Prescribing Outlook 2013 - Development Delayed

Home , Temoporfin

Prescribing

Outlook

New Medicines

September 2014

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 Table 1. Pipeline drugs ...... 9 BNF 1. Gastrointestinal system...... 9 BNF 2. Cardiovascular system...... 11 BNF 3. Respiratory system ...... 17 BNF 4. Central nervous system ...... 21 BNF 5. Infections ...... 26 BNF 6. Endocrine system ...... 33 BNF 7. Obstetrics, gynaecology and urinary-tract disorders ...... 40 BNF 8. Malignant disease and immunosuppression ...... 40 BNF 9. Nutrition and blood ...... 55 BNF 10. Musculoskeletal and joint diseases ...... 56 BNF 11. Eye ...... 61 BNF 13. Skin ...... 63 Table 2. Drugs in Prescribing Outlook 2013 - development delayed...... 66 Table 3. Recent UK drug launches or licence extensions ...... 67 BNF 1. Gastrointestinal system...... 67 BNF 2. Cardiovascular system...... 67 BNF 3. Respiratory system ...... 67 BNF 4. Central nervous system ...... 68 BNF 5. Infections ...... 68 BNF 6. Endocrine system ...... 69 BNF 7. Obstetrics, gynaecology, and urinary-tract disorders ...... 70 BNF 8. Malignant disease and immunosuppression...... 70 BNF 9. Nutrition and blood ...... 71 BNF 10. Musculoskeletal and joint diseases ...... 72 BNF 11. Eye ...... 72 BNF 13. Skin ...... 72 BNF 14. Vaccines ...... 72 Patent expiries 2014 - 2017 ...... 73 Biosimilar developments ...... 75 Index...... 81 Acknowledgements ...... 83

Foreword

Managing new medicines aim of limiting the growth of NHS spending on branded medicines. Growth in the branded medicines bill above the Underpinning the strategic direction for managing new agreed level will result in a ‘PPRS Payment’ being made by medicines is the Department of Health's (DH) report pharmaceutical companies back to the DH with payments Innovation Health and Wealth, Accelerating Adoption and based on the difference between the agreed forecast and Diffusion in the NHS. It sets out the Government’s support the allowed growth level. The overall agreed allowed growth for the NHS to embrace innovation to meet current and rate in the NHS branded medicines bill is 0% for the next two future healthcare challenges and outlines the importance of years and then only a small growth rate (less than 2% per early adoption and uptake diffusion of clinically and cost year), for the remaining three years of the current scheme. effective innovative practices, including medicines. Horizon Future payments will be adjusted if actual growth is above or scanning is essential for this process at many organisational below the agreed forecast. There are exclusions to this; levels so new medicines that improve patient outcomes can further detail is in the question and answer document. be planned for and adopted. Recently, the Medicines and Healthcare Products Regulatory Agency (MHRA) launched For high cost new medicines in the NICE work programme the early access to medicines scheme. This scheme aims to manufacturers have the option to submit a proposal for a give patients with life threatening or seriously debilitating Patient Access Scheme (PAS). This allows NICE to conditions access to medicines that do not yet have a recommend treatments that it might otherwise not find to be licence when there is a clear unmet medical need. It will not cost effective. PAS are either cost (discounts, free stock etc) replace the normal licensing systems but will mean that a or outcome (price variation linked to patient outcomes) based. small number of medicines will be available to patients A list of NICE technologies with an approved PAS can be earlier than normally anticipated. viewed on the NICE website. In Prescribing Outlook current PAS schemes are highlighted if they are relevant to a new Since April 2013, NHS England Area Teams have a medicine in the same therapeutic area, and, although this will strategic medicines management role and are responsible not give an indication of the likely cost of the new medicine, it for commissioning the majority of high cost drugs as well as suggests that subsequent treatment options will have to be all cancer chemotherapy. An updated list has recently been competitive. published (August 2014) of medicines not reimbursed through national prices and are directly commissioned by NICE now has a role to provide support for implementing NHS England. Other useful documents published by NHS NICE guidance. The NICE website has recently been England that outline various mechanisms for the managed redeveloped and support tools including commissioning entry and funding of drugs include: guidance, quality standards and costing templates are accessible from a single page that contains all relevant Individual funding requests (IFRs) documents in a therapeutic area. This year, links to this Implementation and funding of NICE guidance overview page, rather than links to the individual support Experimental and unproven treatments tools are included in monographs in Prescribing Outlook On-going treatment following a NHS England funded trial where relevant. On-going treatment following non-commercially funded clinical trials As of April 2013 Monitor, in conjunction with NHS England, On-going access to treatment following a trial of treatment is responsible for the National Tariff of NHS prices which On-going access to treatment following industry sponsored includes producing the ‘High Cost Drugs’ (HCD) list for drugs clinical trials or funding that are not funded within Tariff. There are a few changes to Specialised commissioning - Clinical commissioning policies the list this year (2014/15 HCD list -see ‘Detailed HCDs’ for Manual for Prescribed Specialised Services 2013/14 the full list). Many drugs on this list are not yet available in Drugs funded by the Cancer Drug Fund the UK but are listed so that commissioners and providers can start a dialogue about funding in advance of launch. In Much of the above guidance focuses on the most expensive Prescribing Outlook for those medicines not listed on the medicines, but how are prices set for medicines and what latest HCD list an ‘educated guess’ as to the potential tariff are the mechanisms for reducing the cost to the NHS? positioning for them has been made. The mechanism agreed between the government and the For the pharmaceutical industry, the cost of bringing a new pharmaceutical industry for setting the NHS cost of new drug to the market is high. It is inevitable that more effort is drugs is known as the Pharmaceutical Price Regulation being put into looking for new uses for, or new formulations Scheme (PPRS). This scheme is negotiated every five of, currently licensed products. Applications for licence years. The latest scheme PPRS 2014 is now being extensions are processed through licensing systems faster implemented and the approach is very different to previous than those for new drugs as less safety and technical data schemes. A question and answer document outlines how it are required. Horizon scanning for licence extensions or operates. Pharmaceutical companies decide whether to join new formulations is more difficult as there is often less the PPRS scheme or not. If they decide not to join they are publicity than for new molecular entities being launched for subject to the alternative statutory scheme which imposes a their first indication. These often receive a lower priority in price cut on individual medicines of 15% of their NHS list terms of managed entry into the NHS as there is precedent price. If they join the scheme they are subject to an overall with the first indication. However, licence extensions can

UKMi September 2014 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. have a significant financial impact, especially for orphan How is the content for pipeline drugs decided? conditions, when there will usually be a different brand name Various criteria are applied to prioritise those medicines in and pricing structure. As drugs for orphan indications are the pipeline likely to have the largest impact. These include often more expensive than for other indications, orphan considering whether: status is highlighted in Prescribing Outlook. the medicine is expected to provide a significant Biosimilars are also driving the development of new improvement in disease management, formulations. Unlike traditional generic drugs these are more the medicine is first-in-class or has a major new costly to develop and take longer to licence. However, as indication, biological drugs are expensive and many are nearing the there are limited alternatives, end of their patent protection the potential for competition is the medicine cost will be high, increasing. It is estimated about 50% of the current UK the target population is large, market for biological medicines spend may be subject to 1 there is likely to be a significant effect on service biosimilar competition by 2019. Unlike chemical generic implications e.g. route/ formulation/ method of delivery, drugs biosimilars are not exactly interchangeable with the originator product and therefore need to be more actively the medicine or disease area is an NHS priority, managed into the NHS. Prescribing Outlook highlights which the medicine has significant additional indications in the biosimilars are in development and when the originator advanced pipeline stage, patent expires so that managed entry can be planned. the medicine is in the EU licensing process, there is likely to be significant media interest. Anon. What are biosimilars and are they important? Drug and Therapeutics Bulletin 2013; 51(5): 57-60. There will be additional, unquantifiable, factors that have implications for the NHS such as local demographics and About Prescribing Outlook publications prescribing preferences which cannot be accommodated in The aim of the annually published Prescribing Outlook series a national document. produced by UK Medicines Information (UKMi) is to assist How is the content for pipeline drugs presented? NHS organisations plan, implement and budget for new medicines or licence extensions and national guidance. It Monographs are organised by BNF category (Table 1). This provides support to commissioners and providers by year, within each BNF category, monographs are further highlighting new medicines and service developments that subdivided by commissioning route in England. This enables may have financial and operational resource implications. readers to more easily focus on which drugs are a priority for The Prescribing Outlook series is produced for primary and them for managed entry into the NHS. secondary care NHS organisations and has a national For the individual drugs there are two types of monograph: perspective. The content and presentation of the series has evolved over the years following consultation with users. Detailed monograph - for launches anticipated in 2014 or 2015 (except chemotherapy drugs) This document is the first in the series that comprises Abbreviated monograph – for launches anticipated in 2016 Prescribing Outlook - New Medicines and Prescribing or 2017 and for all chemotherapy drugs. Outlook - National Developments, and is supported by an This approach has been taken to manage the increasing electronic Cost Calculator. These are all available at number of monographs for licence extensions and new www.ukmi.nhs.uk. The component documents of the formulations. As they are included in the same therapeutic Prescribing Outlook series are published each autumn in line category it allows readers to see the range of drugs due to with annual budget planning timeframes and key outputs be launched for a similar indication. All entries are linked to from NICE. Updates on the progress of individual medicines New Drugs Online (NDO) monographs for more detailed at other times throughout the year can be found on the UKMi information. New Drugs Online database. The layout of each monograph in Prescribing Outlook – New Further specialist medicines information not included in the Medicines is different this year. This is to enable us to series can also be obtained from local and regional convert and publish the table of pipeline drugs as an Excel medicines information centres. See www.ukmi.nhs.uk. spread sheet. During consultation, we found that many users Prescribing Outlook – New Medicines. were laboriously cutting and pasting from the table into a spread sheet to use for local prioritisation exercises. The This publication primarily aims to provide advance Excel spreadsheet will be published shortly after publication information about new medicines (and new licensed of Prescribing Outlook – New Medicines. As always, indications or formulations) with anticipated market launches feedback to the editor on any changes is welcomed. in the next 18 to 24 months. What other information is in Prescribing Outlook – New The content is not comprehensive but focuses on medicines Medicines? with the potential for significant clinical or financial impact on the NHS. Estimates of potential uptake, patient, service and As drugs move from clinical trials through the licensing financial implications are included where possible. process inevitably some don’t make it to market. Some will Reference is made to relevant national guidance and links to have been highlighted in previous editions of Prescribing in-depth independent reviews are included, where available. Outlook so are included in a table (Table 2) just for information. In addition, brief details of drugs launched in the

UKMi September 2014 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. last 12 months are included (Table 3) as this is often useful Prescribing Outlook – Cost Calculator is an Excel for local planning purposes. spreadsheet tool to facilitate estimates of potential prescribing changes for a local population. Access is via As in previous editions of Prescribing Outlook, drugs with www.ukmi.nhs.uk. patents due to expire in the near future are highlighted. It is important that generic options are considered as part of the Please direct comments on Prescribing Outlook – National wider medicines management agenda. This document Developments and the Cost Calculator to: Devika Sennik or includes an ‘educated guess’ as to which drugs have the David Erskine, London and South East Medicines potential for generic competition and an indication whether Information Centre, Guy’s and St. Thomas’ NHS Foundation generic product licence applications are currently in progress Trust. [email protected], in the EU. As for last year a separate section on biosimilar [email protected] drugs is included. Although there are a small number of New Drugs Online (NDO) database includes information biosimilar drugs already on the market many more are in the on medicines in clinical development from late phase II trials pipeline that could have a potentially cost saving impact on to product launch and includes links to evidence-based medicines budgets. reviews up to one year post launch. This database is More detailed information on the medicines listed can be maintained by UKMi and forms the basis of the content of obtained from the UKMi New Drugs Online (NDO) database Prescribing Outlook – New Medicines. It is updated daily and which can be accessed directly from the generic name can be used to produce reports based on a number of hyperlink in this document. criteria including possible launch date, stage of clinical development or pharmaceutical company. Access is free to Please direct comments on Prescribing Outlook – New all with an NHS email address via www.ukmi.nhs.uk but Medicines to the editor: Helen Davis, North West Medicines requires individual registration. Limited access is freely Information Centre, Pharmacy Practice Unit. available to non-registered users via Evidence search [email protected]. (www.evidence.nhs.uk).

Please direct comments and enquiries on New Drugs Online Other UKMi horizon scanning resources to: London Medicines Information Service-Northwick Park, [email protected]. Prescribing Outlook – National Developments estimates the impact on clinical practice and prescribing budgets of national guidance, mainly that issued by NICE. It is intended The information in these resources is the to inform discussions between commissioners and providers, and highlight issues around implementating best available at the time of publication but is guidance. Access is via www.ukmi.nhs.uk. subject to significant change with time.

Abbreviations

AWMSG All Wales Medicines Strategy Group NIHR HSC National Institute for Health Research Horizon Scanning Centre BNF British National Formulary NICE National Institute for Health and Care BTS British Thoracic Society Excellence CCG Clinical Commissioning Group NICE-ES NICE Evidence Summary CDF Cancer Drug Fund NNT Number needed to treat DH Department of Health ns Not significant EMA European Medicines Agency PAS Patient Access Scheme EU European Union RDTC Regional Drug & Therapeutics Centre, HRG Healthcare Resource Group (definition) Newcastle i.m. Intramuscular s.c. Subcutaneous i.v. Intravenous SIGN Scottish Intercollegiate Guidelines Network. L(C)NDG London (Cancer) New Drugs Group SMC Scottish Medicines Consortium MHRA Medicines and Healthcare products SmPC Summary of Product Characteristics Regulatory agency TBC To be confirmed MI Myocardial infarction UKMi United Kingdom Medicines Information MTRAC Midland Therapeutics Review & Advisory US United States Committee NDO New Drugs Online NHSE NHS England

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 3 No responsibility is accepted for the content of documents derived from this original publication. Key

Generic name and formulation [Brand name]; Company Medicines are listed by BNF category and linked to relevant publicly available pages of the NDO database. The company that holds the marketing rights in the EU is listed together with a co-promoter company if relevant. Pharmacology: Therapeutic class and/or mode of action and administration details. Indication: The indication for the product. The closer the drug is to launch the more specific this can be. Current status: PII/III – in phase two/three trials. Filed – licence application has been submitted. Recommended for approval – opinion of the advisory committee of the licensing authority suggests the medicine should be licensed. In the EU a full licence is likely within three months. Licensed – the product has been granted a marketing licence. The company determines launch date. Launched – the medicine is marketed in the EU. If launched elsewhere in the world, but not the UK, there are links to prescribing data. Orphan status – indicated if relevant (see definition page 8). The following apply to US expediated programmes for serious or life-threatening conditions: Breakthough therapy status –preliminary evidence indicates substantial improvement over existing therapies on clinically significant outcomes. Fast-track status –potential to address unmet needs. Priority review – provides significant improvement in safety or effectiveness. All indicate that the drug is likely to pass through licensing systems faster. UK availability: An informed estimate based on knowledge of processes and timescales involved in licensing systems. This is easier to predict when a product may be available once it is has entered the licensing process as known time frames apply. However, once a licence has been granted the company decides when and where to launch; if it is a licence extension the product is available immediately for prescribing. Population: Data on prevalence (number with the disease) and incidence (number of new cases each year) are reported for a 100,000 population, if possible. Sector: An indication of which sector in the NHS the medicine is likely to impact, at least initially. Implications: Factors highlighted include patient options, monitoring or testing requirements and service implications related to medicine delivery. Financial: Cost implications are assessed based on a number of assumptions such as whether the medicine is added to existing therapy or is a competitor in a therapeutic area where budgets are established. However, it is difficult to quantify likely uptake of the medicine. For launched products, costs are taken from the latest published NHS costs. Where a patient access scheme (PAS) may apply this is indicated. Tariff: 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 specified as a high cost drug it is therefore, by default, likely to be included within tariff and will be listed as ‘HRG included’. CDF: Only for chemotherapy drugs, an indication of its listing in the Cancer Drug Fund list. 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. Guidance/ National guidance: Relevant publications (funding source). reviews: NICE - National Institute for Health and Care Excellence: www.nice.org.uk (DH). SMC - Scottish Medicines Consortium. www.scottishmedicines.org.uk (NHS Scotland). SIGN - Scottish Intercollegiate Guidelines Network. www.sign.ac.uk (NHS Scotland). AWMSG - All Wales Medicines Strategy Group. www.wales.nhs.uk/awmsg (NHS). Reviews: Independent reviews and regional guidance that is accessible to all NHS sectors published between 2012 and 2014. L(C)NDG - London (Cancer) New Drugs Group (NHS organisations in Greater London). LMEN – London Medicines Evaluation Network (NHS organisations in Greater London). MTRAC - Midlands Therapeutics Review & Advisory Committee. www.mtrac.co.uk. (Primary Care NHS organisations in the Midlands). NICE-ES – NICE Evidence Summaries produced by NICE Medicines and Prescribing Centre. A critical review of the evidence but it is not NICE guidance. NIHR-HSC- NIHR Horizon Scanning Centre. www.nhsc-healthhorizons.org.uk. (NIHR). RDTC - Regional Drug & Therapeutics Centre. rdtc.nhs.uk. (NHS organisations in the North East of England). UKMi - United Kingdom Medicines Information. www.ukmi.nhs.uk (NHS).

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 4 No responsibility is accepted for the content of documents derived from this original publication.

Summary of predicted launch dates

This list summarises the earliest predicted UK launch date for pipeline drugs listed in Table 1 – Pipeline drugs and biosimilars. 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 8 for more details).

BNF Drug Indication Commis Page BNF Drug Indication Commis Page sioner? sioner? 2014 8 Cabo- Thyroid cancer NHSE 41 zantinib* 1 Teduglutide* Short bowel NHSE 11 syndrome 8 Ramuciru- Gastric cancer NHSE 44 mab* 2 Rivaroxaban Acute coronary CCG 11 syndrome 8 Enzalutamide Prostate cancer NHSE 46 2 Clevidipine Hypertension, CCG 13 8 Sipuleucel-T Prostate cancer NHSE 46 perioperative 8 Trametinib Melanoma NHSE 48 2 Propranolol Infantile CCG 15 8 Benda- Non-Hodgkin’s NHSE 50 haemangioma mustine lymphoma 3 Tiotropium Asthma CCG 17 8 Ibrutinib* Mantle cell NHSE 51 bromide lymphoma 3 Umeclidinium Chronic CCG 18 8 Idelalisib Chronic NHSE 52 obstructive lymphocytic pulmonary disease leukaemia 3 Indacaterol/ Chronic CCG 18 8 Ibrutinib Chronic NHSE 52 glyco- obstructive lymphocytic pyrronium pulmonary disease leukaemia 4 Liraglutide Obesity CCG 23 8 Peginterferon Multiple sclerosis NHSE 53 4 Naltrexone/ Obesity CCG 23 beta-1a bupropion 9 Alipogene Familial lipoprotein NHSE 55 4 Dextrometh- Pseudobulbar CCG 26 tiparvovec lipase deficiency orphan/ affect 10 Ataluren* Duchenne NHSE 59 quinidine muscular 5 Tobramycin Ps.aeruginosa in NHSE 28 dystrophy nebuliser cystic fibrosis 11 Aflibercept Macular oedema CCG 61 5 Daclatasvir Hepatitis C NHSE 29 11 Ciclosporin A Keratoconjunctiv- CCG 62 5 Dolutegravir/ HIV NHSE 32 itis sicca abacavir/ 13 Afamelano- Erythropoietic CCG 65 lamivudine tide* protoporphyria 6 Alogliptin/ Type 2 diabetes CCG 33 2015 pioglitazone mellitus 1 Ustekinumab Crohn’s disease CCG 9 6 Canagliflozin/ Type 2 diabetes CCG 33 metformin mellitus 1 Eluxadoline Irritable bowel CCG 9 syndrome 6 Insulin Type 2 diabetes CCG 34 degludec/ mellitus 1 Lubiprostone Constipation in CCG 10 liraglutide children 6 Bazedoxifene Osteoporosis and CCG 36 2 Edoxaban Prevention of atrial CCG 11 / conjugated menopausal fibrillation estrogens symptoms 2 Edoxaban Venous CCG 11 6 Tolvaptan* Polycystic kidney NHSE 38 thromboembolism disease treatment and prevention 6 Mifepristone* Cushing’s NHSE 39 syndrome 2 Vorapaxar Reduction of CCG 14 atherothrombotic 6 Insulin Type 1 and 2 CCG 75 events glargine diabetes biosimilar 2 Cangrelor Thrombotic events CCG 15 (Abasria) in percutaneous coronary 7 Follitropin Fertility disorders CCG 76 intervention biosimilar (Bemfola) 2 Evolocumab Hyperlipidaemia CCG 16

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 5 No responsibility is accepted for the content of documents derived from this original publication.

BNF Drug Indication Commis Page BNF Drug Indication Commis Page sioner? sioner? 3 House dust Allergic rhinitis, CCG 19 8 Pertuzumab Breast cancer, NHSE 43 mite immuno- asthma and first-line therapy rhinoconjunctivitis 8 Everolimus Breast cancer, NHSE 43 3 Ataluren* Cystic fibrosis NHSE 20 second-line 3 Lumacaftor + Cystic fibrosis, NHSE 21 8 Apaziquone Bladder cancer NHSE 45 ivacaftor* homozygous 8 Paclitaxel* Ovarian cancer NHSE 47 F508del-mutation 8 Olaparib* Ovarian cancer NHSE 47 4 Lisdex- Attention deficit CCG 22 amfetamine hyperactivity 8 Bevacizumab Cervical cancer NHSE 48 disorder 8 Cobimetinib Melanoma NHSE 48 4 Guanfacine Attention deficit CCG 22 8 Ipilimumab Melanoma NHSE 49 hyperactivity disorder 8 Pembrolizu- Melanoma NHSE 49 mab 4 Safinamide Parkinson’s CCG 24 disease- early 8 Talimogene Melanoma NHSE 49 laherpare- 4 Safinamide Parkinson’s CCG 24 pvec disease- mid-late 8 Sonidegib Basal cell NHSE 49 5 Dalbavancin Skin infections CCG 26 carcinoma 5 Oritavancin Skin infections CCG 27 8 Chlor- Cutaneous T-cell NHSE 50 5 Tedizolid Skin infections CCG 27 methine* lymphoma 5 Daclatasvir + Hepatitis C NHSE 30 8 Dasiprotimut- Non-Hodgkin’s NHSE 51 asunaprevir T* lymphoma 5 Ombitasvir/ Hepatitis C NHSE 30 8 Pano- Multiple myeloma NHSE 51 paritaprevir/ binostat* ritonavir 8 Rigosertib* Myelodysplastic NHSE 52 5 Ledipasvir/ Hepatitis C NHSE 31 syndromes sofosbuvir 8 Teriflunomide Multiple sclerosis NHSE 54 6 Insulin Type 1 and 2 CCG 34 10 Apremilast Psoriatic arthritis CCG 56 glargine diabetes mellitus U300 10 Secukinumab Psoriatic arthritis CCG 56 6 Insulin Type 1 and 2 CCG 35 10 Lesinurad Gout CCG 59 inhalation diabetes mellitus 10 Idebenone* Duchenne NHSE 60 6 Odanacatib Osteoporosis, CCG 37 muscular postmenopausal dystrophy 6 Pasireotide* Acromegaly NHSE 39 10 Etanercept Rheumatoid CCG 76 SB-4 arthritis 7 Collagenase Peyronie’s disease CCG 40 biosimilar clostridium histolyticum 10 Infliximab Rheumatoid CCG 77 biosimilar arthritis and all 7 Follitropin Fertility disorders. CCG 77 (Inflectra/ other indications biosimilar Remsima) as for Remicade (Ovaleap) 10 Infliximab Rheumatoid CCG 78 8 Afatinib Head and neck NHSE 41 SB2 arthritis cancer biosimilar 8 Lenvatinib* Thyroid cancer NHSE 41 13 Apremilast Plaque psoriasis CCG 63 8 Afatinib Non-small cell NHSE 41 13 Secukinumab Plaque psoriasis CCG 63 lung cancer 13 Ustekinumab Plaque psoriasis CCG 64 8 Ceritinib Non-small cell NHSE 42 lung cancer 2016 8 Crizotinib Non-small cell NHSE 42 1 Diltiazem Anal fissure CCG 10 lung cancer cream 8 Eribulin Non-small cell NHSE 42 1 Obeticholic Cirrhosis CCG 10 lung cancer acid* 8 Trastuzumab Breast cancer, NHSE 43 2 Andexanet Anticoagulation CCG 13 emtansine first-line alfa reversal 8 Trastuzumab Breast and gastric NHSE 79 2 Ticagrelor Acute coronary CCG 14 CT-P6 cancer syndrome biosimilar 2 Sacubitril/ Heart failure CCG 15 valsartan

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 6 No responsibility is accepted for the content of documents derived from this original publication.

BNF Drug Indication Commis Page BNF Drug Indication Commis Page sioner? sioner? 2 Alirocumab Hyper- CCG 16 9 Sebelipase Lysosomal acid NHSE 55 cholesterolaemia alfa* lipase deficiency 3 Tiotropium Asthma, in CCG 17 10 Apremilast Psoriatic arthritis CCG 57 bromide children in DMARD-naïve 3 Masitinib Severe asthma NHSE 19 10 Ixekizumab Psoriatic arthritis CCG 57 3 Lumacaftor + Cystic fibrosis, NHSE 21 10 Secukinumab Ankylosing CCG 57 ivacaftor heterozygous spondylitis F508del-mutation 10 Secukinumab Rheumatoid CCG 58 4 Lurasidone Bipolar depression CCG 21 arthritis 4 Melatonin Sleep disorders in CCG 22 10 Baricitinib Rheumatoid CCG 58 children arthritis 4 Nabiximols Cancer pain CCG 25 10 Drisapersen* Duchenne NHSE 60 5 Actoxumab/ C. difficile- CCG 28 muscular bezlotoxu- diarrhoea, dystrophy mab prevention 10 Epratuzumab Systemic lupus NHSE 61 5 MK-5172 Hepatitis C NHSE 31 erythematosus 5 Ledipasvir/ Hepatitis C with NHSE 32 10 Rituximab BI Rheumatoid CCG 78 sofosbuvir HIV 695500 arthritis biosimilar 5 Ombitasvir/ Hepatitis C with NHSE 32 paritaprevir/ HIV 10 Rituximab Rheumatoid CCG 78 ritonavir PF-05280586 arthritis biosimilar 6 Insulin Type 1 and 2 CCG 35 peglispro diabetes mellitus 11 Sirolimus* Uveitis NHSE 62 6 Anamorelin Cachexia CCG 37 13 Dimethyl Plaque psoriasis CCG 64 fumarate 6 Enobosarm Cachexia CCG 37 13 Ixekizumab Plaque psoriasis CCG 64 6 Odanacatib Osteoporosis in NHSE 38 men 13 Tofacitinib Plaque psoriasis CCG 65 6 Insulin Type 1 and 2 CCG 75 13 Etanercept Plaque psoriasis CCG 76 glargine MK- diabetes GP2015 1293 biosimilar biosimilar 2017 7 nx 1207 Benign prostatic CCG 40 2 Rivaroxaban Heart failure and CCG 13 hyperplasia coronary artery 8 Brain cancer Glioblastoma NHSE 40 disease vaccine* 2 Ticagrelor Stroke or transient CCG 14 8 Everolimus Breast cancer, NHSE 44 ischaemic attack, first-line prevention 8 Ramuciru- Hepatocellular NHSE 45 2 Mydicar Heart failure NHSE 16 mab* carcinoma 3 Interferon Acute respiratory CCG 19 8 Cabozantinib Prostate cancer NHSE 46 beta 1a, distress syndrome lyophilized* 8 Ipilimumab Prostate cancer NHSE 46 3 Benralizumab Severe asthma NHSE 20 8 Trebananib Ovarian cancer NHSE 47 3 Mepolizumab Churg-Strauss NHSE 20 8 Eribulin* Soft tissue NHSE 48 syndrome sarcoma 4 Leuco- Alzheimer’s CCG 24 8 Vosaroxin* Acute myeloid NHSE 50 thiomethon- disease leukaemia inium 8 Carfilzomib* Multiple myeloma NHSE 51 4 Leuco- Dementia CCG 25 8 Daclizumab Multiple sclerosis NHSE 53 thiomethon- 8 Fingolimod Multiple sclerosis NHSE 53 inium* 8 Rituximab Follicular NHSE 79 4 Scyllo-inositol Alzheimer’s CCG 25 CT-P10 lymphoma disease biosimilar 4 Lu AE58054 Alzheimer’s CCG 25 8 Rituximab BI Follicular NHSE 79 disease 695500 lymphoma 5 Cadazolid C.difficile- CCG 28 biosimilar diarrhoea, treatment

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 7 No responsibility is accepted for the content of documents derived from this original publication.

BNF Drug Indication Commis Page BNF Drug Indication Commis Page sioner? sioner? 5 Danoprevir Hepatitis C NHSE 31 8 Trastuzumab Breast cancer NHSE 80 5 MK-5172 + Hepatitis C NHSE PF-05280014 MK8742 biosimilar 6 Exenatide Type 2 diabetes CCG 32 8 Pegfilgrastim Febrile NHSE 80 mellitus LA-EP2006 neutropenia biosimilar 6 Peptide Type 1 diabetes CCG 35 p277* 9 Eculizumab* Myasthenia gravis NHSE 55 8 Ganetespib Non-small cell NHSE 36 10 Tofacitinib Psoriatic arthritis CCG 57 lung cancer 10 Apremilast Ankylosing CCG 58 8 Defactinib* Mesothelioma NHSE 42 spondylitis 8 Palbociclib Breast cancer, NHSE 43 10 Eteplirsen* Duchenne NHSE 60 first-line muscular dystrophy 8 Regorafenib Hepatocellular NHSE 44 carcinoma 10 Forigerimod Systemic lupus NHSE 61 erythematosus 8 Sorafenib* Renal cell NHSE 45 carcinoma 11 E10030 Age-related CCG 62 macular 8 Custirsen Prostate cancer NHSE 45 degeneration 8 Volasertib* Acute myeloid NHSE 47 Uncertain leukaemia 6 Teplizumab* Type 1 diabetes CCG 36 8 Trastuzumab Breast cancer NHSE 50 ABP 980 8 Sorafenib Breast cancer, NHSE 44 biosimilar second-line 8 Trastuzumab Breast cancer NHSE 80 8 Everolimus Organ rejection NHSE 54 BCD-022 10 Tofacitinib Rheumatoid CCG 58 biosimilar arthritis

*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.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 8 No responsibility is accepted for the content of documents derived from this original publication.

Table 1. Pipeline drugs BNF 1. Gastrointestinal system

Likely CCG commissioned

Ustekinumab injection [Stelara]; Janssen-Cilag Pharmacology: Monoclonal antibody, interleukin antagonist, given i.v. (induction) then s.c. every 8 or 12 weeks. Indication: Crohn’s disease, moderate-to-severe, treatment-refractory, in adults. Current status: PIII UK availability: 2015 (licence extension). Population: Estimates of UK prevalence of Crohn’s disease range from 50-150 per 100,000 people. 20% of patients may have severe active disease and up to 50% may be resistant to, or intolerant of, existing therapy, including TNF inhibitors. Sector: Secondary care. Implications: Likely to compete with i.v. vedolizumab as an option for patients with inadequate response or intolerant of alternatives, including TNF inhibitors, although s.c. injection could be an advantage. Financial: As a further treatment option it will be additional to current costs. Tariff: Specified high cost drug. Efficacy: In the published PII CERTIFI dose-finding study (n=526) the primary outcome of clinical response was achieved in 39.7% of patients receiving ustekinumab (6mg/kg, expected licensed dose) vs. 23.5%, with placebo (p=0.005). The PIII UNITI-1 trial involving 769 patients resistant to, or intolerant of, TNF inhibitors was completed in July 2013, and the UNITI-2 trial has enrolled approximately 612 patients. Patients who complete these trials are eligible to enter the IM-UNITI maintenance trial (maintenance dose is 90mg). Safety: See medicines.org.uk. Guidance/ Guidance: NICE: Inflammatory bowel disease. reviews: Reviews: None.

Eluxadoline oral [MuDelta]; Actavis Pharmacology: Mu-opioid receptor agonist and delta opioid receptor antagonist, first-in-class. Indication: Irritable bowel syndrome (IBS), diarrhoea-predominant. Current status: PIII in EU. Granted fast-track status in the US where filing is anticipated in 2014. UK availability: 2015 Population: According to strict diagnostic criteria (Rome III), 5-11% of people suffer from IBS, although other estimates suggest 10-20% may be sufferers. Only about a third of those affected will seek help from their GP. About one third of patients have diarrhoea-predominant IBS. Sector: Primary care. Implications: IBS is a relatively common disease with few treatment options. As first in a new class, eluxadoline could be useful, especially for patients with a poor response to loperamide. Financial: Eluxadoline is likely to cost more than loperamide and will be either added to, or used instead of, loperamide. Tariff: Likely HRG included. Efficacy: In PIII trials (IBS3001 and IBS3002, n=2,428) patients taking 100mg eluxadoline showed improvement in the primary outcome, a composite response based on abdominal pain and stool consistency vs. placebo. In study 3001, responder rates (weeks 1-26) were 29.3% for 100mg eluxadoline vs. 19.0% for placebo. In study 3002, responder rates were 32.6% and 20.2%, respectively (p=0.001 for both, NNT=8). Safety: The most commonly reported adverse events in clinical trials were constipation and nausea. Guidance/ Guidance: NICE: Irritable bowel syndrome. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 9 No responsibility is accepted for the content of documents derived from this original publication.

Lubiprostone oral [Amitiza]; Sucampo Pharmacology: Chloride channel activator. Indication: Chronic idiopathic constipation in children. Current status: PIII UK availability: 2015 (licence extension). Population: Constipation affects 5-30% of children, and becomes chronic in about one third of patients. Around 95% of childhood constipation is idiopathic, but only around 3-5% present for treatment. Sector: Likely secondary care initially. Implications: Lubiprostone is likely to be used where lifestyle changes and other laxatives have failed. Financial: Lubiprostone currently costs about £28 for a 14 day supply (24 micrograms twice daily). Cost may be reduced in children taking a lower dose. A 12 microgram capsule is not yet available. Other laxatives licensed in children cost between £1 and £7 for 14 days treatment. Tariff: HRG included. Efficacy: One published, uncontrolled trial enrolled 127 patients aged ≤17 years weighing ≥12kg. Lubiprostone dose varied according to age and bodyweight (12-48 microgram daily) and was found to increase the number of spontaneous bowel movements at week one vs. baseline (3.1 vs. 1.5, p<0.0001). A 12 week placebo-controlled PIII trial is underway in patients aged 6-17 years, with an option to enter a 9 month open-label extension study. A further PIII trial investigating a liquid formulation in patients aged between 6 months and 6 years is planned. Safety: See medicines.org.uk for adult safety data. Guidance/ Guidance: NICE: Constipation. reviews: Reviews: None.

Diltiazem topical [Anoheal]; SLA Pharma Pharmacology: Calcium channel blocker, 2% cream. Indication: Chronic anal fissure. Current status: PIII UK availability: 2016 Sector: Primary care. Tariff: Likely HRG included. Guidance/ Guidance: None. reviews: Reviews: NICE-ES January 2013.

Obeticholic acid oral; Intercept Pharmacology: Modified bile acid, farnesoid-X receptor agonist, first-in-class. Indication: Cirrhosis, primary biliary, second-line treatment. Current status: PIII. Orphan status in EU and US. UK availability: 2016 Sector: Secondary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Liver conditions: general and other. reviews: Reviews: NIHR HSC December 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 10 No responsibility is accepted for the content of documents derived from this original publication.

Likely NHSE commissioned

Teduglutide injection [Revestive]; NPS Pharmaceuticals Pharmacology: Glucagon-like peptide-2 analogue, given by s.c. injection. Indication: Short bowel syndrome (SBS). Current status: Licensed in EU September 2012 with orphan status – see prescribing data. Launched in US March 2014. Teduglutide may initially be available on a named patient basis. UK availability: 2014 Population: The estimated UK incidence of SBS is 2 to 5 cases per million people. Sector: Secondary or tertiary care. Implications: Teduglutide is the first drug specifically licensed for SBS, the most common indication for home parenteral nutrition (PN). It may reduce PN volume requirements. Financial: Likely to be expensive and additive to current options. Annual cost per patient of teduglutide in the US is $295,000. Tariff: Specified high cost drug. Efficacy: In a published PIII study (n=86) teduglutide 0.05mg/kg/day was compared with placebo. Reduction in PN of ≥20% at weeks 20-24 was achieved by 63% vs. 30%, respectively (p=0.002, NNT=3). In another published PIII study (n=83) teduglutide 0.10mg/kg did not meet the primary outcome of reduction of ≥20% in PN in weeks 16-24 but an ad-hoc analysis showed teduglutide 0.05mg/kg did meet the primary outcome (46% vs. 6%, p<0.01, NNT=3). In a published extension of this study, both groups had progressive reduction in PN. At week 52, 68% of the 0.05mg/kg and 52% of the 0.10mg/kg group had a ≥20% reduction in PN, and four patients no longer required PN. Safety: See prescribing data. Guidance/ Guidance: NICE: Endocrinal, nutritional and metabolic conditions: general and other. reviews: Reviews: None recent. BNF 2. Cardiovascular system Likely CCG commissioned

Edoxaban oral [Lixiana]; Daiichi Sankyo Pharmacology: Direct factor Xa inhibitor. Indication: Prevention of stroke and systemic embolic events in non-valvular atrial fibrillation (AF). Current status: Filed in EU January 2014. UK availability: 2015 Population: The prevalence of AF is about 1,600 per 100,000 people. Over 57% are at moderate to high risk of stroke and should be offered anticoagulation therapy. NICE estimate less than half of those with AF who need anticoagulation therapy are currently receiving it. Sector: Primary care. Implications: Rivaroxaban, dabigatran and apixaban are licensed for prevention of stroke and systolic embolism in AF. Edoxaban will be a competitor but may help further increase the uptake of anticoagulant therapy in eligible people. Once daily dosing may be important for compliance. Financial: Edoxaban will compete with rivaroxaban, dabigatran and apixaban. Tariff: Likely HRG included. Efficacy: In the published PIII ENGAGE AF-TIMI 48 study (n=21,105) edoxaban (60 or 30mg once daily) was compared with warfarin (target INR of 2-3) in moderate to high risk patients for a median of 2.8 years. Edoxaban was non-inferior to warfarin for prevention of stroke and systemic embolic events, which occurred in 1.18% and 1.61% of those on edoxaban 60mg and 30mg vs. 1.50% on warfarin, (p<0.001 and p<0.01 for non-inferiority). Safety: In the ENGAGE study the rate of major bleeding was lower with edoxaban vs. warfarin (p<0.001). Patients with moderate or severe renal impairment, weight ≤60kg or taking concomitant P-glycoprotein inhibitors (e.g. verapamil, quinidine, dronedarone) received half the dose of edoxaban. Guidance/ Guidance: NICE: Heart rhythm conditions. Edoxaban due September 2015. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 11 No responsibility is accepted for the content of documents derived from this original publication.

Edoxaban oral [Lixiana]; Daiichi Sankyo Pharmacology: Direct factor Xa inhibitor. Indication: Venous thromboembolism (VTE), treatment and secondary prevention. Current status: Filed in EU January 2014. UK availability: 2015 Population: Annual incidence of pulmonary embolism and deep vein thrombosis is about 40 and 100 per 100,000 people, respectively. Sector: Initiated in secondary care and continued in primary care. Implications: Rivaroxaban, dabigatran and apixaban are licensed for treatment of VTE and prevention of recurrent VTE. Edoxaban will be a competitor. Once daily dosing may be important for compliance. Financial: Edoxaban will compete with rivaroxaban, dabigatran and apixaban. Tariff: Likely HRG included. Efficacy: In the published HOKUSAI VTE study (n=8,240), edoxaban (60 or 30mg once daily) was compared with warfarin (target INR of 2-3) in patients with acute VTE who had initially received heparin. Edoxaban was non-inferior to warfarin for the primary outcome of recurrence of symptomatic VTE, which occurred in 3.2% of patients on edoxaban vs. 3.5% on warfarin (p<0.001 for non-inferiority). Safety: In the HOKUSAI study the rate of clinically relevant (major and non-major) bleeding was lower with edoxaban vs. warfarin (p=0.004). As for edoxaban above, the dose was halved in certain patients. Guidance/ Guidance: NICE: Embolism and thrombosis. Edoxaban due October 2015. SIGN: VTE. reviews: Reviews: NIHR HSC February 2012.

Rivaroxaban oral [Xarelto]; Bayer Pharmacology: Direct factor Xa inhibitor. Indication: Prevention of atherothrombotic events after an acute coronary syndrome (ACS) with elevated cardiac biomarkers. Current status: Licensed in the EU May 2013 –see prescribing data. UK availability: 2014 Population: ACS refers to a group of conditions including ST segment elevation myocardial infarction (STEMI), non- STEMI and unstable angina. In England during 2012-13, there were 33,000 hospital admissions for unstable angina and 76,000 for acute MI. Sector: Secondary care initiated, continued in primary care. Implications: Long-term management of ACS includes use of aspirin and another antiplatelet agent (clopidogrel, prasugrel or ticagrelor). Rivaroxaban 2.5mg twice daily is licensed for use in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine. Few patients over 75 years of age were included in the ATLAS study. Financial: Cost will be in addition to existing therapy. Price of 2.5mg tablets is currently not known. Tariff: HRG included. 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, MI or stroke, was reduced in patients on rivaroxaban 2.5mg or 5mg twice daily vs. placebo (8.9% vs.10.7%, p=0.008, NNT=55). 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 medicines.org.uk. Rate of major bleeding unrelated to surgery was increased with rivaroxaban vs. placebo in the above trial (2.1% vs. 0.6%, p<0.001), but risk of fatal bleeding was similar. Guidance/ Guidance: NICE: Acute coronary syndromes. Rivaroxaban due March 2015. SIGN: Heart disease, reviews: Antithrombotics. Reviews: RDTC September 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 12 No responsibility is accepted for the content of documents derived from this original publication.

Rivaroxaban oral [Xarelto]; Janssen-Cilag Pharmacology: Direct factor Xa inhibitor. Indication: Heart failure and coronary artery disease. Current status: PIII UK availability: 2017 (licence extension). Sector: Initiated in secondary care and continued in primary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Heart failure. SIGN: Heart disease. reviews: Reviews: None.

Andexanet alfa injection; Portola Pharmaceuticals Pharmacology: Factor Xa inhibitor antidote, first-in-class.

Indication: Anticoagulation reversal. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Likely HRG included. Guidance/ Guidance: None. reviews: Reviews: None.

Clevidipine injection [Cleviprex]; The Medicines Company Pharmacology: Ultra short-acting dihydropyridine calcium channel antagonist, given by i.v. infusion. Indication: Hypertension, perioperative. Current status: Licensed in UK November 2011 – see prescribing data. Launched in the US. UK availability: 2014 Population: At least 25% of patients undergoing noncardiac surgery have hypertension prior to their surgical procedure. Sector: Secondary care. Implications: Clevidipine is one of only two drugs (the other being esmolol) specifically licensed for the management of perioperative hypertension. Other unlicensed options include glyceryltrinitrate, nicardipine and sodium nitroprusside. Clevidipine may be of use in situations where stringent blood pressure control is required. Financial: Likely to be more expensive than available generic but unlicensed options. Tariff: Likely HRG included. Efficacy: Published results from 3 open-label PIII studies (ECLIPSE 1, 2 & 3), in 1,512 patients undergoing cardiac surgery suggest there was no difference in primary outcome events (death, MI, stroke or renal dysfunction at 30 days) between the clevidipine and the pooled comparator group (glyceryl trinitrate, sodium nitroprusside or nicardipine). Cevidipine was more effective than glyceryl trinitrate (p=0.0006) or sodium nitroprusside (p=0.003) in maintaining blood pressure within the prespecified range (secondary outcome). Safety: See medicines.org.uk. Guidance/ Guidance: NICE: Hypertension. SIGN: Postoperative management. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 13 No responsibility is accepted for the content of documents derived from this original publication.

Ticagrelor oral [Brilique]; AstraZeneca Pharmacology: Antiplatelet. P2Y12 adenosine diphosphate receptor antagonist. Indication: Acute coronary syndrome, myocardial infarction, secondary prevention. Current status: PIII UK availability: 2016 (licence extension). Sector: Initiated in secondary care and continued in primary care. Tariff: HRG included. Guidance/ Guidance: NICE: Acute coronary syndromes. SIGN: Antithrombotics. reviews: Reviews: NIHR HSC August 2013.

Ticagrelor oral [Brilique]; AstraZeneca Pharmacology: Antiplatelet. P2Y12 adenosine diphosphate receptor antagonist Indication: Stroke or transient ischaemic attack (TIA), secondary prevention. Current status: PIII UK availability: 2017 (licence extension). Sector: Initiated in secondary care and continued in primary care. Tariff: HRG included. Guidance/ Guidance: NICE: Stroke and TIA. SIGN: Stroke and TIA. reviews: Reviews: None.

Vorapaxar oral [Zontivity]; MSD Pharmacology: Antiplatelet, thrombin receptor (PAR-1) antagonist, first-in-class. Indication: Reduction of atherothrombotic events in patients with a history of MI and no history of transient ischaemic attack or stroke. Current status: Filed in EU January 2014. Launched in US – see US prescribing data. UK availability: 2015 Population: In the UK, around 1.5 million people have had an MI (about 2,380 per 100,000) and the annual incidence is about 155 per 100,000. Sector: Initiated in secondary care and continued in primary care. Implications: Likely to be added to existing therapies but the associated bleeding risk could make it difficult to establish a place in therapy. Financial: Likely to be considerably more expensive than current options. Tariff: Likely HRG included. Efficacy: In a published PIII study 26,449 patients with prior MI, stroke or peripheral artery disease received 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 (p<0.001, NNT=83). 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 (p<0.001, NNT=63). Safety: In the main study moderate to severe bleeding occurred in 4.2% vs. 2.5% (p<0.001) and intracranial haemorrhage in 1.0% vs. 0.5% (p<0.001) of patients in the vorapaxar and placebo groups, respectively. In the MI subgroup, 3 year estimates for moderate to severe bleeding were 3.4% vs. 2.1% (p<0.001). Guidance/ Guidance: NICE: Peripheral circulatory conditions. SIGN: Prevention of CV disease, Peripheral arterial reviews: disease. Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 14 No responsibility is accepted for the content of documents derived from this original publication.

Cangrelor injection; The Medicines Company Pharmacology: P2Y12 antagonist with a short half-life, given by i.v. infusion. Platelet function is restored in <60 minutes. Indication: Reduction of thrombotic events in percutaneous coronary intervention (PCI). Current status: Filed in EU December 2013. Not recommended for approval in US May 2014. UK availability: 2015 Population: 92,455 PCI procedures were carried out in the UK in 2012. Sector: Secondary care. Implications: For patients undergoing PCI, cangrelor may be suitable 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. Tariff: Likely HRG included. Efficacy: A published 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 revascularisation (7.3% vs. 7.5%). A published PIII trial (n=11,145) compared cangrelor and a loading dose of 300mg or 600mg clopidogrel. The primary outcome (composite of death, MI, revascularisation or stent thrombosis) occurred in 4.7% vs. 5.9%, respectively (p=0.005, NNT=83). Safety: There was no difference between groups in rates of severe bleeding. Guidance/ Guidance: NICE: Acute coronary syndromes. SIGN: Antithrombotics. reviews: Reviews: NIHR HSC November 2012.

Sacubitril/ valsartan oral; Novartis Pharmacology: Neprilysin inhibitor with an angiotensin receptor antagonist, first-in-class. Indication: Chronic heart failure. Current status: PIII UK availability: 2016 Sector: Initiated in secondary care and continued in primary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Heart failure. SIGN: Heart disease. reviews: Reviews: NIHR HSC July 2013.

Propranolol oral [Hemangiol]; Pierre Fabre Pharmacology: Beta blocker. Indication: Infantile haemangioma (IH), proliferating, requiring systemic therapy. Current status: Licensed in EU May 2014. UK availability: 2014 Population: Around 3-5% of infants may be affected by IH and about 10% of these may require treatment (about 6 per 100,000 people/ year). However, there are no reliable recent data for IH. Older data may overestimate incidence due differences in vascular birthmark stratification. Sector: Secondary care. Implications: This will be the first drug licensed for this indication which may lead to more infants being treated. Financial: Likely to cost considerably more than unlicensed alternatives such as corticosteroids. Tariff: Likely HRG included. Efficacy: A published PII trial compared propranolol (2mg/kg/day) with placebo in 40 children aged between 9 weeks and 5 years with IH. At week 24 the reduction in IH volume was 60% vs. 14%, respectively (p=0.01). A PII/III study (n=456) compared four regimens (1 or 3mg/kg/day for 3 or 6 months) to placebo. The primary outcome of complete or nearly complete resolution of IH at week 24 was 60.4% for propranolol 3mg/kg/day for 6 months vs. 3.6% for placebo (p<0.0001, NNT=2). A systematic review of uncontrolled trials found a response rate of over 90%. Safety: See medicines.org.uk. Cardiac monitoring may be required. Guidance/ Guidance: None. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 15 No responsibility is accepted for the content of documents derived from this original publication.

Evolocumab injection; Amgen Pharmacology: Monoclonal antibody, PCSK9 inhibitor given as a s.c. injection. Indication: Hyperlipidaemia, including mixed dyslipidaemia, as monotherapy or with a statin. Current status: PIII UK availability: 2015 Population: The UK population has one of the highest average serum cholesterol levels in the world, with two thirds having a serum cholesterol level greater than 5.2mmol/L. Sector: Secondary care. Implications: Evolocumab will be an additional treatment option as a monotherapy or in combination with a statin or other lipid lowering therapies in patients who are statin intolerant or unable to tolerate an effective dose of a statin, although s.c. administration may limit its use. Likely to be used in high risk individuals who have limited treatment options. Financial: Likely to be significantly more costly than oral lipid lowering options and costs are likely to be additive to current treatment. Tariff: Likely specified high cost drug. Efficacy: In the published LAPLACE-2 study, 2,067 patients were randomised to one of 24 groups to compare evolocumab with placebo or ezetimibe when added to different doses of statin therapies. At weeks 10 and 12, the evolocumab (140mg every 2 weeks, or 420mg monthly) groups achieved a mean reduction in LDL-C from baseline of 66-75% and 63-75%, vs. placebo, and a reduction of 38-45% and 44%, vs. ezetimibe, respectively (p<0.001). In a published 52-week trial in 901 patients with a range of cardiovascular risks, evolocumab added to diet alone, low- or high-dose atorvastatin with or without ezetimibe, reduced mean LDL-C by 57% vs. placebo (p<0.001).

Safety: No safety concerns have been reported to date, with the frequency of adverse events comparable to control. Guidance/ Guidance: NICE: Lipid disorders. reviews: Reviews: NIHR HSC March 2013.

Alirocumab injection; Sanofi Pharmacology: Monoclonal antibody, PCSK9 inhibitor, given as a s.c. injection. Indication: Hypercholesterolaemia, familial and non-familial, third-line. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Lipid disorders. reviews: Reviews: NIHR HSC November 2012. Likely NHSE commissioned

Mydicar injection; Celladon Pharmacology: A first-in-class genetically targeted enzyme replacement therapy intended to restore levels of SERCA2a, a regulator of calcium cycling and contractility, given by intracoronary injection. Indication: Heart failure, chronic, advanced. Current status: PII UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Heart failure. SIGN: Heart disease. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 16 No responsibility is accepted for the content of documents derived from this original publication.

BNF 3. Respiratory system Likely CCG commissioned

Tiotropium bromide inhalation [Spiriva]; Boehringer Ingelheim Pharmacology: Long-acting muscarinic receptor antagonist (LAMA). Indication: Asthma, in addition to at least an inhaled corticosteroid, in adults. Current status: Filed in EU November 2013. UK availability: 2014 (licence extension). Population: There are about 5.2 million people with asthma in the UK, 1 in 10 children and 1 in 12 adults. Sector: Primary care. Implications: Current treatment options in asthma are short- and long-acting beta agonists (LABA) and inhaled corticosteroids. Tiotropium will be the first LAMA licensed for asthma and its place in therapy will need to be determined. Financial: Based on current prices, the tiotropium Respimat inhaler costs about £34 per month. Tariff: HRG included. Efficacy: In two identical published PIII studies, 912 adults received tiotropium 5mcg (Respimat inhaler) or placebo for 48 weeks as add-on therapy to high-dose inhaled corticosteroid and LABA. At 24 weeks, the primary outcome of mean change in forced expiratory volume in 1 second (FEV1) was greater with tiotropium than with placebo in the two trials: a difference of 86±34mL in trial 1 (p=0.01) and 154±32mL in trial 2 (p<0.001). The additional primary outcome of predose (trough) FEV1 also improved in both trials with tiotropium: difference of 88±31mL (p=0.01) and 111±30mL (p<0.001). For another primary outcome tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with a 21% reduction in the risk of a severe exacerbation (hazard ratio, 0.79, p=0.03). Secondary outcomes included proportion with at least one severe exacerbation (26.9% vs. 32.8%, NNT=17), total number of severe exacerbations per-patient year (0.53 vs. 0.66, p=0.046) and proportion of patients with at least one hospitalisation for asthma (3.5% vs. 4.4%, NNT=111). Safety: See medicines.org.uk. Guidance/ Guidance: NICE: Asthma. SIGN: Asthma January 2012. BTS: Asthma January 2012 (update due 2014). reviews: Reviews: None.

Tiotropium bromide inhalation [Spiriva]; Boehringer Ingelheim Pharmacology: Long-acting muscarinic receptor antagonist (LAMA). Indication: Asthma, persistent, moderate-to-severe, in children aged 6-11 years. Current status: PIII UK availability: 2016 (licence extension). Sector: Primary and secondary care. Tariff: HRG included Guidance/ Guidance: NICE: Asthma. SIGN: Asthma January 2012. BTS: Asthma January 2012 (update due 2014). reviews: Reviews: None.

Budesonide/ formoterol inhalation [Bufomix Easyhaler]; Orion Pharmacology: Inhaled corticosteroid and long-acting beta agonist (LABA). Indication: Asthma and chronic obstructive pulmonary disease. Current status: Filed in EU March 2013. UK availability: Uncertain. Sector: Primary care. Tariff: HRG included. Guidance/ Guidance: NICE: Asthma. SIGN: Asthma January 2012. BTS: Asthma January 2012 (update due 2014). reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 17 No responsibility is accepted for the content of documents derived from this original publication.

Umeclidinium inhaler [Incruse]; GlaxoSmithKline Pharmacology: Long-acting muscarinic antagonist (LAMA). Indication: Chronic obstructive pulmonary disease (COPD). Current status: Licensed in EU April 2014. UK availability: 2014 Population: About 900,000 people in the UK have diagnosed COPD, and an estimated 2 million people have COPD that remains undiagnosed. Sector: Primary care. Implications: Umeclidinium will compete with aclidinium, glycopyrronium and tiotropium. Financial: It is likely to be competitively priced with available options which cost about £27-£35 per month. Tariff: HRG included. Efficacy: In a published PIII study 1,191 patients with moderate-to-severe COPD received umeclidinium (UMEC) plus vilanterol (VI), UMEC 125mcg monotherapy or tiotropium monotherapy. UMEC was as effective as UMEC/VI for the primary outcome of trough FEV1 on day 169, difference 22-37ml (p=ns). In a 6 month PIII study (n=1,532), the difference between UMEC 62.5mcg and placebo in the primary outcome of change from baseline in FEV1 at week 24 was 115ml (p<0.001) and difference for UMEC and UMEC/VI was 52ml (p=0.004). In another PIII study (n=246), UMEC improved the mean change from baseline in trough FEV1 on day 85 by 27-152ml vs. placebo (p<0.001). Safety: Frequently reported adverse reactions include nasopharyngitis and upper respiratory tract infection. Guidance/ Guidance: NICE: COPD. reviews: Reviews: None.

Indacaterol/ glycopyrronium inhaler [Ultibro Breezhaler]; Novartis Pharmacology: Fixed-dose combination of a long-acting beta agonist (LABA, indacaterol 85microgram) plus long-acting muscarinic antagonist (LAMA, glycopyrronium 43microgram). Indication: Chronic obstructive pulmonary disease (COPD). Current status: Licensed in EU September 2013 - see prescribing data. UK availability: 2014 Population: As for umeclidinium. Sector: Primary care. Implications: A LABA/LAMA combination is recommended in patients with stable COPD who remain breathless or have exacerbations despite maintenance therapy with a LABA and in whom an inhaled corticosteroid is not suitable or in combination with an ICS and a LABA. Ultibro will be one of the first products with both a LABA and LAMA in one inhaler. Financial: It is likely to be competitively priced to other options. The current monthly cost of the separate indacaterol and glycopyrronium inhalers is about £30 and £28, respectively. Tariff: HRG included. Efficacy: In the PIII SPARK study (n=2,224) indacaterol and glycopyrronium (IND/GLY) reduced the annualised rate of moderate to severe exacerbations vs. GLY by 12% (0.84 vs. 0.95, p=0.038). In the PIII SHINE study 2,144 patients received IND/GLY, IND, GLY, tiotropium or placebo for 26 weeks. The primary outcome of difference in trough FEV1 at week 26 was 0.07L for IND/GLY vs. indacaterol, 0.09L vs. GLY, 0.08L vs. tiotropium and 0.20L vs. placebo (p<0.001 for all comparisons). Safety: See medicines.org.uk for separate indacaterol and glycopyrronium inhalers. Guidance/ Guidance: NICE: COPD. AWMSG: Recommended May 2014. Global Strategy January 2014. reviews: Reviews: LMEN March 2014, NICE-ES February 2014.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 18 No responsibility is accepted for the content of documents derived from this original publication.

House dust mite allergen immunotherapy sublingual [Mitizax]; ALK-Abello/ Abbott Pharmacology: A sublingual tablet containing a 1:1 mixture of allergen extracts. Indication: Allergic rhinitis, allergic asthma and rhinoconjunctivitis. Current status: PIII UK availability: 2015 Population: Allergic rhinitis affects over 20% of the UK population (over 12 million people), with 56% presenting for routine care having moderate or severe disease and 52% with persistent disease. Allergies to house dust mite and pets are common; about 1 in 2 adults with asthma have an allergic component to their disease. Sector: Secondary care. Implications: House dust mite allergen immunotherapy (HDM AIT) would be used third-line in selected patients in whom rigorous allergen avoidance and standard pharmacotherapy fail to control symptoms. Financial: This will be a further treatment option and additional to current costs. Sublingual therapy may be an attractive alternative to s.c. immunotherapy, although treatment duration may be longer. Tariff: Likely HRG included. Efficacy: In the 12-month PIII MERIT study (n=922) the median combined rhinitis symptom and medication score was reduced by 22% for HDM AIT 12 DU dose vs. placebo (p<0.01). The PIII MITRA study in 834 patients with allergic asthma, those who received the 12 DU dose showed a 34% reduction in risk of suffering a moderate-to-severe exacerbation during withdrawal of inhaled corticosteroids (p<0.05). Safety: HDM AIT was well tolerated in the MERIT and MITRA studies. Guidance/ Guidance: NICE: Asthma. SIGN: Asthma January 2012. BTS: Asthma January 2012 (update due 2014). reviews: Reviews: NIHR HSC December 2013.

Interferon beta 1a, lyophilized injection [Traumakine]; Faron Pharmacology: Upregulates CD73 increasing adenosine levels to reduce lung capillary leakage, given by i.v. injection. Indication: Acute respiratory distress syndrome. Current status: PIII in EU with orphan status. UK availability: 2017 Sector: Secondary care. Tariff: Specialised high cost drug. Guidance/ Guidance: None. reviews: Reviews: NIHR HSC June 2014. Likely NHSE commissioned

Masitinib oral; AB Science Pharmacology: Tyrosine kinase inhibitor. Indication: Severe, persistent, corticosteroid-dependent asthma. Current status: PIII UK availability: 2016 Population: As for tiotropium. The prevalence of severe, persistent asthma is around 47 per 100,000 people. Sector: Secondary care. Implications: This will be a novel oral additional treatment option for patients with severe, uncontrolled asthma. Financial: This will be an additional cost to current asthma treatments. Tariff: Specified high cost drug. Efficacy: In a published PII study (n=44), the primary outcome of median change in oral corticosteroid dose at 16 weeks was 12.3mg with masitinib vs. 10mg with placebo, a reduction in dose of -78% vs. -57% (p=ns). The percentage weaned from oral corticosteroids was 35.7% vs. 27.3% (p=ns). A PIII study is ongoing. Safety: The most frequent adverse events were gastrointestinal, rash, peripheral oedema, fatigue and pruritus. Guidance/ Guidance: NICE Asthma. SIGN: Asthma January 2012. BTS: Asthma January 2012 (update due 2014). reviews: Reviews: NIHR HSC September 2012.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 19 No responsibility is accepted for the content of documents derived from this original publication.

Benralizumab injection; AstraZeneca Pharmacology: Fully humanised interleukin-5 receptor (IL-5R) alpha chain monoclonal antibody, which directly depletes eosinophils and neutralises IL-5. Indication: Asthma, in combination with a high-dose inhaled corticosteroid plus a long-acting beta agonist. Current status: PIII UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE Asthma. SIGN: Asthma January 2012. BTS: Asthma January 2012 (update due 2014). reviews: Reviews: None.

Mepolizumab injection [Bosatria]; GlaxoSmithKline Pharmacology: Fully humanised IgG monoclonal antibody specific for interleukin 5 (IL-5), given by s.c. injection. Indication: Churg-Strauss syndrome (eosinophilic granulomatosis with polyangitis). Current status: PIII UK availability: 2017 Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ Guidance: None. reviews: Reviews: None.

Ataluren oral [Translarna]; PTC Therapeutics Pharmacology: Cystic fibrosis transmembrane conductance regulator (CFTR) stimulant which suppresses nonsense mutations, first-in-class. Indication: Cystic fibrosis (CF), nonsense-mutation. Current status: PIII with orphan status in EU and US. UK availability: 2015 Population: CF is the most common life-limiting, autosomal recessively inherited disease in white populations, with a carrier frequency of 1 in 25 and an incidence of 1 in 2,500 live births. Over 9,000 people are affected in the UK. About 10% have CF due to a Class I nonsense mutation in at least one allele of the CFTR gene. Sector: Secondary care. Implications: Ataluren is the first drug for nonsense-mutation CF. Financial: As a further treatment this will be additional to current costs. Tariff: Specified high cost drug. Efficacy: In a published 48-week PIII study (n=238), relative change in the primary outcome of percent-predicted FEV1 from baseline was -2.5% for ataluren vs. -5.5% for placebo (p=ns). However, post-hoc analysis of patients not using chronic inhaled tobramycin did show a significant change of -0.7% vs. -6.4%, respectively (p=0.0082). Safety: Increased creatinine concentration occurred in 15% of those on ataluren vs. <1% on placebo. Guidance/ Guidance: None. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 20 No responsibility is accepted for the content of documents derived from this original publication.

Lumacaftor + ivacaftor oral; Vertex Pharmacology: Cystic fibrosis transmembrane conductance regulator (CFTR) corrector (lumacaftor) and CTFR potentiator (ivacaftor). Indication: Cystic fibrosis (CF), in patients who are homozygous for the F508del-CFTR mutation. Current status: PIII, individual drugs have orphan drug status. UK availability: 2015 (licence extension). Population: CF affects 1 in every 2,500 newborn, with over 9,000 people affected in the UK. The most common mutation is the F508del-mutation which is present on around 67% of CF chromosomes worldwide. Around 8,500 (97%) patients on the CF registry have been genotyped of whom 4,371 (51.7%) are homozygous for the F508del-CFTR mutation. Sector: Secondary care. Implications: This will be the first combination treatment that specifically targets the F508del-CFTR mutation. Financial: This is a further treatment option that will be additional to current costs. Tariff: Likely specified high cost drug. Efficacy: In the identical PIII studies TRAFFIC (n=549) and TRANSPORT (n=559), patients received lumacaftor 600mg daily or 400mg every 12 hours, plus ivacaftor 250mg twice a day, or placebo, for 24 weeks. The mean absolute improvements from baseline compared to placebo in percent predicted FEV1) at week 24 were 2.6-4.0% (p≤0.0004) and mean relative changes were 4.3-6.7% (p≤0.0007). In a pooled analysis, there was a reduction in the number of pulmonary exacerbations of 30-39% (p≤0.0014) for the combination treatment vs. placebo. Safety: The most frequently reported adverse events included infective pulmonary exacerbation, cough, headache and increased sputum. Guidance/ Guidance: NHSE: Clinical commissioning policy March 2013. reviews: Reviews: NIHR HSC February 2014.

Lurasidone oral [Latuda]; Sunovion Pharmacology: Dopamine D2 receptor & serotonin 5HT2A/7 receptor antagonist. Indication: Bipolar depression. Current status: PIII in EU. Launched in US - see prescribing data. UK availability: 2016 (licence extension). Sector: Initiated in secondary care. Tariff: HRG included. Guidance/ Guidance: NICE: Bipolar disorder. SIGN: Bipolar affective disorder. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 21 No responsibility is accepted for the content of documents derived from this original publication.

Melatonin oral [Circadin]; Flynn Pharma Pharmacology: Pineal hormone which acts on MT1 and MT2 receptors involved in circadian rhythm and sleep regulation. Indication: Sleep disorders in children. Current status: PIII

UK availability: 2016 (licence extension). Sector: Secondary care initiated, continued in primary care. Tariff: HRG included. Guidance/ Guidance: NICE: Children and young people. reviews: Reviews: NICE-ES (in children with ADHD) January 2013.

Lisdexamfetamine oral [Elvanse]; Shire Pharmacology: Prodrug of dexamfetamine which acts as a noradrenaline and dopamine reuptake inhibitor. Indication: Attention deficit hyperactivity disorder (ADHD) in adults, newly diagnosed. Current status: Filed in EU March 2014. UK availability: 2015 (licence extension). Licensed (for adults) in US - see prescribing data. Population: Population surveys estimate prevalence of ADHD in adults is 3-4%. Sector: Secondary care initiated, continued in primary care. Implications: A once daily alternative for adults with ADHD after methylphenidate. Financial: Current monthly cost ranges for lisdexamfetamine are £58-£83 and for methylphenidate £5- £51. Tariff: HRG included. Efficacy: In a published PIII study (n=420), the change in ADHD Rating Scale (RS) score at 4 weeks (primary outcome) was -16.2, -17.4 and -18.6 for lisdexamfetamine 30mg, 50mg and 70mg, respectively, vs. placebo (-8.2) (all p<0.0001). Treatment was continued in an open-label single-arm study (n=349) for 12 months. Mean improvement in ADHD-RS score from baseline was 24.8 (p<0.001). In another PIII study (n=116), after receiving treatment for at least 6 months, patients entered a 6-week withdrawal phase on lisdexamfetamine or placebo. The symptom relapse occurred in, 8.9% vs. 75%, respectively (p<0.001). Safety: See medicines.org.uk for Elvanse for children. Guidance/ Guidance: None for adults. reviews: Reviews: None.

Guanfacine oral [Intuniv]; Shire Pharmacology: Selective alpha 2 adrenoreceptor agonist, first-in-class. Indication: Attention deficit hyperactivity disorder (ADHD) in children aged 6 years and over. Current status: Filed in EU March 2014. Launched in US– see prescribing data. UK availability: 2015 Population: The prevalence of ADHD is estimated to be around 2.4% of children in the UK. Sector: Secondary care initiated, continued in primary care. Implications: An additional treatment option for children with ADHD not controlled by other options. Financial: As a further treatment option it will be additional to current costs. Tariff: Likely HRG included. Efficacy: In a PIII study (n=345), least squares mean reduction in ADHD-RS IV for guanfacine monotherapy (2- 4mg daily) at 5 weeks was 16.7 vs. 8.9 for placebo (p<0.001). In a similar PIII study (n=324), mean reduction at 6 weeks was 19.6 for guanfacine (1 to 4mg daily) vs. 12.2 placebo (p<0.02). In a third study (n=333), mean reduction at week 8 was 20.0 vs. placebo 11.0 (p<0.001). Another PIII study (n=461) compared the mean change in ADHD RS-IV at week 8 in patients taking their usual psychostimulant with guanfacine or with placebo. Results were -4.5 (p<0.01), -5.3 (p<0.001), respectively. Safety: Adverse effects include somnolence, fatigue, nausea and hypotension. Postmarketing, hallucinations have recently been added to US prescribing data. Guidance/ Guidance: NICE: Attention deficit disorder. SIGN: Attention deficit and hyperkinetic disorders. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 22 No responsibility is accepted for the content of documents derived from this original publication.

Liraglutide injection; Novo Nordisk Pharmacology: Glucagon-like peptide analogue, given by daily s.c. injection. Indication: Obesity, as an adjunct to diet and exercise. Current status: Filed in EU December 2013. UK availability: 2014 (licence extension but may be available as a different brand). Population: In 2011 in England, 24% of men and 26% of women (>16 years) were classed obese (BMI ≥30kg/m2) and 41% of men and 33% of women were overweight (BMI 25 to <30kg/m2). Sector: Secondary care initiated, continued in primary care. Implications: Liraglutide is in the same class as exenatide, which, although causes weight loss, is not specifically licensed for obesity. The liraglutide dose for obesity is much higher than for diabetes and competitors will be oral antiobesity drugs. It is likely liraglutide injection will be preferentially used in overweight patients with diabetes. Financial: Based on a 3mg daily dose current monthly cost of liraglutide is about £183 vs. £32 for orlistat 120mg 3 times a day. To be competitive the pricing structure for liraglutide for obesity is likely to differ from that for diabetes. Tariff: HRG included. Efficacy: The published PIII SCALE Maintenance study (n=422) compared liraglutide 3mg with placebo over 56 weeks following a 12-week low-calorie dietary run-in. Mean change 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, NNT=4). Significant weight loss with liraglutide has also been reported in two other 56-week PIII studies, SCALE Obesity and Pre-diabetes (n=3,733, 8.0% vs. 2.6% with placebo, p<0.001) and SCALE Diabetes (n=846, 5.9% vs. 2.0% with placebo, p<0.001). In a 20- week published PII study (n=564), mean weight loss with liraglutide (1.2, 1.8, 2.4 or 3mg) ranged from 4.8 to 7.2kg vs. 2.8kg with placebo and 4.1kg with orlistat 360mg/day (p=0.003 for liraglutide 2.4 mg vs. orlistat and p<0.001 for liraglutide 3 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. Guidance/ Guidance: NICE: Obesity. SIGN: Obesity. reviews: Reviews: NIHR HSC October 2013.

Naltrexone/ bupropion oral [Contrave]; Orexigen Pharmacology: Fixed-dose combination of an opioid receptor antagonist (naltrexone 32mg) and dopamine/noradrenaline reuptake inhibitor (bupropion 360mg). Indication: Obesity, in combination with lifestyle modification. Current status: Filed in EU October 2013. UK availability: 2014 Population: As for liraglutide. Sector: Secondary care initiated, continued in primary care. Implications: An additional treatment option before weight-loss surgery in patients who have tried weight management programmes and existing pharmacological therapy. Financial: As a further treatment option it will be additional to current costs. Tariff: HRG included. Efficacy: In published PIII studies of naltrexone/bupropion, COR-I (n=1,742), COR-II (n=1,496) and COR-Diabetes (n=505) the co-primary outcomes were change in body weight and ≥5% weight loss. At week 56 across the 3 studies, Contrave was associated with a reduction in body weight of between 5- 6.5% vs. a reduction of 1.3-1.9% with placebo (p<0.001). The proportion who achieved a ≥5% weight loss was 44.5- 55.6% vs. 16.4-19.8%, respectively, (p<0.001). In another published PIII study COR-BMOD (n=793), change in body weight was 9.3% vs. placebo 5.1% (p<0.001) and ≥5% weight loss of 66.4% vs. 42.5% placebo (p<0.001) at 56 weeks. Safety: Naltrexone 50mg is licensed for opioid and alcohol dependence. Bupropion 150mg is licensed for smoking cessation. See medicines.org.uk. Guidance/ Guidance: NICE: Obesity. SIGN: Obesity. reviews: Reviews: NIHR HSC December 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 23 No responsibility is accepted for the content of documents derived from this original publication.

Safinamide oral; Newron Pharmacology: Alpha-aminoamide, MAO-B inhibitor (selective and reversible)/ sodium and calcium channel antagonist/ dopamine uptake inhibitor/ glutamate release inhibitor, first-in-class. Indication: Parkinson’s disease (PD) early stage, adjunct to dopamine agonist therapy. Current status: Filed in EU December 2013. UK availability: 2015 Population: 200 per 100,000 people have PD, most are aged 50 or over, although 1 in 20 is under the age of 40. Sector: Secondary care initiated, continued in primary care. Implications: As first in a new class this could be attractive for patients poorly controlled on standard therapy. Financial: As a further treatment option it will be additional to current costs. Tariff: Likely HRG included. Efficacy: In a PIII study (n=269), at week 24, the difference in the primary outcome of improved motor symptoms (Unified Parkinson's Disease Rating Scale - UPDRSIII) was -0.4 and -1.9 for safinamide 200mg and 100mg vs. placebo (p=ns, p=0.042, respectively). In a 12 month extension study (n=227) data from safinamide groups were pooled. The primary outcome of time to further intervention showed no difference between groups. In the PIII MOTION study (n=679), significant improvement in UPDRSIII was seen in the safinamide 100mg group. Safety: In PIII studies transient dyskinesia occurred more frequently with safinamide. Guidance/ Guidance: NICE: PD. SIGN: PD. reviews: Reviews: None recent.

Safinamide oral; Newron Pharmacology: Alpha-aminoamide, MAO-B inhibitor (selective and reversible)/ sodium and calcium channel antagonist/ dopamine uptake inhibitor/ glutamate release inhibitor, first-in-class. Indication: Parkinson’s disease (PD), mid-late stage, adjunct therapy. Current status: Filed in EU December 2013. UK availability: 2015 Population: As for safinamide above. Sector: Secondary care initiated, continued in primary care. Implications: As first in a new class this could be attractive for patients poorly controlled on standard therapy. Financial: As a further treatment option it will be additional to current costs. Tariff: Likely HRG included. Efficacy: In the PIII, 24 week SETTLE study (n=549) safinamide 50-100mg daily improved the primary outcome of change in ‘ON’ time by 0.96 hours/day vs. placebo (p<0.01) in patients on stabilised on standard therapy. In another PIII study (n=699) safinamide 50 and 100mg, increased mean ON time by 1.3 hours/day vs. 0.7 hours/day for placebo (p=0.008 and p=0.005, respectively). A published extension study (n=544) did not meet its primary outcome of the mean change in the Dyskinesia Rating Scale scores at 24 months. Safety: As for safinamide above. Guidance/ Guidance: NICE: PD. SIGN: PD. reviews: Reviews: None recent.

Leuco-thiomethoninium oral; TauRx Therapeutics Pharmacology: Tau protein aggregation inhibitor, first-in-class. Indication: Alzheimer’s disease, mild and moderate. Current status: PIII UK availability: 2017 Sector: Secondary care initiated, continued in primary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Dementia. SIGN: Dementia. reviews: Reviews: NIHR HSC August 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 24 No responsibility is accepted for the content of documents derived from this original publication.

Leuco-thiomethoninium oral; TauRx Therapeutics Pharmacology: Tau protein aggregation inhibitor, first-in-class. Indication: Dementia, behavioural variant frontotemporal. Current status: PIII with orphan status. UK availability: 2017 Sector: Secondary care initiated, continued in primary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Dementia. SIGN: Dementia. reviews: Reviews: NIHR HSC October 2013.

Scyllo-inositol oral; Perrigo Pharmacology: Amyloid beta-protein inhibitor, first-in-class. Indication: Alzheimer’s disease, mild to moderate. Current status: PII, accelerated status in the US. UK availability: 2017 Sector: Secondary care initiated, continued in primary care. Tariff: Likely HRG included. Guidance/ NICE: Dementia. SIGN: Dementia. reviews: Reviews: None.

Lu AE58054 oral; Lundbeck Pharmacology: Selective 5HT6 antagonist, first-in-class. Indication: Alzheimer’s disease, mild to moderate, adjunct to donepezil. Current status: PIII UK availability: 2017 Sector: Secondary care initiated, continued in primary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Dementia. SIGN: Dementia. reviews Reviews: None.

Nabiximols oromucosal [Sativex]; Bayer Pharmacology: Cannabinoid receptor agonist. Indication: Cancer pain. Current status: PIII in EU and US with accelerated status in US. Launched in Canada. UK availability: 2016 (licence extension). Sector: Specialised services in primary or secondary care. Tariff: HRG included. Guidance/ Guidance: NICE: Cancer. SIGN: Cancer pain. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 25 No responsibility is accepted for the content of documents derived from this original publication.

Dextromethorphan/ quinidine oral [Nuedexta]; Jenson Pharmacology: Dextromethorphan is a sigma-1 receptor agonist and NMDA antagonist. Quinidine, a CYP2D6 inhibitor, increases plasma levels of dextromethorphan. Indication: Pseudobulbar affect (PBA). Current status: Licensed in EU June 2013 – see prescribing data. UK availability: 2014 Population: PBA can develop in several neurological diseases or following brain injury. The estimated prevalence is up to 500 per 100,000 people, of whom about 14 per 100,000 will have amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). Sector: Secondary or tertiary care. Implications: First drug licensed for this indication. Confirmation of diagnosis is required before treatment as use in other emotional lability conditions would be off-label. This may increase referrals to specialist neurosciences. Although the indication is for treatment of PBA due to any cause, efficacy has only been studied in those with ALS or MS. Financial: Likely to be considerably more expensive than unlicensed alternatives (SSRIs, TCAs, levodopa, amantadine and thyrotropin-releasing hormone). Tariff: Likely HRG included. 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 patients with ALS and MS 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 reported to date, but patients with cardiovascular disorders were excluded from studies. Guidance/ Guidance: NICE: None. reviews: Reviews: None. BNF 5. Infections Likely CCG commissioned

Dalbavancin injection [Dalvance]; Durata Pharmacology: Second-generation glycopeptide antibiotic, two doses given by i.v. infusion once weekly. Indication: Complicated skin and skin structure infections (cSSSI), caused by gram-positive microorganisms. Current status: Filed in EU December 2013. Licensed in US - see prescribing data. UK availability: 2015 Population: In England in 2012-13, there were 4,791 hospital admissions due to local infections of skin and subcutaneous tissue. Staphylococcus aureus is the commonest cause of SSSI. Sector: Secondary care. Implications: An alternative, in patients with severe methicillin-resistant S. aureus (MRSA)-associated SSSI, to antibiotics given daily such as i.v. ceftaroline, daptomycin, teicoplanin and vancomycin (which requires monitoring of blood levels and renal function), and oral linezolid (which requires weekly full blood counts and has significant drug interactions). Dalbavancin could reduce length of hospital stay and/or facilitate administration at home. Financial: Drug cost of alternative i.v. antibiotics vary considerably but dalbavancin has the advantage of reduced administration costs. Tariff: Likely HRG included. Efficacy: In a published pooled analysis of the DISCOVER 1 and 2 studies (n=1,312) two doses of dalbavancin were non-inferior to vancomycin (given for 3 days with the option of switching to oral linezolid for a total of 10-14 days). 79.7% in the dalbavancin group and 79.8% in the vancomycin-linezolid group had an early clinical response at 48 to 72 hours. Outcomes were similar at the end of therapy. In a PIII study (n=220), dalbavancin was non-inferior to a 14-day course of linezolid i.v./oral at 48-96 hours, and at 28 days. Safety: Most common adverse effects are nausea, headache and diarrhoea, but occur less often than with vancomycin. Rapid infusion can cause red-man syndrome. Guidance/ Guidance: NICE: Antibiotic use, Healthcare-associated infections. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 26 No responsibility is accepted for the content of documents derived from this original publication.

Oritavancin injection [Nuvocid]; The Medicines Company Pharmacology: Second-generation glycopeptide antibiotic, single dose given by i.v. infusion over 2-3 hours. Indication: Complicated skin and skin structure infections (cSSSI), caused by gram-positive microorganisms. Current status: Filed in EU and US February 2014. Has fast track and priority review status in the US. UK availability: 2015 Population: As for dalbavancin. Sector: Secondary care. Implications: As for dalbavancin. Oritavancin could reduce length of hospital stay and may avoid need for initial hospitalisation. Financial: As for dalbavancin. Tariff: Likely HRG included. Efficacy: In the published PIII SOLO I trial (n=475), oritavancin was non-inferior to a 7-10 day course of vancomycin for 3 outcomes: clinical response at 48-72 hours occurred in 82.3% vs. 78.9%, respectively, investigator-assessed clinical cure, 79.6% vs. 80.0%, respectively, and proportion of patients with a ≥20% reduction in lesion area, 86.9% vs. 82.9%, respectively. Efficacy outcomes measured according to type of pathogen, including MRSA, were similar in the two treatment groups. Oritavancin was also non-inferior to vancomycin in the SOLO II trial (n=1,019). Clinical response was achieved by 80% and 83% of patients, respectively, 48-72 hours after treatment started (FDA primary outcome), and by 83% and 81% of patients, respectively, 7-14 days after treatment stopped (EMA primary outcome). Safety: In studies, oritavancin was tolerated similarly to vancomycin, except nausea was more common. Other adverse events include headache, vomiting and diarrhoea. Guidance/ Guidance: NICE: Antibiotic use, Healthcare-associated infections. reviews: Reviews: None.

Tedizolid oral and injection [Sivextro]; Cubist Pharmacology: Second-generation oxazolidinone antibiotic, active against methicillin-resistant Staphylococcus aureus (MRSA) and bacteria resistant to first-generation linezolid. Indication: Complicated skin and skin structure infections (cSSSI), caused by gram-positive microorganisms. Current status: Filed in EU February 2014. Licensed in US - see prescribing data. UK availability: 2015 Population: In England in 2012-13, there were 4,791 hospital admissions due to local infections of skin and subcutaneous tissue. Staphylococcus aureus is the commonest cause of SSSI. Sector: Secondary care. Implications: A possibly safer alternative to linezolid, as with tedizolid there are no dietary restrictions, no need for weekly full blood counts or potential for significant interactions with drugs such as MAOI inhibitors, antidepressants or triptans. It offers another option for patients with severe or treatment-resistant cSSSI. Financial: Likely to be priced competitively to newer agents. Tariff: Likely HRG included. Efficacy: The published ESTABLISH-1 study (n=667) showed that a 6-day course of oral tedizolid was non-inferior to a 10-day course of oral linezolid in the primary outcome of early clinical response at 48-72 hours (79.5% for tedizolid vs. 79.4% for linezolid). At day 11, respective rates were 69.3% and 71.9%. In the published ESTABLISH-2 study (n=666) i.v. tedizolid for 6 days with optional oral step-down was shown to be non-inferior to linezolid for 10 days. Safety: Most common adverse reactions are nausea, headache, diarrhoea, vomiting and dizziness. Gastrointestinal adverse events were less frequent with oral and i.v. tedizolid than with linezolid. Guidance/ Guidance: NICE: Antibiotic use, Healthcare-associated infections. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 27 No responsibility is accepted for the content of documents derived from this original publication.

Actoxumab/ bezlotoxumab injection; MSD Pharmacology: Monoclonal antibodies against Clostridium difficile-producing toxin A (actoxumab) and toxin B (bezlotoxumab), given as a single infusion. Indication: Clostridium difficile-associated diarrhoea, prevention of recurrence. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Healthcare-associated infections, Diarrhoea and vomiting. reviews: Reviews: None.

Cadazolid oral; Actelion Pharmacology: Bacterial protein synthesis inhibitor, formulated as a powder for oral suspension. Indication: Clostridium difficile-associated diarrhoea, treatment of first and recurrent episodes. Current status: PIII, with fast track status in the US. UK availability: 2017 Sector: Secondary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Healthcare-associated infections, Diarrhoea and vomiting. reviews: Reviews: None. Likely NHSE commissioned

Tobramycin nebuliser solution [Vantobra]; PARI Pharma Pharmacology: Aminoglycoside antibacterial. Indication: Management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients aged 6 years and older with cystic fibrosis (CF) who cannot use tobramycin dry powder inhalation due to intolerance. Current status: Recommended for approval in the EU June 2014. UK availability: 2014 Population: CF affects over 8,500 children and young adults in the UK and has an incidence of 1 in 2,500 live births. The prevalence of CF in the UK is 1.37 per 10,000 people. Sector: Secondary care. Implications: The eFlow device allows low volume/high concentration tobramycin and shortens treatment time compared to current options. Financial: This will be alternative to tobramycin dry powder for inhalation (TOBI) and nebulised tobramycin (Bramitob), both of which currently cost about £1,800 for 28 days treatment. Vantobra is likely to be competitively priced. Tariff: Specified high cost drug. Efficacy: A 28-day, PII study (n=78), compared Vantobra (150mg/1.5mL) given 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. Average Inhalation time was also assessed as 4-4.5 minutes for Vantobra vs. 16-17 minutes for TOBI. Safety: Maximum tobramycin serum levels were lower than recommended safety thresholds for systemic and inhaled applications. Guidance/ Guidance: NICE: Cystic fibrosis. Tobramycin (dry powder for inhalation). reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 28 No responsibility is accepted for the content of documents derived from this original publication.

Daclatasvir oral [Daklinza]; Bristol Myers Squibb Pharmacology: NS5A replication complex inhibitor, first-in-class. Indication: Chronic hepatitis C virus (HCV) infection in adults, in combination with sofosbuvir. Current status: Licensed in EU August 2014. UK availability: 2014 Population: It is estimated about 216,000 people are chronically infected with hepatitis C in the UK, with about 90% being genotype 1 and genotype 3. Chronic HCV develops in about 80% of those infected and the resulting inflammatory liver disease can lead to hepatic fibrosis and cirrhosis. The progression from infection to cirrhosis is variable in time but on average takes 40 years. About 30% of those who are infected with HCV develop cirrhosis within 20–30 years. Sector: Secondary care. Implications: Daclatasvir is likely to be given for 12-24 weeks depending on treatment history, with sofosbuvir ± ribavirin (RBV) or peg-interferon (PegIFN) + RBV, depending on genotype. In November 2013, the EMA recommended compassionate use of daclatasvir with sofosbuvir in patients at high risk of decompensated liver function or death within 12 months if left untreated, and who have genotype 1 infection. The potential benefit of such combination therapy may extend to patients infected with other HCV genotypes. Financial: Costs will be additive. Daclatasvir is likely to be competitively priced with available options, the cost of which vary from about £1,800 (telaprevir) to £11,600 (sofosbuvir) for 28 days treatment. Boceprevir and telaprevir must be given in combination with ribavirin (£250-300/28 days) and peg-interferon (~£500/28 days). Distribution of telaprevir in the US is to stop in October 2014 because of falling sales. Tariff: Likely specified high cost drug. Efficacy: In a PII study 151 treatment-naïve patients with genotype 2 or 3 were randomised to daclatasvir + PegIFN + RBV for 12 or 16 weeks, or PegIFN + RBV for 24 weeks. The primary outcome of sustained virologic response 24 weeks after completing therapy (SVR24) was higher in those with genotype 2 (83% both in the 12 and 16-week groups) than with genotype 3 (69% and 67%, respectively). SVR24 rates in the PegIFN+RBV treatment group were 63% (genotype 2) and 59% (genotype 3). In a published PII study 48 treatment-naïve patients with genotype 1 received daclatasvir or placebo plus PegIFN + RBV for 48 weeks. The primary outcome of undetectable HCV RNA at 12 weeks after start of treatment was achieved by 75% on daclatasvir 60mg vs. 8% on placebo. Use with sofosbuvir: In a published PII study, 211 patients received daclatasvir + sofosbuvir with or without RBV for 12 weeks (treatment-naïve) or 24 weeks (previous virologic failure with boceprevir or telaprevir + PegIFN + RBV). SVR at 12 weeks was achieved by 98% of patients with genotype 1 in both treatment groups. SVR12 was achieved by 92% of patients with genotype 2 and 89% with genotype 3. High rates of SVR12 were observed among patients with HCV subtypes 1a and 1b (98% and 100%, respectively) and those with CC and non-CC IL28B genotypes (93% and 98%, respectively), as well as among patients who did and did not receive RBV (94% and 98%, respectively). PIII studies are on-going: ALLY 1 (cirrhosis or post-transplant), ALLY 2 (HCV co-infected with HIV) and ALLY 3 (genotype 3). Safety: Adverse effects are similar to placebo in controlled trials. Common adverse events when daclatasvir is used with sofosbuvir include fatigue, headache, and nausea. Guidance/ Guidance: NICE: Hepatitis. SIGN: Hepatitis C. SMC: Due November 2014. reviews: Reviews: NIHR NSC April 2014 (with sofosbuvir).

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 29 No responsibility is accepted for the content of documents derived from this original publication.

Daclatasvir + asunaprevir oral [Daklinza + Sunvepra]; Bristol Myers Squibb Pharmacology: NS5A replication complex inhibitor (daclatasvir) and NS3/4A protease inhibitor (asunaprevir). Indication: Chronic hepatitis C virus (HCV) infection Current status: Filed in the EU January 2014 and has breakthrough therapy status in the US for genotype 1b. UK availability: 2015 Population: As for daclatasvir. Sector: Secondary care. Implications: This is a dual oral regimen, which treats HCV without the need for additional peg-interferon injections and oral ribavirin, resulting in a shorter treatment duration. Financial: As for daclatasvir. These are also likely to be competitively priced with other available options. Tariff: Specified high cost drug. Efficacy: In the PIII multicohort HALLMARK-DUAL study (n=645), daclatasvir + asunaprevir was given for 24 weeks to treatment-naive patients with genotype 1b (arm 1), previous non-responders (arm 2) and those unable to take peg-interferon (PegIFN) and ribavirin (RBV, arm 3). Sustained virological responses at post-treatment week 12 (SVR12, primary outcome) were 91%, 82% and 83%, respectively. In the PIII HALLMARK QUAD study (n=398) patients with genotype 1 or 4 received daclatasvir + asunaprevir + PegIFN + RBV. In an ongoing PIII study 230 patients received either daclatasvir + asunaprevir+ PegIFN + RBV (genotypes 1 and 4) or daclatasvir + PegIFN + RBV (genotypes 2 and 3) or daclatasvir + asunaprevir (treatment-naive genotype 1b). In a published PII study, 101 patients were treated with daclatasvir in addition to other regimens depending on genotype. In those receiving asunaprevir based regimens in addition to daclatasvir the primary outcome of SVR12 rate ranged from 65%-95%. Safety: Most commonly occurring adverse events in the treatment headache, fatigue, nausea and diarrhoea. Guidance/ Guidance: NICE: Hepatitis. SIGN: Hepatitis C. reviews: Reviews: NIHR HSC October 2013.

Ombitasvir/ paritaprevir/ ritonavir oral; AbbVie Pharmacology: Fixed-dose combination of NS5A inhibitor (ombitasvir 25mg), NS3/4A inhibitor (paritaprevir 150mg) and protease inhibitor (ritonavir 100mg). Indication: Chronic hepatitis C virus (HCV) infection, genotype 1, in combination with dasabuvir +/- ribavirin. Current status: Filed in EU May 2014 under accelerated assessment. Granted priority review and breakthrough therapy status in the US. UK availability: 2015 Population: As for daclatasvir. Sector: Secondary care. Implications: This is a novel oral therapy consisting of a co-formulation of 3 drugs for once-daily treatment used in combination with twice daily dasabuvir, without the need for interferon. Financial: As for daclatasvir. Tariff: Likely specified high cost drug. Efficacy: In SAPPHIRE-I, in 631 treatment-naïve patients, SVR12 (sustained virological response 12 weeks after the end of treatment) for dasabuvir + ombitasvir/paritaprevir /ritonavir (co-formulation) + ribavirin (RBV) was 96.2% vs. a historical control rate of 78%. In SAPPHIRE-II, in 394 treatment-experienced patients, the SVR12 for co-formulation + dasabuvir + RBV was 96.3%. Rates were 95.3%, 100% and 95.2% in those with a prior relapse, partial response or null response, respectively vs. a historical control rate of 65%. In PEARL-II (n=179), treatment-experienced non-cirrhotic patients with genotype 1b received the co-formulation + dasabuvir +/- RBV. The SVR12 was 96.6% and 100% (+/- RBV) vs. 64% for historical control. In PEARL-III and –IV, treatment-naïve patients with genotype 1b (n=419) or 1a (n=305) received co-formulation + dasabuvir, +/- RBV. SVR12 was 99.5% and 99% (+/- RBV) for genotype 1b, and 97% and 90.2% (+/- RBV) for genotype 1a. In TURQUOISE-II, 380 patients with Child-Pugh cirrhosis class A were treated for 12 or 24 weeks with the co-formulation + dasabuvir + RBV. The SVR12 was 91.8% and 95.9%, respectively, vs. the estimated rate with a telaprevir-based regimen (47%) and the historical control rate of 54%. Safety: Side effects seen with the co-formulation plus dasabuvir include nausea, pruritis, insomnia, diarrhoea, asthenia, fatigue and headache. Guidance/ Guidance: NICE: Hepatitis. SIGN: Hepatitis C. reviews: Reviews: NIHR HSC August 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 30 No responsibility is accepted for the content of documents derived from this original publication.

Ledipasvir/ sofosbuvir oral; Gilead Pharmacology: Fixed-dose combination of a NS5A serine protease inhibitor (ledipasvir 90mg) and NS5B inhibitor (sofosbuvir 400mg). Indication: Chronic hepatitis C virus (HCV) infection, genotype 1. Current status: Filed in EU March 2014. In February 2014 the EMA approved a compassionate-use programme for ledipasvir/ sofosbuvir (LED/SOF) with or without ribavirin (RBV). UK availability: 2015 Population: As for daclatasvir. Sector: Secondary care. Implications: This fixed-dose combination of two first-in-class oral antivirals used with or without RBV will offer another oral treatment regimen and is likely to be given for 12-24 weeks depending on prior therapy. Financial: Ledipasvir will be an additional cost to that of sofosbuvir, which currently costs £11,600 per month. The fixed-dose combination can be given with or without ribavirin (£250-300 per month). Tariff: Specified high cost drug. Efficacy: In ION-1, 865 treatment-naive patients received LED/SOF +/-RBV for 12 or 24 weeks. The SVR12 (sustained virologic response at 12 weeks after the end of therapy) rates were 99% for 12-week LED/SOF, 97% for 12-week LED/SOF + RBV, 98% for 24-week LED/SOF and 99% for 24-week LED/SOF + RBV, p<0.001 all groups vs. historical control of 60%. In ION-2, 440 patients who had not had a sustained response to prior interferon-based therapy were given LED/SOF +/- RBV for 12 or 24 weeks. Rates for 12-week therapy were 94% for LED/SOF and 96% LED/SOF + RBV. For 24-week therapy rates were 99% for LED/SOF and 99% for LED/SOF +RBV, p<0.001 all groups vs. historical control of 25% (expected rate). In ION-3, 647 treatment-naïve patients with non-cirrhotic genotype 1 received LED/SOF +/- RBV for 8 weeks +/- RBV for 12 weeks. SVR12 rates were 94%, 93% and 95% respectively, p<0.001 for all groups vs. historical control of 60%. Safety: The main side effects were fatigue, headache, nausea and insomnia. See medicines.org.uk (sofosbuvir). Guidance/ Guidance: NICE: Hepatitis. SIGN: Hepatitis C. reviews: Reviews: NIHR HSC August 2013.

MK-5172 oral; MSD Pharmacology: Hepatitis C NS3/4a protease inhibitor. Indication: Hepatitis C infection, treatment-naïve patients, in combination with ribavirin. Current status: PII UK availability: 2016 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Hepatitis. SIGN: Hepatitis C. reviews: Reviews: None.

Danoprevir oral; Roche Pharmacology: Reversible protease inhibitor of the hepatitis C virus. Indication: Hepatitis C infection, treatment-naïve and treatment-experienced patients. Current status: PII UK availability: 2017 Sector: Secondary care. Tariff Likely specified high cost drug. Guidance/ Guidance: NICE: Hepatitis. SIGN: Hepatitis C. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 31 No responsibility is accepted for the content of documents derived from this original publication.

Ledipasvir/ sofosbuvir oral; Gilead Pharmacology: Fixed-dose combination of a NS5A serine protease inhibitor (ledipasvir 90mg) and NS5B inhibitor (sofosbuvir 400mg). Indication: Hepatitis C with HIV co-infection. Current status: PIII UK availability: 2016 (licence extension). Sector: Secondary care. Tariff Specified high cost drug. Guidance/ Guidance: NICE: Hepatitis, HIV and AIDs. SIGN: Hepatitis C. reviews: Reviews: NIHR HSC August 2013.

MK-5172 + MK8742 oral; MSD Pharmacology: Hepatitis C NS3/4a protease inhibitor (MK-5172) + HCV NS5A protease inhibitor (MK-8742). Indication: Hepatitis C infection (genotypes 1, 4, 5 & 6) with HIV co-infection. Current status: PIII UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Hepatitis, HIV and AIDs. SIGN: Hepatitis C. reviews: Reviews: None.

Dolutegravir/ abacavir/ lamivudine oral [Triumeq]; ViiV Healthcare Pharmacology: Fixed-dose combination of integrase inhibitor (dolutegravir 50mg) + HIV reverse transcriptase inhibitors (NRTIs, abacavir 600mg, lamivudine 300mg). Indication: HIV infection in adults and adolescents from 12 years of age. Current status: Recommended for approval in the EU June 2014. Licensed in US – see prescribing data. UK availability: 2014 Population: In 2012, 93,500 to 104,300 people in the UK had HIV. 89% with a CD4 count <350mm3 received therapy. Sector: Secondary care. Implications: The benefits with this combination are its ability to achieve potent response, with a high barrier to resistance in a once daily, single formulation regimen. Financial: Current monthly cost of dolutegravir is about £500 and for Kivexa is about £300. Tariff: Specified high cost drugs (individual components). Efficacy: In a bioequivalence study, Triumeq was shown to be bioequivalent to dolutegravir + Kivexa. Safety: See medicines.org.uk (dolutegravir and Kivexa). Guidance/ Guidance: NICE: HIV and AIDs. British HIV Association: Treatment of HIV-1-positive adults. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 32 No responsibility is accepted for the content of documents derived from this original publication.

BNF 6. Endocrine system Likely CCG commissioned

Alogliptin/ pioglitazone oral [Incresync]; Takeda Pharmacology: Fixed-dose combination preparations containing a dipeptidyl peptidase-4 (DPP-4) inhibitor (alogliptin 12.5mg or 25mg) and a thiazolidinedione (pioglitazone 30mg or 45mg). Indication: Type 2 diabetes mellitus, alone or in combination with metformin, as an adjunct to diet and exercise. Current status: Licensed in EU September 2013 – see prescribing data. UK availability: 2014 Population: Estimated UK prevalence of diagnosed diabetes mellitus was 3.2 million people in 2013. 90% of patients have type 2 diabetes. It is thought a further 630,000 are undiagnosed. Sector: Primary care. Implications: This will be the first DPP-4 inhibitor plus glitazone combination product, although most DPP-4 inhibitors are licensed to be used with pioglitazone. Financial: 28-day cost for DPP-4 inhibitors alone and in combination with metformin is £27-34. Generic pioglitazone is available (<£2/month). An alogliptin/ pioglitazone preparation will have to be competitive. Tariff: HRG included.

Efficacy: In a published 26-week PIII study, mean change in HbA1c from baseline (8.8%) in 655 treatment-naïve patients was -1.7% with alogliptin 25mg/pioglitazone 30mg vs. -1.0% with alogliptin 25mg and -1.2% with pioglitazone 30mg (both p<0.001). Safety: See prescribing data. The MHRA has issued warnings about using pioglitazone in patients with a history of heart failure or bladder cancer. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

Canagliflozin/ metformin oral [Vokanamet]; Janssen-Cilag Pharmacology: Fixed-dose combination containing a sodium-glucose co-transporter-2 inhibitor (canagliflozin 50mg) and an immediate-release biguanide (metformin 850mg or 1000mg), taken twice a day. Indication: Type 2 diabetes mellitus, alone or in combination with other anti-diabetic medicines including insulin. Current status: Licensed in EU April 2014 - see prescribing data. UK availability: 2014 Population: As for alogliptin/ pioglitazone. Sector: Primary care. Implications: NICE has approved canagliflozin for dual therapy with metformin (if a sulfonylurea is contraindicated or not tolerated, or the person is at significant risk of hypoglycaemia), for triple therapy with metformin and a sulfonylurea or pioglitazone, and for use with insulin. Dapagliflozin is also available in a fixed-dose combination preparation with metformin, but is not recommended to be used with pioglitazone. Financial: Canagliflozin costs £50/month (300mg daily) and metformin £1-2/month. The combination formulation is likely to be a similar price to canagliflozin. Tariff: HRG included. Efficacy: PIII studies involving 5,151 patients given once-daily canagliflozin as add-on to metformin, and four PI pharmacokinetic studies confirming bioequivalence of the combination preparation to the individual components, were conducted. Safety: See prescribing data. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 33 No responsibility is accepted for the content of documents derived from this original publication.

Insulin degludec/ liraglutide injection [Xultophy]; Novo Nordisk Pharmacology: Combination preparation containing a long-acting insulin analogue (insulin degludec 100units/ml) with a glucagon-like peptide-1 (GLP-1) analogue (liraglutide 3.6mg/ml), given by once-daily s.c. injection. Indication: Type 2 diabetes mellitus. Current status: Recommended for approval in EU July 2014. UK availability: 2014 Population: As for alogliptin/ pioglitazone. Sector: Primary care. Implications: NICE has made no recommendation on use of liraglutide with insulin. Insulin degludec will be included in the updated NICE diabetes guideline. It is unclear which patients would benefit from therapy with insulin and a GLP-1 analogue, according to current clinical practice. Dose titration could be problematic. Financial: Current costs of prefilled pens are £14 for insulin degludec (100units/ml) and £39 for liraglutide (6mg/ml). A combination product is likely to be competitive. Tariff: HRG included.

Efficacy: In the PIII DUAL I study in 1,663 insulin-naïve patients with type 2 diabetes, change in mean HbA1c from baseline to week 26 was -1.9% with insulin degludec (IDeg)/liraglutide, -1.4% with IDeg and -1.3% with liraglutide (p<0.001). At 52 weeks, mean HbA1c changes from baseline were -1.8%, -1.4% and -1.2%, respectively (p<0.001). 78% of patients on IDeg/liraglutide had HbA1c <7% vs. 63% with IDeg and 57% with liraglutide. In the published PIII DUAL II study (n=413), change in mean HbA1c was -1.9% with IDeg/liraglutide vs. -0.9% with IDeg alone (p<0.001) in patients previously uncontrolled on basal insulin. A 2.7kg weight loss (secondary outcome) was seen for IDeg/liraglutide vs. no change for IDeg (p<0.001). Safety: See medicines.org.uk for individual components. In DUAL I, rates of diarrhoea, nausea and vomiting were higher with IDeg/liraglutide than IDeg alone, but lower than with liraglutide alone. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

Insulin glargine U300 injection [Toujeo]; Sanofi Pharmacology: Long-acting insulin analogue, in a three times more concentrated formulation delivering the same amount of insulin glargine in a smaller volume per injection. Strength is 300units/ml. Indication: Type 1 and 2 diabetes mellitus. Current status: Filed in EU May 2014 and in US July 2014. UK availability: 2015 Population: UK prevalence of diagnosed diabetes mellitus was about 3.2 million people in 2013. Prevalence of insulin use in patients with type 2 diabetes increased from 0.7 to 4.3 per 1,000 people between 1991 and 2010. Sector: Primary care. Implications: NICE recommends insulin glargine as an option for type 1 diabetes. Risks of dosing or administration errors because of the higher strength of Toujeo need to be considered – the MHRA has issued advice on minimising risk with high-strength insulin degludec. Financial: Current cost of Lantus 100units/ml ranges from about £30 (10ml vial) to £42 (5×3ml cartridges/ prefilled pens). Toujeo is expected to be similarly priced. The UK patent for insulin glargine expires in November 2014. The first insulin glargine biosimilar (Abasria) has been recommended for approval in the EU. Tariff: HRG included. Efficacy: The EDITION series of open-label PIII studies have all met their primary outcome of showing a similar reduction in mean HbA1c from baseline to 6 months with Toujeo and Lantus. In the published EDITION I study in 807 patients with type 2 diabetes, mean change was -0.83% in both groups when used with meal-time insulin. From month 3 to 6, Toujeo was associated with a 21% decrease in severe or confirmed nocturnal hypoglycaemia. In the EDITION II study (n=811) mean HbA1c changes were -0.57% with Toujeo and -0.56% with Lantus when added to oral anti-diabetes medicines in patinets with type 2 diabetes uncontrolled by basal insulin. The EDITION III study in 878 uncontrolled, insulin-naïve patients with type 2 diabetes mean HbA1c changes were -1.42% vs. -1.46%, respectively. In the EDITION IV study, results were -0.40% and -0.44%, respectively, in 551 patients with type 1 diabetes using meal-time insulin. Safety: Adverse events with Toujeo are similar to those with Lantus. In an analysis of studies, the rate ratio (per patient-year) of night-time hypoglycaemia was reduced by 31% with Toujeo vs. Lantus (p<0.001)..012). Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 34 No responsibility is accepted for the content of documents derived from this original publication.

Insulin inhalation [Afrezza]; Sanofi Pharmacology: Dry-powder formulation of insulin, ultra rapid-acting, first-in-class. Used at the start of a meal. Indication: Type 1 and 2 diabetes mellitus. Current status: PIII in EU. Licensed in US – see US prescribing data. UK availability: 2015 Population: As for insulin glargine U300. Sector: Primary care. Implications: Needle-free insulin will be attractive to patients, especially those with needle phobia or problems injecting. Exubera (an inhaled insulin formulation launched in 2006 but discontinued due to poor sales) was not approved for use by NICE on cost-effectiveness grounds. Financial: Cost of Afrezza inhaled insulin is not known. In 2006, Exubera cost £1,100 annually. Tariff: HRG included. Efficacy: In a PIII study involving 518 patients with type 1 diabetes using basal insulin, Afrezza decreased mean HbA1c by 0.21% vs. 0.40% with insulin aspart. Fasting blood glucose and bodyweight were also reduced vs. insulin aspart (p=0.003 and p=0.01, respectively). In a PIII study involving 353 insulin- naïve patients with type 2 diabetes, Afrezza in combination with oral antidiabetes medicines decreased mean HbA1c by 0.82% vs. 0.42% with oral medicines alone (p<0.001). Safety: Cough is the most common treatment-related adverse effect. Inhaled insulin is not recommended in patients who smoke because of unknown efficacy and safety. Concerns exist over use in people with colds or other respiratory problems, and how to precisely measure insulin dosage. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

Exenatide implant; Intarcia Therapeutics Pharmacology: Long-acting analogue of glucagon-like peptide 1 (GLP-1) delivered over 3-12 months via the DUROS device, a s.c. implant in the upper arm. Indication: Type 2 diabetes mellitus. Current status: PIII UK availability: 2017 Sector: Primary care. Tariff: HRG included. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

Insulin peglispro injection; Eli Lilly Pharmacology: Basal insulin analogue, given by s.c. injection. Indication: Type 1 and type 2 diabetes mellitus. Current status: PIII UK availability: 2016 Sector: Primary care. Tariff: HRG included. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 35 No responsibility is accepted for the content of documents derived from this original publication.

Peptide p277 injection [DiaPep277]; Andromeda Pharmacology: First-in-class synthetic peptide immunomodulator, comprising 24 amino acids from human heat shock protein 60 (Hsp60), which diminishes or blocks destruction of insulin-secreting beta cells. Given by 3- monthly s.c. injection. Indication: Type 1 diabetes, newly-diagnosed. Current status: PIII, with orphan status in the US. UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

Teplizumab injection; MacroGenics Pharmacology: Humanised monoclonal antibody against CD3 which suppresses T-cell mediated destruction of pancreatic beta cells. Indication: Type 1 diabetes, newly-diagnosed. Current status: PIII, with orphan status in the US. UK availability: Uncertain. Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Diabetes. SIGN: Diabetes. reviews: Reviews: None.

Bazedoxifene/ conjugated estrogens oral [Duavive]; Pfizer Pharmacology: Selective oestrogen receptor modulator (SERM) (bazedoxifine 20mg) plus conjugated oestrogens (0.45mg or 0.625mg), taken once-daily. Indication: Postmenopausal osteoporosis in women at increased risk of fracture, and menopausal symptoms. Current status: Filed in EU July 2012. Launched in US - see prescribing data. UK availability: 2014 Population: It is estimated more than 2 million women have osteoporosis in England and Wales. After the menopause, prevalence of osteoporosis increases markedly with age, from about 2% at 50 years of age to more than 25% at 80 years. Sector: Primary care. Implications: NICE recommends a bisphosphonate first-line for primary prevention of postmenopausal osteoporosis. Raloxifene (a SERM) is not recommended for primary prevention but can be used for secondary prevention. Many preparations are available for menopausal symptoms. Bazedoxifene/conjugated estrogens (BZA/CE) is another option and, as a single tablet, could be attractive. Financial: Current 28-day treatment costs are varied: £0.88 (alendronate 70mg/week), £1-2 (conjugated estrogens for HRT), £17 (raloxifene 60mg/day). BZA/CE is likely to be competitive. Tariff: Likely HRG included. Efficacy: BZA/CE has been evaluated in 5 published PIII Selective Estrogen Menopause and Response to Therapy (SMART) studies. Endometrial safety and changes in bone mineral density (BMD) were assessed in SMART-1 (n=3,397), SMART-4 (n=1,061) and SMART-5 (n=1,843). In SMART-1, over 24 months, rates of endometrial hyperplasia and thickness were similar to placebo (<1%). BMD increases seen in all 3 studies were significantly greater with BZA/CE vs. placebo and in SMART-1, were greater with most doses of BZA/CE vs. raloxifene. Incidence of hot flushes at week 12 was reduced from baseline by 51- 86% with all doses of BZE/CE vs. 17% with placebo in SMART-1, and by 74-80% with BZE/CE vs. 51% with placebo in SMART-2 (n=332). In SMART-3 (n=664), BZA/CE improved vaginal pH and dryness vs. placebo (p≤0.05). Safety: BZA/CE is generally safe and well tolerated. The incidence of bleeding and breast tenderness is similar to that with placebo, and significantly lower than with CE/medroxyprogesterone acetate (p<0.05). Guidance/ Guidance: NICE: Osteoporosis, Menopause. SIGN: Osteoporosis. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 36 No responsibility is accepted for the content of documents derived from this original publication.

Odanacatib oral; MSD Pharmacology: Selective cathepsin-K inhibitor, taken once-weekly. Indication: Osteoporosis in postmenopausal women, primary or secondary prevention, when bisphosphonates are contra-indicated or not successful. Current status: PIII UK availability: 2015 Population: It is estimated more than 2 million women have osteoporosis in England and Wales. After the menopause, prevalence of osteoporosis increases markedly with age, from about 2% at 50 years of age to more than 25% at 80 years. Sector: Primary care. Implications: NICE recommends an oral bisphosphonate first-line for primary and secondary prevention of postmenopausal osteoporosis. Odanacatib will be an alternative to denosumab, teriparatide, strontium ranelate and raloxifene. Financial: Current annual treatment costs of existing options vary: about £200 (raloxifene 60mg/day), £370 (denosumab 60mg 6-monthly), £325 (strontium ranelate 2g/day) and £3,300 (teriparatide 20micrograms/daily). The cost of odanacatib is likely to be competitive. Tariff: Likely HRG included. Efficacy: The POWER study in 16,716 postmenopausal women was closed early in July 2012 after interim analysis showed it met its primary outcomes of significantly reduced rates of vertebral, non-vertebral and hip fracture. However, safety issues were noted which are being followed-up. An extension trial in about 8,200 women will provide additional data. In a PIII study in 214 postmenopausal women with a mean lumbar spine T-score of −1.81 at baseline, increase in lumbar bone mineral density (BMD) over 1 year with odanacatib vs. placebo was 3.5% (p<0.001). In a PII study which enrolled 243 women previously treated with alendronate, BMD changes from baseline at the femoral neck, trochanter, total hip and lumbar spine at 24 months in the odanacatib group (1.7%, 1.8%, 0.8%, and 2.3%, respectively) were significantly different from the placebo group. Safety: Odanacatib has a similar overall incidence of adverse events as placebo. As odanacatib prevents collagen breakdown, data are needed on potential effects on fracture healing and bone structure. Guidance/ Guidance: NICE: Osteoporosis. SIGN: Osteoporosis. reviews: Reviews: None recent for this indication.

Anamorelin oral; Helsinn Pharmacology: Ghrelin receptor agonist, first-in-class. Indication: Anorexia/cachexia associated with non-small cell lung cancer. Current status: PIII, with fast track status in the US. UK availability: 2016 Sector: Secondary care. Tariff: Likely HRG included. Guidance/ NICE: Lung cancer. SIGN: Lung cancer. reviews: Reviews: NIHR HSC December 2013.

Enobosarm oral [Ostarine]; GTx Pharmacology: A first-in-class, non-steroidal selective androgen receptor modulator (SARM). Indication: Cachexia, treatment and prevention in advanced non-small cell lung cancer. Current status: PIII, with fast track status in the US. UK availability: 2016 Sector: Secondary care. Tariff: Likely HRG included. Guidance/ Guidance: NICE: Lung cancer. SIGN: Lung cancer. reviews: Reviews: NIHR HSC November 2012.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 37 No responsibility is accepted for the content of documents derived from this original publication.

Likely NHSE commissioned

Tolvaptan oral [Jinarc]; Otsuka Pharmacology: Selective vasopressin V2-receptor antagonist that reduces cyst fluid accumulation and epithelial cell growth. Indication: Autosomal-dominant polycystic kidney disease (ADPKD) in adults. Current status: Filed in EU December 2013, with orphan status. Not recommended for approval in US August 2013 after priority review, but discussions are ongoing about resubmission. UK availability: 2014 Population: ADPKD is the most common genetic kidney disorder, affecting 100-200 per 100,000 people (at least 60,000 in the UK). It accounts for around 1 in 10 people on dialysis and 1 in 8 with a kidney transplant. About 50% of people with ADPKD have established kidney failure by 60 years of age. Sector: Secondary care initiated. Implications: There are currently no therapies that modify disease course and slow rate of decline in kidney function. Current management options include antihypertensives, dialysis and transplant. In studies tolvaptan was used in patients with an estimated creatinine clearance of at least 60ml/minute (stage 1 or 2 kidney disease). Financial: Based on current prices for the Samsca formulation of tolvaptan, 60-120mg/day will cost about £4,500- £8,900/month. However, as a medicine with orphan status, the cost of Jinarc could be different. Tariff: Specified high cost drug. Efficacy: In the published PIII TEMPO 3:4 trial 1,445 patients received tolvaptan at the highest tolerated of three dose regimens or placebo. At 3 years, mean increase in total kidney volume in the tolvaptan group was 2.8% 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 significantly raised liver enzymes, but these were not associated with liver failure or permanent liver dysfunction The MHRA has issued a safety warning. Guidance/ Guidance: NICE: Chronic kidney disease, Kidney conditions (general and other). Tolvaptan in ADPKD reviews: due August 2015. SIGN: Chronic kidney disease. Reviews: NIHR HSC April 2012.

Odanacatib oral; MSD Pharmacology: Selective cathepsin-K inhibitor, taken once-weekly. Indication: Osteoporosis treatment in men when bisphosphonates are contra-indicated or not successful. Current status: PIII. A licence for use in men will only be submitted once licenced for use in postmenopausal women. UK availability: 2016 Population: Osteoporosis is affects 1 in 5 men over the age of 50, with an estimated lifetime risk of fracture in this age group of 20-30%. Around 50% of men with osteoporosis have secondary causes and treatments such as testosterone may be more appropriate. Sector: Primary care. Implications: The National Osteoporosis Guidelines Group recommends men aged over 50 years should be offered a bisphosphonate first-line. For men who have failed or are unsuitable for bisphosphonate therapy, odanacatib will be an alternative to denosumab and teriparatide. Financial: Current annual treatment costs of denosumab 60mg 6-monthly is £370, and £3,300 for teriparatide 20micrograms/daily. The cost of odanacatib is likely to be competitive. Tariff: Likely HRG included. Efficacy: Results are expected soon from a 2-year PIII study in 294 men randomised to odanacatib once weekly or placebo in addition to calcium carbonate and colecalciferol. Safety: Odanacatib has a similar overall incidence of adverse events as placebo. As odanacatib prevents collagen breakdown, data are needed on potential effects on fracture healing and bone structure. Guidance/ Guidance: NICE: Osteoporosis. SIGN: Osteoporosis. reviews: Reviews: NIHR HSC June 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 38 No responsibility is accepted for the content of documents derived from this original publication.

Mifepristone oral [Corluxin]; Corcept Pharmacology: Once-daily progesterone antagonist with weak anti-androgenic activity that directly blocks the glucocorticoid-II receptor, but not the glucocorticoid-I receptor. Indication: Cushing’s syndrome, in patients with hyperglycaemia who have failed or are unsuitable for surgery. Current status: Filed in EU December 2013 with orphan status. Launched in US– see prescribing data. UK availability: 2014 Population: Cushing’s syndrome affects around 0.6 in 10,000 people in the EU, with higher incidence in people with diabetes, obesity, hypertension or osteoporosis. In obese patients with type 2 diabetes, especially those with poor blood glucose control and hypertension, reported prevalence of Cushing's syndrome is 2-5%. Sector: Secondary care. Implications: An alternative to other therapies that control cortisol levels e.g. unlicensed ketoconazole or metyrapone (both ineffective long-term), or mitotane, or to therapies that reduce blood sugar, such as insulin. Financial: Likely to be expensive. Cost of mifepristone 300mg-1,200mg daily in the US is $6,000-$24,000/month. Mitotane monthly cost is £350-£700/1-2g daily. Mifepristone 200mg tablets are available (£18/tablet) but are unlicensed for this indication. Tariff: Likely HRG included. Efficacy: The published 24-week PIII SEISMIC study assessed mifepristone 300mg-1,200mg in 50 adults with Cushing’s syndrome and type 2 diabetes mellitus/impaired glucose tolerance (C-DM) or a diagnosis of hypertension alone (C-HT). In the C-DM cohort, 60% of patients achieved a ≥25% improvement in glucose tolerance from baseline (p<0.001). Mean HbA1c decreased from 7.43 to 6.29 (p<0.001) and mean fasting plasma glucose decreased from 8.3 to 5.8mmol/L (p<0.03). In the C-HT cohort, 38% of patients achieved a ≥5mmHg reduction in diastolic blood pressure from baseline (p<0.05). Mean weight change was -5.7% (p<0.001). Insulin resistance, depression, cognition and quality of life also improved. Safety: Most common adverse reactions are gastrointestinal effects, fatigue, headache, hypokalaemia, arthralgia, peripheral oedema, hypertension, dizziness and endometrial hypertrophy. QT interval-prolonging drugs should not be used with mifepristone which also interacts with CYP inducers and inhibitors. Guidance/ Guidance: None. reviews: Reviews: None.

Pasireotide LAR injection [Signifor]; Novartis Pharmacology: Somatostatin analogue in a long-acting release (LAR) i.m. injection, given every 4 weeks. Indication: Acromegaly, when surgery is ineffective or not an option. Current status: Filed in EU in late 2013, with orphan status. UK availability: 2015 Population: EU annual incidence of acromegaly is about 3 per million people. About 3,000 in the UK have the condition. Sector: Secondary care. Implications: Pasireotide will compete with other somatostatin analogues, pegvisomant and dopamine agonists. Financial: Current depot therapy includes lanreotide 30mg (£551/month) or octreotide 20mg (£776/month) for initial therapy, dose and/or frequency adjusted according to response. Tariff: Specified high cost drug. Efficacy: In the PIII PASPORT-ACROMEGALY study (n=358), at 12 months, 31.3% on monthly pasireotide LAR vs. 19.2% on monthly octreotide LAR (p=0.007, NNT=8) achieved biochemical control (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 patients switched to pasireotide LAR and 38 to octreotide LAR). A biochemical response was achieved by 21.0% and 2.6%, respectively (NNT=5). In the 6-month PIII PAOLA study (n=198), 15.4% and 20.0% of patients achieved biochemical control with pasireotide LAR 40mg and 60mg, respectively, vs. 0% with octreotide LAR or lanreotide Autogel (p=0.0006 and p<0.0001, respectively). Safety: See medicines.org.uk for short-acting formulation. Hyperglycaemia is more common with pasireotide than with octreotide or lanreotide. Guidance/ Guidance: None. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 39 No responsibility is accepted for the content of documents derived from this original publication.

BNF 7. Obstetrics, gynaecology and urinary-tract disorders Likely CCG commissioned

Collagenase clostridium histolyticum injection [Xiapex]; Swedish Orphan Biovitrum Pharmacology: Defined mixture of proteinases that hydrolyse collagen under physiological conditions, locally injected. Indication: Peyronie’s disease (PsD). Current status: Filed in EU July 2014. Licensed in US – see prescribing data. UK availability: 2015 (licence extension) Population: PsD affects around 3-9% of men. The average age of onset is in the fifth decade with many cases undiagnosed. PsD will improve or resolve spontaneously in about 13% of cases. Sector: Secondary care. Implications: Current therapy incudes oral potassium para-aminobenzoate, intralesional interferon-alpha or verapamil, and surgery. Financial: Xiapex 0.9mg for Dupuytren's contracture currently costs £650, similar doses for PsD are used (0.58mg for up to 8 injections). Interferon-alpha costs about £1,000 for twice weekly dosing for 12 weeks. Tariff: Specified high cost drug (when used in outpatients). Efficacy: A published post-hoc meta-analysis of two identical 52-week PIII studies IMPRESS I and II (n=832 total) showed that patients treated with collagenase had a 34% mean improvement in penile curvature vs. 18% for placebo (representing a mean change -17.0 vs. -9.3 degrees, respectively). The mean change in Peyronie’s disease symptom bother score improved with collagenase treatment (-2.8 vs. -1.8, p=0.004). Safety: See medicines.org.uk. In current indication, injection site reactions are very common. Guidance/ Guidance: NICE: Urological conditions: general and other. Non-NHS guideline: European Association of reviews: Urology. Reviews: None.

nx 1207 injection; Recordati Pharmacology: Pro-apoptopic agent, given by ultrasound-guided transrectal injection into prostatic tissue. Indication: Benign prostatic hyperplasia, in patients with lower urinary tract symptoms not adequately controlled with alpha-blockers. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Lower urinary tract symptoms. reviews: Reviews: None. BNF 8. Malignant disease and immunosuppression Likely NHSE commissioned

Brain cancer vaccine injection [DCVax-L]; Northwest Biotherapeutics Pharmacology: Immunostimulant vaccine manufactured using the patient’s dendritic cells and resected tumour tissue, given by intradermal injection. Indication: Glioblastoma multiforme, first-line adjuvant therapy. Current status: PIII with orphan status. UK availability: 2016 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Brain cancers. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 40 No responsibility is accepted for the content of documents derived from this original publication.

Afatinib oral [Giotrif]; Boehringer Ingelheim Pharmacology: Tyrosine kinase inhibitor irreversibly blocking epidermal growth factor receptors, including HER2. Indication: Head and neck cancer, recurrent and/or metastatic, second-line after platinum-based chemotherapy. Current status: PIII UK availability: 2015 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Head and neck cancers. SIGN: Head and neck cancer. reviews: Review: NIHR HSC March 2013.

Cabozantinib oral [Cometriq]; Swedish Orphan Biovitrum Pharmacology: MET, RET and VEGFR2 tyrosine kinases inhibitor. Indication: Thyroid cancer, medullary, unresectable or advanced. Current status: Licensed in EU March 2014 with orphan status – see prescribing data. Available on a named patient basis in the UK. UK availability: 2014 Sector: Secondary or tertiary care. CDF: Included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Head and neck cancers. reviews: Reviews: NIHR HSC February 2012.

Lenvatinib oral; Eisai Pharmacology: VEGFR1-3, FGFR1-4, KIT and RET tyrosine kinases inhibitor. Indication: Thyroid cancer, differentiated, advanced, radioactive-iodine refractory. Current status: Filed in EU August 2014, with orphan status. Will undergo accelerated assessment in EU. UK availability: 2015 Sector: Secondary or tertiary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Head and neck cancers. reviews: Reviews: None.

Afatinib oral [Giotrif]; Boehringer Ingelheim Pharmacology: Tyrosine kinase inhibitor irreversibly blocking epidermal growth factor receptors, including HER2. Indication: Non-small cell lung cancer, advanced, squamous, second-line after platinum-based chemotherapy. Current status: PIII UK availability: 2015 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Lung cancer. Afatinib is recommended for locally advanced or metastatic EGFR-positive reviews: disease. SIGN: Lung cancer. Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 41 No responsibility is accepted for the content of documents derived from this original publication.

Ceritinib oral [Zykadia]; Novartis Pharmacology: ALK inhibitor. Indication: Non-small cell lung cancer, ALK-positive, locally advanced or metastatic, second-line. Current status: Filed in EU April 2014. Licensed in US with breakthrough therapy status – see prescribing data. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Lung cancer. Ceritinib due January 2016. SIGN: Lung cancer. reviews: Reviews: NIHR HSC March 2013.

Crizotinib oral [Xalkori]; Pfizer Pharmacology: ALK and cMET inhibitor, first-in-class. Indication: Non-small cell lung cancer, advanced, first-line in ALK-positive patients. Current status: PIII UK availability: 2015 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drug Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Lung cancer. SIGN: Lung cancer. reviews: Reviews: None.

Eribulin injection [Halaven]; Eisai Pharmacology: Synthetic analogue of halichondrin B, with tubulin-based antimitotic activity, given by i.v. injection. Indication: Non-small cell lung cancer, advanced, third-line. Current status: PIII UK availability: 2015 (licence extension). Sector: Secondary care. CDF: Not included in Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Lung cancer. SIGN: Lung cancer. reviews: Reviews: NIHR HSC May 2014.

Ganetespib injection; Synta Pharmacology: A second-generation heat shock protein-90 inhibitor, given by i.v. infusion. Indication: Non-small cell lung cancer, advanced, second-line plus. Current status: PIII, with fast track status in the US. UK availability: 2017 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Lung cancer. SIGN: Lung cancer. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 42 No responsibility is accepted for the content of documents derived from this original publication.

Defactinib oral; Verastem Pharmacology: FAK inhibitor. Indication: Malignant pleural mesothelioma, maintenance therapy in patients who have not progressed. Current status: PII, with orphan status in EU and US. UK availability: 2017 Sector: Secondary or tertiary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Lung cancer. SIGN: Lung cancer. reviews: Reviews: None.

Trastuzumab emtansine injection [Kadcyla]; Roche Pharmacology: First-in-class trastuzumab emtansine (T-DM1) is an antibody conjugate of trastuzumab and an antimitotic agent, mertansine (DM1), given by 3-weekly i.v. infusion. Indication: Breast cancer, metastatic, HER2-positive, first-line in combination with pertuzumab. Current status: PIII UK availability: 2015 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drug Fund May 2014 for this indication. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Breast cancer. Trastuzumab emtansine not approved for second-line use (August reviews: 2014). SIGN: Primary breast cancer. Reviews: NIHR HSC June 2012.

Pertuzumab injection [Perjeta]; Roche Pharmacology: HER dimerisation inhibitor, first-in-class. May be synergistic with trastuzumab, which binds to a different HER2 region. Given as a 3-weekly i.v. infusion. Indication: Breast cancer, HER2-positive locally advanced, inflammatory, or early disease, neoadjuvant therapy with trastuzumab, docetaxel and standard chemotherapy regimens. Current status: PIII in EU. Licensed in the US – see prescribing data. UK availability: 2015 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014 for this indication. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Breast cancer. SIGN: Primary breast cancer. reviews: Reviews: NIHR NSC January 2013.

Everolimus oral [Afinitor]; Novartis Pharmacology: mTOR inhibitor. Indication: Breast cancer, locally advanced or metastatic HER2-positive, second- or third-line with trastuzumab and vinorelbine. Current status: PIII UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Breast cancer. SIGN: Primary breast cancer. reviews: Reviews: NIHR HSC February 2012.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 43 No responsibility is accepted for the content of documents derived from this original publication.

Everolimus oral [Afinitor]; Novartis Pharmacology: mTOR inhibitor. Indication: Breast cancer, locally advanced or metastatic HER2-positive, first-line with trastuzumab and paclitaxel. Current status: PIII UK availability: 2016 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Breast cancer. SIGN: Primary breast cancer. reviews: Reviews: NIHR HSC April 2012.

Palbociclib oral; Pfizer Pharmacology: Cyclin-dependent kinase 4 and 6 inhibitors. Indication: Breast cancer, advanced, hormone receptor-positive and HER2-negative, first-line with letrozole. Current status: PIII. Granted breakthrough therapy status in US. UK availability: 2017 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Breast cancer. SIGN: Primary breast cancer. reviews: Reviews: NIHR HSC May 2014.

Sorafenib oral; Bayer Pharmacology: Tyrosine kinase inhibitor that blocks VEGFR, PDGFR and RAF. Indication: Breast cancer, locally advanced or metastatic, HER2 negative, second-line with capecitabine. Current status: PIII UK availability: Uncertain due to negative trial results (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Breast cancer. SIGN: Primary breast cancer. reviews: Reviews: None recent.

Ramucirumab injection [Cyramza]; Eli Lilly Pharmacology: Humanised IgG1 monoclonal antibody against human VEGFR2 antagonist, given by i.v. infusion. Indication: Gastric cancer, advanced, second-line monotherapy. Current status: Filed in the EU October 2013, with orphan status. Licenced in the US, after priority review - see prescribing data. UK availability: 2014 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Stomach cancer. SIGN: Oesophageal and gastric cancer. reviews: Reviews: NIHR HSC September 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 44 No responsibility is accepted for the content of documents derived from this original publication.

Ramucirumab injection [Cyramza]; Eli Lilly Pharmacology: Human VEGFR2 antagonist, given by i.v. infusion. Indication: Hepatocellular carcinoma, unresectable, second-line after sorafenib. Current status: PIII, with orphan status in EU and US. UK availability: 2016 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Liver cancers. reviews: Reviews: NIHR HSC November 2013.

Regorafenib oral [Stivarga]; Bayer Pharmacology: Multi-targeted inhibitor of angiogenic, stromal and oncogenic kinase receptors, taken once daily for the first 21 days of each 28-day cycle. Indication: Hepatocellular carcinoma, unresectable, second-line after sorafenib. Current status: PIII UK availability: 2017 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Liver cancers. reviews: Reviews: None.

Sorafenib oral [Nexavar]; Bayer Pharmacology: Tyrosine kinase inhibitor that blocks VEGFR, PDGFR and RAF. Indication: Renal cell carcinoma, adjuvant therapy in patients at risk of relapse after resection. Current status: PIII with orphan status in EU. UK availability: 2017 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Renal cancer. Sorafenib is not recommended for first- or second-line treatment of reviews: advanced and/or metastatic disease. Reviews: None.

Apaziquone intravesical [Neoquin]; Spectrum Pharmacology: An indoloquinone mitomycin analogue prodrug metabolised to an alkylating agent by the DT-diaphorase enzyme, which is over-expressed by bladder cancer cells. Indication: Bladder cancer, non-muscle invasive, in patients at low or intermediate risk of progression. Current status: PIII in EU. PIII in the US with fast track status. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drug Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Bladder cancer. SIGN: Bladder cancer. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 45 No responsibility is accepted for the content of documents derived from this original publication.

Enzalutamide oral [Xtandi]; Astellas Pharmacology: Androgen-receptor antagonist. Indication: Prostate cancer, metastatic castration-resistant, chemotherapy-naïve patients who have failed androgen deprivation therapy and who are asymptomatic or mildly symptomatic. Current status: Filed in EU April 2014. Filed in the US March 2014, with priority review status. UK availability: 2014 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund for this indication (May 2014). Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Prostate cancer. Enzalutamide is recommended for adults with metastatic, hormone- reviews: relapsed prostate cancer, previously treated with docetaxel. Reviews: NIHR HSC September 2012.

Sipuleucel-T injection [Provenge]; Dendreon Pharmacology: First personalised therapeutic vaccine that stimulates a T-cell response against prostatic acid phosphatase, an antigen expressed in most prostate cancers but not in non-prostate tissue. Given by i.v. infusion every 2 weeks for 3 doses. Indication: Prostate cancer, metastatic castration-resistant, first-line. Current status: Licensed in EU September 2013 - see prescribing data. UK availability: 2014 Sector: Secondary care. CDF: Not included in the Cancer Drug Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Prostate cancer. Sipuleucel-T due February 2015. reviews: Reviews: None recent.

Cabozantinib oral; Exelixis Pharmacology: MET, RET and VEGFR2 inhibitor. Indication: Prostate cancer, metastatic castration-resistant, third-line. Current status: PIII UK availability: 2016 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Prostate cancer. reviews: Reviews: None.

Ipilimumab injection [Yervoy]; Bristol Myers Squibb Pharmacology: Anti-CTLA-4 monoclonal antibody given by i.v. infusion every 3 weeks for 4 doses, then 3-monthly. Indication: Prostate cancer, metastatic castration-resistant, second-line. Current status: PIII UK availability: 2016 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Prostate cancer. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 46 No responsibility is accepted for the content of documents derived from this original publication.

Custirsen injection; Teva Pharmacology: Clusterin inhibitor, given by i.v. infusion. Indication: Prostate cancer, metastatic castration-resistant, second-line. Current status: PIII, with fast track status in the US. UK availability: 2017 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Prostate cancer. reviews: Reviews: NIHR HSC January 2014.

Paclitaxel injection [Paclical]; Oasmia Pharmacology: An encapsulated formulation that increases water solubility of paclitaxel, a tubulin inhibitor, removing need for solvents which cause hypersensitivity reactions. Given by i.v infusion every 3 weeks for 6 cycles. Indication: Ovarian cancer, platinum-sensitive or partially platinum-sensitive, second- or third-line. Current status: PIII with orphan status in EU and US. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Ovarian cancer. SIGN: Ovarian cancer. reviews: Reviews: None recent.

Olaparib oral; AstraZeneca Pharmacology: PARP enzyme inhibitor. Indication: Ovarian cancer, relapsed, platinum-sensitive, gBRCAm-positive, maintenance treatment. Current status: Filed in EU September 2013 with orphan status. Recommended against approval in the US June 2014. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Ovarian cancer. SIGN: Ovarian cancer. reviews: Reviews: NIHR HSC May 2013.

Trebananib injection; Amgen Pharmacology: Angiopoietin-1 and 2 inhibitor, given once-weekly by i.v. injection. Indication: Epithelial ovarian, fallopian tube or primary peritoneal cancer, second-line with paclitaxel. Current status: PIII UK availability: 2016 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Ovarian cancer. SIGN: Ovarian cancer. reviews: Reviews: NIHR HSC January 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 47 No responsibility is accepted for the content of documents derived from this original publication.

Bevacizumab injection [Avastin]; Roche Pharmacology: VEGF inhibitor given by i.v. infusion every 3 weeks. Indication: Cervical cancer, recurrent, persistent or metastatic, in combination with chemotherapy. Current status: PIII. Filed In the US July 2014 with priority review status. UK availability: 2015 (licence extension). Sector: Secondary care. CDF: Included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Cervical cancer. SIGN: Cervical cancer. reviews: Reviews: NIHR HSC May 2014.

Eribulin injection [Halaven]; Eisai Pharmacology: Synthetic analogue of halichondrin B, with tubulin-based antimitotic activity, given by i.v. injection. Indication: Soft tissue sarcoma, advanced, third-line. Current status: PIII, with orphan status in US. UK availability: 2016 (licence extension). Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Cancer - general and other, Sarcoma quality standards due January 2015. reviews: Reviews: None.

Trametinib oral [Mekinist]; GlaxoSmithKline Pharmacology: MEK inhibitor taken once daily. Use in combination with twice-daily dabrafenib overcomes resistance to BRAF inhibition associated with reactivation of MEK. Indication: Malignant melanoma, unresectable or metastatic BRAFV600-positive, first-or second-line monotherapy and first-line in combination with dabrafenib. Current status: Monotherapy approved in EU June 2014 - see prescribing data. Filing for combination therapy withdrawn in EU March 2014, but will be resubmitted. Licensed in the US - see prescribing data. UK availability: 2014 (monotherapy) and uncertain (combination therapy) Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Skin cancer. Trametinib in combination with dabrafenib due September 2014. SIGN: reviews: Cutaneous melanoma. Reviews: NIHR HSC (combination therapy) September 2012.

Cobimetinib oral; Roche Pharmacology: MEK inhibitor. Indication: Malignant melanoma, metastatic, BRAF-positive, first-line in combination with twice-daily vemurafenib. Current status: PIII UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Skin cancer. SIGN: Cutaneous melanoma. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 48 No responsibility is accepted for the content of documents derived from this original publication.

Ipilimumab injection [Yervoy]; Bristol Myers Squibb Pharmacology: Anti-CTLA-4 monoclonal antibody given by i.v. infusion every 3 weeks for 4 doses, then 3-monthly. Indication: Malignant melanoma, resected high-risk stage III, first-line adjuvant therapy. Current status: PIII UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Skin cancer. Ipilimumab is recommended for previously-treated and treatment-naïve reviews: advanced disease. SIGN: Cutaneous melanoma. Reviews: NIHR HSC June 2012.

Pembrolizumab injection; MSD Pharmacology: Humanised monoclonal IgG4 antibody against programmed death-1 (PD-1) protein. Indication: Malignant melanoma, unresectable or metastatic, first- or second-line. Current status: Filed in EU June 2014. Filed in US May 2014, with breakthrough therapy and priority review status. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Skin cancer. SIGN: Cutaneous melanoma. reviews: Reviews: NIHR NSC November 2013.

Talimogene laherparepvec injection; Amgen Pharmacology: Oncolytic virus immunostimulant, injected into tumour sites, given every 2 weeks. Indication: Malignant melanoma, unresectable or metastatic. Current status: PIII UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Skin cancer. SIGN: Cutaneous melanoma. reviews: Reviews: None recent.

Sonidegib oral; Novartis Pharmacology: Smoothened (Smo) inhibitor (formerly known as erismodegib). Indication: Basal cell carcinoma, locally advanced or metastatic. Current status: Filed in EU June 2014. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Skin cancer. SIGN: Primary cutaneous squamous cell carcinoma reviews: Reviews: NIHR HSC January 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 49 No responsibility is accepted for the content of documents derived from this original publication.

Chlormethine topical [Valchlor]; Actelion Pharmacology: Nitrogen mustard, an alkylating agent, formulated as a 0.016% gel applied daily. Indication: Cutaneous T-cell lymphoma, mycosis fungoides-type. Current status: PII with orphan status in EU. Launched in the US – see prescribing data. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Skin cancer. SIGN: Primary cutaneous squamous cell carcinoma. reviews: Reviews: None.

Vosaroxin injection [Qinprezo]; Sunesis Pharmacology: Anticancer quinolone derivative, first-in-class. Indication: Acute myeloid leukaemia, relapsed or refractory, second-line with cytarabine. Current status: PIII with orphan status in EU. PIII with fast track and orphan status in the US. UK availability: 2016 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. reviews: Reviews: NIHR HSC June 2012.

Volasertib injection; Boehringer Ingelheim Pharmacology: Polo-like kinase-1 (PLK-1) inhibitor, given by i.v. infusion 2-weekly. Indication: Acute myeloid leukaemia, first-line in patients ineligible for intensive remission induction therapy. Current status: PIII in EU with orphan status. PIII in the US with breakthrough therapy and orphan status. UK availability: 2017 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. reviews: Reviews: NIHR HSC March 2013.

Bendamustine injection [Levact]; Napp Pharmacology: An alkylating agent with antimetabolite activity, given by i.v. infusion for up to six cycles. Indication: Indolent non-Hodgkin’s lymphoma and mantle cell lymphoma, first-line with rituximab. Current status: Filed in EU. Filed in US December 2011 but additional data requested October 2012. UK availability: 2014 (licence extension). Sector: Secondary care. CDF: Included in the Cancer Drugs Fund for low-grade non-Hodgkin’s lymphoma (May 2014). Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. Bendamustine in progress. reviews: Review: LCNDG April 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 50 No responsibility is accepted for the content of documents derived from this original publication.

Ibrutinib oral; Janssen-Cilag Pharmacology: Bruton’s tyrosine kinase inhibitor, first-in-class. Indication: Mantle cell lymphoma, relapsed or refractory, second-line. Current status: Recommended for approval in EU July 2014 with orphan status. Launched in US - see prescribing data. UK availability: 2014 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. reviews: Reviews: NIHR HSC September 2013.

Dasiprotimut-T injection [BiovaxID]; Biovest Pharmacology: An autologous vaccine consisting of a conjugated lymphoma-associated antigen given about 6 to 12 months after chemotherapy. Five s.c. injections are given over a 6-month period. Indication: Non-Hodgkin’s follicular lymphoma. Current status: Filed in EU January 2014, with orphan status. Available on compassionate use basis. PIII with fast track status in US. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. reviews: Reviews: None recent.

Panobinostat oral [Farydak]; Novartis Pharmacology: Pan-deacetylase inhibitor. Indication: Multiple myeloma, relapsed, with bortezomib and dexamethasone. Current status: Filed in EU June 2014 and in US March 2014, with orphan status. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. Panobinostat due January 2016. reviews: Reviews: NIHR HSC April 2012.

Carfilzomib injection [Kyprolis]; Amgen Pharmacology: Second generation selective and irreversible proteasome inhibitor, first-in-class. Given as i.v. infusion. Indication: Multiple myeloma, relapsed. Current status: PIII in EU with orphan status. Launched in the US – see prescribing data. UK availability: 2016 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Bone and bone marrow cancers. reviews: Reviews: NIHR HSC September 2013, NIHR HSC September 2012.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 51 No responsibility is accepted for the content of documents derived from this original publication.

Rigosertib injection [Estybon]; Baxter Pharmacology: Phosphatidylinositol 3-kinase (PI3K) and polo-like kinase (PLK) inhibitor. Indication: Myelodysplastic syndromes, refractory or relapsed after prior therapy with hypomethylating agents. Current status: PIII with orphan status in EU and US. UK availability: 2015 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. reviews: Reviews: NIHR NSC May 2014.

Idelalisib oral [Zydelig]; Gilead Pharmacology: PI3K-delta inhibitor, first-in-class. Indication: Chronic lymphocytic leukaemia, second plus-line in combination with rituximab, or first-line in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. Follicular or small lymphocytic lymphoma, second- or third-line. Current status: Recommended for approval in EU July 2014, following accelerated review. Licensed in US - see prescribing data. UK availability: 2014 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. reviews: Reviews: NIHR HSC July 2013.

Ibrutinib oral [Imbruvica]; Janssen-Cilag Pharmacology: Bruton’s tyrosine kinase inhibitor, first-in-class. Indication: Chronic lymphocytic leukaemia/small lymphocytic leukaemia, relapsed or refractory, second-line. Current status: Recommended for approval in EU July 2014. Launched in the US - see US prescribing data. UK availability: 2014 Sector: Secondary care. CDF: Not included in the Cancer Drugs Fund May 2014. Tariff: Chemotherapy is locally negotiated. Guidance/ Guidance: NICE: Blood and bone marrow cancers. reviews: Reviews: NIHR HSC July 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 52 No responsibility is accepted for the content of documents derived from this original publication.

Peginterferon beta-1a injection [Plegridy]; Biogen Idec Pharmacology: A PEGylated form of recombinant human interferon-beta-1a, given by s.c. injection every 2 or 4 weeks. Indication: Multiple sclerosis (MS), relapsing-remitting (RRMS). Current status: Licensed in EU July 2014 - see prescribing data. UK availability: 2014 Population: In a population of 100,000, 110 people will have MS and about 5 new cases are diagnosed each year. 80% initially have RRMS and 50% of these go on to develop secondary progressive MS within 10 years. In 2012-13, there were 38,080 hospital admissions due to MS in England. Sector: Initiated in secondary care. Implications: Interferon beta is currently the most frequently used disease modifying agent to treat RRMS. Interferon beta-1a is given by s.c. injection 1 or 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 beta-1a (current annual costs Avonex 30micrograms once weekly £8,500 and Rebif 44micrograms 3 times a week £10,500). Tariff: Specified high cost drug. Efficacy: The published 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, vs. placebo, (p<0.001 and p=0.011). Secondary outcomes including 12-week confirmed disability progression were also met (p<0.04). 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 being followed for up to 4 years. Safety: Most common side effects are injection site reactions, influenza-like illness, fever, headache, myalgia, chills, asthenia and arthralgia. Guidance/ Guidance: NICE: Multiple sclerosis. NHSE: Disease modifying therapies for MS, Fampridine reviews: Reviews: NIHR HSC September 2012.

Daclizumab injection [Zenapax]; Biogen Idec Pharmacology: Interleukin-2 receptor antagonist, humanised monoclonal antibody that binds to CD25. Given by once- monthly s.c. injection. Indication: Multiple sclerosis, relapsing-remitting. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Multiple sclerosis. reviews: Reviews: None.

Fingolimod oral [Gilenya]; Novartis Pharmacology: Sphingosine-1 phosphate receptor modulator. Indication: Multiple sclerosis, primary progressive, first-line. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Multiple sclerosis. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 53 No responsibility is accepted for the content of documents derived from this original publication.

Teriflunomide oral [Aubagio]; Genzyme Pharmacology: The active metabolite of leflunomide, teriflunomide is a dehydrogenase inhibitor. Indication: Multiple sclerosis, prevention in patients with clinically isolated syndrome. Current status: PIII UK availability: 2015 Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Multiple sclerosis. Teriflunomide is recommended in patients with active relapsing- reviews: remitting disease. Reviews: None.

Everolimus oral [Certican]; Novartis Pharmacology: Anti-proliferative mTOR inhibitor. Indication: Prevention of organ rejection, in adults receiving an allogeneic heart, kidney or liver transplant, with low- dose calcineurin inhibitors (ciclosporin or tacrolimus) and corticosteroids. Current status: Filed in the EU via the mutual recognition procedure. Launched in some EU countries and the US (not heart) - see US prescribing data. UK availability: Uncertain. Population: In 2011/12, there were 2,800 kidney transplants in the UK. Latest data show there were 628 liver transplants in 2012/13, and 111 heart transplants in adults and children in England in 2010/11. Sector: Secondary or tertiary care. Implications: Everolimus will be an alternative to other antiproliferatives, with a potentially different side effect profile. It has the potential to reduce the dose required of concomitant calcineurin inhibitors, and so reduce the risk and cost of their associated adverse effects including impaired renal function and malignancy. Financial: Cost of competitor anti-proliferatives varies greatly (generic azathioprine £5, generic mycophenolate £40 and sirolimus £160 per month). Cost of everolimus is unknown for this indication. Current monthly cost for cancer indications is £1,200 (2.5mg daily) and £2,250 (5mg daily). Tariff: Specified high cost drug. Efficacy: In a 6-month published PIII study involving 634 heart transplant patients, the primary composite outcome of death, graft loss or re-transplantation, loss to follow-up, biopsy-proved acute rejection (BPAR) or rejection with haemodynamic compromise occurred in 27% of patients on everolimus 3mg daily, 36% on everolimus 1.5mg daily and 47% on azathioprine (p<0.001 for 3mg and p=0.03 for 1.5mg vs. azathioprine). Compared with a vasculopathy incidence of 53% in the azathioprine group, rates were 30% and 36% for 3mg and 1.5mg, respectively (p=0.01, p=0.045). In a 3-year published PIII equivalence study (n=588), kidney graft loss occurred in 7%, 17% and 11% in the everolimus 1.5mg, 3mg, and mycophenolate 2g daily groups, respectively (p=0.0048 for everolimus 1.5mg vs. 3mg). Efficacy failure (BPAR, graft loss, death or loss to follow-up) occurred in 33%, 39% and 37% of patients (p=0.455 overall), respectively. In a 2-year published study in 719 liver transplant patients, efficacy failure rate was 10% for everolimus plus reduced-dose tacrolimus group vs. 12.5% for tacrolimus alone (p=ns). Safety: See medicines.org.uk. Adverse effects can usually be managed with dose reduction or temporary withdrawal of everolimus. Guidance/ Guidance: NICE: Cardiovascular conditions (general and other), Chronic kidney disease, Kidney reviews: conditions (general and other), Liver conditions (general and other). In progress for heart, kidney and liver transplant rejection. Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 54 No responsibility is accepted for the content of documents derived from this original publication.

BNF 9. Nutrition and blood Likely NHSE commissioned

Alipogene tiparvovec injection [Glybera]; Chiesi Pharmacology: Viral vector-based gene therapy given by i.m. injection as a single treatment to insert a working copy of a defective gene into muscle cells. Indication: Adults with familial lipoprotein lipase deficiency (LPLD) and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The diagnosis of LPLD has to be confirmed by genetic testing. The indication is restricted to patients with detectable levels of LPL protein. Current status: Licensed in the EU - see prescribing data. UK availability: 2014 Population: It is estimated only 1 per million people have LPLD but even fewer will be eligible for this treatment. Sector: Secondary or tertiary care. Implications: First active therapy for this very rare condition, currently managed with strict dietary fat restriction. It is administered by multiple i.m. injections into leg muscles during a single treatment. The small numbers of patients affected and uncontrolled trials makes reliability of results uncertain. Financial: Likely to be very expensive. Tariff: Specified high cost drug. Efficacy: In three uncontrolled studies (CT-AMT-011-01, CT-AMT-011-02, CT-MT-011-03) alipogene tiparvovec showed a ≥40% reduction in triglyceride levels in some patients. The effects on pancreatitis were hard to determine due to the limited number of events and variability in historical pancreatitis rates. In a 2-year follow on study of CT-AMT-011-01 (n=14), alipogene tiparvovec was well tolerated and half of the patients showed a ≥40% reduction in fasting triglycerides between 3 and 12 weeks. Safety: Most common adverse effect is pain in the legs after administration. Guidance/ Guidance: None. reviews: Reviews: None recent.

Sebelipase alfa injection; Synageva BioPharma Pharmacology: Recombinant human lysosomal acid lipase, given by i.v. infusion. Indication: Lysosomal acid lipase deficiency (Wolman disease). Current status: PIII, with orphan status in EU. Breakthrough therapy status in US. UK availability: 2016 Sector: Secondary or tertiary care. Tariff: Specified high cost drug. Guidance/ Guidance: None. reviews: Reviews: NIHR HSC June 2012.

Eculizumab injection [Soliris]; Alexion Pharmacology: Recombinant humanised monoclonal IgG2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement, given by i.v infusion. Indication: Myasthenia gravis, refractory. Current status: PIII with orphan status in the EU. UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: None. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 55 No responsibility is accepted for the content of documents derived from this original publication.

BNF 10. Musculoskeletal and joint diseases Likely CCG commissioned

Apremilast oral [Otezla]; Celgene Pharmacology: Phosphodiesterase type 4 inhibitor, down-regulates inflammatory response. Indication: Psoriatic arthritis (PsA) when DMARDs or anti-TNFs have failed, are not tolerated or are contraindicated. Current status: Filed in EU January 2014 (licence application includes psoriasis). Launched in - see prescribing data. UK availability: 2015 Population: Estimates of UK prevalence of severe PsA vary widely. NIHR HSC suggests about 60,000 people in England are affected, other estimates suggest up to 1% of the population may be affected. NICE indicate 1,248 people in England annually will respond to and continue TNF-alpha inhibitor therapy. Sector: Secondary care initiation, primary care continuation. Implications: Apremilast is likely to be used after conventional systemic therapies. As an oral preparation, it has an advantage over parenteral biological therapies. Financial: Production costs, and thus price, is likely to be lower than for biologicals (£8,000-£11,000/year, PAS for golimumab). US price is about 75% of most biologicals. Administration costs will be lower. Tariff: Specified high cost drug. Efficacy: PIII trials (PALACE 1, n=504, PALACE 2, n=495 and PALACE 3, n=495) involved adults with active PsA who failed existing therapy, randomised to apremilast 20mg, 30mg, or placebo. Primary outcome was ACR20 (20% improvement in signs and symptoms) after 16 weeks. In PALACE 1 (published), 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 and benefits are maintained at 52 weeks. All are on-going with total planned durations of 4.5 years. Safety: Most common adverse reactions: diarrhoea, nausea and headache. US prescribing data highlight increased risk of depressive symptoms and also weight loss. CYP450 inducers may reduce efficacy. Guidance/ Guidance: NICE: Arthritis, Psoriasis. Apremilast due August 2015. SIGN: Psoriasis and PsA. reviews: Reviews: NIHR HSC January 2013.

Secukinumab injection; Novartis Pharmacology: First-in-class, fully human monoclonal antibody to interleukin-17A (IL-17A), given by s.c. injection. Indication: Psoriatic arthritis (PsA), second or third-line. Current status: PIII UK availability: 2015 Population: As for apremilast above, the proportion intolerant or unresponsive to TNF-alpha inhibitors is not known. Sector: Secondary care. Implications: Secukinumab is a new option for patients not responding to current therapy. Financial: As a further treatment option after failure of current therapies, it will be additional to current costs. It is likely to be similarly priced to current biological therapies (PAS for golimumab). Tariff: Specified high cost drug. Efficacy: In the on-going FUTURE-1 and FUTURE-2 (planned n=600, n=400) studies, the primary outcome is ACR20 response in patients on secukinumab 75 or 150mg vs. placebo at 24 weeks. Extension studies will assess long term efficacy and safety (up to five years). Another on-going study (planned n=400) is examining use of an autoinjector device using 150 and 300mg doses of secukinumab. Safety: Across all trials, adverse events have been similar to comparators, including etanercept. Guidance/ Guidance: NICE: Arthritis, Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: NIHR HSC September 2012.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 56 No responsibility is accepted for the content of documents derived from this original publication.

Apremilast oral [Otezla]; Celgene Pharmacology: Phosphodiesterase type 4 inhibitor, down-regulates inflammatory response. Indication: Psoriatic arthritis in DMARD-naïve patients. Current status: PIII in EU. Launched in US for active psoriatic arthritis – see prescribing data. UK availability: 2016 Sector: Secondary care initiation, primary care continuation. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: NIHR HSC January 2013.

Ixekizumab injection; Eli Lilly Pharmacology: Humanised monoclonal antibody to interleukin 17, for s.c. administration. Indication: Psoriatic arthritis. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Arthritis, Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: None.

Tofacitinib oral [Xeljanz]; Pfizer Pharmacology: Inhibitor of Janus kinase 3, first-in-class. Indication: Psoriatic arthritis. Current status: PIII UK availability: 2017 Sector: Secondary care initiation, primary care continuation. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Arthritis, Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: None.

Secukinumab injection; Novartis Pharmacology: First-in-class fully-human monoclonal antibody to interleukin-17A (IL-17A), for s.c. administration. Indication: Ankylosing spondylitis, second-line. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Arthritis. reviews: Reviews: NIHR HSC November 2012.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 57 No responsibility is accepted for the content of documents derived from this original publication.

Apremilast oral [Otezla]; Celgene Pharmacology: Phosphodiesterase type 4 inhibitor, down-regulates inflammatory response. Indication: Ankylosing spondylitis. Current status: PIII UK availability: 2017 Sector: Secondary care initiation, primary care continuation. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Arthritis. reviews: Reviews: NIHR HSC November 2012.

Secukinumab oral; Novartis Pharmacology: First-in-class, fully human monoclonal antibody to interleukin-17A, given by s.c. injection. Indication: Rheumatoid arthritis in patients not responding to, or intolerant of, TNF-alpha antagonists. Current status: PIII UK availability: 2016 Sector: Secondary care initiation, primary care continuation. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Arthritis. SIGN: Rheumatoid arthritis. reviews: Reviews: NIHR HSC September 2012.

Baricitinib oral; Eli Lilly Pharmacology: Selective inhibitor of Janus-associated kinase (JAK) 1 and JAK2, JAK3-sparing. Indication: Rheumatoid arthritis. Current status: PIII UK availability: 2016 Sector: Secondary care initiation, primary care continuation. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Arthritis. SIGN: Rheumatoid arthritis. reviews: Reviews: None.

Tofacitinib oral [Xeljanz]; Pfizer Pharmacology: First-in-class inhibitor of Janus kinase 3. Indication: Rheumatoid arthritis, second-line after failure of DMARD. Current status: PIII UK availability: Uncertain due to rejection by CHMP in July 2013 of initial licence application. Sector: Secondary care initiation, primary care continuation. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Arthritis. SIGN: Rheumatoid arthritis. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 58 No responsibility is accepted for the content of documents derived from this original publication.

Lesinurad oral; AstraZeneca Pharmacology: Selective inhibitor of URAT1, a renal transporter that regulates uric acid excretion, first-in-class. Indication: Gout, second-line. Current status: PIII UK availability: 2015 Population: UK prevalence of gout is about 1.5% but only about 61% are eligible for urate-lowering therapy. Of these about 5% are estimated to be unable to take allopurinol (about 450 per 100,000). Sector: Secondary care initiation, primary care continuation. Implications: First in a new class, with potential to improve treatment of patients poorly controlled on current therapy. Financial: As a new drug, likely to increase cost in this therapeutic area. Tariff: Likely HRG included. Efficacy: In the PIII LIGHT study, 214 patients unable to take allopurinol or febuxostat with serum uric acid ≥6.5mg/dl (population mean at baseline was 9.3mg/dl) received lesinurad or placebo. More patients achieved the primary outcome of serum uric acid <6.0mg/dl at 6 months on lesinurad than placebo (p<0.01). Similar PIII trials, CLEAR 1 and CLEAR 2 (each over 600 patients), compared lesinurad plus allopurinol to allopurinol alone. These studies have completed but results are not yet available. Safety: In the LIGHT study, lesinurad was associated with serum creatinine elevations and renal adverse events. Guidance/ Guidance: NICE: Arthritis. reviews: Reviews: NIHR HSC January 2013. Likely NHSE commissioned

Ataluren oral [Translarna]; PTC Therapeutics Pharmacology: Dystrophin synthesis stimulant, exact mechanism of action is uncertain. Indication: Duchenne muscular dystrophy (DMD) resulting from a nonsense mutation (nm) in the dystrophin gene, in ambulatory patients aged 5 years and older. Current status: Conditional licence with orphan drug status granted in EU August 2014. This allows marketing for one year before results from an ongoing PIII trial are available. UK availability: 2014 Population: About 1,500 boys in the UK are known to have DMD at any one time. Of these, about 10-15% (about 150 to 195 patients) have the nonsense mutation (nmDMD). Sector: Secondary or tertiary care. Implications: Current options (corticosteroids) can delay but not prevent loss of walking ability. Ataluren targets the underlying defect in nmDMD, but will benefit only a small proportion of all DMD patients. It is likely to be additional to current therapy in ambulant patients but could prolong independence and delay complications. Significant patient or carer pressure for use is likely. Financial: Likely to be very expensive. Tariff: Specified high cost drug. Efficacy: Conditional licence is based on a published PII trial in 174 boys with nmDMD or nm Becker MD, age ≥5 years treated with 40 or 80mg/kg ataluren daily or placebo. At week 48, mean change from baseline in the primary outcome of 6-minute walk distance did not reach statistical significance for either dose. Post- hoc secondary analyses suggest a possible benefit with the lower dose. A larger PIII study (n=220 target) is in progress and final approval will depend on its results. Safety: Most common adverse effects include headache, nausea and vomiting. Guidance/ NICE: None. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 59 No responsibility is accepted for the content of documents derived from this original publication.

Idebenone oral [Sovrima]; Santhera Pharmacology: Coenzyme Q10 analogue that enhances mitochondrial respiratory chain function. Indication: Duchenne Muscular Dystrophy (DMD). Current status: PIII, orphan drug status in EU and US. UK availability: 2015 Population: DMD affects 1 in 3,600 to 1 in 6,000 live male births. About 100 boys are diagnosed in the UK annually and about 1,500 are known to have the disease at any one time. Sector: Secondary care. Implications: Unlike ataluren, idebenone would potentially be suitable for all affected patients. If effective, therapy will be life-long. In view of the limited options, this will be attractive. Financial: Idebenone cost will be additional to other treatment costs and, as an orphan drug, it is likely to be expensive. Tariff: Likely specified high cost drug. Efficacy: The PIII DELOS study compared idebenone 900mg daily vs. placebo in 240 boys aged 10 to 18 years. Results suggest the primary outcome of change in predicted peak expiratory flow over 52 weeks was reduced by 66% for idebenone vs. placebo (p=0.04). Safety: Frequency of adverse events in trials was comparable to placebo. Guidance/ NICE: None. reviews: Reviews: None.

Drisapersen injection; Prosensa Pharmacology: Dystrophin synthesis stimulant. Antisense oligonucleotide that corrects reading of faulty dystrophin gene with exon 51 mutations, for s.c. injection. Indication: Duchenne muscular dystrophy resulting from a mutation in the dystrophin gene at exon 51. Current status: PIII with orphan status in EU and US. Breakthrough therapy designation in US. UK availability: 2016 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ NICE: None. reviews: Reviews: NIHR HSC September 2012.

Eteplirsen injection; Sarepta Therapeutics Pharmacology: Dystrophin synthesis stimulant. Antisense oligonucleotide that corrects reading of faulty dystrophin gene with exon 51 mutations, for i.v. injection. Indication: Duchenne muscular dystrophy resulting from a mutation in the dystrophin gene at exon 51. Current status: PII with orphan status in EU and US. UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ NICE: None. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 60 No responsibility is accepted for the content of documents derived from this original publication.

Epratuzumab injection [Epratucyn]; UCB Pharmacology: Humanised monoclonal antibody that binds to and modulates CD22 antigen on B-cells, given by weekly i.v infusion. Indication: Systemic lupus erythematosus (SLE). Current status: PIII, with fast-track status in US. UK availability: 2016 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ NICE: SLE. reviews: Reviews: None.

Forigerimod injection [Lupuzor]; ImmuPharma Pharmacology: Oligopeptide that modulates a subset of CD4 T cells, given by monthly s.c. injection. Indication: Systemic lupus erythematosus (SLE). Current status: PIII with fast-track status in US. UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ NICE: SLE. reviews: Reviews: None. BNF 11. Eye Likely CCG commissioned

Aflibercept intravitreal injection [Eylea]; Bayer Pharmacology: A fully human, soluble VEGF receptor fusion protein that binds VEGF-A and placental growth factor, given by intravitreal injection. Indication: Macular oedema, secondary to branch retinal vein occlusion (BRVO). Current status: Filed in EU June 2014. UK availability: 2014 (licence extension). Population: Data from studies suggest a prevalence of 5.2 cases per 1,000 people of retinal vein occlusion, of which 4.42 are BRVO and 0.8 central RVO, typically occurring in patients >50 years of age. Sector: Secondary care. Implications: BRVO is three times more common than central RVO, which aflibercept is already licensed for. It is an alternative to dexamethasone implant, ranibizumab and laser therapy. Financial: List price of aflibercept is £816 per dose (PAS available), of ranibizumab is £742 per dose (PAS available) and dexamethasone implant is £870. Tariff: Specified high cost drug. Efficacy: In the PIII VIBRANT study, 183 patients received aflibercept 2mg monthly or laser treatment. The primary outcome at week 24 (gaining 15 letters in best-corrected visual acuity from baseline) was achieved by 53% vs. 27%, respectively (p<0.001). At week 24, patients initially randomised to aflibercept continued with dosing every two months, while those who initially received laser continued unless they qualified for rescue therapy with aflibercept. Safety: See medicines.org.uk. Guidance/ Guidance: None. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 61 No responsibility is accepted for the content of documents derived from this original publication.

Ciclosporin A ophthalmic emulsion [Ikervis]; Santen Pharmacology: Ciclosporin is an immunomodulating drug that reduces ocular inflammation by enhancement or restoration of lacrymal gland secretion. Presented as a 0.1%w/w ophthalmic emulsion applied once daily. Indication: Severe keratoconjunctivitis sicca (dry eye). Current status: Filed in EU December 2013. UK availability: 2014 Population: Dry eye syndrome is a common condition affecting up to a third of those aged over 65 years. It can have significant effects on quality of life and common vision-related daily activities, such as driving and reading. Sector: Secondary care. Implications: Currently ophthalmic ciclosporin preparations are unlicensed in the UK. Financial: Likely to be more expensive then topical tear replacement treatments. Tariff: HRG included. Efficacy: A 6-month PIII study (n=492), showed improvements in ciclosporin-treated patients vs. vehicle in mean corneal fluorescein staining change from baseline at month 1 (-0.77 vs. -0.52, p=0.002), month 3 (-0.92 vs. -0.70, p=0.030) and month 6 (-1.05 vs. -0.82, p=0.009). Another PIII study followed by an extension phase to assess sustainability of effect is ongoing. Safety: No major safety issues. Unlicensed ophthalmic ciclosporin products have been available for many years. Guidance/ Guidance: NICE: Ciclosporin for treating dry eye disease due August 2015. reviews: Reviews: NIHR HSC June 2012.

E10030 injection; Novartis Pharmacology: Anti-PDGF pegylated aptamer given by intravitreal injection, first-in-class. Indication: Age-related macular degeneration (wet), in combination with anti-VEGF therapy. Current status: PIII UK availability: 2017 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: None. reviews: Reviews: None. Likely NHSE commissioned

Sirolimus injection [Opsiria]; Santen Pharmacology: Blocks leukocyte activation and production of inflammatory cytokines by inhibiting mTOR, given by intravitreal injection. Indication: Uveitis, (posterior, non-infectious). Current status: PIII in EU with orphan status. UK availability: 2016 Sector: Secondary care. Uveitis is a specialised service Tariff: Likely specified high cost drug. Guidance/ Guidance: None. reviews: Reviews: NIHR HSC January 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 62 No responsibility is accepted for the content of documents derived from this original publication.

BNF 13. Skin Likely CCG commissioned

Apremilast oral [Otezla]; Celgene Pharmacology: Type 4 cyclic nucleotide phosphodiesterase inhibitor, first-in-class. Indication: Plaque psoriasis, moderate-to-severe. Current status: Filed in EU January 2014. UK availability: 2015 Population: The prevalence of psoriasis in England is estimated to be 1.3-2.2%, with plaque psoriasis accounting for 90% of cases. About 20% of people have moderate to severe disease (230-400 per 100,000 people). Sector: Secondary care initiation, primary care continuation. Implications: Likely to be used as an additional option after current first line systemic treatments have failed or are contraindicated and before moving on to biologics. Financial: As an oral formulation, drug and administration costs are likely to be lower than biologic therapies. PAS available for ustekinumab. Tariff: Specified high cost drug. Efficacy: In two ongoing PIII studies apremilast is compared with placebo for 16 weeks, followed by a 16 week maintenance phase where the placebo group are switched to active treatment and a 16 week randomised withdrawal phase. In ESTEEM 1 (n=844), at 16 weeks 33.1% of patients achieved the primary outcome of PASI-75 (75% reduction in symptoms) vs. 5.3% on placebo (p<0.0001, NNT=4). Around a third of patients were systemic and/or phototherapy treatment-naïve and nearly 30% had prior biologic therapy. In ESTEEM 2 (n=413), 28.8% of patients achieved PASI-75 vs. 5.8% on placebo at 16 weeks (p<0.0001, NNT=4). A PIII study vs. placebo with etanercept active comparator, in biologic naïve patients, is ongoing. Safety: Adverse effects include diarrhoea, nausea and upper respiratory tract infection. Guidance/ Guidance: NICE: Psoriasis. Apremilast due August 2015. SIGN: Psoriasis and PsA. reviews: Reviews: NIHR HSC January 2013.

Secukinumab injection; Novartis Pharmacology: Fully human monoclonal antibody targeting interleukin-17A (IL-17A) given by s.c. injection weekly for the first 5 weeks and then monthly, first-in-class. Indication: Plaque psoriasis, moderate-to-severe. Current status: Filed in EU and US December 2013. UK availability: 2015 Population: As for apremilast above. Sector: Secondary care. Implications: Likely to be used second line to standard treatments, as an alternative to available biologics but it targets a different immunological mediator to current options. Likely to be marketed in self-administration device. Financial: Likely to be similar to other biologics (£9,500-£13,500/year). PAS available for ustekinumab. Tariff: Specified high cost drug. Efficacy: In the 52-week PIII ERASURE study (n=738), the co-primary outcomes of PASI-75 and Investigators Global Assessment (IGA) at 12 weeks was achieved by 72% on 150mg secukinumab, 82% on 300mg and 5% on placebo (p<0.001) and 51%, 65% and 2% respectively (p<0.001). In the PIII FIXTURE study (n=1,306), for 150mg, 300mg and placebo 12-week PASI-75 was 67%, 77%, 5% (p<0.001) and IGA was 51%, 63% and 3% respectively (p<0.001). Comparison vs. etanercept was a secondary outcome with PASI 75 and IGA achieved by 44% and 27% on etanercept (p<0.001 for superiority of both secukinumab doses vs. etanercept). In FEATURE (pre-filled syringes) and JUNCTURE (auto-injector) secukinumab was superior (p<0.0001) to placebo for PASI-75 and IGA at week 12. SCULPTURE is assessing fixed interval 4-weekly dosing vs. ‘retreatment as needed’ in secukinumab responders, SIGNATURE is assessing secukinumab in those who failed on TNF-alpha inhibitors and a PIII study is comparing secukinumab with ustekinumab. PIII extension studies (n=1,144 and n=674) are collecting 2-year data. Safety: Adverse effects include nasopharyngitis, headache, respiratory tract infections and diarrhoea. Neutropenia has been reported in PII studies. Guidance/ Guidance: NICE: Psoriasis. Secukinumab due July 2015. SIGN: Psoriasis and PsA. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 63 No responsibility is accepted for the content of documents derived from this original publication.

Ustekinumab injection [Stelara]; Janssen-Cilag Pharmacology: Fully human monoclonal antibody that inhibits interleukin 12 and interleukin 23, given by s.c. injection at 0 and 4 weeks and every 12 weeks thereafter. Indication: Plaque psoriasis, moderate-to-severe, in adolescents. Current status: PIII UK availability: 2015 (licence extension). Population: The prevalence of psoriasis in those aged between 10 and 19 years is around 1.4% which suggests that around 40,000 children and adolescents in this age group are affected by psoriasis in the UK. The estimated prevalence of people with severe psoriasis currently eligible for biological therapy in England is 1.1% of those with psoriasis, equivalent to around 717 adolescents in England and Wales. Sector: Secondary care. Implications: Etanercept is currently the only licensed option for this indication in children and adolescents. If ustekinumab dosing schedule follows that of adults then it will be attractive as fewer doses will be required vs. etanercept. Financial: Cost of initial 24 weeks treatment with ustekinumab 45mg based on list price is £8,588 (week 0, 4, 12 and 24) but a PAS is available. Cost for 24 weeks etanercept 50mg (weekly) is £4,290. Tariff: Specified high cost drug. Efficacy: In the PIII CADMUS study 110 adolescents aged 12 to 18 years received low dose (0.375 mg/kg for <60kg or fixed doses of 22.5mg or 45mg based on weight), high dose (0.75mg/kg for <60 kg or fixed doses of 45mg or 90 mg based on weight) or placebo. The primary outcome is the proportion of patients who achieve a Physician’s Global Assessment score of cleared or minimal disease at 12 weeks. The study is completed but results not published. Safety: See medicines.org.uk. Guidance/ Guidance: NICE: Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: NIHR HSC June 2013.

Dimethyl fumarate oral; Almirall Pharmacology: Fumaric acid derivative. Indication: Plaque psoriasis, moderate-to-severe. Current status: PIII UK availability: 2016 Sector: Secondary care initiation, primary care continuation. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: NIHR HSC December 2013.

Ixekizumab injection; Eli Lilly Pharmacology: Fully human anti–interleukin-17 monoclonal antibody, given by s.c. injection. Indication: Plaque psoriasis, moderate to severe. Current status: PIII UK availability: 2016 Sector: Secondary care. Tariff: Likely specified high cost drug. Guidance/ Guidance: NICE: Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 64 No responsibility is accepted for the content of documents derived from this original publication.

Tofacitinib oral [Xeljanz]; Pfizer Pharmacology: Janus kinase 3 inhibitor. Indication: Chronic plaque psoriasis, moderate to severe. Current status: PIII UK availability: 2016 Sector: Secondary care initiation, primary care continuation. Tariff: Specified high cost drug. Guidance/ Guidance: NICE: Psoriasis. SIGN: Psoriasis and PsA. reviews: Reviews: NIHR HSC November 2012. Likely NHSE commissioned

Afamelanotide implant [Scenesse]; Clinuvel Pharmacology: Analogue of α-melanocyte-stimulating hormone (α-MSH), delivered via a biodegradable, controlled release, subcutaneous implant given every 2 months. First in class. Indication: Prevention of erythropoietic protoporphyria (EPP). Current status: Filed in EU February 2012 with orphan status, EMA extended review period to June 2014. Launched in Italy (2010). UK availability: 2014 Population: EPP is an inherited disorder characterised by protoporphyrin accumulation and cutaneous manifestations of photosensitivity such as pain, redness and swelling. EPP worldwide prevalence is estimated between 1 per 75,000 and 1 per 200,000 but there may be 5,000-10,000 people worldwide with EPP. Sector: Secondary or tertiary care. Implications: There are currently no treatments available for EPP. Management strategies include avoiding sun exposure and using sunscreens. Financial: Likely to be expensive. Tariff: Specified high cost drug. Efficacy: In the 12-month PIII CUV017 study (n=91), afamelanotide reduced the total number of days that patients experienced pain (p=0.0023) and pain severity (p=0.0017) vs. placebo. 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 (primary outcome, p=0.044) and a lower total median pain score (secondary outcome, 6.0 vs. 17.5, p=0.035). In a 6 month PIII US study CUV039 (n=93) afamelanotide failed to show significant benefit vs. placebo for the primary outcome of duration of direct sunlight exposure between 10:00 and 18:00 hours on days when no pain was experienced (p=0.107). The EMA has extended its review period to June 2014 to examine the results of CUV039. Safety: No serious safety concerns reported, but long term data are lacking. Guidance/ Guidance: None. reviews: Reviews: None recent.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 65 No responsibility is accepted for the content of documents derived from this original publication.

Table 2. Drugs in Prescribing Outlook 2013 - development delayed Generic and trade name Company Indication and reason for delay. Belagenpumatucel-L NovaRx Non-small cell lung cancer, second-line. injection Corporation Development discontinued following poor PIII results. Lucanix Bevacizumab injection Roche Breast cancer, early HER2-positive, adjuvant therapy. Avastin Development discontinued following poor PIII results. Dacomitinib oral Pfizer Non-small cell lung cancer, advanced, second-line plus. Development discontinued following poor PIII results. Desmoteplase injection Lundbeck Stroke, acute ischaemic, within 9 hours of symptom onset. Development status uncertain after poor PIII results. Golimumab injection MSD Juvenile idiopathic arthritis, polyarticular, poor response to methotrexate. Simponi Development status uncertain. Insulin degludec/ insulin Novo Nordisk Diabetes, type 1 and type 2 in adults aspart injection Licensed in the EU. Launch plans for the UK uncertain. Ryzodeg Laquinimod oral Teva Multiple sclerosis, relapsing remitting, first or second-line therapy. Nerventra Not recommended for approval due to safety concerns. See EMA Q&A. Masitinib oral AB Science Pancreatic cancer, advanced, first-line in combination with chemotherapy. Masiviera Not recommended for approval in the EU due to concerns about effectiveness in the overall group of study patients. See EMA Q&A. Masitinib oral AB Science Rheumatoid arthritis not responding to standard therapy. Remains in PIII in EU. Nalfurafine injection Fresenius Pruritus, uraemic dialysis-related. Winfuran Medical Care EU filing withdrawn after CHMP issued a negative opinion due to concerns about effectiveness. See EMA Q&A. Omacetaxine Hospira Chronic myelogenous leukaemia, after failure of two tyrosine kinase inhibitors. mepesuccinate injection Launched in the US after accelerated approval but remains in PIII in EU. Omapro Marketing rights transferred from Teva to Hospira in April 2014. Pazopanib oral GlaxoSmith- Ovarian cancer, maintenance after first-line chemotherapy. Votrient Kline EU filing withdrawn after a provisional opinion by CHMP that the benefits of treatment did not outweigh the risks. See EMA Q&A. Rivaroxaban oral Bayer Prevention of stent thrombosis in acute coronary syndrome (ACS). Xarelto EU plans uncertain. Questions raised in the US suggest it will not be approved for this indication in the US with current data. Serelaxin injection Novartis Acute heart failure, decompensated. Reasanz Not recommended for approval in the EU due to concerns about effectiveness. See EMA Q&A. Sorafenib oral Bayer Hepatocellular carcinoma, adjuvant therapy. Nexavar Development status uncertain after poor PIII results. Trametinib oral GlaxoSmith- Malignant melanoma, unresectable or metastatic BRAFV600-positive, first-line Mekinist Kline in combination with dabrafenib. EU filing for combination therapy withdrawn. Updated PIII data will be presented in a resubmission. Dabrafenib was licensed as monotherapy for unresectable or metastatic malignant melanoma in July 2014. Vintafolide injection MSD Ovarian cancer, advanced platinum-resistant, folate receptor (FR)-positive, Vynfinit second-line. EU filing withdrawn following poor PIII results. Conditional licence had already been granted. Development suspended. See EMA Q&A.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 66 No responsibility is accepted for the content of documents derived from this original publication.

Table 3. Recent UK drug launches or licence extensions (Sep 2013 to Aug 2014)

Generic and brand Indication and relevant guidance. Full prescribing information can be found on the electronic name. Company. medicines compendium at medicines.org.uk via brand name link. BNF 1. Gastrointestinal system Golimumab Licence extension: Treatment of moderate to severe ulcerative colitis in adults – second-line. Simponi - SmPC Guidance: NICE: Inflammatory bowel disease. Golimumab due January 2015. MSD SMC: Due September 2014. Reviews: LMEN March 2014. Vedolizumab Licensed indication: Treatment of moderate to severe ulcerative colitis, second-line. Entyvio - SmPC Guidance: NICE: Inflammatory bowel disease. Vedolizumab due April 2015. Takeda Reviews: NIHR HSC April 2013. Vedolizumab Licensed indication: Treatment of moderate to severe Crohn's disease, second-line. Entyvio - SmPC Guidance: NICE: Inflammatory bowel disease. Vedolizumab due June 2015. Takeda Reviews: NIHR HSC April 2013. Lubiprostone Licensed indication: Treatment of chronic idiopathic constipation. Amitiza - SmPC Guidance: Constipation. Lubiprostone. SMC: Not approved. Sucampo Reviews: NIHR HSC July 2012. BNF 2. Cardiovascular system

Apixaban Licence extension: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), Eliquis - SmPC and prevention of recurrent DVT and PE. Bristol Myers Squibb/ Guidance: NICE: Embolism and thrombosis. Apixaban due June 2015. SIGN: VTE. Pfizer Reviews: NIHR HSC August 2013. Dabigatran Licence extension: Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), Pradaxa - SmPC and prevention of recurrent DVT and PE. Boehringer Ingelheim Guidance: NICE: Embolism and thrombosis. Dabigatran due October 2014. SMC: Due October 2014. SIGN: VTE. Reviews: None recent. Defibrotide Licensed indication: Treatment of hepatic veno-occlusive disease in adults and children Defitelio - SmPC undergoing haematopoietic stem cell transplant. Jazz Guidance: NICE: Cardiovascular conditions: general and other. SMC: Approved June 2014. Reviews: LNDG September 2013. Lomitapide Licensed indication: Homozygous familial hypercholesterolaemia in adults. Lojuxta - SmPC Guidance: NICE: Lipid disorders. SMC: Not approved. SIGN: Cardiovascular disease. Aegerion Reviews: None. Macitentan Licensed indication: Pulmonary arterial hypertension in adults. Opsumit - SmPC Guidance: NICE: Hypertension. SMC: Restricted use. Actelion Reviews: None. Riociguat Licensed indication: Pulmonary arterial hypertension and chronic thromboembolic pulmonary Adempas - SmPC hypertension. Bayer Guidance: NICE: Hypertension. SMC: Due December 2014. Reviews: None recent. BNF 3. Respiratory system Fluticasone furoate/ Licensed indication: Asthma in adults and adolescents aged 12 years and older. vilanterol Guidance: NICE: Asthma. SMC: Approved. SIGN: Asthma. AWMSG: Recommended. Relvar Ellipta - SmPC Reviews: NICE-ES March 2014, RDTC January 2014. GlaxoSmithKline Fluticasone furoate/ Licensed indication: Chronic obstructive pulmonary disease (COPD) in adults. vilanterol Guidance: NICE: COPD. SMC: Restricted use. AWMSG: Recommended. Relvar Ellipta - SmPC Reviews: MTRAC March 2014, NICE-ES June 2013. GlaxoSmithKline

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 67 No responsibility is accepted for the content of documents derived from this original publication.

Olodaterol Licensed indication: Chronic obstructive pulmonary disease (COPD). Striverdi Respimat - Guidance: NICE: COPD. SMC: Not approved. AWMSG: In progress. SmPC Reviews: None. Boehringer Ingelheim Umeclidinium/ Licensed indication: Chronic obstructive pulmonary disease (COPD). vilanterol Guidance: NICE: COPD. SMC: Not approved. AWMSG: In progress. Anoro - SmPC Reviews: NIHR HSC February 2012, NICE-ES due September 2014. GlaxoSmithKline Ivacaftor Licence extension: Cystic fibrosis in patients aged six years and older who have one of the Kalydeco - SmPC following gating (class III) CFTR gene mutations: G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R. Vertex Guidance: NICE: Cystic fibrosis. NHSE: Clinical commissioning policy March 2012. Reviews: NIHR HSC August 2014. Omalizumab License extension: Chronic spontaneous urticaria in adults and children aged over 12 years who Xolair - SmPC have had an inadequate response to H1 antihistamines. Novartis Guidance: NICE: Skin conditions: general and other, Omalizumab due April 2015. Reviews: NIHR HSC September 2012. BNF 4. Central nervous system Fentanyl New formulation: Buccal film for breakthrough pain in adults with cancer who are already Breakyl - SmPC receiving maintenance opioid therapy for chronic cancer pain. Meda Guidance: NICE: Cancer. SIGN: Cancer pain. SMC: Not approved. Reviews: None. Granisetron patch New formulation: Prevention of nausea and vomiting associated with moderately or highly Sancuso - SmPC emetogenic chemotherapy in adults. ProStrakan Guidance: NICE: Complications of cancer. SMC: Approved. Reviews: UKMi November 2013. Aripiprazole New formulation: Schizophrenia – once-monthly i.m. depot injection. Abilify Maintena - SmPC Guidance: NICE: Psychosis and Schizophrenia. SMC: Approved. SIGN: Schizophrenia. Otsuka AWMSG: Recommended. Reviews: NICE-ES March 2014. Loxapine Licensed indication: Acute agitation associated with schizophrenia or bipolar disorder. Adasuve - SmPC Guidance: NICE: Psychosis and Schizophrenia. Bipolar disorder, Loxapine. Grupo Ferrer SIGN: Schizophrenia, Bipolar disorder. Reviews: RDTC June 2013, LNDG February 2013. Lurasidone Licensed indication: Schizophrenia. Latuda - SmPC Guidance: NICE: Psychosis and schizophrenia. SMC: Due October 2014. Takeda SIGN: Schizophrenia. AWMSG: In progress. Reviews: NICE-ES April 2013. Paliperidone Licence extension: Schizophrenia in adolescents aged 15 years and older. Invega - SmPC Guidance: NICE: Psychosis and schizophrenia. SIGN: Schizophrenia. Janssen-Cilag Reviews: None. Zonisamide Licence extension: Epilepsy, adjunct in adolescents and children aged six years and older. Zonegran - SmPC Guidance: NICE: Epilepsy. SMC: Restricted use. SIGN: Epilepsy in adults. Eisai Reviews: NICE-ES March 2014. Botulinum A toxin A Licence extension: Stroke-associated ankle disability. Botox- SmPC Guidance: SMC: Not approved. Allergan Reviews: NIHR HSC February 2014. BNF 5. Infections Bedaquiline Licensed indication: Tuberculosis, pulmonary multi-drug resistant. Sirturo - SmPC Guidance: NICE: Tuberculosis. WHO: interim guidance on use of bedaquiline June 2013. Janssen-Cilag Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 68 No responsibility is accepted for the content of documents derived from this original publication.

Delamanid Licensed indication: Tuberculosis, pulmonary multi-drug resistant. Deltyba - SmPC Guidance: NICE: Tuberculosis. Reviews: None. Otsuka Posaconazole New formulation: Treatment and prophylaxis of fungal infection, oral formulation. Noxafil - SmPC Guidance: None. MSD Reviews: None recent. Cobicistat Licensed indication: HIV infection. Tybost - SmPC Guidance: NICE: HIV and AIDs. SMC: Not approved. BHIVA: HIV-1 infection. Gilead Reviews: None. Dolutegravir Licensed indication: HIV infection in adults and adolescents from age 12 years. Tivicay - SmPC Guidance: NICE: HIV and AIDs. SMC: Approved. AWMSG: In progress. BHIVA: HIV-1 infection. ViiV Healthcare Reviews: LMEN January 2014. Elvitegravir Licensed indication: HIV infection in adults. Vitekta - SmPC Guidance: NICE: HIV and AIDs. BHIVA: HIV-1 infection. Gilead Reviews: None. Simeprevir Licensed indication: Chronic hepatitis C infection (genotype 1 and 4) in adults – treatment- Olysio - SmPC experienced / treatment-naïve / with sofosbuvir. Janssen-Cilag Guidance: NICE: Hepatitis. Simeprevir due January 2015. SMC: Due September 2014. SIGN: Hepatitis C. Reviews: NIHR HSC treatment naïve September 2012, failed interferon September 2012. Sofosbuvir Licensed indication: Chronic hepatitis C infection. Sovaldi - SmPC Guidance: NICE: Hepatitis. Sofosbuvir due November 2014. SMC: Restricted use. Gilead SIGN: Hepatitis C. Reviews: NIHR HSC September 2012. BNF 6. Endocrine system Alogliptin Licensed indication: Type 2 diabetes mellitus. Vipidia - SmPC Guidance: NICE: Diabetes. SMC: Not approved, resubmission due September 2014. Takeda SIGN: Diabetes. AWMSG: In progress. Reviews: MTRAC May 2014, NICE-ES May 2013. Alogliptin/ metformin Licensed indication: Type 2 diabetes mellitus. Vipdomet - SmPC Guidance: NICE: Diabetes. SMC: Due September 2014. SIGN: Diabetes. AWMSG: In progress. Takeda Reviews: None. Canagliflozin Licensed indication: Type 2 diabetes mellitus. Invokana - SmPC Guidance: NICE: Diabetes. Canagliflozin due January 2016. SMC: Restricted use. Janssen-Cilag SIGN: Diabetes. Reviews: RDTC March 2014. Dapagliflozin/ Now formulation: Type 2 diabetes mellitus. metformin Guidance: NICE: Diabetes. SMC: Restricted use. SIGN: Diabetes. Xigduo - SmPC Reviews: None recent. Bristol Myers Squibb/ AstraZeneca EEIG Insulin degludec Licence extension: Type 2 diabetes mellitus, in combination with GLP-1 receptor agonists. Tresiba - SmPC Guidance: NICE: Diabetes. SIGN: Diabetes. Novo Nordisk Reviews: NICE-ES September 2013. Linagliptin/ metformin Licence extension: Type 2 diabetes mellitus, in combination with insulin. Jentadueto - SmPC Guidance: NICE: Diabetes. SIGN: Diabetes. AWMSG: Recommended. Boehringer Ingelheim Reviews: None. Liraglutide Licence extension: Type 2 diabetes mellitus, in combination with insulin. Victoza - SmPC Guidance: NICE: Diabetes. SIGN: Diabetes. Novo Nordisk Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 69 No responsibility is accepted for the content of documents derived from this original publication.

BNF 7. Obstetrics, gynaecology, and urinary-tract disorders Botulinum A toxin Licence extension: Overactive bladder. (onabotulinum-toxin A) Guidance: NICE: Urinary incontinence. SMC: Not approved. SIGN: Urinary incontinence. Botox - SmPC Reviews: NICE-ES September 2012. Allergan Solifenacin/ tamsulosin Licensed indication: Benign prostatic hyperplasia-associated lower urinary tract symptoms. Vesomni - SmPC Guidance: NICE: Lower urinary tract symptoms. SMC: Approved. Astellas Reviews: None. Alprostadil Licensed indication: Erectile dysfunction. Vitaros - SmPC Guidance: NICE: Sexual health: general and other. Takeda Reviews: None. Avanafil Licensed indication: Erectile dysfunction. Spedra - SmPC Guidance: NICE: Sexual health: general and other. A. Menarini Reviews: NICE-ES August 2014, MTRAC August 2014. Farmaceutica Dapoxetine Licensed indication: Premature ejaculation. Priligy - SmPC Guidance: NICE: Sexual health: general and other. SMC: Not approved. A. Menarini Reviews: NICE-ES May 2014, LMEN January 2014, MTRAC November 2013, RDTC October Farmaceutica 2012. Levonorgestrel Licensed indication: Contraception for up to three years. Jaydess - SmPC Guidance: NICE: Contraception. Bayer Reviews: NICE-ES June 2014. BNF 8. Malignant disease and immunosuppression Sorafenib Licence extension: Thyroid cancer, differentiated, locally advanced or metastatic, radioactive- Nexavar - SmPC iodine refractory. Bayer Guidance: NICE: Head and neck cancers. Reviews: None recent. Afatinib Licensed indication: Locally advanced or metastatic non-small cell lung cancer, EGFR mutation. Giotrif - SmPC Guidance: NICE: Lung cancer, Afatinib. SMC: Approved. SIGN: Lung cancer. Boehringer Ingelheim Reviews: None recent. Trastuzumab Licensed indication: Breast cancer, HER2-positive, unresectable locally advanced or metastatic. emtansine Guidance: NICE: Breast cancer. Trastuzumab emtansine due August 2014. Kadcyla - SmPC SMC: Restricted use. SIGN: Primary breast cancer. Roche Reviews: None recent. Trastuzumab/ New formulation: Subcutaneous formulation, HER2-positive early and metastatic breast cancer. hyaluronidase Guidance: NICE: Breast cancer. SMC: Due September 2014. SIGN: Primary breast cancer. Herceptin - SmPC Reviews: NICE-ES March 2013. Roche Regorafenib Licence extension: Gastrointestinal stromal tumours, metastatic or unresectable, third-line. Stivarga - SmPC Guidance: NICE: Stomach cancer. SIGN: Oesophageal and gastric cancer. Bayer Reviews: None. Regorafenib Licensed indication: Colorectal cancer, metastatic, second and subsequent line. Stivarga - SmPC Guidance: NICE: Colorectal cancer. Regorafenib suspended. SIGN: Colorectal cancer. Bayer Reviews: None recent. Paclitaxel albumin- Licence extension: Metastatic pancreatic carcinoma, first-line in combination with gemcitabine. bound Guidance: NICE: Pancreatic cancer. Paclitaxel due January 2015. SMC: Not approved. Abraxane - SmPC AWMSG: In progress. Celgene Reviews: NIHR HSC January 2013. Bevacizumab Licence extension: Ovarian, fallopian tube or primary peritoneal cancer, platinum-resistant. Avastin - SmPC Guidance: NICE: Ovarian cancer. SIGN: Ovarian cancer. Roche Reviews: NIHR HSC January 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 70 No responsibility is accepted for the content of documents derived from this original publication.

Leuprorelin Licence extension: Prostate cancer, neo-adjuvant treatment prior to radiotherapy. Prostap - SmPC Guidance: NICE: Prostate cancer. AWMSG: In progress. Takeda Reviews: None. Radium-223 dichloride Licensed indication: Bone metastases in adults with castration-resistant prostate cancer. Xofigo - SmPC Guidance: NICE: Prostate cancer, Metastases, Radium-223 dichloride due September 2014. Bayer Reviews: None recent. Dabrafenib Licensed indication: Unresectable or metastatic melanoma, BRAF V600 mutation. Tafinlar - SmPC Guidance: NICE: Skin cancer, Dabrafenib due December 2014. SIGN: Cutaneous melanoma. GlaxoSmithKline Reviews: None recent. Ipilimumab Licence extension: Advanced (unresectable or metastatic) melanoma, first-line. Yervoy - SmPC Guidance: NICE: Skin cancer, Ipilimumab. SIGN: Cutaneous melanoma. Bristol Myers Squibb Reviews: None recent. Rituximab New formulation: Subcutaneous formulation for non-Hodgkin's lymphoma. MabThera - SmPC Guidance: NICE: Blood and bone marrow cancers. SMC: Restricted use. AWMSG: In progress. Roche Reviews: NICE-ES due August 2014. Pixantrone Licensed indication: Aggressive non-Hodgkin’s B-cell lymphoma, relapsed or refractory. Pixuvri - SmPC Guidance: NICE: Blood and bone marrow cancers. Pixantrone. Cell Therapeutics Reviews: None recent. Bortezomib Licence extension: Multiple myeloma, with dexamethasone or pegylated liposomal doxorubicin. Velcade - SmPC Guidance: NICE: Blood and bone marrow cancers. AWMSG: In progress. Janssen-Cilag Reviews: NIHR HSC September 2012. Obinutuzumab Licensed indication: Chronic lymphocytic leukaemia, first-line in combination with chlorambucil. Gazyvaro - SmPC Guidance: NICE: Blood and bone marrow cancers. Roche Reviews: NIHR HSC June 2012. Ofatumumab Licence extension: Chronic lymphocytic leukaemia, first-line with chlorambucil or bendamustine. Arzerra - SmPC Guidance: NICE: Blood and bone marrow cancers. GlaxoSmithKline Reviews: NIHR HSC February 2012. Alemtuzumab Licensed indication: Relapsing remitting multiple sclerosis. Lemtrada - SmPC Guidance: NICE: Multiple sclerosis. Alemtuzumab. SMC: Approved. Genzyme Reviews: None recent. Dimethyl fumarate Licensed indication: Relapsing remitting multiple sclerosis. Tecfidera - SmPC Guidance: NICE: Multiple sclerosis, Dimethyl fumarate. SMC: Approved. Biogen Idec Reviews: None recent. Teriflunomide Licensed indication: Relapsing remitting multiple sclerosis. Aubagio - SmPC Guidance: NICE: Multiple sclerosis. Teriflunomide. SMC: Restricted use. Genzyme Reviews: None recent. BNF 9. Nutrition and blood Lipegfilgrastim Licensed indication: Chemotherapy-induced neutropenia. Lonquex - SmPC Guidance: NICE: Complications of cancer. SMC: Restricted use. Teva AWMSG: Recommended with restrictions. Reviews: None. Colestilan Licensed indication: Hyperphosphataemia in dialysed adults with chronic kidney disease. BindRen - SmPC Guidance: NICE: Chronic kidney disease. SMC: Not approved. AWMSG: In progress. Mitsubishi Pharma Reviews: UKMi December 2013. Elosulfase alfa Licensed indication: Mucopolysaccharidosis type IVA (Morquio A syndrome). Vimizim - SmPC Guidance: NICE: Draft scope March 2014. BioMarin Reviews: NIHR HSC June 2012.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 71 No responsibility is accepted for the content of documents derived from this original publication.

Eltrombopag Licensed indication: Thrombocytopenia associated with hepatitis C infection in adults. Revolade - SmPC Guidance: NICE: Blood conditions, Hepatitis. SMC: Approved. SIGN: Hepatitis C. GlaxoSmithKline AWMSG: Recommended. Reviews: None. BNF 10. Musculoskeletal and joint diseases Canakinumab Licence extension: Juvenile idiopathic arthritis, systemic disease in patients aged ≥2 years. Ilaris - SmPC Guidance: NICE: Arthritis. SMC: Not approved. Novartis Reviews: NICE-ES March 2014. Tocilizumab New formulation: Subcutaneous preparation for active rheumatoid arthritis. RoActemra - SmPC Guidance: NICE: Arthritis. SMC: Restricted use. Roche Reviews: None. Certolizumab pegol Licence extension: Active psoriatic arthritis. Cimzia - SmPC Guidance: NICE: Arthritis. SMC: Restricted use. AWMSG: In progress. UCB Reviews: NICE-ES June 2014. Ustekinumab Licence extension: Active psoriatic arthritis. Stelara - SmPC Guidance: NICE: Arthritis. Ustekinumab. SMC: Approved. SIGN: Psoriasis and PsA. Janssen-Cilag Reviews: NIHR HSC September 2012. Certolizumab pegol Licence extension: Severe active axial spondyloarthritis. Cimzia - SmPC Guidance: NICE: Arthritis. SMC: Approved. AWMSG: In progress. UCB Pharma Reviews: None. Denosumab Licence extension: Osteoporosis in men at increased risk of fracture. Prolia - SmPC Guidance: NICE: Osteoporosis. Amgen Reviews: None recent. BNF 11. Eye Aflibercept Licence extension: Macular oedema secondary to central retinal vein occlusion. Eylea - SmPC Guidance: NICE: Macular oedema and retinal vein occlusion, Aflibercept. SMC: Approved. Bayer Reviews: None. Aflibercept Licence extension: Diabetic macular oedema. Eylea - SmPC Guidance: NICE: Macular oedema and retinal vein occlusion, Aflibercept due June 2015. Bayer SMC: Due November 2014. Reviews: NIHR HSC June 2013. BNF 13. Skin Brimonidine Licensed indication: Facial erythema of rosacea. Mirvaso - SmPC Guidance: NICE: Skin conditions: general and other. Galderma Reviews: NICE-ES July 2014, RDTC June 2014. BNF 14. Vaccines Human papillomavirus Licence extension: Prevention of premalignant anal lesions and anal cancers. vaccine Guidance: DH: routine vaccination schedule 2013/14. Gardasil - SmPC Reviews: None. Sanofi Pasteur MSD Immunoglobulin Licensed indication: Primary and secondary immunodeficiencies. HyQvia - SmPC Guidance: None. Baxter Reviews: None. Meningococcal group- Licensed indication: Prevention of meningococcal disease caused by Neisseria meningitidis B vaccine group B. Bexsero - SmPC Guidance: DH: routine vaccination schedule 2013/14. JCVI: Position statement March 2014. Novartis Reviews: None.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 72 No responsibility is accepted for the content of documents derived from this original publication.

Patent expiries 2014 - 2017

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, see below). Expiry dates below take account of the SPC and any paediatric extension. The table also 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 a generic/biosimilar product will be available in the UK as patent issues differ between countries. Patent legislation is complex and the information below should be used as a guide only. On 26 January 2007, regulation (EC) No. 1901/2006 came into force. This provides the legislative framework to promote development of medicines for use in children. An incentive is the possibility of an extension to the duration of a SPC covering a marketed product. Before this regulation came into force, the maximum duration of an SPC was five years. Now, an SPC covering a product may be extended by six months beyond the term that would otherwise apply. This extension of the term applies to all authorised indications for the product (including the non-paediatric indications). Drugs with a granted paediatric extension are indicated ♦. Note that patent expiries are subject to change when new extensions (SPC or paediatric) are granted or if court decisions alter the patent status of a drug. In addition, the patent expiries detailed only cover the basic, manufacturing patent. Additional patents on formulations and uses can influence when a generic or biosimilar becomes available commercially.

Drug Patent expiry Generic or Drug Patent expiry Generic or date (includes biosimilar date (includes biosimilar paediatric available/ in paediatric available/ in extension ♦) development extension ♦) development

2014 Estradiol + drospirenone May 2015 Alemtuzumab Feb 2014 Glatiramer May 2015 Temoporfin Feb 2014 Insulin glargine May 2015♦ Yes Zanamivir Feb 2014 Tenecteplase Jun 2015 Anakinra May 2014 Etanercept Jul 2015♦ Escitalopram oxalate May 2014 Yes Rasburicase Jul 2015 Abacavir Jun 2014 Yes Bivalirudin Aug 2015 Ulipristal acetate Jun 2014 Strontium ranelate Aug 2015 Trastuzumab Jul 2014 Etoricoxib Sep 2015 Yes Verteporfin Jul 2014 Nateglinide Sep 2015 Palivizumab Aug 2014 Sirolimus Sep 2015 Cetuximab Sep 2014 Alitretinoin Oct 2015 Paliperidone Oct 2014 Palonosetron Nov 2015 Celecoxib Nov 2014 Yes Pimecrolimus Nov 2015 Icatibant acetate Nov 2014 Lopinavir/ritonavir Dec 2015 Almotriptan Dec 2014 Yes Eletriptan hydrobromide Dec 2015 Brinzolamide Dec 2014 Frovatriptan Dec 2015 Yes Pertuzumab Dec 2014 Pemetrexed Dec 2015 2015 2016 Sevelamer Jan 2015 Yes Botulinum toxin type B Jan 2016 Corifollitropin alfa Feb 2015 Yes Emtricitabine Jan 2016 Infliximab Feb 2015♦ Yes Linezolid Jan 2016 Yes Paricalcitol Mar 2015 Agomelatine Feb 2016 Darifenacin Mar 2015 Oseltamivir Feb 2016 Yes Tegafur + uracil Mar 2015 Tiotropium Mar 2016♦ Aripiprazole Apr 2015♦ Bexarotene Apr 2016 Clofarabine May 2015 Tolvaptan Apr 2016♦

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 73 No responsibility is accepted for the content of documents derived from this original publication.

Darbepoetin alfa Jun 2016 Tramadol HCl Apr 2017 Rupatadine Jul 2016 Peginterferon alfa-2a May 2017 Telithromycin Jul 2016 Olopatidine May 2017 Voriconazole Jul 2016♦ Yes Tegafur + gimeracil + May 2017 oteracil Agalsidase /beta Aug 2016 Nitisinone Jun 2017 Adefovir dipivoxil Sep 2016 Rosuvastatin calcium Jun 2017 Yes Ciclesonide Sep 2016 Dutasteride Jul 2017 Valganciclovir Sep 2016 Yes Doripenem Aug 2017 Entecavir Oct 2016 Omalizumab Aug 2017 Travoprost Nov 2016 Yes Pegfilgrastim Aug 2017 Imatinib mesilate Dec 2016♦ Yes Tigecycline Aug 2017 2017 Ivabradine Sep 2017 Velaglucerase alfa Jan 2017 Prasugrel Sep 2017 Bosentan monohydrate Feb 2017 Ezetimibe Oct 2017 Olmesartan medoxomil Feb 2017 Pegvisomant Nov 2017 Bimatoprost Mar 2017 Tadalafil Nov 2017 Caspofungin Apr 2017♦ Abatacept Dec 2017♦ Ertapenem Apr 2017 Retigabine Dec 2017 Melatonin Apr 2017 Parecoxib Apr 2017

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 74 No responsibility is accepted for the content of documents derived from this original publication.

Biosimilar developments

What are biosimilars? Biosimilars is the EU term for ‘generic’ biological medicines also known as ‘follow-on’ biologics in the US or ‘subsequent entry’ biologics in Canada. Unlike conventional ‘chemical’ pharmaceuticals, which are generally low molecular weight organic compounds, biologicals are large complex proteins that cannot be copied exactly. To gain a licence, the manufacturer must provide the EMA with data to show that their biosimilar is physically, chemically, biologically and clinically similar to the approved originator or reference product. This data is 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. Biological drugs are expensive and biosimilars are seen as a cost-saving alternative. Marketed biosimilars are currently 5- 20% cheaper than the originator products. However, they are not viewed as being interchangeable with the originator product; the MHRA recommends prescribing biological products by brand name (1). Patent expiry of biologics is the driver of biosimilar development. For this reason in the table below the UK availability date is reflective of the patent expiry date rather than the date the biosimilar is licensed. As for patents associated with ‘chemical’ generics, this is a complex and commercially sensitive area. There are situations where the UK patent has expired some years ago but there is currently no generic option. The same applies to biosimilar drugs which are more costly and complicated to bring to the market. However, there are also situations where a number of generics are already licensed, and often available elsewhere in the EU, but patent extensions and legal challenges prevent marketing the UK. The same applies to biosimilars, so it becomes difficult to anticipate actual UK availability. Added to this, manufacturers of originator products seek to retain their market share by reformulating to simplify administration, or by offering competitive discounts. 1. MHRA Drug Safety Update, February 2008.

Likely CCG commissioned

Insulin glargine injection [Abasria]; Eli Lilly Pharmacology: As for reference product – Lantus. Given by s.c. injection. Indication: Diabetes mellitus, type 1 and 2, adults, adolescents and children aged 2 years and above. Current status: Recommended for approval June 2014. UK availability: 2014 (Lantus patent expiry November 2014). Population: As for reference product. Sector: Primary care. Implications: Therapeutic equivalence to Lantus demonstrated. It is unclear what presentations will be available. Financial: Likely to be cheaper than Lantus. Tariff: HRG included. Efficacy: PIII studies vs. Lantus have been completed: ELEMENT 1 in 550 adults with type 1 diabetes used in combination with insulin lispro and ELEMENT 2 in 606 adults with type 2 diabetes used with oral hypoglycaemics. Safety: In comparative studies adverse events and immunogenicity profile was similar for Abasria and Lantus. Guidance/ None specific to this product. reviews:

Insulin glargine MK-1293 injection; Biogen Idec Pharmacology: As for reference product – Lantus. Given by s.c. injection. Indication: Diabetes mellitus, type 1 and 2. Current status: PIII UK availability: 2016 (Lantus patent expiry November 2014). Sector: Primary care. Tariff: HRG included. Guidance/ None specific to this product. reviews:

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 75 No responsibility is accepted for the content of documents derived from this original publication.

Etanercept SB-4 injection; Biogen Idec Pharmacology: As for reference product – Enbrel. Given by s.c. injection. Indication: Rheumatoid arthritis, moderate-to-severe, despite methotrexate. Current status: PIII UK availability: 2015 (Enbrel patent expiry October 2015) Population: As for reference product. Implications: Enbrel is licensed for use in methotrexate naïve patients as well as a range of other indications. The licensing authorities may approve use of the biosimilar for the same indications as the reference product without the need for clinical studies in all indications. Sector: Secondary care. Financial: Likely to be cheaper than Enbrel. Tariff: Specified high cost drug. Efficacy: A PIII trial comparing etanercept SB-4 with Enbrel in 498 patients with moderate to severe rheumatoid arthritis, despite treatment with methotrexate, was due to complete June 2014. Safety: As for reference product. Guidance/ None specific to this product. reviews:

Etanercept GP2015 injection; Sandoz Pharmacology: As for reference product – Enbrel. Given by s.c. injection. Indication: Psoriasis, chronic plaque, moderate to severe. Current status: PIII UK availability: 2016 likely date of licence (Enbrel patent expiry October 2015). Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ None specific to this product. reviews:

Follitropin injection [Bemfola]; Finox Biotech Pharmacology: As for reference product – Gonal-f. Bemfola is presented as a single-use disposable pen device, Gonal-f is available as a multidose vial requiring reconstitution and a prefilled pen device. Indication: Fertility disorders. Current status: Approved in EU March 2014. See EPAR and prescribing data. UK availability: 2014 (Gonal-f patent expired 2009). Population: As for reference product. Sector: Secondary care. Implications: Presentation could be more attractive to patients than the reference product. Will be competitor to Ovaleap. Financial: Likely to be cheaper than prefilled pen version of reference product. Tariff: HRG included. 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 December 2013 with completion due December 2014. It is enrolling 1,106 women undergoing in vitro fertilisation and has a primary outcome of clinical pregnancy rate. Safety: As for reference product. Guidance/ None specific to this product. reviews:

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 76 No responsibility is accepted for the content of documents derived from this original publication.

Follitropin injection [Ovaleap]; Teva Pharmacology: As for reference product – Gonal-f. Ovaleap is presented as a multi-use cartridge for use with Ovaleap Pen device. Gonal-f is available as a multidose vial requiring reconstitution and a prefilled pen device. Indication: Fertility disorders, as for Gonal-f. Current status: Approved in EU September 2013. See prescribing data. UK availability: 2015 (Gonal-f patent expired 2009). Population: As for reference product. Sector: Secondary care. Implications: Presentation could be more attractive to patients than the reference product. Will be competitor to biosimilar Bemfola. Financial: Likely to be cheaper than prefilled pen version of the reference product. Tariff: HRG included. Efficacy: An international PIII study in 280 women undergoing assisted reproductive technologies compared Ovaleap to Gonal-f, administered for up to 3 cycles. The primary outcome was number of cumulus oocyte complexes retrieved. Safety: As for reference product. Guidance/ AWMSG not endorsed February 2014 due to non submission reviews:

Infliximab injection [Inflectra/Remsima]; Hospira/Napp Pharmacology: As for reference product – Remicade, including administration details. Indication: Rheumatoid arthritis, adult and paediatric Crohn’s disease, adult and paediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis. Current status: Approved in EU September 2013. See EPAR. Inflectra was launched in some EU countries in February 2014. UK availability: 2015 (Remicade patent expiry February 2015). Population: As for reference product. Sector: Secondary care. Implications: There are a number of infliximab biosimilar preparations in development. This likely to be the first to the UK market. Financial: Will be significantly cheaper than the list price of Remicade. Tariff: Specified high cost drug. Efficacy: Data submitted to the EU licensing authority demonstrating similarity between Inflectra and Remicade consisted of two main clinical trials: a pharmacokinetic study in 257 patients with ankylosing spondylitis (AS) and an efficacy and safety study in 617 patients with rheumatoid arthritis (RA). The AS trial showed comparable profiles between Inflectra and Remicade at steady state (after 5 doses of 5 mg/kg). Data regarding the similarity at 3 mg/kg were provided from the RA study which achieved its primary outcome of demonstrating non-inferiority for ACR20 response rate at week 30, further supported by data at week 54. The EMA concluded Inflectra was biosimilar to Remicade and data allow for extrapolation to all other indications of Remicade. Safety: Adverse drug reactions observed with Inflectra and Remicade were similar with no marked differences in immunogenicity profiles up to 54 weeks. A higher number of serious infections, including active tuberculosis were observed with Inflectra in the RA study but the EMA concluded it was most likely due to chance. Serious infections will be closely monitored post-marketing of Inflectra via various registries as will rare adverse events due to Remicade. Guidance/ NIHR HSC Inflectra psoriatic arthritis May 2013. reviews: NIHR HSC Inflectra ankylosing spondylitis May 2013.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 77 No responsibility is accepted for the content of documents derived from this original publication.

Infliximab SB2 injection; Biogen Idec Pharmacology: As for reference product – Remicade, including administration details. Indication: Rheumatoid arthritis RA, treatment experienced (see note in implications below). Current status: PIII trial ongoing in the UK with primary data collection due August 2014. UK availability: 2015 (Remicade patent expiry February 2015). Population: As for reference product. Sector: Secondary care. Implications: Although only being studied in the RA population, experience with Inflectra above suggests this may be sufficient for an EU licence to be granted for all the indications Remicade is currently licensed for. Financial: This infliximab biosimilar will have to compete with Inflectra above which is likely to be the first available in the UK. Tariff: Specified high cost drug. Efficacy: A PIII trial comparing SB2 with Remicade in 584 patients with moderate to severe RA despite methotrexate therapy is ongoing. The primary outcome is ACR20 response at 30 weeks with study completion due August 2014. A pharmacokinetic study in 159 healthy volunteers that compared SB2 with EU and US sourced Remicade has completed. Safety: As for reference product. Guidance/ None specific to this product. reviews:

Rituximab BI 695500 injection; Boehringer Ingelheim Pharmacology: As for reference product – MabThera. Given by i.v. infusion. Indication: Rheumatoid arthritis, moderate to severe. Current status: PIII UK availability: 2016 (MabThera patent expired 2012). Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ None specific to this product. reviews:

Rituximab PF-05280586 injection; Pfizer Pharmacology: As for reference product – MabThera. Given by i.v. infusion. Indication: Rheumatoid arthritis, moderate to severe. Current status: PII UK availability: 2016 (MabThera patent expired 2012). Sector: Secondary care. Tariff: Specified high cost drug. Guidance/ None specific to this product. reviews:

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 78 No responsibility is accepted for the content of documents derived from this original publication.

Likely NHSE commissioned

Rituximab CT-P10 injection; Sandoz Pharmacology: As for reference product – MabThera. Given by i.v. infusion. Indication: Follicular lymphoma, advanced. Current status: PIII UK availability: 2016 (MabThera patent expired 2012). Sector: Secondary care. CDF: Rituximab not included. Tariff: Chemotherapy. Guidance/ None specific to this product. reviews:

Rituximab BI 695500 injection; Boehringer Ingelheim Pharmacology: As for reference product – MabThera. Given by i.v. infusion. Indication: Follicular lymphoma, first-line. Current status: PIII UK availability: 2016 (MabThera patent expired 2012). Sector: Secondary care. CDF: Rituximab not included. Tariff: Chemotherapy. Guidance/ None specific to this product. reviews:

Trastuzumab CT-P6 injection [Credima] Hospira Pharmacology: As for reference product – Herceptin. Given by i.v. infusion.

Indication: Breast cancer, HER 2 positive, early and metastatic. Gastric cancer, HER2 positive. Current status: Filed in EU for all above indications. UK availability: 2015 (Herceptin patent expiry July 2014). Population: As for reference product. Sector: Secondary care. Implications: Credima will provide competition for Herceptin i.v. infusion. However, Herceptin for s.c. administration is now available. There are a number of other trastuzumab biosimilars for i.v. infusion in development due for launch 2017 or beyond. Financial: Likely to be cheaper than Herceptin. CDF: Trastuzumab not listed. Tariff: Chemotherapy. Efficacy: A PIII trial comparing Credima with Herceptin as neoadjuvant and adjuvant treatment in patients with HER2-positive, early-stage breast cancer in 532 patients began in April 2014. The PIII COMPARE study compared Credima with Herceptin , both in combination with paclitaxel, as first-line therapy in 475 patients with metastatic breast cancer. The primary outcome was overall response rate. Results demonstrate therapeutic equivalence. No studies in gastric cancer can be located. Safety: As for reference product. No difference in serious adverse events in pooled data from comparative trials is noted. Guidance/ None specific to this product. reviews:

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 79 No responsibility is accepted for the content of documents derived from this original publication.

Trastuzumab ABP 980; Amgen Pharmacology: As for reference product – Herceptin. Given by i.v. infusion. Indication: Breast cancer, HER2 positive early disease. Current status: PIII UK availability: 2017 (Herceptin patent expiry July 2014). Sector: Secondary care. CDF: Trastuzumab not listed. Tariff: Chemotherapy. Guidance/ None specific to this product. reviews:

Trastuzumab BCD-022; Biocad Pharmacology: As for reference product – Herceptin. Given by i.v. infusion. Indication: Breast cancer, HER2 positive metastatic disease, first-line. Current status: PIII UK availability: 2017 (Herceptin patent expiry July 2014). Sector: Secondary care. CDF: Trastuzumab not listed. Tariff: Chemotherapy. Guidance/ None specific to this product. reviews:

Trastuzumab PF-05280014; Pfizer Pharmacology: As for reference product – Herceptin. Given by i.v. infusion. Indication: Breast cancer, HER2 positive metastatic disease, first-line, neoadjuvant. Current status: PIII UK availability: 2017 (Herceptin patent expiry July 2014). Sector: Secondary care. CDF: Trastuzumab not listed. Tariff: Chemotherapy. Guidance/ None specific to this product. reviews:

Pegfilgrastim LA-EP2006 injection; Sandoz Pharmacology: As for reference product – Neulasta. Given by s.c. injection. Indication: Febrile neutropenia in patients with cancer receiving chemotherapy. Current status: PIII. Company are preparing data for regulatory filing. UK availability: 2017 (Neulasta patent expiry August 2017). Sector: Secondary care. Tariff: Tariff excluded. Guidance/ None specific to this product. reviews:

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 80 No responsibility is accepted for the content of documents derived from this original publication.

Index

A. Menarini Farmaceutica ...... 70 BNF ...... 3 Delamanid ...... 69 AB Science ...... 19, 66 Boehringer Ingelheim .. 17, 41, 50, 67, Deltyba ...... 69 Abasria ...... 75 68, 69, 70, 78, 79 Dendreon ...... 46 Abbott ...... 19 Bortezomib ...... 71 Denosumab ...... 72 AbbVie ...... 30, 32 Bosatria ...... 20 Desmoteplase ...... 66 Abilify Maintena ...... 68 Botox...... 68, 70 Dextromethorphan/ quinidine ...... 26 Abraxane ...... 70 Botulinum A toxin ...... 68, 70 DH ...... 3 Actavis ...... 9 Brain cancer vaccine ...... 40 DiaPep277 ...... 36 Actelion ...... 28, 50, 67 Breakyl ...... 68 Diltiazem ...... 10 Actoxumab/ bezlotoxumab ...... 28 Brilique ...... 14 Dimethyl fumarate ...... 64, 71 Adasuve ...... 68 Brimonidine ...... 72 Dolutegravir ...... 69 Adempas ...... 67 Bristol Myers Squibb .. 29, 30, 46, 49, Dolutegravir/ abacavir/ lamivudine ... 32 Aegerion ...... 67 67, 69, 71 Drisapersen ...... 60 Afamelanotide ...... 65 Budesonide/ formoterol ...... 17 Duavive ...... 36 Afatinib ...... 41, 70 Bufomix ...... 17 Durata ...... 26 Afinitor ...... 43, 44 Cabozantinib ...... 41, 46 E10030...... 62 Aflibercept ...... 61, 72 Cadazolid ...... 28 Eculizumab ...... 55 Afrezza ...... 35 Canagliflozin ...... 69 Edoxaban ...... 11, 12 Alemtuzumab ...... 71 Canagliflozin/ metformin ...... 33 Eisai ...... 41, 42, 48, 68 Alexion ...... 55 Canakinumab ...... 72 Eli Lilly ...... 35, 44, 45, 57, 58, 64, 75 Alipogene tiparvovec ...... 55 Cangrelor ...... 15 Eliquis ...... 67 Alirocumab ...... 16 Carfilzomib ...... 51 Elosulfase alfa ...... 71 ALK-Abello ...... 19 CCG ...... 3 Eltrombopag ...... 72 Allergan ...... 68, 70 Celgene ...... 56, 57, 58, 63, 70 Eluxadoline ...... 9 Almirall ...... 64 Cell Therapeutics ...... 71 Elvanse ...... 22 Alogliptin ...... 69 Celladon ...... 16 Elvitegravir ...... 69 Alogliptin/ metformin ...... 69 Ceritinib ...... 42 EMA ...... 3 Alogliptin/ pioglitazone ...... 33 Certican ...... 54 Enobosarm ...... 37 Alprostadil ...... 70 Certolizumab pegol ...... 72 Entyvio ...... 67 Amgen ...... 16, 47, 49, 51, 72, 80 Chiesi ...... 55 Enzalutamide ...... 5, 46 Amitiza ...... 10, 67 Chlormethine ...... 50 Epratucyn ...... 61 Anamorelin...... 37 Ciclosporin A ...... 62 Epratuzumab ...... 61 Andexanet alfa ...... 13 Cimzia ...... 72 Eribulin ...... 42, 48 Andromeda ...... 36 Circadin ...... 22 Estybon ...... 52 Anoheal ...... 10 Clevidipine ...... 13 Etanercept GP2015 biosimilar ...... 76 Anoro ...... 68 Cleviprex ...... 13 Etanercept SB-4 biosimilar ...... 76 Apaziquone ...... 45 Clinuvel ...... 65 Eteplirsen ...... 60 Apixaban ...... 67 Cobicistat ...... 69 EU ...... 3 Apremilast ...... 56, 57, 58, 63 Cobimetinib ...... 48 Everolimus ...... 43, 44, 54 Aripiprazole ...... 68 Colestilan ...... 71 Evolocumab ...... 16 Arzerra ...... 71 Collagenase clostridium histolyticum 40 Exelixis ...... 46 Astellas ...... 46, 70 Cometriq ...... 41 Exenatide implant ...... 35 AstraZeneca ...... 14, 20, 47, 59, 69 Contrave ...... 23 Eylea ...... 61, 72 Asunaprevir...... 30 Corcept ...... 39 Faron ...... 19 Ataluren ...... 20, 59 Corluxin ...... 39 Farydak ...... 51 Aubagio ...... 54, 71 Credima ...... 79 Fentanyl ...... 68 Avanafil ...... 70 Crizotinib ...... 42 Fingolimod ...... 53 Avastin ...... 48, 66, 70 Cubist...... 27 Finox Biotech ...... 76 AWMSG ...... 3, 4 Custirsen ...... 47 Fluticasone furoate/ vilanterol ...... 67 Baricitinib ...... 58 Cyramza ...... 44, 45 Flynn Pharma ...... 22 Baxter ...... 52, 72 Dabigatran ...... 67 Follitropin biosimilar ...... 76, 77 Bayer .. 12, 25, 44, 45, 61, 66, 67, 70, Dabrafenib ...... 71 Forigerimod ...... 61 71, 72 Daclatasvir ...... 29, 30 Fresenius Medical Care ...... 66 Bazedoxifene/conjugated oestrogens.. Daclizumab ...... 53 Galderma ...... 72 36 Dacomitinib ...... 66 Ganetespib ...... 42 Bedaquiline ...... 68 Daiichi Sankyo ...... 11, 12 Gardasil ...... 72 Belagenpumatucel-L ...... 66 Daklinza ...... 29, 30 Gazyvaro ...... 71 Bemfola ...... 76 Dalbavancin ...... 26 Genzyme ...... 54, 71 Bendamustine ...... 50 Dalvance ...... 26 Gilead ...... 31, 32, 52, 69 Benralizumab ...... 20 Danoprevir ...... 31 Gilenya ...... 53 Bevacizumab ...... 48, 66, 70 Dapagliflozin/ metformin ...... 69 Giotrif ...... 41, 70 Bexsero ...... 72 Dapoxetine ...... 70 GlaxoSmithKline 18, 20, 48, 66, 67, 68, BindRen ...... 71 Dasabuvir ...... 30 71, 72 Biocad...... 80 Dasiprotimut-T ...... 51 Glybera ...... 55 Biogen Idec ...... 53, 71, 75, 76, 78 DCVax-L ...... 40 Golimumab ...... 66, 67 BioMarin ...... 71 Defactinib ...... 43 Granisetron patch ...... 68 BiovaxID ...... 51 Defibrotide...... 67 Grupo Ferrer ...... 68 Biovest ...... 51 Defitelio ...... 67 GTx ...... 37

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 81 No responsibility is accepted for the content of documents derived from this original publication.

Guanfacine ...... 22 Lubiprostone ...... 10, 67 Paclitaxel ...... 47 Halaven ...... 42, 48 Lucanix ...... 66 Paclitaxel albumin-bound ...... 70 Helsinn ...... 37 Lumacaftor + ivacaftor ...... 21 Palbociclib ...... 44 Hemangiol ...... 15 Lundbeck ...... 25, 66 Paliperidone ...... 68 Herceptin ...... 70 Lupuzor ...... 61 Panobinostat ...... 51 Hospira ...... 66, 77, 79 Lurasidone ...... 21, 68 PARI Pharma ...... 28 House dust mite immunotherapy ..... 19 MabThera ...... 71 PAS ...... 3 HRG ...... 3 Macitentan ...... 67 Pasireotide ...... 39 Human papillomavirus vaccine ...... 72 MacroGenics ...... 36 Pazopanib ...... 66 HyQvia ...... 72 Masitinib ...... 19, 66 Pegfilgrastim LA-EP2006 biosimilar . 80 Ibrutinib ...... 51, 52 Masiviera ...... 66 Peginterferon beta-1a ...... 53 Idebenone ...... 60 Meda ...... 68 Pembrolizumab ...... 49 Idelalisib ...... 52 Mekinist ...... 48, 66 Peptide p277 ...... 36 Ikervis ...... 62 Melatonin ...... 22 Perjeta...... 43 Ilaris ...... 72 Meningococcal group-B vaccine ...... 72 Perrigo ...... 25 Imbruvica ...... 52 Mepolizumab ...... 20 Pertuzumab ...... 43 Immunoglobulin ...... 72 MHRA ...... 3 Pfizer36, 42, 44, 57, 58, 65, 66, 67, 78, ImmuPharma ...... 61 Mifepristone ...... 39 80 Incresync ...... 33 Mirvaso ...... 72 Pierre Fabre ...... 15 Incruse ...... 18 Mitizax ...... 19 Pixantrone ...... 71 Indacaterol/ glycopyrronium ...... 18 Mitsubishi Pharma ...... 71 Pixuvri ...... 71 Inflectra ...... 77 MK-5172 ...... 31 Plegridy ...... 53 Infliximab biosimilar ...... 77 MK-5172 + MK8742 o ...... 32 Portola Pharmaceuticals ...... 13 Infliximab SB2 biosimilar ...... 78 MSD .. 14, 28, 31, 32, 37, 38, 49, 66, Posaconazole ...... 69 Insulin degludec ...... 69 67, 69 Pradaxa ...... 67 Insulin degludec/ insulin aspart ...... 66 MTRAC ...... 3, 4 Priligy ...... 70 Insulin degludec/ liraglutide ...... 34 MuDelta ...... 9 Prolia ...... 72 Insulin glargine biosimilar ...... 75 Mydicar ...... 16 Propranolol ...... 15 Insulin glargine MK-1293 biosimilar . 75 Nabiximols ...... 25 Prosensa ...... 60 Insulin glargine U300 ...... 34 Nalfurafine...... 66 Prostap...... 71 Insulin inhalation ...... 35 Naltrexone/ bupropion ...... 23 ProStrakan ...... 68 Insulin peglispro ...... 35 Napp ...... 50, 77 Provenge ...... 46 Intarcia Therapeutics ...... 35 Neoquin ...... 45 PTC Therapeutics ...... 20, 59 Intercept ...... 10 Nerventra ...... 66 Qinprezo ...... 50 Interferon beta 1a, lyophilized ...... 19 Newron ...... 24 Radium-223 dichloride...... 71 Intuniv ...... 22 Nexavar ...... 45, 66, 70 Ramucirumab ...... 44, 45 Invega ...... 68 NHSE ...... 3 RDTC ...... 3, 4 Invokana ...... 69 NICE ...... 3, 4 Reasanz ...... 66 Ipilimumab ...... 46, 49, 71 NICE-ES ...... 3 Recordati ...... 40 Ivacaftor ...... 68 NIHR HSC...... 3, 4 Regorafenib...... 45, 70 Ixekizumab...... 57, 64 NNT ...... 3 Relvar Ellipta ...... 67 Janssen-Cilag .. 9, 13, 33, 51, 52, 64, Northwest Biotherapeutics...... 40 Remsima ...... 77 68, 69, 71, 72 Novartis . 15, 18, 39, 42, 43, 44, 49, 51, Revestive ...... 11 Jaydess ...... 70 53, 54, 56, 57, 58, 62, 63, 66, 68, 72 Revolade ...... 72 Jazz ...... 67 NovaRx Corporation ...... 66 Rigosertib ...... 52 Jenson ...... 26 Novo Nordisk ...... 23, 34, 66, 69 Riociguat ...... 67 Jentadueto ...... 69 Noxafil ...... 69 Rituximab ...... 71 Jinarc ...... 38 NPS Pharmaceuticals ...... 11 Rituximab BI 695500 biosimilar . 78, 79 Kadcyla ...... 43, 70 Nuedexta ...... 26 Rituximab CT-P10 biosimilar ...... 79 Kalydeco ...... 68 Nuvocid ...... 27 Rituximab PF-05280586 biosimilar .. 78 Kyprolis ...... 51 nx 1207 ...... 40 Rivaroxaban ...... 12, 13, 66 L(C)NDG ...... 3, 4 Oasmia ...... 47 RoActemra ...... 72 Laquinimod ...... 66 Obeticholic acid ...... 10 Roche ...... 31, 43, 48, 66, 70, 71, 72 Latuda...... 21, 68 Obinutuzumab ...... 71 Ryzodeg ...... 66 Ledipasvir/ sofosbuvir ...... 31, 32 Odanacatib...... 37, 38 Sacubitril/ valsartan ...... 15 Lemtrada ...... 71 Ofatumumab ...... 71 Safinamide ...... 24 Lenvatinib ...... 41 Olaparib ...... 47 Sancuso ...... 68 Lesinurad ...... 6, 59 Olodaterol ...... 68 Sandoz ...... 76, 79, 80 Leuco-thiomethoninium ...... 24, 25 Olysio ...... 69 Sanofi ...... 16, 34, 35 Leuprorelin ...... 71 Omacetaxine mepesuccinate ...... 66 Sanofi Pasteur MSD ...... 72 Levact ...... 50 Omalizumab ...... 68 Santen...... 62 Levonorgestrel ...... 70 Omapro ...... 66 Santhera ...... 60 Linagliptin/ metformin ...... 69 Ombitasvir/ paritaprevir/ ritonavir 30, 32 Sarepta Therapeutics ...... 60 Lipegfilgrastim ...... 71 Opsiria ...... 62 Sativex ...... 25 Liraglutide ...... 5, 23, 69 Opsumit ...... 67 Scenesse ...... 65 Lisdexamfetamine ...... 22 Orexigen ...... 23 Scyllo-inositol ...... 25 Lixiana ...... 11, 12 Orion ...... 17 Sebelipase alfa ...... 55 LNDG...... 4 Oritavancin ...... 27 Secukinumab ...... 56, 57, 58, 63 Lojuxta ...... 67 Ostarine ...... 37 Serelaxin ...... 66 Lomitapide ...... 67 Otezla ...... 56, 57, 58, 63 Shire ...... 22 Lonquex ...... 71 Otsuka ...... 38, 68, 69 SIGN ...... 3, 4 Loxapine ...... 68 Ovaleap ...... 77 Signifor ...... 39 Lu AE58054 ...... 25 Paclical ...... 47 Simeprevir ...... 69

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 82 No responsibility is accepted for the content of documents derived from this original publication.

Simponi ...... 66, 67 Teriflunomide ...... 54, 71 Verastem ...... 43 Sipuleucel-T ...... 46 Teva ...... 47, 66, 71, 77 Vertex ...... 21, 68 Sirolimus ...... 62 The Medicines Company ..... 13, 15, 27 Vesomni ...... 70 Situro ...... 68 Ticagrelor ...... 14 Victoza ...... 69 Sivextro ...... 27 Tiotropium bromide ...... 17 ViiV Healthcare ...... 32, 69 SLA Pharma ...... 10 Tivicay ...... 69 Vimizim ...... 71 SMC ...... 3, 4 Tobramycin nebuliser ...... 28 Vintafolide ...... 66 SmPC ...... 3 Tocilizumab ...... 72 Vipdomet ...... 69 Sofosbuvir ...... 69 Tofacitinib ...... 57, 58, 65 Vipidia ...... 69 Solifenacin/tamsulosin ...... 70 Tolvaptan ...... 38 Vitaros ...... 70 Soliris ...... 55 Toujeo ...... 34 Vitekta ...... 69 Sonidegib ...... 49 Trametinib ...... 48, 66 Vokanamet ...... 33 Sorafenib ...... 44, 45, 66, 70 Translarna ...... 20, 59 Volasertib ...... 50 Sovaldi ...... 69 Trastuzumab ABP 980 biosimilar .... 80 Vorapaxar ...... 14 Sovrima ...... 60 Trastuzumab BCD-022 biosimilar .... 80 Vosaroxin ...... 50 Spectrum ...... 45 Trastuzumab CT-P6 biosimilar ...... 79 Votrient...... 66 Spedra ...... 70 Trastuzumab emtansine ...... 43, 70 Vynfinit ...... 66 Spiriva...... 17 Trastuzumab PF-05280014 biosimilar . Winfuran ...... 66 Stelara ...... 9, 64, 72 80 Xalkori ...... 42 Stivarga ...... 45, 70 Trastuzumab/ hyaluronidase ...... 70 Xarelto...... 12, 13, 66 Striverdi Respimat ...... 68 Traumakine ...... 19 Xeljanz ...... 57, 58, 65 Sucampo ...... 10, 67 Trebananib ...... 47 Xiapex ...... 40 Sunesis ...... 50 Tresiba ...... 69 Xigduo ...... 69 Sunovion ...... 21 Triumeq ...... 32 Xofigo ...... 71 Sunvepra ...... 30 Tybost ...... 69 Xolair ...... 68 Swedish Orphan Biovitrum ...... 40, 41 UCB ...... 61, 72 Xtandi ...... 46 Synageva BioPharma ...... 55 UCB Pharma ...... 72 Xultophy ...... 34 Synta ...... 42 UKMi ...... 3, 4 Yervoy ...... 46, 49, 71 Tafinlar ...... 71 Ultibro ...... 18 Zenapax ...... 53 Takeda ...... 33, 67, 68, 69, 70, 71 Umeclidinium ...... 18 Zonegran ...... 68 Talimogene laherparepvec ...... 49 Umeclidinium/ vilanterol ...... 68 Zonisamide ...... 68 TauRx Therapeutics ...... 24, 25 Ustekinumab ...... 9, 64, 72 Zontivity ...... 14 Tecfidera ...... 71 Valchlor ...... 50 Zydelig ...... 52 Tedizolid ...... 27 Vantobra ...... 28 Zykadia ...... 42 Teduglutide ...... 11 Vedolizumab ...... 67 Teplizumab ...... 36 Velcade ...... 71

Acknowledgements

Key contributors:

Helen Davis, North West MI Centre. Nicola Watts, 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: Anne Henshaw, Cheshire & Merseyside CSU. Alison Alvey, South West MI and Training Centre. Ashley Marsden, North West MI Centre. Liz Arkell, University Hospital of South Manchester NHS Scott Mercer, Guy’s & St. Thomas’ NHS Foundation Trust/ NHS Foundation Trust. England. Lindsay Banks, North West MI Centre. Paul Mooney, Royal Liverpool & Broadgreen University Hospitals Nicky Bird, Mansfield & Ashfield CCG. NHS Trust. Karoline Brennan, North West MI Centre. Malcolm Qualie, NHS England. Kath Carter, University Hospitals of Leicester NHS Trust /NHS Christine Randall, North West MI Centre. England. Amanda Rawlings, Mansfield & Ashfield CCG. Slak Dhadli, Southern Derbyshire CCG. Andrew Ritchings, Mid Cheshire Hospitals NHS Foundation Trust. Mary Weatherstone, Anglia CSU David Erskine, London and South East MI Centre. Gail Woodland, Welsh MI centre and All Wales Medicines Sue Gough, Wessex Drug & MI Centre Strategy Group. Simone Henderson, North West MI Centre.

UKMi September 2014 Solely for use within the NHS and not for commercial use. page 83 No responsibility is accepted for the content of documents derived from this original publication.