adjuvant therapy (n=388, p<0.05 vs. treatment groups). Disease-free survival was 18.9 months, 16.9 months and 13.3 months, respectively (p<0.05 vs. treatment groups). Safety: See medicines.org.uk.

Apaziquone Indication: Current status: Predicted National guidance: intravesical Bladder cancer, non- PIII in EU. UK NICE: Urological cancer, bladder cancer launch: Neoquin muscle invasive (NMIBC), PIII in the US with due 2014. Spectrum in patients at low or fast track status. 2014/2015 SIGN: Bladder cancer. intermediate risk of progression. Reviews: None. Target population: UK incidence of NMIBC Implications: Apaziquone will be an alternative to intravesical mitomycin, is about 13 per 100,000 people. After epirubin and doxorubicin in patients at low or intermediate risk of surgery, intravesical chemotherapy reduces progression. BCG vaccine is used in high-risk patients. risk of recurrence at 1 year by up to 44% Financial: Apaziquone may displace current options. (depending on the number of doses). Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary care. negotiated. Pharmacology: An indoloquinone mitomycin analogue prodrug metabolised to an alkylating agent by the DT-diaphorase enzyme, which is over-expressed by bladder cancer cells. Efficacy: Two PIII trials (SPI-611 and SPI-612) each recruiting 800 patients have investigated use of a single dose of apaziquone following transurethral resection of bladder tumours. Individually they did not meet their primary outcomes but pooled analysis showed apaziquone reduced the rate of tumour recurrence at 2 years (p=0.017). In a published PII study of 46 patients who underwent surgical excision of all but one superficial lesion, 67% had complete histological disappearance of the remaining lesion 2-4 weeks after 6 once-weekly instillations of apaziquone. After 24 months, 50% of responders were recurrence-free, with a median response duration of 18 months. Overall recurrence-free survival was 39%. Two ongoing placebo-controlled PIII studies (SPI-1011 and SPI-1012) are investigating 6-weekly instillations. Safety: Adverse effects include cystitis, dysuria, haematuria and abdominal pain.

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Sipuleucel-T Indication: Current status: Predicted National guidance: injection Prostate cancer (PC), Recommended for UK NICE: PC pathway; docetaxel, Provenge metastatic castration- approval in EU launch: sipuleucel-T due Feb 2014. Dendreon resistant – first-line. Jun 2013. 2013 Reviews: NIHR HSC Apr 2011. Launched in US – see prescribing information. Target population: In the UK, the incidence Implications: Sipuleucel-T will compete with docetaxel and first-line of PC is 134 per 100,000 men. 55-65% abiraterone acetate. It may prolong survival and have improved tolerability develop metastatic disease and over 90% over existing therapies. become resistant to standard hormonal Financial: Cost in the US is $93,000 for 3 doses. therapy (castration-resistant). Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary care. negotiated. Pharmacology: First personalised therapeutic vaccine that stimulates a T-cell response against prostatic acid phosphatase, an antigen expressed in most PCs but not in non-prostate tissue. Given by i.v. infusion every 2 weeks for 3 doses. Efficacy: In published PIII trials, patients had leukapheresis followed 3 days later by infusion of sipuleucel-T or control (autologous peripheral blood mononuclear cells that had not been activated). In the IMPACT study (n=512), median overall survival (OS) was 25.8 months for sipuleucel-T vs. 21.7 months for control (HR 0.78, p=0.03). Median time to objective disease progression (TTP) was 14.6 weeks vs. 14.4 weeks, respectively (p=ns). In the D9901 study (n=127), median TTP for sipuleucel-T was 11.7 weeks vs. 10.0 weeks for placebo (1.45, p=0.052) and median OS was 25.9 months and 21.4 months, respectively (1.7, p=0.01). In a meta-analysis of 3 trials (n=737), median OS of patients who received sipuleucel-T vs. the control group was longer (0.73, p=0.001) but median TTP was not (p=ns). Safety: Pre-medication is required to prevent acute infusion reactions (commonly chills, fever and fatigue).

Ipilimumab Indication: Current status: Predicted National guidance: injection Prostate cancer (PC), PIII. UK licence NICE: PC pathway; abiraterone, Yervoy metastatic castration- extension: docetaxel, enzalutamide due Feb 14; not Bristol Myers resistant – second-line. 2014 recommended – . Squibb Reviews: NIHR HSC Dec 2011. Target population: UK incidence of PC is Implications: Second-line treatments include abiraterone, cabazitaxel and 134 per 100,000 men. 55-65% develop enzalutamide. Ipilimumab may provide an additional treatment option for metastases and >90% become resistant to patients with a poor prognosis. hormonal therapy (castration-resistant). Financial: Ipilimumab costs £52,500 per dose for a 70kg person. A PAS is in About 40% of these men receive first-line place for second-line abiraterone. therapy (NICE recommends docetaxel), and of these about 75% may receive second-line Likely commissioning route: NHSE. PbR: Chemotherapy is locally therapy (24 per 100,000 men). negotiated. Sector: Secondary care. Pharmacology: Anti-CTLA-4 monoclonal antibody given by i.v. infusion every 3 weeks for 4 doses, then 3-monthly. Efficacy: A placebo-controlled PIII trial is assessing the effect of ipilimumab monotherapy following radiotherapy on overall survival in 800 men previously treated with docetaxel. Data are due soon. In a PII trial (n=24), decreases in serum prostate- specific antigen (PSA) levels of >50% were seen in 12.5% of patients treated with ipilimumab. One patient had a confirmed response lasting 246 days, one had a response of ≥79 days, and a third had an unconfirmed response. Safety: See medicines.org.uk.

Custirsen Indication: Current status: Predicted Reviews: None. injection Prostate cancer, PIII in EU. UK Likely commissioning route: NHSE. launch: OncoGenex metastatic castration- PIII in US with fast PbR: Chemotherapy is locally resistant, first/second-line. track status. 2015 negotiated. Pharmacology: Clusterin inhibitor.

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Cabozantinib Indication: Current status: Predicted Reviews: None oral Prostate cancer, PIII. UK licence Likely commissioning route: NHSE. extension: Cometriq castration-resistant – third- PbR: Chemotherapy is locally Exelixis line. 2015 negotiated. Pharmacology: MET, RET and VEGFR2 inhibitor.

Radium-223 Indication: Current status: Predicted National guidance: chloride Prostate cancer (PC), Filed in EU Dec UK NICE: PC pathway, denosumab injection castration-resistant 2012. launch: (metastases in PC) due TBC, radium- Alpharadin (patients with bone Licensed in US 2013 223 due Feb 2014, denosumab (in solid Bayer metastases). after priority tumours other than prostate). review. See US Reviews: No recent reviews. prescribing information. Target population: UK incidence of PC is Implications: Radium-233 could improve quality of life and delay disease 134 per 100,000 men. 55-65% develop progression. It is potentially an alternative/additive option to palliative metastases and >90% become resistant to therapies. standard hormonal therapy (castration- Financial: Cost is unknown but may displace other therapies. resistant). Over 90% with advanced disease develop bone metastases which can lead to Likely commissioning route: NHSE. PbR: Chemotherapy is locally fractures, uncontrollable bone pain and negotiated. spinal cord compression. Sector: Secondary care. Pharmacology: A first-in-class radiopharmaceutical that targets bone metastases. Given i.v. monthly for up to 6 cycles. Efficacy: The published PIII ALSYMPCA study (n=921) was stopped early after meeting its primary outcome. Median overall survival (OS) was 14.9 months in the radium-223 group vs. 11.3 months for placebo (HR 0.7, p<0.0001). Radium-223 delayed median time to first skeletal-related event vs. placebo (15.6 vs. 9.8 months, respectively, HR 0.66, p<0.001). In a published PII study (n=64), median change in alkaline phosphatase was -65.6% in the radium-223 group vs. 9.3% in the placebo group (p<0.001); median OS was 16.3 months vs. 11.6 months (p=0.066). In a published PII study (n=100), pain was significantly reduced at 8 weeks in 56% of men given a single dose of radium-223. Safety: Most common adverse effects are nausea, diarrhoea, vomiting, peripheral oedema and anaemia.

Pazopanib Indication: Current status: Predicted National guidance: oral Ovarian cancer (OC) – Filed in EU Aug UK licence NICE: OC pathway, quality standard; Votrient maintenance after first-line 2013. extension: first-line – paclitaxel; not recommended – GlaxoSmith- chemotherapy. 2014 bevacizumab. Kline SIGN: Ovarian cancer. Reviews: NIHR HSC Apr 2011. Target population: UK incidence of OC is Implications: Pazopanib will be used in addition to current therapies but 21 per 100,000 people. Most women have may delay need for second-line chemotherapy. advanced disease and 75% receive first-line Financial: Cost of pazopanib 800mg daily is £2,200/month. platinum chemotherapy; between 70 and 80% respond (11-13 per 100,000). Of these Likely commissioning route: NHSE. PbR: Chemotherapy is locally 55-75% relapse within 2 years. negotiated. Sector: Secondary care. Pharmacology: Multi-targeted tyrosine kinase receptor inhibitor. Efficacy: In a PIII trial (n=940) assessing the effect of pazopanib monotherapy for 2 years in OC (91% advanced disease), that has not progressed after first-line chemotherapy, median progression-free survival (PFS) was 17.9 months with pazopanib vs. 12.3 months with placebo (HR 0.77, p=0.0021). Overall survival data are immature. In a published PII trial (n=36) with pazopanib monotherapy, 31% of patients achieved the primary outcome of ≥50% decrease in cancer antigen-125 levels. Stable disease was seen in 56% of patients, with median duration of 80 days. At 6 months, 17% remained progression-free. Safety: See medicines.org.uk.

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Paclitaxel Indication: Current status: Predicted National guidance: injection Ovarian cancer (OC), PIII with orphan UK NICE: As for pazopanib above plus OC Paclical platinum-sensitive or status. launch: recurrent, advanced – paclitaxel, Oasmia partially platinum-sensitive 2014 pegylated liposomal doxorubicin and – second- or third-line. ; not recommended – bevacizumab, . SIGN: Ovarian cancer. Reviews: NIHR HSC Dec 2011. Target population: As for pazopanib above. Implications: Compared to current formulations, Paclical may cause fewer Sector: Secondary care. adverse effects, requires no pre-medication and may allow higher doses. Financial: Cost unknown but will displace other taxanes. Cost of currently available paclitaxel is £3,600 for six cycles (body surface area of 1.7m2). Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: A new formulation of paclitaxel encapsulated to increase its water solubility, removing the need for solvents which can cause hypersensitivity reactions. Given by i.v infusion every 3 weeks for 6 cycles. Efficacy: The PIII OAS-07OVA trial is comparing Paclical (250mg/m2) with Taxol (175mg/m2), both in combination with carboplatin, in 790 women with OC who have relapsed more than 6 months after first- or second-line chemotherapy. The final patient was treated in early 2013. Interim analysis indicates Paclical reduces levels of the biomarker, cancer antigen-125 (CA-125), to similar levels as Taxol. Safety: Requires no pre-medication.

Vintafolide Indication: Current status: Predicted National guidance: injection Ovarian cancer (OC), Filed in EU Nov UK NICE: As for paclitaxel above plus Vynfinit advanced platinum- 2012 with orphan launch: vintafolide due Jul 2014. MSD resistant, folate receptor status. 2014 SIGN: Ovarian cancer. (FR)-positive – second- line. Reviews: NIHR HSC Dec 2011. Target population: As for pazopanib above. Implications: Vintafolide added to doxorubicin will provide a more targeted Between 90 and 100% of tumours are FR- treatment for patients whose disease recurs within 6 months of positive. chemotherapy. They are unlikely to respond to further platinum therapy and Sector: Secondary care. have few options, with 10-40% responding to non-platinum agents. Financial: Likely to be expensive. Cost of the radiopharmaceutical diagnostic test technetium Tc99m etarfolatide is unknown. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: conjugated to a folate molecule. It enters tumour cells via the folate receptor, which is over- expressed by most OC tumour cells. Given as an i.v. infusion in combination with pegylated liposomal doxorubicin (PLD). Efficacy: The PII PRECEDENT study involved 162 women who had relapsed within 6 months of platinum chemotherapy. Progression-free survival (PFS) was 21.7 weeks in those on vintafolide plus PLD and 11.7 weeks in those on PLD alone (HR 0.63, p=0.03). PFS in patients with at least one FR-positive tumour site was 24.6 weeks in the vintafolide plus PLD group vs. 7.6 weeks in the PLD only group (0.6, p=0.04); in patients in whom all tumour sites were FR-positive it was 24.0 vs. 6.6 weeks, respectively (0.4, p<0.02). The PIII PROCEED trial (n=640) is similar in design with results due in 2014. Safety: Adverse effects include neutropenia, anaemia, fatigue and hand/foot syndrome.

Bevacizumab Indication: Current status: Predicted National guidance: injection Ovarian cancer (OC), PIII. UK licence NICE: As for vintafolide above. extension: Avastin advanced platinum- SIGN: Ovarian cancer. Roche resistant – second-line in 2014 combination. Reviews: NIHR HSC Jan 2013. Target population: As for pazopanib above. Implications: Bevacizumab will be used in addition to current Most patients receive platinum chemotherapies and may delay disease progression. chemotherapy a second or third time before Financial: Current cost of 10 doses (15mg/kg) for a 65kg woman is £23,000. developing resistance. Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary care. negotiated. Pharmacology: Vascular endothelial growth factor antagonist given by i.v. infusion every 3 weeks. Efficacy: In the PIII AURELIA trial, 361 women were randomised to chemotherapy (liposomal doxorubicin, paclitaxel or topotecan) alone or with bevacizumab (10mg/kg every 2 weeks or 15mg/kg every 3 weeks) until progression. Median progression-free survival (PFS) was 6.7 months in the bevacizumab group and 3.4 months in the control group (HR 0.48, p<0.001). The objective response rate was 30.9% vs. 12.6%, respectively (p=0.001). Safety: See medicines.org.uk. Gastrointestinal perforations and fistulas occurred in 2% of women receiving bevacizumab plus chemotherapy and in none of the control group.

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Olaparib Indication: Current status: Predicted Reviews: NIHR HSC May 2013. oral Ovarian cancer, relapsed, PII with orphan UK Likely commissioning route: NHSE. launch: AstraZeneca platinum-sensitive, status in EU. PbR: Chemotherapy is locally gBRCAm positive. 2015 negotiated. Pharmacology: PARP .

Trebananib Indication: Current status: Predicted Reviews: NIHR HSC Jan 2013. injection Epithelial ovarian, fallopian PIII. UK Likely commissioning route: NHSE. launch: Amgen tube or primary peritoneal PbR: Chemotherapy is locally cancer, recurrent disease. 2015 negotiated. Pharmacology: -1 and 2 inhibitor.

Eribulin Indication: Current status: Predicted Reviews: None. injection Soft tissue sarcoma, PIII with orphan UK licence Likely commissioning route: NHSE. extension: Halaven advanced – third-line. status in US. PbR: Chemotherapy is locally Eisai Pharmacology: 2015 negotiated. Synthetic analogue of halichondrin B, with tubulin-based antimitotic activity.

Ipilimumab Indication: Current status: Predicted National guidance: injection Malignant melanoma, PIII. UK licence NICE: Skin tumours, melanoma due Apr Yervoy resected high-risk stage III extension: 2015. Bristol Myers – first-line adjuvant 2014 SIGN: Cutaneous melanoma. therapy. Squibb Reviews: NIHR HSC Jun 2012. Target population: UK incidence of Implications: There is currently no standard adjuvant therapy. Interferon is malignant melanoma is about 21 per 100,000 of uncertain benefit and causes significant toxicity. Ipilimumab given after people, and is doubling every 10-20 years. surgery may prevent melanoma recurrence. 7% of 15-64 year olds present with advanced Financial: Ipilimumab costs £52,500 per dose for a 70kg person. (III/IV) disease compared with 20% aged ≥65. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Sector: Secondary care. Pharmacology: Anti-CTLA-4 monoclonal antibody given by i.v. infusion every 3 weeks for 4 doses, then 3-monthly. Efficacy: A placebo-controlled PIII study is investigating the efficacy of ipilimumab in 950 adults with confirmed lymph node metastases, who have undergone complete resection of stage III melanoma. The primary outcome is recurrence-free survival and initial results are expected in 2013 or 2014. In a published PII trial (n=75), 56% of patients with stage III or IV melanoma given adjuvant ipilimumab were relapse-free and 86% alive at 2 years. An on-going PIII study is comparing adjuvant ipilimumab with high-dose interferon alfa-2b. Safety: See medicines.org.uk.

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Dabrafenib Indication: Current status: Predicted National guidance: oral Malignant melanoma, Licensed in EU UK licence NICE: As for ipilimumab above plus Tafinlar unresectable or metastatic Sep 2013. extension: dabrafenib due TBC, vemurafenib, V600E GlaxoSmith- BRAF -positive – first- Licensed in US - 2013 ipilimumab (first-line) due Jun 2014. Kline line. see prescribing SIGN: Cutaneous melanoma. information. Reviews: NIHR HSC Aug 2011. Target population: As for ipilimumab above. Implications: Dabrafenib will compete with vemurafenib, providing an About 50% are BRAFV600-positive (80-90% alternative to i.v. dacarbazine which has a low response rate. A test is V600E and 10-20% V600K) which is needed to identify BRAFV600E-positive patients. associated with increased tumour Financial: Likely to be similarly priced to vemurafenib (£7,000 per month). aggressiveness. Likely commissioning route: NHSE. PbR: Chemotherapy is locally Sector: Secondary care. negotiated. Pharmacology: BRAFV600E kinase inhibitor taken twice daily. Efficacy: In the published BREAK-3 trial, 250 adults with previously untreated, stage IV or unresectable stage III BRAFV600E - positive melanoma were randomised to dabrafenib or 3-weekly cycles of i.v. dacarbazine. Median PFS was 5.1 months for dabrafenib vs. 2.7 months for dacarbazine; dabrafenib reduced risk of disease progression or death by 70% (HR 0.30, p<0.0001). There was no difference in overall survival (HR 0.61) but data are immature. 50% of patients on dabrafenib had a confirmed objective response vs. 6% on dacarbazine. Safety: Photosensitivity, which is common with vemurafenib, occurs rarely with dabrafenib.

Ipilimumab Indication: Current status: Predicted National guidance: injection Malignant melanoma, PIII in EU. UK licence NICE: As for ipilimumab above plus extension: Yervoy unresectable or metastatic Launched in US - vemurafenib, ipilimumab (first-line) due Bristol Myers – first-line with see prescribing 2014/2015 Jun 2014, dabrafenib due TBC. Squibb dacarbazine. information. SIGN: Cutaneous melanoma. Reviews: No recent reviews. Target population: As for ipilimumab above. Implications: A therapeutic option for patients whose tumours do not have Sector: Secondary care. BRAF mutations, which may improve response rates and survival when added to current first-line standard of care (dacarbazine). Financial: Ipilimumab costs £52,500 per dose for a 70kg person. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Anti-CTLA-4 monoclonal antibody given by i.v. infusion every 3 weeks for 4 doses, then 3-monthly. Efficacy: In the published 024 study, 502 patients were randomised to receive dacarbazine with or without ipilimumab. Median overall survival (OS) in the ipilimumab plus dacarbazine group was 11.2 months vs. 9.1 months in the dacarbazine alone group (HR 0.72, p<0.001). OS rates at 1 year were 47.3% vs. 36.3%, at 2 years were 28.5% vs. 17.9%, and at 3 years were 20.8% vs. 12.2%, respectively (0.72, p<0.001). There was a 24% reduction in risk of progression in the ipilimumab plus dacarbazine group vs. the dacarbazine group (0.76, p=0.006). Safety: See medicines.org.uk.

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Trametinib Indication: Current status: Predicted National guidance: oral Malignant melanoma, Filed in EU Feb UK NICE: As for ipilimumab above plus Mekinist unresectable or metastatic 2013. launch: ipilimumab (second-line), vemurafenib, V600 GlaxoSmith- BRAF -positive – first-or Monotherapy is 2014 dabrafenib due TBC, ipilimumab (first- Kline second-line monotherapy licensed in US - line) due Jun 2014. and first-line in see prescribing SIGN: Cutaneous melanoma. combination with information. dabrafenib. Combination Reviews: NIHR HSC (monotherapy) therapy filed in US Aug 2011, NIHR HSC (combination Jul 2013. therapy) Sep 2012. Target population: As for dabrafenib above. Implications: Trametinib, like dabrafenib and vemurafenib, are alternatives About 50% of patients progress within about to i.v. dacarbazine which has a response rate of 5-15% and improves 6 months of starting a BRAF or MEK progression-free survival (PFS) by only a few months. A test is needed to inhibitor. identify BRAFV600-positive patients. Combination therapy offers the possibility Sector: Secondary care. of improved survival and better tolerability. Financial: US cost of trametinib is $8,700/month. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: A mitogen-activated extracellular signal regulated kinase-1 (MEK) inhibitor taken once daily. Use in combination with twice-daily dabrafenib overcomes resistance to BRAF inhibition associated with reactivation of MEK. Efficacy: Results from the published PIII METRIC study (n=322) show trametinib monotherapy increased PFS and overall survival (OS) at 6 months vs. chemotherapy (dacarbazine or paclitaxel). Median PFS was 4.8 months vs. 1.5 months, respectively (HR 0.45, p<0.001); respective OS rates were 81% and 67% (0.54, p=0.01, NNT 7). A published PII study showed patients previously treated with a BRAF inhibitor (n=40) were unresponsive to trametinib monotherapy, unlike BRAF inhibitor-naïve patients (n=57); median PFS was 1.8 months and 4.0 months, respectively. In a published PII trial (n=162) of dabrafenib-trametinib combination therapy, median PFS was 9.4 months vs. 5.8 months in patients given dabrafenib alone (0.39, p<0.001); objective response rates were 76% and 54%, respectively (p=0.03). 41% of patients were alive and progression-free at 1 year vs. 9% (p<0.001, NNT 3). PIII trials are comparing trametinib plus dabrafenib with vemurafenib (COMBI-v; n=694) or dabrafenib (COMBI-d; n=340) alone; initial results are expected in 2014. Safety: Dose-limiting skin adverse effects occur less frequently with combination therapy, but the rate of pyrexia is higher.

Talimogene Indication: Current status: Predicted Reviews: No recent reviews. laherparepvec Malignant melanoma, PIII. UK Likely commissioning route: NHSE. injection launch: unresectable or metastatic. PbR: Chemotherapy is locally Amgen Pharmacology: 2015 negotiated. Oncolytic virus immunostimulant.

Cobimetinib Indication: Current status: Predicted Reviews: None. oral Malignant melanoma, PIII. UK Likely commissioning route: NHSE launch: Roche metastatic, BRAF positive, PbR: Chemotherapy is locally with vemurafenib – first- 2015 negotiated. line. Pharmacology: MEK inhibitor.

Erismodegib Indication: Current status: Predicted Reviews: NIHR HSC Jan 2013. oral Basal cell carcinoma, PII. UK Likely commissioning route: NHSE. launch: Novartis locally advanced or PbR: Chemotherapy is locally metastatic. 2015 negotiated. Pharmacology: Smoothened (Smo) inhibitor.

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Rituximab Indication: Current status: Predicted National guidance: injection Non-Hodgkin's lymphoma Filed in EU Dec UK NICE: NHL - rituximab (follicular, first- MabThera (NHL) - s.c. formulation. 2012. launch: line), rituximab (follicular maintenance). Roche 2013 Reviews: None. Target population: All patients with NHL for Implications: Availability of s.c. formulation could reduce outpatient whom i.v. rituximab is currently indicated. preparation and administration time and may facilitate homecare delivery. Those with poor venous access may be Biosimilar i.v. formulations of rituximab are likely to be available in 2015. initial candidates. Financial: Likely to be the same cost as the current i.v. formulation but future Sector: Secondary care. availability of biosimilar i.v. formulations may affect pricing strategy. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Anti-CD20 monoclonal antibody plus recombinant human hyaluronidase for s.c. administration. Efficacy: The PIII SABRINA open-label study assessed s.c. vs. i.v. administration of rituximab in 530 patients with follicular NHL receiving induction and maintenance therapy. The stage 1 primary outcome of non-inferiority of the Ctrough,SC:Ctrough,IV ratio at cycle 7 of induction was met and analysis showed similar investigator-assessed overall response rates (84.4% for i.v. vs. 90.5% for s.c.). Stage 2 of the trial is on-going and will assess overall survival. Safety: See medicines.org.uk. Injection site reactions are possible.

Benda- Indication: Current status: Predicted National guidance: mustine Non-Hodgkin’s lymphoma Filed in EU. UK licence NICE: As for rituximab above plus NHL- injection extension: (NHL), advanced low- Filed in US Dec bendamustine first-line due Jul 2014. Levact grade - first-line with 2011 but 2013 Reviews: LCNDG Apr 2013. Napp rituximab. additional data requested in Oct 2012. Target population: The UK incidence of Implications: Bendamustine could be used instead of standard NHL is about 20 per 100,000 people and chemotherapy regimens which have more adverse effects. about 40% present with indolent (low-grade) Financial: Bendamustine is currently licensed for second-line use in NHL. disease, usually advanced (stage III or IV). Cost of a 12-dose course is about £6,500. Sector: Secondary care. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: An alkylating agent with activity, given by i.v. infusion for up to six cycles. Efficacy: In the published PIII non-inferiority StiL trial, 549 patients newly diagnosed with stage III or IV indolent or mantle- cell lymphoma were randomised to bendamustine or standard therapy. At median follow-up of 45 months, median PFS was 69.5 months for bendamustine vs. 31.2 months for standard therapy (HR 0.58, p<0.0001). In the ongoing PIII BRIGHT study (n=477) bendamustine was non-inferior to standard therapy for complete response rate (31% vs. 25%, p<0.03). Safety: See medicines.org.uk. In the StiL trial bendamustine resulted in lower rates of alopecia, haematological toxicity, infections, peripheral neuropathy and stomatitis than standard therapy (all p<0.003) but skin reactions were more common.

Dasiprotimut- Indication: Current status: Predicted National guidance: T injection Non-Hodgkin’s lymphoma PIII with orphan UK As for rituximab above. launch: BiovaxID (NHL), low-grade follicular status and plans Reviews: No recent reviews. Biovest disease. to file in EU in 2014 International 2013. Available on compassionate use basis. Fast track status in US. Target population: The UK incidence of Implications: The company believes dasiprotimut-T may eliminate the risk of follicular NHL is 5-7 per 100,000 and most rituximab resistance and increase utility of other therapies. A subgroup of present with stage III or IV disease. These patients with the IgM isotype may be more responsive to treatment; US patients are considered for chemotherapy authorities have requested additional data to confirm this. and will be eligible for this vaccine if they Financial: Additive to current options after first-line treatment but may delay have prolonged remission. need for other therapies. Sector: Secondary care. Likely commissioning route: NHSE. PbR: Uncertain. Pharmacology: An autologous vaccine consisting of a conjugated lymphoma-associated antigen given about 6 months after chemotherapy. Five s.c. injections are given over a 6 month period. Booster vaccination may be required after 3 years. Efficacy: In the prematurely closed PIII BV301 trial 117 patients who maintained a complete response to initial chemotherapy were given dasiprotimut-T or control vaccine. Median disease-free survival was 30.6 vs. 17 months, respectively (p<0.05). At 36 months, 61% of patients on dasiprotimut-T were disease-free vs. 37% of control patients (NNT=4). These data, together with data from two long-term PII trials will be used in the EU licence application. In another PIII study, in 35 IgM-positive patients given dasiprotimut-T made with IgM isotype, 5-year tumour-free rates were 42% vs.11% in patients receiving control vaccine (NNT=3). Median time to relapse was 52.9 vs. 28.7 months, respectively (HR 0.34, p=0.002). Safety: To date no serious adverse effects have been reported.

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Bortezomib Indication: Current status: Predicted National guidance: injection Multiple myeloma (MM), Filed in EU Oct UK licence NICE: MM - bortezomib (monotherapy, Velcade relapsed or progressive 2012. extension: relapsed), lenalidomide (after at least Janssen-Cilag disease - combined with 2013 one prior therapy). or Reviews: NIHR HSC Sep 2012. pegylated doxorubicin. Target population: The UK incidence of MM Implications: Current options in this setting include bortezomib monotherapy is about 8 per 100,000 and prevalence is and lenalidomide plus dexamethasone. This licence extension will provide about 16 per 100,000 people. Of these, 39% further options with the possibility of delaying disease progression further. have relapsed MM and of these 65% will Financial: Cost of 32 doses (8 cycles) is about £24,000. have received 2 or more prior therapies. Patients typically relapse 3 or 4 times before Likely commissioning route: NHSE. PbR: Chemotherapy is locally developing treatment resistance. negotiated. Sector: Secondary care. Pharmacology: A given by i.v. injection. Efficacy: In a published PIII study bortezomib plus pegylated liposomal doxorubicin (PLD) was compared with bortezomib monotherapy in 646 patients. Interim data show the primary outcome of median time to progression was 6.5 months for bortezomib vs. 9.3 months with PLD plus bortezomib (HR 1.82, p<0.001). The 15-month survival rate was 65% vs. 76%, respectively (p=0.03) and overall response rate was 41% vs. 44%, respectively (p=ns). Safety: See medicines.org.uk.

Carfilzomib Indication: Current status: Predicted National guidance: injection Multiple myeloma (MM), PIII in EU with UK NICE: As for bortezomib above. launch: Kyprolis relapsed and refractory – orphan status and Reviews: NIHR HSC Sep 2012. Onyx third-line. plans to file 2013. 2014 Launched in US - see prescribing information. Target population: As for pomalidomide Implications: US indication is monotherapy use in relapsed MM after at above. The majority of patients are expected least 2 prior therapies; this is likely to be the initial indication in the EU. There to receive third-line therapy. is currently no standard third-line option in the UK. Sector: Secondary care. Financial: US cost is $10,000 per cycle for an average patient, making it the most expensive drug in the US for MM. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Second generation selective and irreversible proteasome inhibitor, first-in-class. Efficacy: The US licence is based on a published PII single-arm study in 266 patients with a median of 5 prior therapies, including bortezomib, lenalidomide, and thalidomide. The overall response rate was 23.7%. Median overall survival, a secondary outcome, was 15.6 months. The ongoing PIII FOCUS study compares carfilzomib with best supportive care after treatment with at least 3 prior therapies. The primary outcome is overall survival. Comparative studies with bortezomib (ENDEAVOR) and in combination with lenalidomide and dexamethasone (ASPIRE) are ongoing. Safety: Adverse effects are similar to other proteasome inhibitors but low rates of peripheral neuropathy have been reported.

Daratumumab Indication: Current status: Predicted Reviews: None. injection Multiple myeloma, PII. UK Likely commissioning route: NHSE. launch: Janssen-Cilag recurrent/ refractory – Granted fast track PbR: Chemotherapy is locally second-line. and breakthrough 2015 negotiated. Pharmacology: therapy status in Humanised anti-CD38 US. monoclonal antibody. Omacetaxine Indication: Current status: Predicted Reviews: None. meppe- Chronic myelogenous PIII in EU with UK Likely commissioning route: NHSE. succinate leukaemia (CML), after orphan status. launch: injection PbR: Chemotherapy is locally failure of two tyrosine Launched in US– Uncertain. negotiated. Synribo kinase inhibitors. see prescribing Teva Pharmacology: information. Protein synthesis inhibitor.

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Vosaroxin Indication: Current status: Predicted Reviews: NIHR HSC Jun 2013. injection Acute myeloid leukaemia, PIII with orphan UK Likely commissioning route: NHSE. launch: Sunesis first relapse or refractory, status in EU and PbR: Chemotherapy is locally with . US. 2016 negotiated. Pharmacology: Anticancer quinolone derivative.

Obinutuzu- Indication: Current status: Predicted National guidance: mab Chronic lymphocytic Filed in EU Apr UK NICE: CLL - Bendamustine, fludarabine, injection leukaemia (CLL), first-line 2013 with orphan launch: rituximab. Gazyva in patients with co- status. 2014 Reviews: NIHR HSC Jun 2012. Roche morbidities unable to have Filed in US with standard therapy. breakthrough therapy status. Target population: UK annual incidence of Implications: An alternative for patients with co-morbidities who cannot have CLL is 4.2 per 100,000 people, increasing to FCR (fludarabine, cyclophosphamide, rituximab). Current options include over 30 per 100,000 in those over 80 years chlorambucil or bendamustine (both with/without rituximab) or reduced dose of age. FCR. It will compete with ofatumumab below. Sector: Secondary care. Financial: Alternative monthly treatment costs: chlorambucil £56, bendamustine £966, rituximab £1,572. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Humanised anti-CD20 monoclonal antibody given by i.v. infusion. Efficacy: In an interim analysis (n=589) of the on-going PIII CLL11 trial investigating obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil vs. chlorambucil alone in 781 patients, median progression-free survival (PFS) was 23 months for obinutuzumab and chlorambucil vs. 10.9 months for chlorambucil alone (p<0.01). The primary outcome of improved PFS with obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil has been met; data will be released in Dec 2013. Safety: Adverse events are similar to other anti-CD20 monoclonal antibodies.

Ofatumumab Indication: Current status: Predicted National guidance: injection Chronic lymphocytic PIII in EU with UK licence As for obintuzumab above. extension: Arzerra leukaemia (CLL), first-line orphan status. Reviews: NIHR HSC Feb 2012. GlaxoSmith- in patient with co- 2014 Kline morbidities unable to have standard therapy. Target population: As for obintuzumab Implications: As for obinutuzumab above with which it will compete. above. Financial: As for obinutuzumab above and cost for ofatumumab 100mg is Sector: Secondary care. £1,820/month. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: Humanised anti-CD20 monoclonal antibody given by i.v. infusion. Efficacy: In the on-going PIII COMPLEMENT-1 trial (n=447) median progression-free survival was 22.4 months for ofatumumab and chlorambucil vs. 13.1 months for chlorambucil alone (HR 0.57, p<0.01). More data are due to be released in Sept 2013. Safety: See medicines.org.uk.

Idelalisib Indication: Current status: Predicted Reviews: None. oral Chronic lymphocytic PIII. UK Likely commissioning route: NHSE. launch: Gilead leukaemia - second-line. PbR: Chemotherapy is locally Sciences Pharmacology: 2015 negotiated. Phosphatidylinositol 3- kinase delta (PI3K-delta) inhibitor.

Ibrutinib Indication: Current status: Predicted Reviews: None. oral Mantle cell lymphoma, PIII with orphan UK Likely commissioning route: NHSE. launch: Janssen-Cilag refractory/relapsed – status in EU. PbR: Chemotherapy is locally second-line. Filed in US Jul 2015 negotiated. Pharmacology: 2013 with orphan Bruton’s tyrosine kinase and breakthrough inhibitor - first-in-class. therapy status.

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Ibrutinib Indication: Current status: Predicted Reviews: NIHR HSC Jul 2013. oral Chronic lymphocytic PIII in EU. UK Likely commissioning route: NHSE. launch: Janssen-Cilag leukaemia (CLL), relapsed/ Filed in US Jul PbR: Chemotherapy is locally refractory - second line. 2013. 2015 negotiated. Pharmacology: Bruton’s tyrosine kinase inhibitor – first-in-class.

Chlormethine Indication: Current status: Predicted National guidance: topical Cutaneous T-cell PII with orphan UK NICE: Skin tumours launch: Valchlor lymphoma (CTCL), status in EU. Reviews: None. Ceptaris mycosis fungoides (MF). Licensed in US 2014 Therapeutics with orphan and fast track status. Target population: The UK incidence of Implications: First-line options for early stage MF include topical therapy, CTCL is 4 per million people. MF accounts radiotherapy and phototherapy. Unlicensed topical formulations of for about 72% of CTCL. 71% of patients chlormethine have been used for many years but are cumbersome to present with early stage disease; disease prepare and use and global supply shortages have limited availability of raw progression occurs in 34%. ingredient. A solution licensed in France was discontinued in 2012. Sector: Secondary care. Financial: As the first licensed topical formulation of chlormethine it is likely to be expensive. Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated. Pharmacology: , an alkylating agent, formulated as a 0.02% gel applied daily. Efficacy: In a published PII study (n=260) chlormethine 0.02% gel was compared with a 0.02% ointment formulation applied daily for up to 12 months. The primary outcome (response rate based on composite assessment of index lesion severity) was achieved by 59% and 48% of patients, respectively, demonstrating non-inferiority. Safety: In the above study, 20% of patients on gel and 17% on ointment withdrew due to drug-related skin irritation.

Rigosertib Indication: Current status: Predicted Reviews: None. injection Myelodysplastic PIII with orphan UK Likely commissioning route: NHSE. Estybon syndromes, status in EU and launch: refractory/relapsed. PbR: Chemotherapy is locally Baxter US. 2015 negotiated. Pharmacology: Phosphatidylinositol 3- kinase (PI3K) and polo-like kinase (PLK) inhibitor.

Alemtuzumab Indication: Current status: Predicted National guidance: injection Multiple sclerosis (MS, Recommended for UK NICE: Multiple sclerosis (update due Lemtrada relapsing-remitting (RRMS) approval in EU launch: Oct 2014), fingolimod, natalizumab, beta Genzyme active disease defined by Jun 2013. 2013 interferon and glatiramer, alemtuzumab clinical or imaging features. due Apr 2014, dimethyl fumarate due Jan 2014, laquinimod due Feb 2014, teriflunomide due Jan 2014. Reviews: No recent reviews. Target population: In a population of Implications: This is a new class of drug for MS and as a single annual 100,000, 110 people will have MS and 39 will treatment may be attractive. Use is likely to be in the second-line setting. have RRMS. 31% of these are on, or will Financial: Cost of Lemtrada may be similar to other options; beta-interferon have received, disease modifying agents. In costs up to £10,500 per year and fingolimod is around £19,500/year (PAS in 2011-12, there were 33,566 hospital place). There may be additional monitoring costs. admissions due to MS in England. Likely commissioning route: NHSE. PbR: Specified high cost drug. Sector: Secondary care. Pharmacology: Monoclonal CD52 antibody given by i.v. infusion daily for 5 days as a first annual treatment course, and as a 3 day course in the second year. An on-going extension study will help define a subsequent treatment regimen. Efficacy: Two published PIII studies, CARE-MS 1 in 581 patients with early, active RRMS who had received no prior therapy, and CARE_MS II in 840 patients who had relapsed on prior therapy, compared alemtuzumab to high dose s.c. interferon beta-1a. Both studies met the primary outcome of relapse rate at 2 years (a 55% and 49% reduction vs. interferon, respectively, p<0.0001). CARE-MS II also met the co-primary outcome of time to 6-month sustained accumulation of disability (42% reduction vs. interferon, p=0.008), but CARE-MS I did not. Interim results from the first year of the PIII extension to the CARE-MS I & II studies suggest less than 20% of patients received a third course of alemtuzumab and 67% and 55% in the studies, respectively, remained relapse-free through to year 3. Safety: Over 3 years, 30% of patients in the CARE studies on alemtuzumab developed autoimmune thyroid disease, 1% immune thrombocytopenia and 0.3% nephropathy. Regular monitoring for autoimmune disease may be required.

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Peginterferon Indication: Current status: Predicted National guidance: beta-1a Multiple sclerosis (MS), Filed in the EU Jul UK As for alemtuzumab above. injection launch: relapsing-remitting disease 2013. Reviews: NIHR HSC Sep 2012. Plegridy (RRMS). 2014 Biogen Idec Target population: As for alemtuzumab Implications: Interferon is currently the most frequently used disease above. modifying agent to treat RRMS. Interferon beta-1a (Rebif) is given by s.c. Sector: Initiated in secondary care. injection 3 times a week. A less frequent administration schedule will be attractive to users, but it will have to complete with oral options. Financial: Likely to be more expensive than non-pegylated interferon. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: A PEGylated form of recombinant human interferon-beta-1a given s.c. every 2 or 4 weeks. Efficacy: The PIII ADVANCE study (n=1,516) reported a reduction in annual relapse rate at 1 year of 36% and 28% with peginterferon beta-1a given every 2 or 4 weeks, respectively (p<0.001 and p<0.02 vs. placebo). Secondary outcomes including 12-week confirmed disability progression were also met. After 1 year, patients on placebo were re-randomised to one of the peginterferon beta-1a arms for a further year. Patients then have the option of enrolling in an open-label extension study ATTAIN and followed for up to 4 years. Safety: No unexpected safety issues reported.

Laquinimod Indication: Current status: Predicted National guidance: oral Multiple sclerosis (MS), Filed in EU Jul UK As for alemtuzumab above. launch: Teva relapsing remitting 2012. Reviews: NIHR HSC Aug 2011. (RRMS), first or second- More data needed 2013 line therapy. for US licensing. Target population: As for alemtuzumab Implications: Around 30% of patients with RRMS are on, or have received, above. disease modifying agents; 74% on interferons and 26% on glatiramer. NICE Sector: Secondary care. estimated that fingolimod, the first licensed oral preparation for RRMS, could take up to 15% of the interferon share of the market. Financial: Beta-interferon costs up to £10,500/year and fingolimod costs about £19,500/year based on list price (PAS in place). There may be price competition as more oral agents become available. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: SAIK compound, an immune defence regulator. Efficacy: In the published 2-year PIII ALLEGRO study (n=1,106), laquinimod 0.6mg daily reduced the mean annualised relapse rate (ARR) vs. placebo (0.3 vs. 0.39, p=0.002) and reduced the risk of disability progression (11.1% vs. 15.7%, HR 0.64, p=0.01). The mean cumulative numbers of lesions on MRI scan were lower in the laquinimod group. In the PIII BRAVO study, laquinimod did not reduce the ARR vs. placebo whereas beta-interferon did. The on-going PIII CONCERTO study (n=1,800) is evaluating effect of laquinimod 0.6mg and 1.2mg daily on confirmed disability progression at 24 months. Safety: Adverse events include headaches, nasopharyngitis and back pain. Increases in liver enzymes are reported.

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Teriflunomide Indication: Current status: Predicted National guidance: oral Multiple sclerosis (MS), Licensed in EU UK As for alemtuzumab above. launch: Aubagio relapsing remitting disease Sep 2013. Reviews: NIHR HSC Aug 2011. Sanofi (RRMS) – monotherapy. Launched in US - 2013 see prescribing information. Target population: As for alemtuzumab Implications: Another oral option for the treatment of RRMS, at a cost likely above. to be lower than oral fingolimod. Sector: Secondary care initiated. Financial: In the US, teriflunomide costs slightly less than interferon beta-1a and about 30% less than fingolimod. There is a UK PAS for fingolimod. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: The active metabolite of leflunomide, teriflunomide is a dehydrogenase inhibitor. Efficacy: In the published 2-year PIII TEMSO study (n=1,088), the annualised relapse rate (ARR) was 0.37 for patients on either 7mg or 14mg terflunomide daily vs. 0.54 for placebo (p<0.001). In the TOWER study (n=1,169), the ARR was 0.32 for teriflunomide 14mg vs. 0.50 for placebo (p<0.0001) and there was a 31.5% reduction (p=0.04 vs. placebo) in the risk of 12- week sustained accumulation of disability (SAD). Although the reduction in ARR in the 7mg group (0.39) was statistically significance vs. placebo, the 12-week SAD was not. In the PIII TENERE trial, the risk of treatment failure (primary outcome, defined as a confirmed relapse, or discontinuation of treatment for any reason) was similar among the 324 patients randomised to teriflunomide 7mg or 14mg or to beta-interferon (48.6%, 37.8% and 42.3%, respectively). Safety: As an active metabolite of leflunomide adverse effects of teriflunomide are anticipated to be similar. See medicines.org.uk.

Dimethyl Indication: Current status: Predicted National guidance: fumarate Multiple sclerosis (MS), Recommended for UK As for alemtuzumab above. oral launch: relapsing-remitting disease approval in EU Reviews: NIHR HSC Dec 2011. Tecfidera (RRMS) – monotherapy. Mar 2013. 2013 Biogen Idec Launched in US - see prescribing information. Target population: As for alemtuzumab Implications: The majority of patients on disease modifying agents are above. treated with beta-interferon which is not tolerated by many. Effective oral Sector: Initiated in secondary care. preparations may make treatment more convenient and acceptable, increasing the proportion of patients treated. Financial: In the US the price for Tecfidera is between that for teriflunomide and fingolimod. There is a UK PAS in place for fingolimod. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: A derivative of fumaric acid with dual immunosuppressive and cytoprotective actions. Efficacy: Two PIII studies, DEFINE (n=1,237) and CONFIRM (n=1,417) have been published. In DEFINE, 27% and 26% of patients on dimethyl fumarate 240mg 2 and 3 times a day, respectively, relapsed over 2 years vs. 46% on placebo (p<0.001). The annualised relapse rates (ARR) were 0.17, 0.19 and 0.36, respectively. In CONFIRM, the ARRs for the corresponding groups were 0.22, 0.20 and 0.40 (p<0.001 vs. placebo), and in the glatiramer arm, 0.29 (p<0.01 vs. placebo). In a post-hoc analysis, 3- times daily dimethyl fumarate was more effective than glatiramer in reducing the ARR (p<0.05). Active treatment was associated with a reduction in disability progression vs. placebo (34-38% p=0.01) in DEFINE but not CONFIRM. There were fewer new gadolinium enhancing lesions with active treatment in both studies. Safety: Flushing and gastrointestinal effects are the most frequent adverse events.

Daclizumab Indication: Current status: Predicted Reviews: None. injection Multiple sclerosis, PIII. UK Likely commissioning route: NHSE. launch: Zenapax relapsing-remitting. PbR: Specified high cost drug. Biogen Pharmacology: 2015 2 receptor antagonist, humanised monoclonal antibody that binds to CD25.

Fingolimod Indication: Current status: Predicted Reviews: No recent reviews. oral Multiple sclerosis, primary PIII. UK licence Likely commissioning route: NHSE. extension: Gilenya progressive. PbR: Specified high cost drug. Novartis Pharmacology: 2015 Oral sphingosine-1 phosphate receptor modulator.

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Teriflunomide Indication: Current status: Predicted National guidance: oral Multiple sclerosis (MS), PIII. UK licence As for alemtuzumab above. extension: Aubagio clinically isolated syndrome Reviews: None. Sanofi (CIS). 2014 Target population: 85% of cases of MS are Implications: Interferons and glatiramer are licensed to treat CIS and heralded by a clinically isolated syndrome although they have been shown to reduce conversion rates to MS over 2-3 (CIS) of demyelination, but people who years, only a marginally significant gain in terms of disability has been experience a CIS have a less than 50% risk demonstrated over 3 to 5 years. Teriflunomide will provide an oral treatment of developing MS within five years. Use of option. disease modifying drugs after a CIS is only Financial: In the US, teriflunomide costs less than interferon beta-1a. recommended if there is also MRI evidence showing high likelihood of developing MS. Likely commissioning route: NHSE. PbR: Specified high cost drug. Sector: Initiated in secondary care. Pharmacology: The active metabolite of leflunomide, teriflunomide is a dehydrogenase inhibitor. Efficacy: In the PIII TOPIC trial (n=618) patients on teriflunomide 7mg and 14mg daily had a mean reduction in risk of conversion to clinically definite MS over 2 years of 37% and 43%, respectively vs. placebo (p=0.03 and p=0.009). The average duration of teriflunomide exposure was around 16 months. Safety: As an active metabolite of leflunomide adverse effects of teriflunomide are anticipated to be similar. See medicines.org.uk. BNF 9. Nutrition and blood

Eltrombopag Indication: Current status: Predicted National guidance: oral Thrombocytopenia (TCP), Recommended for UK licence NICE: TCP- eltrombopag. extension: Revolade associated with hepatitis C approval in EU Jul SIGN: Management of hepatitis C. infection. 2013. 2013 GlaxoSmith- Reviews: None. Kline Launched in US - see prescribing information. Target population: About 216,000 people in Implications: Eltrombopag will be used where thrombocytopenia prevents the UK are infected with hepatitis C (340 per starting, or limits the ability to maintain, optimal interferon-based therapy. 100,000). In a systematic review, prevalence Financial: Eltrombopag costs between £770 and £3,080/month (25mg to of hepatitis C associated TCP was 0.16- 100mg/day). 45.4%. More than half of the studies reported a TCP prevalence of ≥24%. Likely commissioning route: Uncertain – depending on complexity of patient. PbR: Specified high cost drug. Sector: Secondary care initiated. Pharmacology: receptor agonist given orally in doses determined by platelet count. Efficacy: Two PIII studies, ENABLE 1 (n=715) and ENABLE 2 (n=805) treated patients with open-label eltrombopag for 9 weeks. Patients who achieved a platelet count that enabled antiviral therapy to be started were randomised to continued eltrombopag or placebo, plus peginterferon alfa and ribavirin for 24 or 48 weeks depending on genotype. The primary outcome was the proportion of patients who achieved a sustained virological response 24 weeks after antiviral therapy had finished. This was achieved by 23% vs. 14% of eltrombopag and placebo groups, respectively (p<0.01) in ENABLE 1 and 19% vs.13% (p=0.02) in ENABLE 2. Non-responders could take part in ENABLE-ALL. Safety: See medicines.org.uk. The ocular safety of eltrombopag has been investigated in the long-term LENS study.

Elosulfase Indication: Current status: Predicted National guidance: alfa Mucopolysaccharidosis Filed in EU Apr UK None relevant. injection launch: IVA (Morquio A 2013 with orphan Reviews: NIHR HSC Jun 2012. Vimizim syndrome). status and 2014 BioMarin accelerated assessment. Target population: Mucopolysaccharidosis Implications: There are no licensed treatments for this condition. type IVA affects less than 15 in 100,000 Financial: Cost is likely to be expensive and similar to other treatments for people in the EU. mucopolysaccharidosis diseases (galsulfase, idursulfase, laronidase). Sector: Lysosomal storage disorders are Likely commissioning route: NHSE. PbR: Likely specified high cost drug. specialised services. Pharmacology: GALNS enzyme replacement therapy, given by a 4-hour i.v. infusion. Efficacy: A PIII trial randomised 176 patients to elosulfase alfa weekly, every other week or placebo. The study met the primary outcome with a mean increase of 22.5 metres in six-minute walk distance vs. placebo at 24 weeks in subjects on weekly treatment (p<0.02). Treatment given every 2 weeks did not differ from placebo. Safety: Long-term safety and efficacy are being assessed in an open-label extension study and a 240 week study.

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Alipogene Indication: Current status: Predicted National guidance: tiparvovec Lipoprotein lipase Licensed in EU UK None relevant. injection launch: deficiency, familial, in Oct 2012 with Reviews: No recent reviews. Glybera adults with pancreatitis orphan status – 2013 via a Chiesi despite dietary restrictions. see prescribing restricted information. access programme Target population: An estimated 30 - 50 Implications: Dietary restriction is currently the only management option. people in the UK may be eligible for Diagnosis has to be confirmed by genetic testing. Patients must adhere to a treatment in the next 5 years. lipid-restricted diet and need short-term (12 weeks) immunosuppression with Sector: Secondary care. ciclosporin and mycophenolate mofetil. The product contains genetically- modified organisms requiring use of biosafety procedures. Financial: Likely to be expensive. Likely commissioning route: NHSE. PbR: Likely specified high cost drug. Pharmacology: Single treatment gene therapy given by i.m. injection at multiple-sites in a single session. It is delivered frozen in a patient-specific pack containing the correct amount of vials per patient, calculated according to weight. Efficacy: In a published PII/III study (n=14), alipogene was administered as multiple injections into leg muscles on a single occasion under spinal anaesthesia. All patients maintained a low fat diet. 50% achieved the primary outcome of at least 40% reduction in triglycerides vs. baseline 3 to 12 weeks after dosing. In a published PII/III study, 5 patients received 1 x 1012 gc/kg. 14 weeks after injection, mean total plasma triglyceride levels fell by about 60% (p<0.01 vs. controls). All patients in the above trials have entered continuation studies lasting several years. Safety: In the PII/III study of 14 patients, 12 (86%) had injection site events.

Sodium Indication: Current status: Predicted National guidance: phenyl- Urea cycle disorders. Licensed in EU UK None relevant. butyrate launch: Aug 2013 - see Reviews: SMC due Nov 2013. oral granules prescribing 2013 Pheburane information. Lucane Pharma Target population: In the EU less than 2 per Implications: Sodium phenylbutyrate Ammonaps (940mg/g) granules are million people are affected. already available. Pheburane contains less sodium phenylbutyrate per gram Sector: Urea cycle disorders are a (483mg/g) due to a coating used to mask the unpleasant taste. This tasteless specialised service. formulation is designed to improve compliance. Financial: Cost of Ammonaps is £860 for 250g sodium phenylbutyrate. Likelihood for better compliance may increase the price of Pheburane. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: A conjugated metabolite is excreted in the urine, leading to reduced nitrogen and ammonia levels. Efficacy: A bioequivalence study between Pheburane 483 mg/g granules and Ammonaps 940mg/g granules was submitted in the licence application. As Ammonaps is the reference product, no new clinical studies are needed. Safety: See medicines.org.uk for Ammonaps, and prescribing information for Phenburane.

Sebelipase Indication: Current status: Predicted Reviews: NIHR HSC Jun 2012. alfa Lysosomal acid lipase PIII with orphan UK Likely commissioning route: NHSE. injection launch: deficiency. status in EU and PbR: Likely specified high cost drug. Synageva Pharmacology: US and 2015 BioPharma breakthrough Recombinant human therapy status in lysosomal acid lipase. US.

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BNF 10. Musculoskeletal and joint diseases

Canakinumab Indication: Current status: Predicted National guidance: injection Juvenile idiopathic arthritis Recommended for UK licence NICE: JIA - etanercept, tocilizumab extension: Ilaris (JIA), systemic disease in approval in EU Jul Reviews: No recent reviews. Novartis patients aged ≥ 2 years 2013 with orphan 2013 with inadequate response status. Launched to NSAIDs and systemic in US - see corticosteroids. prescribing information. Target population: NICE estimate the target Implications: Likely to be a competitor to tocilizumab, with more convenient population for tocilizumab in JIA is around administration (s.c. vs. i.v.) but much higher price. 372 individuals in England. Financial: Monthly cost for 30kg child of canakinumab is nearly £10,000 Sector: Secondary care. (single dose of 4mg/kg) assuming no vial sharing vs. about £700 for tocilizumab (two doses of 8mg/kg); a PAS is in place for tocilizumab for JIA. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: Interleukin-1 beta inhibitor, given by s.c. injection. In the US it is given every 4 weeks. Efficacy: Two PIII trials published together (β-SPECIFIC 1 and 2) examined single dose (β-SPECIFIC 1, n=84) and longer- term (β-SPECIFIC 2, n=177) efficacy in patients aged 2 to 19 years. In β-SPECIFIC 1, the primary outcome (an adapted JIA ACR 30 response) was achieved by 84% patients on canakinumab, vs. 10% on placebo (p<0.001) by day 15. The β- SPECIFIC 2 study started with an open-label phase; those who responded and achieved steroid tapering by 32 weeks (n=100) were randomised to a placebo-controlled withdrawal phase. Risk of flare was lower for those on canakinumab vs. those switched to placebo; 74% on canakinumab had no flare vs. 25% in the placebo group (HR 0.36, p=0.003, NNT=2). Safety: See medicines.org.uk. In clinical trials, there were 7 cases of macrophage activation syndrome.

Golimumab Indication: Current status: Predicted National guidance: injection Juvenile idiopathic arthritis PIII. UK licence As for canakinumab above. extension: Simponi (JIA), polyarticular, poor Reviews: None. MSD response to . 2014 Target population: NICE estimate around Implications: A competitor to etanercept with the advantage of once- 600 children with polyarticular JIA would be monthly dosing vs. twice-monthly dosing for etanercept. eligible for etanercept, of whom over 300 Financial: Golimumab is currently more expensive than etanercept and the would be maintained on it long-term. etanercept patent expires in 2015; biosimilar formulations are in Sector: Secondary care. development. A PAS is in place for golimumab use in adults with arthritis and for tocilizumab for systemic JIA. Likely commissioning route: NHSE. PbR: Specified high cost drug. Pharmacology: A monoclonal TNF-alpha inhibitor, given by monthly s.c. injection. Efficacy: In the PIII GO-KIDS study, 173 patients with JIA aged under 16 at diagnosis, at least 5 involved joints, and poor response to methotrexate were randomised to monthly golimumab 30mg/m2 or placebo after a 16-week open-label run-in to identify those showing at least 30% response to golimumab. Primary outcome is disease flare between weeks 16 to 48 with results due in 2013. Safety: See medicines.org.uk.

Masitinib Indication: Current status: Predicted Reviews: None. oral Rheumatoid arthritis not PIII. UK Likely commissioning route: CCG. launch: AB Science responding to standard PbR: Likely specified high cost drug. therapy. 2015 Pharmacology: .

Secukinumab Indication: Current status: Predicted Reviews: NIHR HSC Sep 2012. injection Rheumatoid arthritis, when PIII. UK Likely commissioning route: CCG. launch: Novartis TNF-alpha inhibitors are PbR: Likely specified high cost drug. ineffective or not tolerated. 2015 Pharmacology: Monoclonal interleukin IL- 17A inhibitor.

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Ustekinumab Indication: Current status: Predicted National guidance: injection Psoriatic arthritis (PsA), Recommended for UK licence NICE: Psoriasis pathway, PsA Stelara active disease when approval in EU Jul extension: subsection; PsA - etanercept, infliximab Janssen-Cilag response to DMARDS is 2013. 2013 and adalimumab, golimumab, inadequate. ustekinumab (due May 2014). SIGN: Psoriasis and PsA. Reviews: NIHR HSC Sept 2012. Target population: UK prevalence of severe Implications: This will provide an alternative to TNF-alpha inhibitors; trial PsA is uncertain. NICE suggest 1,248 people evidence suggests it may be useful in patients unresponsive to this group. per year in England will respond to and Financial: Annual cost is similar to that of the TNF-alpha inhibitors for continue TNF-alpha inhibitor therapy. patients weighing <100kg; a PAS is in place for patients with psoriasis who Sector: Secondary care. weigh >100kg. Likely commissioning route: CCG. PbR: Specified high cost drug. Pharmacology: Monoclonal antibody, inhibiting IL-12 and IL-23 given by s.c. injection every 12 weeks. Efficacy: In two PIII trials, PSUMMIT 1 (n=615) and PSUMMIT 2 (n=312) the primary outcome was ACR20 response (20% improvement in signs and symptoms) after 24 weeks. Patients received ustekinumab 45mg, 90mg, or placebo at 0, 4, then every 12 weeks. PSUMMIT 1 excluded patients with prior use of TNF-alpha inhibitors, PSUMMIT 2 did not. In PSUMMIT 1, more patients on ustekinumab (42.4% on 45mg, 49.5% on 90mg) achieved ACR20 vs. 22.8% on placebo (p<0.0001 for both comparisons, NNT=5 and 4, respectively). In PSUMMIT 2, 43.7%, 43.8% and 20.2%, respectively achieved ACR20 (p<0.001, NNT=4 for both). In anti-TNF-experienced patients 37-41% achieved ACR20 vs. 59-73% in naïve patients. Safety: See medicines.org.uk.

Apremilast Indication: Current status: Predicted National guidance: oral Psoriatic arthritis (PsA) - PIII with plans to UK As for ustekinumab above. launch: Celgene where other options are file in EU second Reviews: NIHR HSC Jan 2013. ineffective/contra-indicated. half of 2013. 2014 Licence application also to Filed in US May include plaque psoriasis. 2013. Target population: As for ustekinumab Implications: Apremilast is likely to be used after conventional systemic above. therapies, but as an oral preparation, it may be used before parenteral Sector: Primacy care (after initiation in biological therapies. secondary care). Financial: Production costs, and therefore price, are likely to be lower than for biological (PAS for golimumab). Administration costs will be lower. Likely commissioning route: CCG. PbR: Likely specified high-cost drug. Pharmacology: Phosphodiesterase-4 inhibitor. Efficacy: In PIII trials (PALACE 1, n=504; PALACE 2, n=495; and PALACE 3, n=495) adults with active PsA who failed existing therapy were randomised to apremilast 20mg, 30mg, or placebo. Primary outcome was ACR20 (20% improvement in signs and symptoms) after 16 weeks. In PALACE 1, response rate for 20mg was 31.3% (p<0.05 vs. placebo, NNT=8); 30mg, 41.0% (p<0.0001, NNT=5) and placebo 19.4%. Results in PALACE 2 and 3 are similar. All studies are on-going with total planned durations of 4.5 years. Results of a PII study are published. Safety: In a pooled analysis of PALACE 1, 2, and 3, adverse effects included diarrhoea, nausea, headache and upper respiratory tract infections. Incidence of serious adverse events was similar in active and placebo groups.

Secukinumab Indication: Current status: Predicted Reviews: NIHR HSC Nov 2012. injection Psoriatic arthritis, after PIII. UK Likely commissioning route: CCG. launch: Novartis failure of conventional PbR: Likely specified high cost drug. DMARD. 2015 Pharmacology: Monoclonal interleukin IL- 17A inhibitor.

Secukinumab Indication: Current status: Predicted Reviews: NIHR HSC Nov 2012. injection Ankylosing spondylitis, PIII. UK Likely commissioning route: CCG. launch: Novartis second or third-line. PbR: Likely specified high cost drug. Pharmacology: 2015 Monoclonal interleukin IL- 17A inhibitor.

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Pegloticase Indication: Current status: Predicted National guidance: injection Gout prophylaxis, where Licensed in EU UK NICE: Pegloticase Jun 2013. launch: Krystexxa xanthine oxidase inhibitors Jan 2013 – see Reviews: No recent reviews. Savient have failed or are contra- prescribing 2013 indicated. information. Target population: The manufacturer Implications: NICE does not currently recommend pegloticase as, although estimates about 2,700 people in England and effective at lowering urate levels, it is not cost-effective at the £30,000 per Wales may be eligible; NICE estimates that QALY threshold and can cause serious adverse reactions. It would be a the guidance would affect about 8 people per competitor to canakinumab (also not recommended by NICE). 100,000 in England. Financial: Pegloticase cost is £1,770 per vial (about £23,000 for 6 months Sector: Secondary care. therapy) and would require fortnightly day case admission as infusion plus minimum observation period for severe allergic reactions is 3.5 hours. Canakinumab cost is about £1,000 per dose (max. 2 doses in 6 months). Likely commissioning route: CCG. PbR: Specified high cost drug. Pharmacology: A polyethylene glycol conjugate of recombinant uricase given by a 2-hour i.v. infusion every 2 weeks. Efficacy: The published PIII GOUT1 and 2 studies randomised 225 patients to pegloticase bi-weekly or monthly, or placebo, for 6 months. The primary outcome, plasma uric acid <6.0mg/dL 80% of the time at 3 and 6 months, was met in GOUT1 by 47% of patients (bi- weekly, p<0.001) and 20% (monthly, p<0.05) and in GOUT2 by 38% (p=0.001) and 49% (p<0.001), respectively. Safety: Anaphylaxis (including anaphylactic shock) in about 6.5% of patients and infusion reactions (26%) are reported; premedication with antihistamines and corticosteroids is mandated in prescribing information.

Lesinurad Indication: Current status: Predicted Reviews: NIHR HSC Jan 2013. oral Gout, second-line. PIII. UK Likely commissioning route: CCG. launch: AstraZeneca Pharmacology: PbR: Likely HRG included. 2015 Selective urate transporter- 1 inhibitor.

Odanacatib Indication: Current status: Predicted Reviews: NIHR HSC Jun 2013. oral Osteoporosis in men when PIII. UK Likely commissioning route: CCG. launch: MSD bisphosphonates contra- PbR: Likely HRG included. indicated or not successful. 2015 Pharmacology: Selective cathepsin-K inhibitor.

Ataluren Indication: Current status: Predicted National guidance: oral Duchenne muscular Filed in EU Dec UK None relevant. launch: Translarna dystrophy, nonsense- 2012 with orphan Reviews: No recent reviews. PTC mutation (nmDMD). status. 2013 Therapeutics Target population: DMD affects 1 in 3,600 Implications: Current options (corticosteroids) can delay but not prevent to 6,000 male births in the UK; about 100 loss of walking ability. Ataluren is the first therapy to target the underlying boys are diagnosed annually and UK defect in nmDMD, but will benefit only a small proportion of all DMD patients. prevalence is about 1,500. Around 10-15% It is likely to be additional to current therapy in ambulant patients but could have a nonsense mutation (nm), prolong independence and delay complications. corresponding to 150-195 patients in the UK Financial: Likely to be expensive. who may be eligible. Likely commissioning route: NHSE. PbR: Likely specified high cost drug. Sector: Secondary care. Pharmacology: Dystrophin synthesis stimulant, mechanism of action is uncertain. Efficacy: Licence application is based on a PII trial in boys (n=174) with nm Duchenne or Becker MD, aged ≥5 years treated with 40mg/kg or 80mg/kg ataluren daily or placebo. At week 48, mean change from baseline in the primary outcome of 6- minute walk distance failed to reach statistical significance for both doses. However, post-hoc secondary analyses suggest there may be a benefit with the lower dose. A larger PIII study (n=220 target) is in progress. Safety: Ataluren was well tolerated in trials.

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Idebenone Indication: Current status: Predicted National guidance: oral Duchenne muscular PIII with orphan UK None relevant. launch: Sovrima dystrophy (DMD). status. Reviews: None. Takeda 2014 Target population: As for ataluren above. Implications: Unlike ataluren above, if licensed, idebenone would potentially Patients are living longer due to intensive be suitable for all affected patients with DMD. symptomatic respiratory and cardiac support. Financial: Likely to be expensive. Sector: Secondary care. Likely commissioning route: NHSE. PbR: Likely specified high cost drug. Pharmacology: Coenzyme Q10 analogue that enhances mitochondrial respiratory chain function. Efficacy: The on-going PIII DELOS study compares idebenone 900mg daily with placebo in 260 boys aged 10 to 18 years. The primary outcome is percentage change in predicted peak expiratory flow as a measure of respiratory function, over 52 weeks. Trial completion is expected late 2013. The PII DELPHI trial (n=21) results have been published. Idebenone 450mg daily did not show a significant difference from placebo at 12 months in the primary outcome of effect on peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. Patients completing DELPHI entered the open-label DELPHI-extension study and received 450mg or 900mg (based on weight) for 24 months. This study completed in 2011 but results have yet to be published. Safety: Idebenone has been well tolerated in trials.

BNF 11. Eye

Aflibercept Indication: Current status: Predicted National guidance: intravitreal Macular oedema, Recommended UK licence NICE: Aflibercept due Apr 2014, injection secondary to central retinal for approval in EU extension: , costing template, Eylea vein occlusion (CRVO). Jul 2013. 2013 dexamethasone. Bayer Launched in US - Reviews: NIHR HSC May 2011. see prescribing information. Target population: RVO affects 1–2% of Implications: A new treatment option that will compete with ranibizumab people aged over 40 years. In England and injection and dexamethasone implant. Wales about 17 per 100,000 people will Financial: Based on current prices, aflibercept cost is £816/month and require treatment for macular oedema dexamethasone implant cost is £870. PASs are in place for ranibizumab for following CRVO annually. wet age-related macular degeneration and diabetic macular oedema. Sector: Secondary care. Likely commissioning route: CCG. PbR: Specified high cost drug. Pharmacology: Vascular endothelial growth factor inhibitor (VEGF) and inhibitor given monthly. Efficacy: In the published PIII GALILEO study (n=177), at 6-months, 60.2% on aflibercept 2mg monthly and 22.1% on control treatment, gained ≥15 letters of vision from baseline (p<0.01). The mean number of letters gained was 18 vs. 3.3, respectively (p<0.01). In the published PIII COPERNICUS (n=189), at 6 months, ≥15 letters were gained by 56.1% on aflibercept vs. 12.3% on placebo (p<0.01). Those on aflibercept gained a mean of 17.3 letters vs. a mean loss of 4 letters with placebo, p<0.01. From week 24 to week 52, all patients received aflibercept as needed. At 12 months, ≥15 letters were gained by 55.3% on aflibercept vs. 30.1% on placebo (p<0.01). Those on aflibercept gained a mean of 16.2 letters vs. a mean of 3.8 letters with placebo, p<0.01. Safety: See medicines.org.uk.

Aflibercept Indication: Current status: Predicted National guidance: intravitreal Diabetic macular oedema PIII. UK licence NICE: Diabetes pathway, quality injection extension: (DMO). standard, fluocinolone implant (rapid Eylea 2014. review due Nov 2013) ranibizumab,

Bayer costing template. Reviews: NIHR HSC Jun 2013, LNDG Feb 2011. Target population: About 322 patients with Implications: A new treatment option that will compete with ranibizumab. diabetes have DMO per 100,000 people. 39% Financial: As for aflibercept above. of these have clinically significant macular oedema, which can lead to blindness. Likely commissioning route: CCG. PbR: Specified high cost drug. Sector: Secondary care.

Pharmacology: Vascular endothelial growth factor inhibitor (VEGF) and placental growth factor inhibitor given monthly. Efficacy: The 12-month results of the PIII VIVID-DME and VISTA-DME trials of aflibercept 2mg monthly vs. aflibercept every 2 months vs. laser photocoagulation are available. In VIVID-DME mean change from baseline in best corrected visual acuity was 10.5 letters, 10.7 letters and 1.2 letters in the three groups, respectively. The results for VISTA-DME were 12.5, 10.7 and 0.2 letters, respectively (p<0.01 for both trials, both aflibercept groups vs. laser). Safety: See medicines.org.uk.

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Aflibercept Indication: Current status: Predicted Reviews: None. intravitreal Macular oedema, PIII. UK licence Likely commissioning route: CCG. injection extension: secondary to branch retinal PbR: Specified high cost drug. Eylea vein occlusion (BRVO). 2015 Bayer Pharmacology: As for aflibercept above. BNF 13. Skin

Apremilast Indication: Current status: Predicted National guidance: oral Psoriasis, plaque, PIII. UK NICE: Psoriasis pathway, assessment Celgene moderate to severe. launch: and management, commissioning guide, 2014 costing report, quality standards; ustekinumab , adalimumab, infliximab, efalizumab and etanercept. SIGN: Psoriasis. Reviews: NIHR HSC Jan 2013. Target population: Estimated prevalence of Implications: Likely to be licensed for use after conventional systemic psoriasis in England is 1.63%; about 20% of therapies, but as an oral preparation may be considered for use before people have moderate to severe disease (20 parenteral biological therapies. However, unlike established therapies, long - per 100,000). Plaque psoriasis is the most term efficacy and safety data are lacking. common form, affecting 80-90% of people. It Financial: Production costs, and therefore drug price, are likely to be lower is estimated 1.1% of people with psoriasis are than for biologicals (which cost £8,000-£11,000/year). Administration costs eligible for biological treatment (7,100). will also be lower. Sector: Primary and secondary care. Likely commissioning route: CCG. PbR: Likely specified high cost drug. Pharmacology: Inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4). Efficacy: On-going studies of apremilast vs. placebo include PIII ESTEEM 1 and 2 (n=1,257 combined) and a PIIIb study (n=240) vs. etanercept and placebo. The PIIIb study has enrolled only biological-naïve patients. In a published PIIb study (n=352) the primary outcome, 75% reduction in Psoriasis Area and Severity Index (PASI 75) at week 16, was achieved in 41% of patients on apremilast vs. 6% on placebo (p<0.0001). In ESTEEM 1, PASI 75 at 16 weeks was achieved by 33.1% of patients on apremilast vs. 5.3% on placebo (p<0.0001). Higher scores were seen in systemic- and biologic-naïve subjects vs. placebo (38.7% vs. 7.6%; p<0.0001 and 35.8% vs. 5.9%; p<0.0001, respectively). Safety: No major safety issues have been reported.

Tofacitinib Indication: Current status: Predicted National guidance: oral Psoriasis, plaque, PIII. UK As for apremilast above. launch: Xeljanz moderate to severe. Reviews: NIHR HSC Nov 2012. Pfizer 2014 Target population: As for apremilast above. Implications: Tofacitinib will compete with other second line treatments in Sector: Primary and secondary care. adults who are candidates for systemic therapy. It has the advantage of oral administration but safety concerns may be an issue. This may limit its use to patients who have failed on an established biological. Financial: In the US, it has been priced about 7% cheaper ($24,666 a year) compared to etanercept and adalimumab. Likely commissioning route: CCG. PbR: Specified high cost drug. Pharmacology: An immunosuppressant, (JAK) 3 inhibitor (5 or 10mg twice daily). Efficacy: Completed PIII studies include two 1-year placebo controlled trials (1 & 2 both n=825) with Physician´s Global Assessment (PGA) and PASI 75 response at week 16 as the co-primary outcomes, a 12-week trial (n=1,100) vs. etanercept with a primary outcome of PGA, and a withdrawal and re-treatment study (n=684). An open-label long-term safety study (n=3,200) is on-going. In a published PIIb dose-ranging study (2, 5 and 15mg twice daily), PASI 75 at week 12, was reported in 25%, 41% and 67% of patients, respectively, vs. 2% in patients on placebo. Safety: Major concerns about its overall safety profile including serious infections, certain cancers, gastro-intestinal perforations, liver damage and hyperlipidaemia were among the reasons the CHMP recommended against approval in the EU for rheumatoid arthritis in April 13.

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Secukinumab Indication: Current status: Predicted National guidance: injection Psoriasis, plaque, PIII. UK As for apremilast above. launch: Novartis moderate to severe. Reviews: NIHR HSC Apr 2012. 2014

Target population: As for apremilast above. Implications: Secukinumab targets a different immunological mediator to Sector: Secondary care. currently available biological therapies and is likely to be used as an alternative to existing biologicals in patients who have failure, contraindication or intolerance to standard systemic treatments. Financial: Likely to be around the same price as other biologicals (£8,000- £11,000/year). Likely commissioning route: CCG. PbR: Likely specified high cost drug. Pharmacology: First-in-class fully human monoclonal interleukin-17A (IL-17A) antibody given by s.c .injection as 5, weekly loading doses then monthly maintenance doses (150 or 300mg). Efficacy: There are a number of on-going PIII studies, including four 1-year studies, FIXTURE (n=1,264), ERASURE (n=720), FEATURE (n=171) and JUNCTURE (n=171). The latter two use autoinjectors; only one study, FIXTURE, has an active control arm (etanercept). The primary outcomes are PASI scores and Investigators´ Global Assessment (IGA) at week 12. Two on-going PIII extension studies (n=1,220 and n=740) are collecting 2 additional years of data from either continuous or interrupted treatment regimens. Three PII dose-ranging studies have been published (one, two, three) showing effectiveness in induction and maintenance, but did not employ the regimen adopted in PIII studies. Safety: Neutropenia has been reported.

Propranolol Indication: Current status: Predicted National guidance: oral Infantile haemangioma Filed in EU Apr UK None relevant. launch: Pierre Fabre (IH), proliferating, requiring 2013. Reviews: None. systemic therapy. 2014

Target population: Around 3-5% of infants Implications: This will be the first drug licensed for this indication which may be affected by IH and about 10% of may lead to more affected infants being considered for treatment. these may require treatment during the Financial: Likely to cost considerably more than currently used unlicensed proliferative stage, equating to about 6 cases alternatives such as corticosteroids and propranolol products. per 100,000 people per year. Likely commissioning route: CCG. PbR: Likely HRG included. Sector: Secondary care. Pharmacology: Beta-blocker. Efficacy: A published PII trial compared propranolol or placebo for 6 months in 40 children aged between 9 weeks and 5 years with facial IH or IH at sites with potential for disfigurement. At week 24 the reduction in IH volume was 60% vs.14%, respectively (p=0.01). A PIII trial (n=460) has been completed but has yet to be published. A systematic review of uncontrolled trials reported a response rate over 90%. Safety: See medicines.org.uk. Cardiac monitoring may be required.

Afamelanotide Indication: Current status: Predicted National guidance: implant Erythropoietic Filed in EU Feb UK None relevant. launch: Scenesse protoporphyria (EPP). 2012 with orphan Reviews: No recent reviews. Clinuvel status. Launched 2013 in Italy (2010) and Switzerland (2012). Target population: EPP affects <2 per Implications: There are no other specific EPP treatments. Options include 100,000 people in the EU. Protoporphyrin staying indoors, sun-blocking clothes and sunscreen. accumulates in the skin and causes severe Financial: Likely to be expensive. photosensitivity with sun exposure leading to burning, erythema and pain. Likely commissioning route: NHSE. PbR: Specified high cost drug. Sector: Secondary or tertiary care. Pharmacology: Synthetic analogue of alpha-melanocyte-stimulating hormone which induces the synthesis of melanin. Given as a controlled release dissolvable s.c implant. Efficacy: In the PIII CUV029 study 74 patients received afamelanotide or placebo once every 60 days, over 9 months. Afamelanotide was associated with fewer phototoxic reactions measured by visual analogue scale (primary outcome; p=0.044) and a lower total median pain score (secondary outcome; 6.0 vs. 17.5, p=0.035). In the 12-month PIII CUV017 crossover trial 91 patients received afamelanotide or placebo implants every 2 months. Afamelanotide reduced the total number of days on which patients experienced pain (p<0.003) and all individual daily pain scores were lower vs. placebo (p<0.002). The US PIII CUV039 study (n=93) completed in April 2013 but results have not yet been made public. The EMA has delayed its decision on approval, possibly waiting for the results of this study. Safety: No specific concerns have been identified.

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BNF 14. Vaccines

Meningo- Indication: Current status: Predicted National guidance: coccal group- Meningococcal B disease Licensed in the UK DH routine vaccination schedule B vaccine (MenB) immunisation, EU Jan 2013 - launch: 2013/14. injection invasive disease caused by see prescribing 2013/2014 JCVI recommendation Jun 2013. Bexsero Neisseria meningitidis information. Reviews: None. Novartis group B in subjects >2 months old. Target population: In the UK, the number of Implications: Surveys suggest the vaccine may cover around 73% of MenB cases of meningitis has halved over the last strains circulating in the UK. Although the vaccine has been shown to decade to around 25 per 100,000 in children induce an immune response, effectiveness against invasive MenB disease <1 year of age and to <2 per 100,000 in all has not been established. ages. Around 80% were caused by MenB. In Financial: The Joint Committee on Vaccination and Immunisation (JCVI) 2011/12, there were 613 lab-confirmed cases has recommended against including this in the routine immunisation of MenB and 33 deaths. Around 1 in 10 who programme as they do not consider it likely to be cost effective. survive will suffer major disabilities. Likely commissioning route: CCG. PbR: Not applicable. Sector: Primary care. Pharmacology: Quadrivalent vaccine (4CMenB) given as a 2 or 3 dose course, possibly followed by a booster dose. Efficacy: Results of a primary and booster PIII study have been published. In the primary study, 3,630 infants received routine vaccinations at 2, 4 and 6 months of age, either alone or with MenB vaccine. One month after the final dose, 84-100% of infants had a serological response to 4 reference MenB strains, without a clinically significant effect on the immunogenicity of routine vaccines. In the booster phase, 1,555 subjects aged 12 months received MenB vaccine either with or 1 month prior to MMR varicella-zoster virus vaccine. Over 95% showed a protective response to all four MenB vaccine components. A further PII/III study in infants which met all primary outcomes has been published. On-going studies are assessing persistence of antibody levels 5 years post-vaccination, and efficacy in children, adolescents and young adults. Safety: See prescribing information.

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Table 2. Drugs in Prescribing Outlook 2012 - development delayed Generic and Company Indication and reason for delay. trade name Celgene Small cell lung cancer. Calsed Development status uncertain following poor PIII results. Apixaban Pfizer Venous thromboembolism prevention in medically ill patients. Eliquis Development status uncertain in EU. Other new oral anticoagulant drugs have ceased development for this indication. Pfizer Renal cell carcinoma. Inlyta Development discontinued following poor PIII results. Farletuzumab Eisai Ovarian cancer. The company is reviewing the development strategy in view of negative PIII results. Imatinib Novartis Pulmonary arterial hypertension. Ruvise EU filing withdrawn. The company stated it would not be able to address concerns about benefit-risk assessment within the timetable for the application procedure. See EMA Q&A. Lorcaserin Arena Obesity. Belviq EU filing withdrawn. The company stated it would not be able to address all of the concerns within the timetable for the application. See EMA Q&A. Mipomersen Genzyme Hypercholesterolaemia (familial), homozygous and severe heterozygous. Kynamro Not recommended for approval in EU as licensing authority could not conclude that benefits outweigh risks. See EMA Q&A. Peginesatide Takeda Anaemia due to chronic kidney disease in adults on dialysis. Omontys EU filing withdrawn. The company stated that it would not be able to address concerns regarding the hypersensitivity reactions within the timetable for the application procedure. See EMA Q&A. Phentermine/ Vivus Obesity. topiramate Not recommended for approval in EU as licensing authority could not conclude that Qsiva benefits outweigh risks. See EMA Q&A. Prasugrel Eli Lilly Acute coronary syndrome (ACS), medical management. Efient Development status uncertain following poor PIII results.

Ridaforolimus Merck Bone and soft tissue sarcoma. oral EU filing withdrawn based on a provisional view that data were not sufficient to permit Jenzyl licensing. See EMA Q&A. Strontium Servier Osteoarthritis. ranelate A review of strontium ranelate is underway following evaluation of safety data showing an sachet increased risk of serious heart problems, including heart attack. Protelos Tertomotide KAEL- Pancreatic cancer. GemVax Still in PIII trials but recent data from two studies failed to demonstrate any survival benefit. Astellas Renal cell carcinoma. Development discontinued. Tofacitinib Pfizer Rheumatoid arthritis. Xeljanz Not recommended for approval in EU due to overall safety concerns. See EMA Q&A.

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Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name. Indication and relevant guidance. Full prescribing information can be found on the electronic Company. medicines compendium at medicines.org.uk via brand name link. BNF 1. Gastrointestinal system Adalimumab Licence extension: Treatment of severe active Crohn's disease in patients aged 6 to 17 years Humira - SmPC – second-line. AbbVie Guidance: NICE: Crohn’s disease pathway. SMC: Restricted use. AWMSG: Recommended. Reviews: No recent reviews. Linaclotide Licensed indication: Treatment of moderate to severe irritable bowel syndrome (IBS) with Constella - SmPC constipation in adults. Almirall Guidance: NICE: IBS pathway. SMC: restricted use. AWMSG: Not endorsed. Reviews: MTRAC Jun 2013, NICE-MPC Apr 2013, RDTC Mar 2013. Racecadotril Licensed indication: Treatment of acute diarrhoea in infants (older than 3 months), children Hidrasec - SmPC and adults when causal treatment is not possible. Abbott Guidance: SMC: Not approved adults/children. AWMSG: Not endorsed adults/ not recommended children. Reviews: NICE-MPC adults/children Mar 2013, RDTC children Nov 2012. BNF 2. Cardiovascular system Apixaban Licence extension: Prevention of stroke and systemic embolism in adults with non-valvular Eliquis - SmPC atrial fibrillation. Bristol Myers Squibb Guidance: NICE: Stroke pathway, apixaban, atrial fibrillation. SMC: Approved. Pfizer Reviews: RDTC Dec 2012, NPC Nov 2011. Rivaroxaban Licence extension: Pulmonary embolism (PE) – treatment, and prevention of recurrent PE and Xarelto - SmPC deep vein thrombosis. Bayer Guidance: NICE: VTE pathway, rivaroxaban. SIGN: Venous thromboembolism. SMC: Approved.

Reviews: RDTC Mar 2013. BNF 3. Respiratory system Aclidinium Licensed indication: Symptom relief in chronic obstructive pulmonary disease (COPD). Eklira Genuair - SmPC Guidance: NICE: COPD pathway. SMC: Approved. AWMSG: Recommended. Almirall Reviews: NICE-MPC Jan 2013, MTRAC Nov 2012, RDTC Oct 2012, NPC/UKMi Nov 2011. Beclometasone/ Licence extension: Regular maintenance treatment and ‘as needed’ for adults with asthma. formoterol Guidance: NICE: Asthma. SIGN: Asthma. Fostair - SmPC Review: NICE-MPC Jun 2013. Chiesi C1-esterase inhibitor Licence extension: Hereditary angioedema – pre-procedure prevention of acute attacks in (human) adults and children. Berinert - SmPC Guidance: AWMSG: Recommended. CSL Behring Reviews: None. Colistimethate sodium Licensed indication: Cystic fibrosis – chronic lung infection with Pseudomonas aeruginosa in Colobreathe - SmPC patients aged six years and older. Forest Laboratories Guidance: NICE: Colistimethate sodium. Reviews: None. Fluticasone propionate/ Licensed indication: Regular maintenance treatment for asthma. formoterol fumarate Guidance: NICE: Asthma. SIGN: Asthma. SMC: Approved. Flutiform - SmPC Reviews: NICE-MPC Oct 2012, MTRAC Sep 2012. Napp Glycopyrronium Licensed indication: Symptom relief in adults with chronic obstructive pulmonary disease. bromide Guidance: NICE: COPD pathway. SMC: Approved. AWMSG: Recommended. Seebri Breezhaler-SmPC Reviews: NICE-MPC Jan 2013, RDTC Nov 2012, MTRAC Nov 2012. Novartis

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Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name. Indication and relevant guidance. Full prescribing information can be found on the electronic Company. medicines compendium at medicines.org.uk via brand name link. Ivacaftor Licensed indication: Cystic fibrosis in patients aged six years and older who have a G551D Kalydeco - SmPC mutation in the CFTR gene. Vertex Guidance: SMC: Not approved. AWMSG: Terminated, available for use in Wales. Reviews: No recent reviews. Pirfenidone Licensed indication: Idiopathic pulmonary fibrosis. Esbriet - SmPC Guidance: NICE: IPF pathway, pirfenidone. SMC: Restricted use. InterMune Reviews: LNDG Dec 2011. BNF 4. Central nervous system Aripiprazole Licence extension: Moderate to severe manic episodes in bipolar I disorder in adolescents Abilify - SmPC aged 13 years and older. Otsuka Guidance: NICE: Aripiprazole. SMC: Due Sep 2013. Reviews: None. Atomoxetine Licence extension: Attention deficit/hyperactivity disorder in adults, but only when pre-existing Strattera - SmPC symptoms during childhood can be confirmed by a third-party. Eli Lilly Guidance: NICE: ADHD pathway. SIGN: Attention deficit and hyperkinetic disorders. Reviews: None. Etoricoxib Licence extension: Pain associated with dental surgery. Arcoxia - SmPC Guidance: SMC: Not approved. AWMSG: Not endorsed. MSD Reviews: None. Lisdexamfetamine Licensed indication: Attention deficit/hyperactivity disorder in children aged six years and over dimesylate – second-line. Elvanse - SmPC Guidance: NICE: ADHD pathway. SIGN: Attention deficit and hyperkinetic disorders. Shire SMC: Approved. AWMSG: In progress. Reviews: NICE-MPC May 2013. Nalmefene Licensed indication: Reduction of alcohol consumption in adults with alcohol dependence. Selincro - SmPC Guidance: NICE: Alcohol use: pathway. SIGN: Alcohol dependence. SMC: Due Oct 13. Lundbeck AWMSG: In progress. Reviews: NIHR HSC Sep 2012, RDTC due TBC. Naloxone Licensed indication: Reversal of opioid-induced respiratory depression, emergency use in the Prenoxad - SmPC home or other non-medical setting. Martindale Guidance: None. Reviews: None. Perampanel Licensed indication: Epilepsy in patients aged 12 years and older – adjunctive therapy of Fycompa - SmPC partial seizures. Eisai Guidance: NICE: Epilepsy pathway. SMC: Restricted use. AWMSG: Restricted use. Reviews: NICE-MPC Dec 2012, NETAG Oct 2012, NIHR HSC Apr 2011. Tafamidis Licensed indication: Transthyretin amyloidosis. Vyndaqel - SmPC Guidance: SMC: Not approved. AWMSG: Not endorsed. Pfizer Reviews: No recent reviews. BNF 5. Infections Ceftaroline Licensed indication: Complicated skin and soft tissue infections (cSSTI) or community Zinforo - SmPC acquired pneumonia (CAP). AstraZeneca Guidance: NICE: Pneumonia due TBC. SMC: Restricted use in cSSTI; not approved for CAP. AWMSG: Restricted use in cSSTI; not recommended for CAP. Reviews: LNDG Sep 2012. Elvitegravir/ cobicistat/ Licensed indication: HIV-1 infection. emtricitabine/ tenofovir Guidance: SMC: Approved. AWMSG: In progress. Stribild - SmPC Reviews: LNDG Jan 2013. Gilead

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Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name. Indication and relevant guidance. Full prescribing information can be found on the electronic Company. medicines compendium at medicines.org.uk via brand name link. Rifaximin Licensed indication: Hepatic encephalopathy. Targaxan - SmPC Guidance: SMC: Due Sep 2013. Norgine Reviews: No recent reviews. BNF 6. Endocrine system Dapagliflozin Licensed indication: Type 2 diabetes mellitus – monotherapy and add-on. Forxiga - SmPC Guidance: NICE: Diabetes: pathway, dapagliflozin. SIGN: Diabetes. SMC: Restricted use. AstraZeneca Reviews: MTRAC Feb 2013, RDTC Dec 2012, LNDG Nov 2012, NPC/UKMI Mar 2011. Hydrocortisone MR Licensed indication: Adrenal insufficiency. Plenadren - SmPC Guidance: SMC: Not approved. AWMSG: Not endorsed. ViroPharma Reviews: UKMi Oct 2012. Insulin degludec Licensed indication: Diabetes mellitus. Tresiba - SmPC Guidance: NICE: Diabetes: pathway. SMC: Not approved. AWMSG: Not endorsed. Novo Nordisk SIGN: Diabetes. Reviews: MTRAC Feb 2013, NICE-MPC - T1DM and T2DM Nov 2012, RDTC Aug 2012, NPC/UKMi - T2DM Mar 2012, NIHR HSC - T1DM and T2DM Jan 2011. Insulin glargine Licence extension: Diabetes mellitus in children aged two to less than six years. Lantus - SmPC Guidance: NICE: Diabetes: pathway. SMC: Restricted use. AWMSG: Recommended. Sanofi SIGN: Diabetes. Reviews: None. Linagliptin Licence extension: Type 2 diabetes mellitus– with insulin. Trajenta - SmPC Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Restricted use. Boehringer Ingelheim AWMSG: Recommended. Reviews: RDTC Mar 2012. Linagliptin/metformin Licensed indication: Type 2 diabetes mellitus. Jentadueto - SmPC Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Restricted use. Boehringer Ingelheim AWMSG: Recommended. Reviews: None. Lixisenatide Licensed indication: Type 2 diabetes mellitus. Lyxumia - SmPC Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Due Sep 2013. Sanofi AWMSG: In progress. Reviews: NICE-MPC Jan 2013. Pasireotide Licensed indication: Cushing's disease. Signifor - SmPC Guidance: SMC: Not approved. AWMSG: Not endorsed. Novartis Reviews: NETAG Jul 2012, LNDG Feb 2012. Saxagliptin/metformin Licensed indication: Type 2 diabetes mellitus. Komboglyze - SmPC Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Restricted use. Bristol Myers Squibb- Reviews: None. AstraZeneca EEIG BNF 7. Obstetrics, gynaecology, and urinary-tract disorders Botulinum A toxin Licensed extension: Urinary incontinence (UI) in adults with detrusor overactivity in a Botox - SmPC neurologic condition in patients unresponsive to/intolerant of antimuscarinic medication. Allergan Guidance: NICE: UI in neurological disease pathway. SMC: Due Oct 2013. SIGN: UI. AWMSG: In progress. Reviews: NICE-MPC Sep 2012. Medroxyprogesterone Licensed indication: Contraception, three-monthly subcutaneous injection. acetate Guidance: None. Sayana - SmPC Reviews: None. Pfizer

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Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name. Indication and relevant guidance. Full prescribing information can be found on the electronic Company. medicines compendium at medicines.org.uk via brand name link. Mirabegron Licensed indication: Overactive bladder – with symptoms of urge urinary incontinence (UI), Betmiga - SmPC urgency and urinary frequency. Astellas Guidance: NICE: Mirabegron. SIGN: UI. SMC: Approved. Reviews: MTRAC Aug 2013, LNDG Mar 2013, RDTC Feb 2013. Nomegestrol acetate/ Licensed indication: Contraception, oral. estradiol Guidance: SMC: Not approved. AWMSG: Not endorsed. Zoely - SmPC Reviews: NICE-MPC due Oct 2013. MSD Tadalafil Licence extension: Benign prostatic hyperplasia. Cialis - SmPC Guidance: SMC: Not approved. AWMSG: Not endorsed. Eli Lilly Reviews: NICE-MPC May 2013, RDTC Apr 2013. BNF 8. Malignant disease and immunosuppression

Abiraterone acetate Licence extension: Metastatic, castration-resistant, prostate cancer after failure of androgen Zytiga - SmPC deprivation therapy and when chemotherapy is not yet clinically indicated. Janssen-Cilag Guidance: NICE: PC pathway, Abiraterone. SMC: Not approved. Reviews: LCNDG Jan 2013. Aflibercept Licensed indication: Colorectal cancer (CRC), metastatic – second-line. Zaltrap - SmPC Guidance: NICE: CRC pathway, aflibercept due Oct 2013. SIGN: CRC.SMC: Not approved. Sanofi Reviews: None. Axitinib Licensed indication: Advanced renal cell carcinoma – second-line. Inlyta - SmPC Guidance: NICE: Overdue. SMC: Not approved. Pfizer Reviews: LCNDG Jan 2013. Bevacizumab Licence extension: Platinum-sensitive epithelian ovarian (OC), fallopian tube or primary Avastin - SmPC peritoneal cancer. Roche Guidance: NICE: OC pathway, bevacizumab. SIGN: OC. SMC: Not approved. Reviews: No recent reviews. Bevacizumab Licence extension: Metastatic colorectal cancer (CRC) in adults who have already been Avastin - SmPC treated with bevacizumab and chemotherapy. Roche Guidance: NICE: CRC pathway. SIGN: CRC. Reviews: None. Bortezomib Licence extension: Multiple myeloma – subcutaneous administration. Velcade - SmPC Guidance: NICE: Bortezomib. SMC: Approved. AWMSG: Recommended. Janssen-Cilag Reviews: None. Bortezomib Licence extension: Multiple myeloma – re-treatment with bortezomib. Velcade - SmPC Guidance: NICE: Bortezomib. Janssen-Cilag Reviews: None. Bortezomib Licence extension: Multiple myeloma – first-line induction treatment of adults eligible for high- Velcade - SmPC dose chemotherapy and stem cell transplantation. Janssen-Cilag Guidance: NICE: Bortezomib due Jan 2014. Reviews: NIHR HSC Apr 2011. Licensed indication: Chronic myeloid leukaemia, -positive – second- Bosulif - SmPC line. Pfizer Guidance: NICE: Haemato-oncology. SMC: Due Nov 2013. Reviews: No recent reviews. Brentuximab Licensed indication: Hodgkin’s lymphoma – relapsed/refractory post autologous stem cell Adcetris - SmPC transplant (ASCT) or when ASCT unsuitable. Takeda Guidance: NICE: Haemato-oncology. SMC: Not approved. AWMSG: Not endorsed. Reviews: NIHR HSC Jan 2011.

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Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name. Indication and relevant guidance. Full prescribing information can be found on the electronic Company. medicines compendium at medicines.org.uk via brand name link. Brentuximab Licensed indication: Relapsed/refractory systemic anaplastic large cell lymphoma. Adcetris - SmPC Guidance: SMC: Not approved. AWMSG: Not endorsed. Takeda Reviews: LCNDG Mar 2013, NIHR HSC Jan 2011. Licensed indication: ALK-positive non-small cell lung cancer, advanced – second line. Xalkori - SmPC Guidance: NICE: Lung cancer: pathway, crizotinib due Sep 2013. SIGN: Lung cancer. Pfizer SMC: Not approved, resubmission due Oct 2013. Reviews: LCNDG Nov 2012. Licensed indication: Acute myeloid leukaemia (AML) in patients aged at least 65 years who Dacogen- SmPC are unsuitable for standard chemotherapy. Janssen-Cilag Guidance: NICE: Decitabine. SMC: Not approved. AWMSG: Not endorsed. Reviews: No recent reviews. Enzalutamide Licensed indication: Prostate cancer, metastatic, castration-resistant – second-line. Xtandi - SmPC Guidance: NICE: PC pathway. SMC: Due Nov 2013. Astellas Reviews: NIHR HSC Feb 2012. Lapatinib Licence extension: HER2-positive, hormone receptor-negative metastatic breast cancer (BC) Tyverb - SmPC that has progressed on prior trastuzumab – in combination with trastuzumab and chemotherapy. GlaxoSmithKline Guidance: NICE: Advanced BC pathway. AWMSG: Restricted use. Reviews: NIHR HSC Feb 2012. Lenalidomide Licence extension: Myelodysplastic syndromes associated with a 5q chromosomal deletion in Revlimid - SmPC patients with transfusion-dependent anaemia. Celgene Guidance: NICE: Lenalidomide due Dec 2013. Reviews: LCNDG Jan 2013. Pertuzumab Licensed indication: Breast cancer (BC), metastatic HER2-positive disease – first-line with Perjeta - SmPC trastuzumab and docetaxel. Roche Guidance: NICE: Advanced BC pathway, pertuzumab due Nov 2013. SMC: Due Oct 2013. Reviews: LCNDG Mar 2013. Pomalidomide Licensed indication: Multiple myeloma, relapsed or refractory – in combination with Imnovid - SmPC Celgene dexamethasone, third-line. Guidance: None. Reviews: NIHR HSC Nov 2012. Licensed indication: Chronic myeloid leukaemia and acute lymphoblastic leukaemia. Iclusig - SmPC Guidance: CML- bosutinib draft guidance, imatinib resistant/ intolerant patients Ariad Reviews: NIHR HSC Sep 2012. Rituximab Licence extension: Vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated. MabThera - SmPC Guidance: NICE: Rituximab due Nov 2013. Roche Reviews: NIHR HSC Dec 2011. Licensed indication: Disease-related splenomegaly or symptoms in adults with chronic Jakavi - SmPC idiopathic myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis. Novartis Guidance: NICE: Ruxolitinib. SMC: Not approved. Reviews: RDTC Jan 2013, LCNDG Jun 2012. Triptorelin SR New formulation: Prostate cancer, six-monthly preparation. Decapeptyl SR - SmPC Guidance: NICE: PC pathway. Ipsen Reviews: NICE-MPC due Nov 2013. Licensed indication: Basal cell carcinoma, metastatic or locally advanced. Erivedge - SmPC Guidance: None. Roche Reviews: LCNDG Feb 2013.

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Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name. Indication and relevant guidance. Full prescribing information can be found on the electronic Company. medicines compendium at medicines.org.uk via brand name link. BNF 9. Nutrition and blood Deferasirox Licence extension: Treatment of chronic iron overload in patients aged at least 10 years with Exjade - SmPC non-transfusion-dependent thalassemia syndrome. Novartis Guidance: SMC: Not approved. AWMSG: Not endorsed. Reviews: None. Ferumoxytol Licensed indication: Iron deficiency anaemia in chronic kidney disease (CKD). Rienso - SmPC Guidance: NICE: Anaemia in CKD pathway. SIGN: CKD. SMC: Restricted use. AWMSG: Takeda Restricted use. Reviews: LNDG Oct 2012, NIHR HSC Jan 2011. BNF 10. Musculoskeletal and joint diseases Abatacept New formulation: Rheumatoid arthritis (RA), moderate-to-severe active, subcutaneous Orencia - SmPC formulation. Bristol Myers Squibb Guidance: NICE: RA pathway. SIGN: RA. SMC: Restricted use. Reviews: None. Canakinumab Licence extension: Gouty arthritis – second-line. Ilaris - SmPC Guidance: SMC: Not approved. AWMSG: Not endorsed. Novartis Reviews: NICE-MPC Jul 2013. Etanercept Licence extension: Paediatric use in juvenile idiopathic arthritis, oligoarticular, enthesitis- Enbrel - SmPC related or psoriatic. Pfizer Guidance: NICE: Etanercept. SMC: Restricted use. AWMSG: In progress. Reviews: None. Tocilizumab Licence extension: Rheumatoid arthritis (RA) – monotherapy in inadequate responders to RoActemra - SmPC DMARDs or methotrexate. Roche Guidance: NICE: RA pathway. SIGN: RA. SMC: Restricted use. Reviews: None. Tocilizumab Licence extension: Juvenile idiopathic polyarthritis, polyarticular – second-line after RoActemra - SmPC methotrexate. Roche Guidance: None. Reviews: NIHR HSC Jul 2012. BNF 11. Eye Aflibercept Licensed indication: Wet age related macular degeneration (AMD). Eylea - SmPC Guidance: NICE: Wet AMD. SMC: Approved. Bayer Reviews: LNDG Mar 2013, NETAG Dec 2012. Fluocinolone acetonide Licensed indication: Diabetic macular oedema - second-line. Iluvien - SmPC Guidance: NICE: Fluocinolone. SMC: Not approved. Alimera Sciences Reviews: LNDG Feb 2011. Ocriplasmin Licensed indication: Symptomatic vitreomacular traction, including macular hole. Jetrea - SmPC Guidance: NICE: Ocriplasmin due Oct 2013. SMC: Due Sep 2013. Alcon Reviews: NIHR HSC Sep 2011. Ranibizumab Licence extension: Visual impairment due to choroidal neovascularisation secondary to Lucentis - SmPC pathologic myopia. Novartis Guidance: SMC: Due Nov 2013. Reviews: NIHR HSC Aug 2011.

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Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name. Indication and relevant guidance. Full prescribing information can be found on the electronic Company. medicines compendium at medicines.org.uk via brand name link. BNF 12. Ear, nose and oropharynx Azelastine Licensed indication: Moderate to severe seasonal and perennial allergic rhinitis. hydrochloride/ Guidance: SMC: Due Dec 2013. fluticasone propionate Reviews: None. Dymista - SmPC Meda BNF 13. Skin Aminolaevulinic acid Licensed indication: Actinic keratosis of mild to moderate intensity on the face and scalp. Ameluz - SmPC Guidance: SMC: Approved. AWMSG: In progress. Spirit Healthcare Reviews: None. Imiquimod 3.75% Licensed indication: Actinic keratosis on the face and scalp in immunocompetent adults. Zyclara - SmPC Guidance: None. MEDA Reviews: MTRAC Jun 2013, RDTC Apr 2013. Ingenol mebutate Licensed indication: Actinic keratosis in adults – first-line. Picato - SmPC Guidance: SMC: Approved. AWMSG: Recommended. LEO Pharma Reviews: MTRAC Jun 2013, RDTC Apr 2013, NICE-MPC Mar 2013.

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Patent expiries 2013 - 2015

Generic medicines have a significant impact on prescribing budgets and can offset, to some extent, costs associated with the introduction of new medicines. Generic products can be marketed once the patent on the original product has expired although manufacturers may apply for a Supplementary Protection Certificate (SPC) to extend the effective patent life by up to 5 years (5½ years if it includes a Paediatric Investigation Plan). Expiry dates below take account of SPCs. The table highlights those drugs where there is a greater potential for the availability of a generic/biosimilar product. In addition, the table indicates where a licence for a generic/biosimilar product is in the latter stages of the EU licensing process or is already available in the EU. However, it does not follow that the generic/biosimilar product will be available in the UK as patent issues may differ between countries. Patent legislation is complex and the information below should be used as a guide only.

* Drugs which have the greatest potential for generic/biosimilar preparations becoming available. # Drugs where generic/biosimilar products are in later stages of EU licensing or are licensed in EU (see also over the page). Patent extended by 6 months (paediatric extension).

Expiry Drug Expiry Drug Expiry Drug date date date

2013 2014 2015 Feb Montelukast Feb Alemtuzumab Feb Infliximab * Fosphenytoin sodium Mar Darifenacin Ganirelix Zanamivir * / uracil Mar Dorzolamide/ timolol # Mar Somatropin (synthetic Apr Aripiprazole * hGH) Zidovudine/ lamivudine May Apr Memantine HCl Daclizumab Glatiramer May Anakinra Apr Basiliximab Insulin glargine Escitalopram oxalate May Jun Nepafenac Jun Abacavir Tirofiban Tenecteplase Hydroxyethyl starch Zoledronic acid # Jul Etanercept Moxifloxacin Jun Capecitabine # Rasburicase Ulipristal acetate * Nevirapine # Aug Bivalirudin Jul Trastuzumab Sildenafil # Strontium ranelate Jul Etonogestrel Sep Etoricoxib Aug Palivizumab Aug Raloxifene HCl # Nateglinide Sep Cetuximab * Rizatriptan # Sirolimus Panitumumab Clopidogrel hydrogen Tiotropium * Oct Aripiprazole * sulphate Oct Nelfinavir mesylate Oct Irbesartan/ Nov Palonosetron hydrochlorothiazide Paliperidone Pimecrolimus Nov Efavirenz Nov Insulin glargine Dec Eletriptan Rituximab * Icatibant acetate Frovatriptan Dec Telmisartan # Dec Almotriptan Lopinavir/ ritonavir

Bevacizumab Pemetrexed Brinzolamide *

Omalizumab

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Biosimilar developments

What are biosimilars? Biosimilars are ‘generic’ biological medicines. Unlike conventional pharmaceuticals, which are generally low molecular weight organic compounds with a defined chemical structure, biologicals are large complex proteins that cannot be copied exactly. To gain a licence, the manufacturer must provide the EMA with adequate data to show that their biosimilar is physically, chemically, biologically and clinically similar to the approved originator product. This data will be derived from extensive laboratory analysis of molecular characteristics, in vitro and in vivo studies in multiple species of animals and phase I studies in humans to define pharmacokinetics, pharmacodynamics and toxicity. In addition, phase III studies are performed to show clinical efficacy and safety; post-marketing risk management plans and phase IV studies assess safety in routine practice. Consequently, development of a biosimilar is more costly and protracted (up to eight years) compared to that of a standard generic medicine. What biosimilars are currently available or will soon be available? Three drugs are currently available in the UK in biosimilar formulations: , epoetin and somatropin. These are reasonably simple protein structures compared to monoclonal antibodies. The first monoclonal antibody biosimilar to be submitted for marketing approval in the EU, infliximab, is in the final stages of the licensing process; two brands of the same infliximab biosimilar (Inflectra and Remsima) were recommended for approval by the EMA in June 2013 with all the same indications as the originator product, Remicade, even though clinical studies have only been carried out in adults with ankylosing spondylitis (PI studies) and rheumatoid arthritis (PIII studies). Launch of infliximab biosimilar, if licensing is confirmed, will be delayed until the patent protecting the originator product expires. What is the impact of biosimilars? Marketed biosimilars are currently 5-20% cheaper than the originator products. Celltrion has stated that Remsima will cost at least 30% less than Remicade. Originators will no doubt seek to retain their market share; for example, by making their products more attractive by reformulating to simplify administration, or by offering competitive discounts. What other biosimilars are in the pipeline? The table below gives details of those medicines identified elsewhere in this document (Patent expiries) for which biosimilars are in clinical development. Further information on biosimilars that could be licensed in the UK in the near future is given in the table on the following page.

Drug name Patent Biosimilar Disease/Indication Highest Company expiry development stage relevant to EU Bevacizumab 2014 BI 695502 Cancer PI Boehringer Ingelheim Etanercept 2015 SB4 Rheumatoid arthritis PIII Samsung Bioepis GP 2015 Plaque psoriasis PIII Sandoz AFOLIA Pre-registration Finox Infliximab 2015 CT P13 All inflammatory indications Recommended for Celltrion, Hospira (Inflectra, for which the originator is approval Jun 2013 Remsima) licensed Insulin 2015 LY 2963016 Diabetes Pre-registration Eli Lilly/ Boehringer glargine Ingelheim Rituximab 2013 BI 695500 Rheumatoid arthritis PIII Boehringer Ingelheim BI 695500 Non-Hodgkin's lymphoma PIII Boehringer Ingelheim SAIT-101 Rheumatoid arthritis PIII Samsung MK-8808 Follicular lymphoma PIII Merck GP 2013 Follicular lymphoma PIII Sandoz Trastuzumab 2014 ABP-980 Breast cancer PIII Amgen CT P06 Breast cancer PIII Celltrion/ Hospira (CT-P6) Gastric cancer Celltrion/ Hospira

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Infliximab Indication: Current status: Predicted UK CT P13 Rheumatoid arthritis, adult and paediatric Crohn’s Recommended for launch: injection disease, adult and paediatric ulcerative colitis, approval in EU Jun 2013. 2014/2015 Inflectra/ ankylosing spondylitis, psoriatic arthritis and First monoclonal antibody (Patent expiry 2015) Remsima psoriasis. to have gone through the Hospira/ EU biosimilar regulatory Celltrion process. Pharmacology: Monoclonal tumour necrosis factor alpha (TNF-a) inhibitor. Originator product - Remicade. Efficacy: Rheumatoid arthritis: CT P13 was compared to Remicade in a 54-week PIII study in 606 patients also receiving methotrexate. At all assessment points, there were no clinically significant differences between the two groups in efficacy or safety outcomes. In a PIII trial, safety was similar to that of the branded product, and in particular there was no statistically significant difference in the ratio of patients who developed anti-drug antibodies.

Follitropin Indication: Current status: Predicted UK alfa XM 17 Fertility disorders: anovulation unresponsive to Recommended for launch: injection clomifene citrate; stimulation of multifollicular approval in EU Jul 2013. 2013 Ovaleap development in women undergoing assisted (Patent expired 2009) Teva reproduction; with luteinising-hormone (LH) for stimulation of follicular development in severe LH and FSH deficiency; stimulation of spermatogenesis in men. Pharmacology: Human recombinant follicle stimulating hormone (FSH). Originator product – Gonal-f. Efficacy: An international PIII study in 280 women undergoing assisted reproductive technologies compared XM17 to Gonal-f, administered for up to three cycles. The primary outcome was number of cumulus oocyte complexes retrieved.

Follitropin Indication: Current status: Predicted UK alfa AFOLIA Fertility disorders. Filed in the EU in Dec launch: injection 2012. 2014 Bemfola (Patent expired 2009) Finox Pharmacology: Human recombinant follicle stimulating hormone (FSH). Originator product – Gonal-f. Uses a different injector device to Gonal-f that reduces administration to three steps. Efficacy: A single-blind European PIII study comparing Bemfola vs. Gonal-f in 410 women during the first or second cycle of assisted reproductive treatment has been completed. The primary outcome was the number of retrieved oocytes. A second PIII study vs. Gonal-f started in the US in May 2013. It is enrolling 1,106 women undergoing in vitro fertilisation and has a primary outcome clinical pregnancy rate.

Insulin Indication: Current status: Predicted UK glargine Diabetes mellitus type 1 and 2 (T1DM, T2DM) Filed in the EU in Jul launch: LY 2963016 2013. 2014/2015 injection (Patent expiry 2015) Eli Lilly/ Boehringer Ingelheim Pharmacology: Recombinant human insulin analogue. Originator product - Lantus. Efficacy: Two PIII studies vs. Lantus have been completed: ELEMENT 1 in 400 adults with T1DM in which it was used in combination with insulin lispro and ELEMENT 2 in 606 adults with T2DM used in combination with oral hypoglycaemics.

Trastuzumab Indication: Current status: Predicted UK CT P06 Breast cancer, HER 2 positive, early and PIII. launch: injection metastatic. Gastric cancer, HER2 positive. Filed in Korea in Jun 2014/2015 Hospira/ 2013 for the range of (Patent expiry 2014) Celltrion indication for which Herceptin is licensed. Pharmacology: Anti-HER2 monoclonal antibody. Originator product - Herceptin. Efficacy: A PIII study in 383 patients with HER2+ metastatic breast cancer showed CT-P6 and trastuzumab, both in combination with paclitaxel, to have equivalent efficacy in terms in overall response rate and safety profile when given as first-line therapy every 3 weeks.

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Index

AB Science ...... 19, 36, 53 Belagenpumatucel-L ...... 32 Dapagliflozin ...... 63 Abatacept ...... 66 Belviq ...... 60 Dapagliflozin/metformin ...... 27 Abbott ...... 61 Bemfola ...... 70 Daratumumab ...... 46 AbbVie ...... 61 Bendamustine ...... 45 Dasiprotimut-T ...... 45 Abilify ...... 62 Berinert ...... 61 DCVax-L ...... 30 Abiraterone ...... 64 Betmiga ...... 64 Decapeptyl ...... 65 ABT450/ ritonavir/ ABT267/ Bevacizumab ...... 9, 34, 41, 64 Decitabine ...... 65 ABT333 ...... 25 Bevacizumab biosimilar ...... 69 Deferasirox ...... 66 Aclidinium ...... 61 Bexsero ...... 59 Defibrotide ...... 8, 17 Actoxumab/bezlotoxumab ...... 25 Biogen ...... 50 Defitelio ...... 17 Adalimumab ...... 61 Biogen Idec ...... 49, 50 Dendreon ...... 39 Adasuve ...... 20 BioMarin ...... 51 Desmoteplase ...... 15 Adcetris ...... 64, 65 BiovaxID ...... 45 Dextromethorphan/ quinidine 8, 21 Adempas ...... 16 Biovest International ...... 45 Dimethyl fumarate ...... 10, 50 Aegerion Pharmaceuticals ...... 16 Boehringer Ingelheim ... 13, 30, 31, Dolutegravir ...... 23 Afamelanotide ...... 58 32, 63, 69, 70 Doxorubicin heat-sensitive ...... 37 Afatinib ...... 30, 31, 32 Bortezomib ...... 46, 64 Duavive ...... 28 Afinitor ...... 35 Bosulif ...... 64 Dymista ...... 67 Aflibercept ...... 56, 57, 64, 66 Bosutinib ...... 64 Efient ...... 60 Afrezza ...... 27 Botox ...... 29, 63 Eisai ...... 31, 32, 42, 60, 62 Alcon ...... 66 Botulinum A toxin ...... 29, 63 Eklira Genuair ...... 61 Alemtuzumab ...... 10, 48 Brain cancer vaccine ...... 30 Eli Lilly ...... 37, 60, 62, 64, 69, 70 Alimera Sciences ...... 66 Brentuximab ...... 64, 65 Eliquis ...... 13, 60, 61 Alipogene tiparvovec ...... 52 Bristol Myers Squibb .... 25, 27, 39, Elosulfase alfa ...... 10, 51 Alirocumab ...... 16 42, 43, 61, 63, 66 Eltrombopag ...... 10, 51 Allergan ...... 29, 63 Budesonide/ formoterol ...... 19 Elvanse ...... 62 Almirall ...... 61 Bufomix Easyhaler ...... 19 Elvitegravir/ cobicistat/ Alogliptin ...... 26 C1-esterase inhibitor ...... 61 emtricitabine/ tenofovir ...... 62 Alogliptin/metformin ...... 26 Cabozantinib ...... 31, 40 Enbrel ...... 66 Alpharadin ...... 40 Calsed ...... 60 Enobosarm ...... 33 Ameluz ...... 67 Canagliflozin ...... 26 Enzalutamide ...... 65 Amgen ...... 16, 42, 44, 69 Canagliflozin/metformin ...... 26 Eribulin ...... 32, 42 Aminolaevulinic acid ...... 67 Canakinumab ...... 53, 66 Erismodegib ...... 44 Amrubicin ...... 60 Cangrelor ...... 15 Erivedge ...... 65 Anamorelin ...... 33 Carfilzomib ...... 46 Esbriet ...... 62 Apaziquone ...... 38 Ceftaroline ...... 62 Espanda ...... 18 Apixaban ...... 13, 60, 61 Celgene ...... 54, 57, 60, 65 Estybon ...... 48 Apremilast ...... 10, 54, 57 Celltrion ...... 69, 70 Etanercept ...... 66 Arcoxia ...... 62 Celsion ...... 37 Etanercept biosimilar ...... 69 Arena ...... 60 Ceptaris Therapeutics ...... 48 Etoricoxib ...... 62 Ariad ...... 65 Chiesi ...... 52, 61 Everolimus ...... 8, 35 Aripiprazole ...... 62 Chlormethine ...... 48 Evolcumab ...... 16 Arzerra ...... 47 Cialis ...... 64 Exelixis ...... 31, 40 Astellas ...... 60, 64, 65 Clevidipine ...... 17 Exenatide ...... 27 AstraZeneca ...... 27, 42, 55, 62, 63 Cleviprex ...... 17 Exjade ...... 66 Asunaprevir/daclatasvir ...... 25 Clinuvel ...... 58 Eylea...... 56, 57, 66 Ataluren ...... 10, 20, 55 Cobicistat ...... 23 Farletuzumab ...... 60 Atomoxetine ...... 62 ...... 44 Ferumoxytol ...... 66 Aubagio ...... 50, 51 Colistimethate sodium ...... 61 Fingolimod ...... 50 Auxilium ...... 30 Collagenase clostridium Finox ...... 69, 70 Avastin ...... 34, 41, 64 histolyticum ...... 30 Fluocinolone acetonide ...... 66 AWMSG ...... 4 Colobreathe ...... 61 Fluticasone propionate/ Axitinib ...... 60, 64 Cometriq ...... 31, 40 formoterol fumarate ...... 61 Azelastine hydrochloride/ Constella ...... 61 Flutiform ...... 61 fluticasone propionate ...... 67 Crizotinib ...... 65 Follitropin alfa biosimilar ...... 70 Baxter ...... 48 CSL Behring ...... 61 Forest Laboratories...... 61 Bayer .... 14, 16, 30, 35, 36, 37, 38, Custirsen ...... 39 Forxiga ...... 63 40, 56, 57, 61, 66 Dabigatran ...... 13 Fostair ...... 61 Bazedoxifene/conjugated Dabrafenib ...... 9, 43 Fresenius Medical Care ...... 19 estrogens...... 28 Daclizumab ...... 50 Fycompa ...... 62 Beclometasone/formoterol ...... 61 Dacogen ...... 65 Ganetespib ...... 32 Bedaquiline ...... 22 Dacomitinib ...... 32 Gazyva ...... 47

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Gentium ...... 17 Latuda ...... 20 Olaparib ...... 42 Genzyme ...... 20, 48, 60 LDK378 ...... 32 Omacetaxine meppesuccinate . 46 Gilead ...... 23, 24, 25, 62 Lemtrada ...... 48 Omalizumab ...... 19 Gilead Sciences ...... 47 Lenalidomide ...... 65 Omontys ...... 60 Gilenya ...... 50 Lenvatinib ...... 31 OncoGenex ...... 39 Giotrif ...... 30, 31, 32 LEO Pharma ...... 67 Onyx ...... 46 GlaxoSmithKline ..... 18, 40, 43, 44, Lesinurad ...... 55 Orencia ...... 66 47, 51, 65 Levact ...... 45 Orion Pharma ...... 19 Glybera ...... 52 Linaclotide ...... 61 Ostarine ...... 33 Glycopyrronium bromide ...... 61 Linagliptin ...... 63 Otsuka ...... 62 Golimumab ...... 11, 53 Linagliptin/ metformin ...... 63 Otsuka Pharmaceuticals ...... 29 Grupo Ferrer ...... 20 Liraglutide ...... 21 Ovaleap ...... 70 GTXi ...... 33 Lisdexamfetamine dimesylate ... 62 Paclical ...... 41 Halaven ...... 32, 42 Lixisenatide ...... 63 Paclitaxel ...... 41 Helsinn ...... 33 LNDG ...... 4 Palbociclib ...... 35 Herceptin ...... 34 Lojuxta ...... 16 Pari Pharma ...... 22 Hidrasec ...... 61 Lomitapide ...... 16 Pasireotide ...... 28, 63 Hospira ...... 69, 70 Lorcaserin ...... 60 Pazopanib ...... 9, 40 Humira ...... 61 Loxapine ...... 20 Peginesatide ...... 60 Hydrocortisone ...... 63 Lucane Pharma ...... 52 Peginterferon beta-1a ...... 49 Ibrutinib ...... 47 Lucanix ...... 32 Pegloticase ...... 55 Iclusig ...... 65 Lucentis ...... 66 Perampanel ...... 62 Idebenone ...... 56 Lumacaftor ...... 20 Perjeta ...... 65 Idelalisib ...... 47 Lundbeck ...... 15, 62 Pertuzumab ...... 65 Ilaris ...... 53, 66 Lurasidone ...... 20 Pfizer .... 13, 28, 32, 35, 57, 60, 61, Iluvien ...... 66 Lyxumia ...... 63 62, 63, 64, 65, 66 Imatinib ...... 60 MabThera ...... 45 Pheburane ...... 52 Imiquimod ...... 67 MannKind Corporation ...... 27 Phentermine/ topiramate ...... 60 Imnovid ...... 65 Martindale ...... 62 Picato ...... 67 Indacaterol/ glycopyrronium ...... 18 Masitinib ...... 9, 19, 36, 53 Pierre Fabre ...... 58 Inflectra ...... 70 Meda ...... 67 Pirfenidone ...... 62 Infliximab biosimilar ...... 69, 70 Medroxyprogesterone acetate .. 63 Plegridy ...... 49 Ingenol mebutate ...... 67 Mekinist ...... 44 Plenadren ...... 63 Inlyta ...... 60, 64 Meningococcal group-B vaccine 59 Pomalidomide ...... 65 Insulin inhaled ...... 27 Merck ...... 60, 69 Ponatinib ...... 65 Insulin degludec ...... 63 Mipomersen ...... 60 Pradaxa ...... 13 Insulin degludec/ insulin aspart .. 8, Mirabegron ...... 64 Prasugrel ...... 60 27 MSD 11, 15, 25, 41, 53, 55, 62, 64 Prenoxad ...... 62 Insulin glargine ...... 63 MTRAC ...... 4 Propranolol ...... 58 Insulin glargine biosimilar .... 69, 70 Nalfurafine ...... 19 Protelos ...... 60 Intarcia therapeutics ...... 27 Nalmefene ...... 62 Provenge ...... 39 Intercept ...... 12 Naloxone ...... 62 PTC Therapeutics ...... 55 InterMune ...... 62 Napp ...... 45, 61 Qsiva ...... 60 Invokana ...... 26 Neoquin ...... 38 Racecadotril ...... 61 Ipilimumab ...... 9, 39, 42 NETAG ...... 4 Radium-223 ...... 40 Ipsen ...... 65 Nexavar ...... 30, 35, 37, 38 Ramucirumab ...... 37 Ivacaftor ...... 62 NHSC ...... 4 Ranibizumab ...... 66 Jakavi ...... 65 NICE ...... 4 RDTC ...... 4 Janssen-Cilag .. 22, 24, 26, 46, 47, NICE-MPC ...... 4 Regorafenib ...... 9, 36, 37 48, 54, 64, 65 Nomegestrol acetate/ estradiol . 64 Remsima ...... 70 Jenson ...... 21 Norgine ...... 63 Revestive ...... 12 Jentadueto ...... 63 Northwest Biotherapeutics ...... 30 Revlimid ...... 65 Jenzyl ...... 60 Novartis 17, 18, 19, 28, 32, 35, 44, Revolade ...... 51 Jetrea ...... 66 50, 53, 54, 58, 59, 60, 61, 63, ...... 60 Kadcyla ...... 33, 34 65, 66 Rienso ...... 66 KAEL-GemVax ...... 60 NovaRx Corporation ...... 32 Rifaximin ...... 63 Kalydeco ...... 62 Novo Nordisk ...... 21, 27, 63 Rigosertib ...... 48 Kinaction ...... 36 NPC ...... 4 Riociguat ...... 16 Komboglyze ...... 63 NPS Pharmaceuticals ...... 12 Rituximab ...... 9, 45, 65 Krystexxa ...... 55 Nuedexta ...... 21 Rituximab biosimilar...... 69 Kynamro ...... 60 Oasmia ...... 41 Rivaroxaban ...... 8, 14, 15, 61 Kyprolis ...... 46 Obeticholic acid...... 12 RoActemra ...... 66 L(C)NDG ...... 4 Obinutuzumab ...... 10, 47 Roche ... 33, 34, 41, 44, 45, 47, 64, Lantus ...... 63 Ocriplasmin ...... 66 65, 66 Lapatinib ...... 65 Odanacatib ...... 55 Ruvise ...... 60 Laquinimod ...... 10, 49 Ofatumumab ...... 10, 47 Ruxolitinib ...... 65

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Ryzodeg ...... 27 Sunesis ...... 47 Umeclidinium ...... 18 Samsca ...... 29 Synageva BioPharma ...... 52 Umeclidinium/ vilanterol ...... 18 Samsung ...... 69 Synribo ...... 46 Ustekinumab ...... 54 Samsung Bioepis ...... 69 Synta ...... 32 Valchlor ...... 48 Sandoz ...... 69 Tadalafil ...... 64 Vantobra ...... 22 Sanofi ...... 16, 50, 51, 63, 64 Tafamidis ...... 62 Vedolizumab ...... 11, 12 Savient ...... 55 Tafinlar ...... 43 Velcade ...... 46, 64 Saxagliptin/metformin ...... 63 Takeda . 11, 12, 20, 26, 56, 60, 64, Vertex ...... 20, 62 Sayana ...... 63 65, 66 Victoza ...... 21 Scenesse ...... 58 Talimogene laherparepvec ...... 44 ViiV healthcare UK ...... 23 Sebelipase alfa...... 52 Targaxan ...... 63 Vimizim ...... 51 Secukinumab ...... 53, 54, 58 Tecfidera ...... 50 Vintafolide ...... 9, 41 Seebri Breezhaler ...... 61 Teduglutide ...... 12 Vipdomet ...... 26 Selincro ...... 62 Teriflunomide ...... 10, 50, 51 Vipidia ...... 26 Serelaxin ...... 17 Tertomotide ...... 60 ViroPharma ...... 63 Servier ...... 60 Teva ...... 46, 49, 70 Vismodegib ...... 65 Shire ...... 62 The Medicines Company .... 15, 17 Vivus ...... 60 SIGN ...... 4 ThermoDox ...... 37 Vosaroxin ...... 47 Signifor ...... 28, 63 Tivozanib ...... 60 Votrient ...... 40 Simeprevir ...... 24 Tobramycin ...... 22 Vyndaqel ...... 62 Simponi ...... 11, 53 Tocilizumab ...... 66 Vynfinit ...... 41 Sipuleucel-T ...... 39 Tofacitinib ...... 57, 60 Winfuran ...... 19 Situro ...... 22 Tolvaptan ...... 8, 29 Xalkori ...... 65 SMC ...... 4 Trajenta ...... 63 Xarelto ...... 14, 61 Sodium phenylbutyrate ...... 52 Trametinib ...... 9, 44 Xeljanz ...... 57 Sofosbuvir ...... 24 Translarna ...... 55 Xiapex ...... 30 Sofosbuvir/ledipasvir ...... 25 Trastuzumab biosimilar ...... 69, 70 Xolair ...... 19 Sorafenib ...... 30, 35, 37, 38 Trastuzumab emtansine . 8, 33, 34 Xtandi ...... 65 Sovrima ...... 56 Trastuzumab/ hyaluronidase . 9, 34 Yervoy ...... 39, 43 Spectrum ...... 38 Trebananib ...... 42 Zaltrap ...... 64 Spirit Healthcare ...... 67 Tresiba ...... 63 Zenapax ...... 50 Stelara ...... 54 Triptorelin ...... 65 Zinforo ...... 62 Stivarga ...... 36, 37 Tybost ...... 23 Zoely ...... 64 Strattera ...... 62 Tyverb ...... 65 Zyclara ...... 67 Stribild ...... 62 UKMi ...... 4 Zytiga ...... 64 Strontium ranelate ...... 60 Ultibro Breezhaler ...... 18

Acknowledgements

Key contributors:

Helen Davis, North West MI Centre. Sue Gough, Wessex Drug & MI Centre. Alexandra Denby, London MI Service - Northwick Park. Justine Howard, North West MI Centre. Stephen Erhorn, Regional Drug & Therapeutics Centre, Newcastle. Joanne McEntee, North West MI Centre. Jim Glare, West Midlands MI Service. Christine Proudlove, North West MI Centre. Peter Golightly, Trent MI Centre. Jill Rutter, North West MI Centre.

The following are acknowledged for commenting on draft versions, providing professional advice or technical and quality assurance support:

Alison Alvey, South West MI and Training Centre. Ashley Marsden, North West MI Centre. Liz Arkell, University Hospital of South Manchester NHS Helen Potter, Cheshire, Warrington & Wirral Area Team NHS Foundation Trust. England. Lindsay Banks, North West MI Centre. Christine Randall, North West MI Centre. David Erskine, London and South East MI Centre. Gail Woodland, Welsh MI centre and All Wales Medicines Simone Henderson, North West MI Centre. Strategy Group.

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