October Horizon Scanning Research & 2016 Intelligence Centre

Solanezumab for mild dementia due to Alzheimer’s disease

NIHR HSRIC ID: 4777

Lay summary

Solanezumab is a new drug to treat Alzheimer’s disease in people with mild symptoms. Solanezumab is delivered straight into the blood and binds to the abnormal proteins in the brain which helps to clear them, this is thought to delay the disability associated with Alzheimer’s disease. At the moment, there are no drugs that treat the underlying problem that causes Alzheimer’s disease and no known cure.

This briefing is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

Horizon Scanning Research & Intelligence Centre University of Birmingham [email protected] www.hsric.nihr.ac.uk @OfficialNHSC TARGET GROUP

• Alzheimer’s disease (AD): mild dementia due to AD; alone or in combination with symptomatic standard of care.

TECHNOLOGY

DESCRIPTION

Solanezumab (LY2062430, M266, MAb266) is a humanised directed against amyloid-beta (Aβ), a thought to play a central role in the pathogenesis of AD. Solanezumab is thought to exert its therapeutic effect by binding to soluble Aβ and increasing its clearance from the brain. It is expected that treatments that increase the clearance of Aβ might delay the disability associated with AD.

In the phase III clinical trials, solanezumab is administered by intravenous (IV) infusion 400mg once every four weeks for 80 weeks1. Solanezumab does not currently have Marketing Authorisation in the EU for any indication.

INNOVATION and/or ADVANTAGES

If licensed, solanezumab may provide a novel, additional treatment option for this patient group, whose therapeutic options are currently limited.

DEVELOPER

Eli Lilly and Company Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Dementia is a chronic progressive mental disorder, which is largely irreversible and characterised by a widespread impairment of mental function2,3. It adversely affects higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgement. AD is the most common form of dementia. It is a degenerative cerebral disease with characteristic neuropathological and neurochemical features3.

AD is usually insidious in onset and develops over several years. People with AD may find it increasingly difficult to undertake everyday activities such as shopping, socialising, communication, and recognising people and places. In the later stages of the disease, physical impairments can include problems with eating (including dysphagia), incontinence, unsettled behaviour, and behaviour that challenges. AD may also be associated with loss of confidence and feelings of fear, confusion, apathy, stigma, and depression. The effects of AD are heterogeneous and vary from patient to patient3. Horizon Scanning Research & Intelligence Centre

A common tool to measure cognitive functioning is the mini mental state examination (MMSE)4. The MMSE is scored out of 30. Although scores of 24 or less are strongly associated with dementia in an appropriate clinical context, scores of >24 can be seen in some people with mild dementia. A score of ≥20 suggests mild dementia, 13 – 20 suggests moderate dementia, and ≤12 indicates severe dementia. On average, the MMSE score of a person with Alzheimer's declines about two to four points each year5.

CLINICAL NEED and BURDEN OF DISEASE

The number of people with dementia in the UK is estimated to be 850,000, representing 1.3% of the UK population6,7. AD accounts for around 60% of all dementia cases3,8. The UK incidence of AD in people over the age of 65 years was an estimated 4.9 per 1,000 person- years in 20113. Approximately 64% of people with AD are estimated to have mild to moderate disease3.

In 2014-15, there were 4,866 hospital admissions in England due to AD (ICD-10 G30), resulting in 9,364 finished consultant episodes and 318,152 bed days9. Expert opinion suggests the number of hospital admissions related to Alzheimer’s disease may be higher than this figure as many patients are admitted for a different reason but AD is a significant factora. Expert opinion also suggests that AD is associated with longer durations of hospital stay and, for many diseases, worse outcomeb. In 2014 in England and Wales, 11,298 deaths were registered in which Alzheimer’s disease was the underlying cause of death (ICD-10 G30)10.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal. Donepezil, galantamine, rivastigmine and for the treatment of Alzheimer's disease (TA217). March 2011.

• NICE clinical guideline in development. Dementia - assessment, management and support for people living with dementia and their carers (CG42 update). Expected September 2017. • NICE clinical guideline. Dementia: Supporting people with dementia and their carers in health and social care (CG42). November 2006.

• NICE guideline. Older people: independence and mental wellbeing (NG32). December 2015. • NICE guideline. Older people with social care needs and multiple long-term conditions (NG22). November 2015. • NICE guideline. Dementia, disability and frailty in later life – mid-life approaches to delay or prevent onset (NG16). October 2015.

• NICE quality standard. Mental wellbeing of older people in care homes (QS50). December 2013.

a Expert personal opinion

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• NICE quality standard. Quality standard for supporting people to live well with dementia (QS30). April 2013. • NICE quality standard. Dementia quality standard (QS1). June 2010.

• NICE advice. Management of aggression, agitation and behavioural disturbances in dementia: valproate preparations (ESUOM41). March 2015. • NICE advice. Management of aggression, agitation and behavioural disturbances in dementia: carbamazepine (ESUOM40). March 2015. • NICE advice. Low-dose antipsychotics in people with dementia (KTT7). January 2015.

NHS England Policies and Guidance

• NHS England. Enhanced Service Specification: facilitating timely diagnosis and support for people with dementia 2015/16. • NHS England. Dementia diagnosis and management-A brief pragmatic resource for general practitioners. February 2015. • NHS commissioning Board. Commissioning for quality and innovation (CQUIN): Improving dementia and delirium care. February 2015. • NHS England. 2013/14 NHS Standard Contract for Neurosciences: Specialised (Adult). D04/S/a. • NHS England. 2013/14 NHS Standard Contract for Complex Disability Equipment: alternative and augmentative communication/communication aids (all ages). DO1/S/b.

Other Guidance

• NHS Clinical Knowledge Summary. Dementia. 201611. • European Federation of Neurological Societies. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. 201012. • British Association of Psychopharmacology. Clinical practice with anti-dementia drugs. 201013. • European Medicines Agency. Guideline on medicinal products for the treatment of Alzheimer’s disease and other dementias. 200814. • Scottish Intercollegiate Guidelines Network. Management of patients with dementia (86). 200615.

CURRENT TREATMENT OPTIONS

There is currently no disease modifying treatment for AD. Treatment aims to promote independence, maintain function, and treat symptoms; including non-cognitive (such as hallucinations, delusions, anxiety, marked agitation and associated aggressive behaviour), cognitive, behavioural, and psychological symptoms2. Non-pharmacological management options include: cognitive stimulation, social support, increasing assistance with day-to-day activities, information and education, carer support groups, community dementia teams, home nursing and personal care, community services (such as meals-on-wheels), befriending services, day centres, respite care, and care homes2,3. Pharmacological options for mild to moderate AD include acetylcholinesterase inhibitors such as donepezil, galantamine, and rivastigmine. These drugs can temporarily reduce some symptoms of the condition in some people6.

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EFFICACY and SAFETY

Trial EXPEDITION, EXPEDITION 2, EXPEDITION EXT, NCT00905372, 6747, NCT00904683, 11934, NCT01127633, 11935, H8A-MC-LZAM; H8A-MC-LZAN; H8A-MC-LZAO; solanezumab vs placebo; solanezumab vs placebo; solanezumab; phase III. phase III. phase III. Sponsor . Eli Lilly and Company. Eli Lilly and Company. Status Published. Published. Ongoing. Source of Publication16, trial Publication16, trial registry1. Publication18, trial information registry17. registry19. Location Argentina, Brazil, Canada, EU (incl UK), USA and EU (incl UK), USA, Japan and USA. other countries. Canada and other countries. Design Randomised, placebo- Randomised, placebo- Uncontrolled, single arm. controlled. controlled. Participants n=1,012; aged ≥55 yrs; n=1,040; aged ≥55 yrs; n=975; aged ≥55 yrs; mild to moderate AD; mild to moderate AD; probable AD; completed MMSE score of 16-26; MMSE score of 16-26; participation in modified Hachinski MHIS score of ≤4; Geriatric NCT00905372 and ischemia scale (MHIS) Depression Scale score NCT00904683 trials. score of ≤4; Geriatric ≤6; pt must have a reliable Depression Scale score caregiver who is in ≤6; pt must have a reliable frequent contact (≥10 hrs caregiver who is in per week). frequent contact (≥10 hrs per week). Schedule Randomised to Randomised to All patients administered solanezumab 400mg; or solanezumab 400mg; or solanezumab 400mg IV placebo; both IV every 4 placebo: both IV every 4 once every 4 wks for 100 wks for 80 wks wks for 80 wks. wks.

Follow-up Active treatment 80 wks, Active treatment 80 wks, Active treatment 100 wks, follow-up 80 wks. follow-up 80 wks. follow-up 104 wks. Primary AD assessment scale- AD assessment scale - Number of pts with one or outcomes cognitive subscore (ADAS- cognitive subscore 14-Item more drug-related adverse Cog11); AD cooperative scale (ADAS-Cog14). event (AE) or serious AE. study-activities of daily living inventory (ADCS- ADL). Secondary Clinical dementia rating- CDR-SB; NPI; vMRI; ADAS-Cog14; ADCS-ADL; outcomes sum of boxes (CDR-SB) MMSE; RUD-Lite; EQ-5D CDR-SB; NPI; RUD-Lite; score; neuropsychiatric proxy; QoL-AD; plasma EQ-5D proxy; QoL-AD; inventory (NPI); volumetric ; ADAS- MMSE; vMRI; ADAS- magnetic resonance Cog11; ADAS-Cog12; Cog11; plasma amyloid imaging (vMRI); MMSE; ADCS-ADL. beta; amyloid plaque resource utilization in burden in the brain using dementia-lite (RUD-Lite); positron emission EuroQol 5-dimensional tomography (PET). health-related quality of life scale proxy version (EQ- 5D proxy); quality of life in Alzheimer's disease (QoL- AD); plasma solanezumab and amyloid beta.

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Key results No significant improvement No significant improvement Treatment differences in the primary outcomes. in the primary outcomes. between early-start and The modelled difference The modelled difference delayed-start (previously between groups between groups received placebo) groups (solanezumab minus (solanezumab minus for ADAS-Cog14 and placebo) in change from placebo) in change from ADCS-iADL were similar to baseline was -0.8 for baseline was -1.3 for differences at the end of ADAS-cog11 (P=0.24) and ADAS-cog11 (P=0.06) and the EXPEDITION and the -0.4 for ADCS-ADL 1.6 for ADCS-ADL EXPEDITION 2 trials. (P=0.64). There were no (P=0.08). There was a Treatment differences in significant treatment- treatment difference cognition and function related differences in the favouring solanezumab in were preserved at 108 change in scores on the MMSE score, with a weeks. MMSE (P=0.06), the CDR- difference of 0.8 points SB (P=0.51), or the NPI (P=0.01). There were no (P=0.29), nor were there significant treatment- significant differences in related differences in CDR- the change in scores on SB (P=0.17) or the NPI the EQ-5D, RUD-Lite, or (P=0.85). QOL-AD scales. Among patients who had mild AD, there was a significant treatment effect on ADCS-ADL score, with a modelled difference between groups of 2.3 points (P=0.04) at week 80. There were no significant treatment- related differences MMSE (P=0.10), CDR-SB (P=0.22), NPI (P=0.58), EQ-5D, RUD-Lite, or QOL- AD. Adverse Serious AEs: low frequency with no apparent association Deaths, serious AEs, effects reported with solanezumab. Deaths: 24 with discontinuations due to an (AEs) solanezumab, 19 with placebo. AE, and the incidence of AEs occurring in ≥5% included: cardiac, eye, increases in Amyloid gastrointestinal, metabolic and nutritional, Related Imaging musculoskeletal and connective-tissue, nervous system, Abnormalities (ARIA)-H psychiatric, renal and urinary, respiratory, thoracic, and (signals attributable to mediastinal, skin and subcutaneous-tissue, and vascular microhaemorrhages and disorders; administrative-site conditions; infections and haemosiderosis) were infestations; injury and poisoning; and neoplasms evenly distributed across (benign, malignant, and unspecified). treatment regimen groups. The severity of changes in ARIA-H was evenly distributed across groups. Eight patients in the delayed-start group and 11 in the early-start group experienced ARIA-E (signal attributable to vasogenic oedema and inflammation of vessels) ; ARIA-E was not related to symptoms in any patient. Cardiac disorders, cardiac ischemic-related and cardiac arrhythmia–related events, suicidal ideation or

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behaviour, infusion-related reactions, and haemorrhagic stroke did not differ across groups. Expected - - Study completion date reporting reported as August 2020. date

Trial EXPEDITION 3, EXPEDITION PRO, A4 study, NCT02008357, NCT01900665, 15136, NCT02760602, 16349, 15275, H8A-MC-LZAZ; H8A-MC-LZAX; mild AD; H8A-MC-LZBE, 2016- adults at risk of memory solanezumab vs placebo; 000108-27; prodromal AD; loss and cognitive decline; phase III. solanezumab vs placebo; solanezumab vs placebo; phase III. phase III. Sponsor Eli Lilly and Company. Eli Lilly and Company. Eli Lilly and Company. Status Ongoing. Ongoing. Ongoing. Source of Trial registry20. Trial registry21. Trial registry22. information Location EU (incl UK), USA, EU (incl UK), USA, Australia, Canada, Japan Canada, Australia and Canada and other and USA. Japan. countries. Design Randomised, placebo- Randomised, placebo- Randomised, placebo- controlled. controlled. controlled Participants n=2,100 (planned); aged n=2,450 (planned); aged n=1,150 (planned); aged 55-90 yrs; mild AD; MMSE 55-85 yrs; prodromal AD 65-85 yrs; MMSE score score 20-26; probable AD according to National 25-30; global clinical according to National Institute on Aging- dementia rating scale Institute of Neurological Alzheimer's Association score of 0; logical memory and Communicative (NIA-AA) diagnostic II score 6-18; florbetapir Disorders and Stroke- criteria; scores 17-28 on PET scan evidence of Alzheimer’s disease and Montreal cognitive brain amyloid pathology; related disorders assessment (MoCA); no acetylcholinesterase association (NINCDS- scores <27 on free recall inhibitor and/or memantine ADRDA) criteria;; MHIS cut-off score from the free treatment. score ≤4; geriatric and cued selective depression scale score ≤6; reminding test; MHIS score florbetapir PET scan or ≤4; functional activities cerebrospinal fluid questionnaire consistent with the scores >0; florbetapir PET presence of amyloid scan or CSF consistent pathology; pt must have a with the presence of reliable caregiver who is in amyloid pathology. frequent contact (≥10 hrs per week). Schedule Randomised to Randomised to Randomised to solanezumab 400mg; or solanezumab 400mg; or solanezumab 400mg; or placebo; both IV every 4 placebo; both IV once placebo; both IV once wks for 76 wks. All pts who every 4 wks. every 4 wks for 168 wks. complete the trial and decide to continue will have solanezumab 400mg IV every 4 wks for up to an additional 104 weeks. Follow-up Active treatment 76 wks, Active treatment up to 2 Active treatment for 168 follow-up 80 wks. yrs, follow-up 16 wks after wks, follow-up 168 wks. last dose of study drug.

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Primary ADAS-Cog14. ADAS-Cog14. ADCS preclinical outcome/s Alzheimer cognitive composite. Secondary AD cooperative study- Alzheimer's Disease Cognitive function index; outcome/s instrumental activities of Cooperative ADCS-ADL-Prevention daily living (ADCS-iADL); Study/Activities of Daily Questionnaire score; mean ADAS-Cog11; MMSE; Living scale adapted for composite summary ADCS-ADL; functional Mild Cognitive Impairment uptake value ratio; CSF tau activities questionnaire patients (ADCS-MCI-ADL); biomarkers; CSF amyloid (FAQ); CDR-SB; NPI; MMSE; MoCA; FAQ; beta; vMRI. RUD-Lite; QoL-AD; EQ-5D NPI; CDR-SB; repeatable proxy; integrated battery for the assessment Alzheimer's disease rating of neuropsychological scale (iADRS); cognition status (RBANS); free and and function; plasma cued selective reminding amyloid-beta species; test (FCSRT); RUD-Lite; vMRI; pharmacokinetics; EQ-5D; QoL-AD; florbetapir PET Scan; CSF concentration of plasma amyloid-beta amyloid-beta peptide; concentration. concentration of plasma solanezumab; vMRI; florbetapir PET standardized uptake value ratio; CSF amyloid-beta; CSF tau proteins; neocortical tau deposits using 18F-AV-1451 PET. Expected Primary completion date Study completion date Study completion date reporting reported as October 2016. reported as April 2021. reported as October 2020. date

Trial NCT00749216, 12025, H8A-JE-LZAK; NCT00329082, 6649, H8A-MC-LZAJ; solanezumab; phase II. solanezumab vs placebo; phase II. Sponsor Eli Lilly and Company. Eli Lilly and Company. Status Complete but published in abstract. Published. Source of Abstract23, trial registry24. Publication25, trial registry26. information Location Japan. USA. Design Randomised. Randomised, placebo-controlled. Participants n=33; aged ≥50 yrs; mild to moderate AD n=52; aged ≥50 yrs; mild to moderate AD; according to NINCDS-ADRDA criteria; received acetylcholinesterase inhibitors or MHIS score ≤4; MMSE of 15-26; GDS memantine for ≥4 months prior to study. ≤10. Schedule Randomised to 400mg IV solanezumab Randomised to: once a week; once every 4 weeks; or Arm 1: solanezumab, 100mg IV, once a once every 8 weeks. week; Arm 2: solanezumab, 100mg IV, once every 4 weeks; Arm 3: solanezumab, 400mg IV, once every week; Arm 4: solanezumab, 400mg IV, once every 4 weeks; Arm 5: placebo, IV, once a week. Follow-up Active treatment period 2 months, follow- Active treatment period 12 weeks, follow- up period 6 months. up period 1 year. Primary AEs. Safety and tolerability. outcome/s Secondary Extended ADAS-Cog; ADAS-Cog11, ADAS-Cog14,

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outcome/s pharmacodynamics; pharmacokinetics. pharmacokinetics; pharmacodynamics; amyloid beta plasma levels. Key results Solanezumab was safe and well-tolerated There were no significant differences in up to 400mg once a week in Japanese ADAS-Cog14 or ADAS-Cog11 from AD pts. baseline in any group compared to placebo: Arm 1: ADAS-Cog14, -0.5 (95%CI -5.1 to 4.1) p=1.00; ADAS-Cog11, 0.2 (95%CI - 4.3 to 4.6) p=1.00; Arm 2: ADAS-Cog14, 1.9 (95%CI -2.9 to 6.7) p=0.994; ADAS-Cog11, 1.5 (95%CI - 3.1 to 6.0) p=1.00; Arm 3: ADAS-Cog14, 0.7 (95%CI -3.9 to 5.3) p=1.00; ADAS-Cog11, -1.3 (95%CI - 5.8 to 3.1) p=1.00; Arm 4: ADAS-Cog14, -1.1 (95%CI -5.9 to 3.6) p=1.00; ADAS-Cog11, -1.2 (95%CI - 5.8 to 3.3) p=1.00. Clinical laboratory values, CSF cell counts, and MRI scans unchanged. Adverse There were no serious adverse events Serious AEs, 8 patients (arms not effects related to solanezumab; although reported) ulcer haemorrhage, pancreatitis, (AEs) treatment-emergent adverse events were chest pain, infection, lumbar puncture reported in 8 patients from the once every , subdural hematoma, syncope, 8 wks group (66.7%), 5 patients from the agitation, ovarian cyst, and skin ulcer. once every 4 wks group (50.0%), and 5 Treatment-emergent AEs not significantly patients from the once a week group different across treatment groups. (45.5%). Adverse events reported were mild or moderate except one event. Only one event (pain in extremity) was judged as severe but was not related to the study drug or a study procedure Expected Abstract presented at ICAD 2010b. - reporting date

ESTIMATED COST and IMPACT

COST

The cost of solanezumab is not yet known. The cost of other selected treatments specifically licensed for Alzheimer’s disease are listed in the following table.

Drug Dose Cost for 28 days treatment 27 Donepezil (5mg) 5mg once daily for one month then increased to a £1 maximum of 10mg if necessary. Galantamine (8mg) 4mg twice daily for 4 weeks then increased to 8mg twice £25 daily for 4 weeks; maintenance 8-12mg twice daily. Rivastigmine (1.5mg) Initially 1.5mg twice daily, increased in steps of 1.5mg £7 twice daily at intervals of at least 2 weeks. Memantine (10mg) Initially 5mg once daily, increased in steps of 5mg at £2 weekly intervals to a maximum of 20mg daily.

b Company provided information

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The company states that current licensed treatments only treat the symptoms of AD, as solanezumab is expected to slow disease progression there is no relevant comparator on the marketc.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other  No impact identified

Impact on Health and Social Care Services

 Increased use of existing services: patients  Decreased use of existing services: will require regular monitoring. Patients will decreased used in social care if patients need confirmation that they are amyloid deteriorate more slowlyd. positive which means they will require a lumbar puncture with CSF analysis or an amyloid PET scand.

 Re-organisation of existing services  Need for new services: if licensed solanezumab would require IV administration in a day care setting in an acute unit/hospital. No current memory or dementia services are geared up to administer IV treatments every 4 weeks to large numbers of subjects. Therefore new services will need to be created or a greater use of existing facilities within acute NHS trustsd.

 Other  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs: costs associated with  Other reduction in costs lumbar puncture and CSF analysis are in the region of £750. Experts estimates amyloid PET scans to cost around £1,500d.

 Other  None identified Other Issues

 Clinical uncertainty or other research question  None identified identified: current studies only look at 2-3 years of AD, research is required into the frequency of administration needed and the long term efficacyd.

c Company provided information d Expert personal opinion

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REFERENCES

1 ClinicalTrials.gov. Effect of passive immunization on the progression of Alzheimer's disease: LY2062430 versus placebo. www.clinicaltrials.gov/ct2/show/NCT00904683 Accessed 08 September 2016. 2 National Institute for Health and Clinical Excellence. Dementia: Supporting people with dementia and their carers in health and social care. Clinical guideline CG42. London: NICE; November 2006. 3 National Institute for Health and Clinical Excellence. Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease. Technology appraisal TA217. London: NICE; March 2011. 4 Alzheimer’s Society. Helping you to assess cognition – A practical toolkit for clinicians. www.alzheimers.org.uk/site/scripts/download_info.php?fileID=2532 Accessed 10 October 2016. 5 Alz.org. Tests for Alzheimer’s Disease and Dementia. www.alz.org/alzheimers_disease_steps_to_diagnosis.asp Accessed 10 October 2016. 6 Alzheimer’s Society. Statistics. www.alzheimers.org.uk/statistics Accessed 07 September 2016. 7 NHS Choices. Alzheimer’s disease. www.nhs.uk/conditions/Alzheimers- disease/Pages/Introduction.aspx Accessed 07 September 2016. 8 Luengo-Fernandez R, Leal J and Gray A. Dementia 2010: the economic burden of dementia and associated research funding in the United Kingdom. Alzheimer’s Research Trust;2010. 9 Health & Social Care Information Centre. Hospital episode statistics for England. Admitted Patient Care, 2014-15. www.hscic.gov.uk 10 Office for National Statistics. Deaths registered in England and Wales (series DR) - 2014. www.ons.gov.uk 11 NHS Clinical Knowledge Summaries. Dementia. August 2016. cks.nice.org.uk/dementia#!topicsummary Accessed 07 September 2016. 12 Hort J, O’Brien JT, Gainotti G et al. EFNS guidelines for the diagnosis and management of Alzheimer’s disease. European Journal of Neurology 2010;17(10):1236-1248. 13 O’Brien JT and Burns A (on behalf of the British Association for Psychopharmacology Dementia Consensus Group). Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology. Journal of Psychopharmacology 2011;25(8):997-1019. 14 European Medicines Agency. Guideline on medicinal products for the treatment of Alzheimer’s disease and other dementias. London:EMEA;2008. 15 Scottish Intercollegiate Guidelines Network. Management of patients with dementia. National clinical guideline 86. Edinburgh: SIGN; February 2006. 16 Doody RS, Thomas RG, Farlow M et al. Phase 3 trials of solanezumab for mild to moderate Alzheimer’s disease. The New England Journal of Medicine 2014;370(4):311-321. 17 ClinicalTrials.gov. Effect of LY2062430, an anti-amyloid beta monoclonal antibody, on the progression of Alzheimer's disease as compared with placebo. www.clinicaltrials.gov/ct2/show/NCT00905372 Accessed 08 September 2016. 18 Liu-Seifert H, Siemers E, Holdridge KC et al. Delayed-start analysis: Mild Alzheimer's disease patients in solanezumab trials, 3.5 years. Alzheimer’s & Dementia: Translational Research & Clinical Interventions 2015;1(2):111-121. 19 ClinicalTrials.gov. Continued efficacy and safety monitoring of solanezumab, an anti-amyloid β antibody in patients with Alzheimer's disease. www.clinicaltrials.gov/ct2/show/NCT01127633 Accessed 08 September 2016. 20 ClinicalTrials.gov. Effect of passive immunization on the progression of mild Alzheimer's disease: solanezumab (LY2062430) versus placebo. www.clinicaltrials.gov/ct2/show/NCT01900665 Accessed 08 September 2016. 21 ClinicalTrials.gov. A 24-month, phase 3, multicenter, placebo-controlled study of efficacy and safety of solanezumab versus placebo in prodromal Alzheimer's disease. www.clinicaltrials.gov/show/NCT02760602 Accessed 09 September 2016. 22 ClinicalTrials.gov. Anti-amyloid treatment in asymptomatic Alzheimer's disease (A4 study). www.clinicaltrials.gov/ct2/show/NCT02008357 Accessed 09 September 2016.

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23 Goto T, Fujikoshi S, Uenaka K et al. Solanezumab was safe and well-tolerated for Asian patients with mild-to-moderate Alzheimer's disease in a multicenter, randomized, open-label, multi-dose study. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association 2010;6(4):S308. 24 ClinicalTrials.gov. Solanezumab safety study in Japanese patients with Alzheimer’s disease. www.clinicaltrials.gov/ct2/show/NCT00749216 Accessed 08 September 2016. 25 Farlow M, Arnold SE, van Dyck CH et al. Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimer’s & Dementia 2012;8(4):261-271. 26 ClinicalTrials.gov. Effects of LY2062430 in subjects with mild-to-moderate Alzheimer’s disease and in healthy volunteers. www.clinicaltrials.gov/ct2/show/NCT00329082 Accessed 08 September 2016. 27 Joint Formulary Committee. British National Formulary. BNF October 2016. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com

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