Special Supplement Clinical Trials on Alzheimer’S Disease in Europe Contents

Issue 31 October 2019

Special Supplement Clinical trials on Alzheimer’s disease in Europe Contents

3 Foreword 4 Understanding clinical trials Contact Alzheimer Europe 6 Clinical Trials Watch 14, rue Dicks L-1417 Luxembourg 13 Recent failed disease-modifying treatment trials +352 29 79 70 16 The academic perspective on recent clinical trials and on +352 29 79 72 www.alzheimer-europe.org the future of AD research [email protected] @AlzheimerEurope 19 Acknowledgements alzheimer.europe 19 Further information and references

Alzheimer Europe gratefully acknowledges the grant provided Board by Janssen, which led to the production of this report. Chairperson: Iva Holmerová (Czech Republic) Vice-Chairperson: Charles Scerri (Malta) Honorary Secretary: Jim Pearson (UK – Scotland) Honorary Treasurer: Maria do Rosário Zincke dos Reis (Portugal) th Members Want to fi nd out more about clinical trials at the 29 Helen Rochford-Brennan, Chairperson of the European Working Group of People with Alzheimer Europe Conference #29AEC in The Hague? Dementia (Ireland) Stefanie Becker (Switzerland) Join our special symposium SS3 “Clinical trials Marco Blom (Netherlands) in Alzheimer’s disease” on Thursday 24 October Sabine Jansen (Germany) Pat McLoughlin (Ireland) 2019, from 12.45–13.45 in room Princess Ariane. Sirpa Pietikäinen (Finland) Jesús Rodrigo (Spain) Karin Westerlund (Sweden)

Staff Jean Georges, Executive Director Christophe Bintener, Project Offi cer Cindy Birck, Project Offi cer Kate Boor Ellis, Communications Offi cer Angela Bradshaw, Project Offi cer Ana Diaz, Project Offi cer Dianne Gove, Director for Projects Gwladys Guillory, Event and Conference Coordinator Owen Miller, Policy Offi cer Aideen O’Brien, Administrative Assistant Stefanie Peulen, Finance Offi cer Grazia Tomasini, Administrative Assistant

Photo Credit Innovative Medicines Initiative (IMI)

Layout: The Publishing Bureau

2 Dementia in Europe SPECIAL SUPPLEMENT

Foreword

Alzheimer Europe has started to cover this subject in 2014 with the aim to build an accessible, user-friendly, web-based resource that can help people with dementia and their carers to gain and share better information about clinical trials for the “prevention and treatment of Alzheimer’s dementia and other types of dementia.”

I am very pleased to welcome our readers of prevention of Alzheimer’s disease and other scientists are confronted with, there is a com- our Dementia In Europe magazine to this spe- dementias in an accessible format. At that monality in learning from these failed clinical cial supplement about clinical trials. time, only Phase III clinical trials recruiting trials. It is encouraging to see that new direc- participants in at least two European coun- tions in Alzheimer’s disease research are Clinical trials represent an essential step tries were included. In 2018, thanks to the being considered and that a major emphasis toward the development of new ways to pre- funding from the EU health programme, the is placed on early intervention and prevention. vent, diagnose and treat dementia. A range resource was further expanded to include of clinical trials is being conducted at a Euro- Phase II and III studies that are being con- We hope you will find this special supple- pean level. People with dementia or those ducted in all European countries. ment helpful in outlining the Phase II and who are at risk of developing it and healthy III clinical trials that are currently investi- volunteers are needed today to help advance The special supplement will give you a com- gating drugs for Alzheimer’s disease and/ Alzheimer’s disease research. However, the prehensive insight into our Clinical Trials or dementia in Europe, whilst also providing pathways to access to these clinical trials Watch and we hope that you will share our a useful reference for our member organi- are complex. It is apparent that information interest and commitment to this important sations wishing to promote clinical trials about clinical trials is not easily accessible. research topic. The supplement begins with participation in their countries. People cannot find information on the clini- an introduction on and explanation of clinical cal trials related to their own diseases. trials. We have also included a section on the I want to acknowledge the contribution of rationale behind the Clinical Trials Watch and the people involved in this work. My thanks For that reason, Alzheimer Europe has how it was conceived. Next, Phase II and III go to Cindy Birck, Project Officer at Alzheimer started to cover this subject in 2014 with clinical trials that are currently investigating Europe, who coordinates the Clinical Trials the aim to build an accessible, user-friendly, drugs for Alzheimer’s disease and/or demen- Watch and wrote this report. I would like to web-based resource that can help peo- tia in Europe are listed. thank the European Group of People with ple with dementia and their carers to gain Dementia (EWGPWD) and the pharmaceuti- and share better information about clini- This is followed by an overview of the recent cal companies who are providing insightful cal trials for the prevention and treatment Phase III clinical trials that failed to show feedback on the Clinical Trials Watch. of Alzheimer’s dementia and other types of significant results supporting their clinical dementia. Alzheimer Europe reached out to outcomes. Although pharmaceutical compa- Lastly, if you are reading this during our 29th both researchers and people with dementia nies have invested heavily in various potential Alzheimer Europe conference (#29AEC) in and involved them in the provision of infor- disease-modifying drugs for Alzheimer’s The Hague, I would like to invite you to join mation on clinical trials in a language that is disease, the past years have brought some the special symposium on “Clinical trials in both understandable and accessible for peo- disappointing results. Alzheimer’s disease” on Thursday 24 October ple with dementia and scientifically accurate from 12.45 to 13.45 pm. A special thanks goes and checked by the researchers involved. This We also feature an interview with Craig to Janssen who provided a special grant for this resulted in the launch in 2016 of our Clinical Ritchie in this special supplement. We are supplement and the conference symposium. Trials Watch, a new service bringing together very grateful for his willingness to share his up-to-date information on clinical trials thoughts and experiences so far. It is evi- Jean Georges investigating drugs for the treatment and dent that despite the many challenges that Executive Director, Alzheimer Europe

Dementia in Europe 3 biotechnology companies, hospitals, aca- Understanding clinical trials demic institutions, other organisations or individuals. They are usually conducted at hospitals or clinics. Relevance in the What is a clinical trial? Alzheimer’s disease field A clinical trial (also called interventional What are the types To date there is no preventative or curative study) is a biomedical/health-related research of clinical trials? treatment for Alzheimer’s disease. Some study conducted to evaluate the effects on drugs exist for Alzheimer’s disease that humans of a new medical treatment. In most There are two main types of clinical studies: can, for some people, temporarily alleviate cases, clinical trials refer to a research study interventional and observational. some of their symptoms, such as mem- conducted in people to determine whether ory loss and confusion. There are currently treatments are safe and effective. The word yy Interventional clinical studies are clini- four drugs approved and currently used in “treatment” most often refers to new drugs cal trials conducted to determine whether symptomatic treatment: donepezil (Aricept, but may also refer to new technology, device, a candidate drug, a new combination of 1996), rivastigmine (Exelon, 2000), galan- vaccine, surgical procedures, therapy or meth- drugs, experimental treatment or therapy tamine (Razadyne, 2001) and memantime ods of prevention, screening and diagnosis is safe and effective. (Namenda, 2003). Three of the four available of a disease. yy Observational clinical studies investigate drugs – donepezil, rivastigmine and galan- health issues and outcomes in large groups tamine – are known as acetylcholinesterase Clinical research is key of people. The participants do not receive inhibitors and are prescribed to treat symp- any investigational treatment or drug. toms related to memory, thinking, language, for advancing medicine, Instead, researchers observe participants judgment and other thought processes in leading to new interventions by monitoring their health over a period people with mild to moderate Alzheimer’s and improving medications – of time to collect data about the disease. dementia. The fourth drug, memantine, notably in the field of Alzheimer’s regulates the activity of a different neuro- “ Different types of interventional clinical trials transmitter in the brain known as glutamate. disease research at a time when can be categorised according to their objec- Memantine is prescribed to improve memory, the disease is becoming more tives and the way they are organised. Below attention, reason, language and the ability to are descriptions of some different types of perform simple tasks in people with moder- prevalent with the ageing of the clinical trials that exist in addition to treat- ate to severe Alzheimer’s dementia. world’s population.” ment trials:

Every product that is utilised in clinical prac- yy Prevention trials involve tests to find ways tice has been rigorously tested. Clinical trials to prevent particular diseases or medical It is a long and difficult are carefully designed and reviewed with a conditions in people who have never had journey to bring new number of parameters in order to generate them or to prevent them from reoccurring. treatments to the market, meaningful results. In a clinical trial, par- They can include the use of medicines, life- ticipants receive the above interventions style changes or dietary supplements. involving decades of research according to the protocol created by the yy Diagnostic and screening trials are aimed “and a series of clinical studies investigators. Research participants can at finding new or better ways to detect and on human participants.” expect to receive either the drug being tested diagnose a particular medical condition. or a placebo treatment (a substance identi- cal in appearance to the drug being tested Clinical research is key for advancing med- with no active therapeutic effect; this refers What are the phases icine, leading to new interventions and to the control group). Every clinical trial fol- of clinical trials? improving medications - notably in the field lows a protocol that describes inclusion and of Alzheimer’s disease research at a time exclusion criteria such as age, specific dis- Clinical trials are conducted in a series of when the disease is becoming more preva- ease or health history to determine the target steps called Phases. They advance through lent with the ageing of the world’s population. population that may participate in the trial. four Phases (literally Phase I, II, III and IV) to There are several drugs currently in develop- The protocol also outlines the design, meth- test if a drug/treatment is safe and effective ment and testing. However, it is a long and ods, dosage, duration and target outcomes in humans, find the appropriate dosage and difficult journey to bring new treatments to of the trial. identify side effects. Each step has its own the market, involving decades of research and purpose and the number of people involved a series of clinical studies on human partic- Clinical trials can be sponsored and funded increases as the trial progresses from one ipants, known as clinical trials. by government agencies, pharmaceutical or Phase to the next one.

4 Dementia in Europe SPECIAL SUPPLEMENT

yy Phase I trial tests an experimental treatment or a drug in a small group of people, often healthy people (20–80), for a short period of time. The purpose is to study the safety of the drug, identify side effects, determine a safe dosage range and see how the body reacts to the drug (e.g. how it is absorbed, distributed and eliminated from the body). It is the first investigation of a new drug in people after successful laboratory and animal testing. yy Phase II trial determines the right dosage and effectiveness of a drug in treating a particular disease and further studies its safety in a large number (100–300) of participants who have the disease/condition that the drug is intended to treat. The study typically assigns participants to different treatment groups, where each group can receive different doses. yy Phase III trial is performed on larger groups (1000–3000) of research participants with a disease/condition to confirm the effectiveness of the new drug, monitor its side effects and study different dosages. Phase III is the last stage before clinical approval for a new drug. These trials are longer in duration than Phase II open to everyone who meets the eligibility To date there is no trials, involve a much larger group of vol- criteria but only to people in that particular unteers than Phase I and II trials and are population, who are specifically invited to preventative or curative often multinational. participate. Participants are usually informed treatment for Alzheimer’s yy Phase IV trial is also known as post-mar- at the time they are recruited into the main disease. Some drugs exist for keting study. The aim is to monitor the trial that they may be eligible to participate Alzheimer’s disease that can, long-term safety and effectiveness of in an extension study. After the completion “ a drug in large populations once it is of the main trial, some research participants for some people, temporarily approved by regulatory authorities and may be invited to enrol in the extension study. alleviate some of their made available to the public. In most cases, during an extension trial, participants receive the drug over a long period symptoms.” There are also some clinical trials that have to gather information about long-term safety an extension trial. These studies are not and tolerability.

Figure 1. Overview of the four clinical trials Phases

Phase I Phase II Phase III Phase IV

Safety & Dosage Efficacy & Side effects Safety & Efficacy Post-market safety monitoring yy 20–80 healthy volunteers yy 100–300 people with the yy 1000–3000 people with the yy All people using the treat- yy Several months disease disease ment after it has been yy Several months to 2 years yy 1–4 years approved

Dementia in Europe 5 dementias, in an accessible format. The Clini- Clinical Trials Watch cal Trials Watch is not an exhaustive resource of information. It contains information about clinical trials that are: Background and objectives of the database In 2018, the Harris Poll conducted the y Currently recruiting participants largest global survey about Alzheimer’s y Conducted in at least one European country Only a small body of research exists that has disease on behalf of Novartis, Amgen y In phase II and phase III. examined the personal experiences of partic- and Banner Alzheimer’s Institute and ipants enrolled in a clinical trial. In particular, in association with Alzheimer’s Disease Since its development, Alzheimer Europe con- research on people with dementia and their International. The survey was conducted tinues to develop and improve its innovative experiences of taking part in a clinical trial, among 10,095 adults living in 10 coun- online resource providing dementia-friendly their needs and problems encountered is tries and highlighted the importance information on clinical trials. very limited. of raising awareness on how to get involved in Alzheimer’s disease research. Information about clinical trials and experi- Findings reported that a majority of Methodology mental treatments is very relevant for people participants (79%) would be willing to living with dementia, their families and also participate in medical research specif- Who is involved in this work? for the general public. The demand from peo- ically about Alzheimer’s disease but ple for information about ongoing clinical 70% said it is diffi cult to fi nd out about For this new resource, Alzheimer Europe trials has been growing for many years. Many the latest developments in medical collaborated closely, with members of its people are willing to participate in clinical tri- research and 75% had no idea how to European Working Group of People with als and for many this opportunity should be get involved with medical research. Dementia (EWGPWD) from 2014–2016 and a right (Locock et al, 2011). also asked several pharmaceutical companies conducting trials feedback on how to The accessibility to clinical trials remains suitable for them. This type of information is present basic information. Five members of problematic and very much dominated by oft en diffi cult to fi nd and generally written in the European Working Group of People with the medical profession. These issues become language that is diffi cult to understand (e.g. Dementia, all living with dementia, were even more complex in dementia as oft en peo- large amount of complex information, jargon). involved in the development of an easy-to- ple with dementia experience diffi culties for read template with information about trials accessing, understanding information or Considering the above, Alzheimer Europe and in helping to ensure that the information making informed decisions. Moreover, oft en, decided in 2014 to propose the develop- provided in each template is understandable the carer has to be involved at some level. ment of a user-friendly web-based resource for a lay person, regardless of whether the that can help people with dementia and their person has (or not) a diagnosis of dementia. Although new regulations have been put in carers to gain and share better information place in Europe about transparency and the about clinical trials for the prevention and Once a new trial is identifi ed, Alzheimer type of information that should be accessi- treatment of dementia. In September 2016, Europe develops a table containing basic ble to the public, user-friendly information Alzheimer Europe announced the launch of information about it. The contents are based about clinical trials is scarce and participants the resulting Clinical Trials Watch - a service on the information available on public reg- are confronted with a number of practical bringing together up-to-date information on istries, such as the US and EU Clinical Trials and emotional challenges. It is very limited clinical trials investigating drugs for the treat- Registries. ClinicalTrials.gov and the EU Clin- for people to fi nd a clinical trial that may be ment and prevention of Alzheimer’s and other ical Trials Database (EudraCT) provide the

The European Working Group of People with Dementia – EWGPWD – was launched by Alzheimer Europe and its member associations in 2012. The group is composed entirely of people with dementia who are nominated by their national Alzheimer associations. They work to ensure that the activities, projects and meetings of Alzheimer Europe duly refl ect the priorities and views of people with dementia.

6 Dementia in Europe SPECIAL SUPPLEMENT

major source of information for the Clinical Trials Watch. They are the largest registries of the end, the later stages. It also doesn’t clinical trials that should give complete, accu- mean we have to sit back, waiting to die rate and updated information about trials. We and exist with no chance of a useful life. use the public registries labelling interven- We all need a future, a purpose, a focus, tional Phase II and III trials that are recruiting and a life full of hope. And this is what tak- participants in Europe. ing part in research, gives us! This is what research gave me, it gave me the hope and The pharmaceutical company or study spon- knowledge we needed to carry on living sors running the trial are asked to provide our life with dementia. We all need to work feedback on the contents of the table and together if any progress is to be made in to check that the information included are research, for us to take part, we might need scientifically accurate. In the meantime, Taking part in research as an expert by extra support. The professionals involved, each easy-to-read document is reviewed by experience means that you need correct also need support to work with us and to a member of the European Working Group information about all clinical trials that better understand what’s going on with of People with Dementia to ensure that the might be relevant, what is required and regards to our diagnosis. Being enabled information provided is understandable for expected, from all involved, which is acces- and supported, not disabled, is just what a lay person before being published on the sible, easy to read and understand, that is needed, this dementia-friendly informa- Alzheimer Europe website. is exactly what Alzheimer Europe has tion resource on clinical trials does just this, produced with their dementia friendly it helps make possible to still contribute What do the tables contain? resource on clinical trials. A demen- and live alongside dementia. tia diagnosis does not mean we are all The tables provide information on active suddenly at the later stage of dementia, Chris Roberts, phase II and III clinical trials for Alzheimer’s there is a beginning and middle before Vice-chair, EWGPWD disease and/or dementia. All the clinical trials included are currently recruiting participants in at least one European country. However, it is important to bear in mind that recruitment How many trials are We also identified seven compounds may not happen in all countries at the same reported in the CTW? (BIIB092, RO7105705, ABBV-8E12, BI 425809, time. The content is updated regularly, based Nefl amapimod, Liraglutide, Lemborexant) on information available on public registries. The CTW was developed three years ago that are being investigated in Phase II clin- Each table contains the following sections: (at the time of print) and 37 clinical trials ical trials, those are European ongoing have already been reported via this service. studies but new participants are not cur- 1. Study information Although some trials have been removed rently being recruited or enrolled. 2. Information about the drug that will be since they are no longer recruiting partic- tested in the study ipants, new trials have also been added, Smart-Age is another active Phase II trial 3. Information about participating in the resulting in 17 clinical trials currently reported investigating the eff ects of polyamine sup- trial in the database (as of 25 September, 2019). plementation on cognition and biomarkers in 4. Who can participate in this study? older adults with subjective cognitive decline. 5. Where and when will the study be Phase II trials This trial is listed as recruiting participants in conducted? Germany on the public registry clinicaltrials. 6. Information for your doctor As part of our Clinical Trials Watch, we identifi ed gov but the recruitment status has not been eight Phase II clinical trials currently recruiting updated since March 2017. At the time of print, All tables can be found on the Alzheimer participants for the treatment of Alzheimer’s this trial is suggested to be an ongoing study Europe website. In addition, an accessible disease and /or dementia in Europe. They are that has completed its recruitment. easy read version of each study is also availa- investigating eight diff erent agents (ABvac40, ble as a pdf. One easy list provides the names ACI-24, CPHPC, ORY-2001, RO7105705, LM11A-31- The detailed list of active Phase II clinical tri- of all studies currently being conducted in BHS, IONIS-MAPTRx, Valaciclovir). als can be found in table 1. Europe. However, a better way to fi nd relevant information on trials is by searching by coun- You need information that is correct, accessible and easy- try or condition. This allows users to only fi nd to-read and understand, about all clinical trials that might those studies that are currently recruiting or planning to recruit participants in their coun- be relevant, and to know what is expected - that is exactly what try or for their condition (at risk, prodromal, Alzheimer Europe has produced.” mild, moderate, severe dementia, agitation). “ Chris Roberts

Dementia in Europe 7 Table 1. Agents in Phase II of Alzheimer’s disease drug development in Europe

Name of Name of Target Condition Study sponsor Recruitment status the drug the study

Amnestic mild cognitive Amyloid-related ABvac40 / impairment or very mild Araclon Biotech Recruiting (immunotherapy) Alzheimer’s disease Amyloid-related ACI-24 ACI-24-1801 Mild Alzheimer’s disease AC Immune Recruiting (immunotherapy) Amyloid-related (small University College CPHPC DESPIAD Mild Alzheimer’s disease Recruiting molecule) London Epigenetic Mild-moderate Alzheimer’s ORY-2001 ETHERAL Oryzon Genomics Recruiting (small molecule) disease Moderate Alzheimer’s RO7105705 LAURIET Tau (immunotherapy) Genentech Recruiting disease Neuroprotection (small Mild-moderate Alzheimer’s LM11A-31-BHS / PharmatrophiX Recruiting molecule) disease Tau Ionis IONIS-MAPTRx MAPT-CS1 Mild Alzheimer’s disease Recruiting (RNA-based) Pharmaceuticals Neuroprotection & Valaciclovir VALZ-Pilot inflammation (antiviral Early Alzheimer’s disease Hugo Lovheim Recruiting agent) Neuroprotection (dietary People with subjective Charite University Polyamine SmartAge Recruiting supplement) cognitive decline Berlin

Mild cognitive impairment BIIB092 TANGO Tau (immunotherapy) due to Alzheimer’s disease Biogen Active, not recruiting or mild Alzheimer’s disease

Prodromal to mild RO7105705 TAURIEL Tau (immunotherapy) Genentech Active, not recruiting Alzheimer’s disease

ABBV-8E12 AWARE Tau (immunotherapy) Early Alzheimer’s disease AbbVie Active, not recruiting

Neurotransmitter based Cognitive impairment due Boehringer BI 425809 / Active, not recruiting (small molecule) to Alzheimer’s disease Ingelheim

Inflammation (small Neflamapimod REVERSE-SD Mild Alzheimer’s disease EIP Pharma Active, not recruiting molecule) Metabolic function Imperial College Liraglutide ELAD Mild Alzheimer’s dementia Active, not recruiting (small molecule) London Mild to moderate Neurotransmitter based Lemborexant / Alzheimer’s disease Eisai Active, not recruiting (small molecule) dementia

8 Dementia in Europe SPECIAL SUPPLEMENT

Accessibility to clinical trials remains problematic and is aims to enrol people with early Alzheimer’s disease who will receive BAN24-01 or pla- dominated by the medical profession. These issues become cebo for 18 months. The company expects even more complex in dementia as oft en people with dementia to expand the recruitment in Europe in the experience diffi culties accessing and understanding information.” coming months and the trial is set to run until 2024. As can be seen from fi gure 3, there “It is possible to rank European countries as a positive trend of effi cacy in one of the are signifi cant diff erences between European indicated in fi gure 2, which shows the num- masitinib doses tested. Final analysis are countries in terms of number of Phase III clin- ber of active Phase II clinical trials recruiting expected by the end of 2019. In August 2019, ical trials open for recruitment. There is no research participants in Europe. There is no AZTherapies announced that the company country where it is possible for research par- country where it is possible for research par- completed enrolment for its Phase III COG- ticipants to enrol in all 9 recruiting Phase III ticipants to enrol in all eight identifi ed Phase NITE trial, testing the safety and effi cacy of its clinical trials. UK, Spain, France and Poland II clinical trials. Only 11 European countries investigational drug ALZT-OP1 for the treat- are among the countries with most Phase (Austria, Czech Republic, Finland, France, ment of early Alzheimer’s disease. The study III trials. In a number of smaller and mostly Germany, Italy, Netherlands, Poland, Spain, is still ongoing, participants are receiving an Eastern European countries (Albania, Aus- Sweden, UK) are recruiting participants in intervention or being examined, but no new tria, Bosnia & Herzegovina, Cyprus, Estonia, Phase II trials. Sweden, Spain, UK and France participants are being enrolled. In September Greece, Iceland, Israel, Ireland, Jersey, Latvia, are among the countries with most phase II 2019, Acadia Pharmaceuticals announced that Luxembourg, Malta, Monaco, Montenegro, trials. In all other European countries, it is the HARMONY Phase III study will be stopped Netherlands, Norway, Romania, Slovakia, impossible for volunteers to enrol in Phase early for positive effi cacy as Pimavanserin met Slovenia, Switzerland), it is impossible for II clinical trials, as none of the identifi ed clin- its primary endpoints on people with demen- volunteers to enrol in Phase III clinical tri- ical trials are recruiting in those countries. tia-related psychosis. als, as none of the identifi ed clinical trials are recruiting in those countries. Details of pos- Phase III trials Besides that, in March 2019, Eisai began a sible participation of research participants in Phase III trial called Clarity AD in the US. It Phase III clinical trials can be found in table 3. A number of Phase III clinical trials investigating drugs for Alzheimer’s disease and/ or dementia are also being conducted. As indicated in table 2, Alzheimer Europe has identifi ed 9 Phase III clinical trials investigating diff erent compounds (Brexpiprazole, Gantenerumab, TRx0237, Guanfacine, Mir- tazapine, AVP-786, Omega-3 treatment, COR388) that are currently recruiting research participants in at least one European country (as of 25 September, 2019).

Furthermore, three other compounds (Mas- 2 itinib, ALZT-OP1 and Pimavanserin) are being examined. AB Science completed Phase III recruitment of masitinib in people with 5 confi rmed mild to moderate Alzheimer’s disease in mid-2018. In June 2019, AB Science reported that their pre-planned interim analysis of the Phase III study data had detected 4 1 2 1 1 3 1 1

Figure 2. Phase II clinical trials open for 4 recruitment in Europe – numbers shown per country refer to number of trials currently open (as of 25 September 2019)

Dementia in Europe 9 Table 2. Agents in Phase III of Alzheimer’s disease drug development in Europe

Name of Name of Target Condition Study sponsor Recruitment status the drug the study

Agitation associated Neurotransmitter based Otsuka Brexpiprazole / with dementia of the Recruiting (small molecule) Pharmaceutical Alzheimer’s type Mild to moderate Inflammation (small COR388 GAIN Alzheimer’s disease Cortexyme Recruiting molecule) dementia

Amyloid-related Early (prodromal to mild) Hoffmann-La Gantenerumab GRADUATE1 Recruiting (immunotherapy) Alzheimer’s disease Roche

Amyloid-related Early (prodromal to mild) Hoffmann-La Gantenerumab GRADUATE2 Recruiting (immunotherapy) Alzheimer’s disease Roche

TauRx TRx0237 LUCIDITY Tau (small molecule) Early Alzheimer’s disease Recruiting Therapeutics

Subjective memory University Omega-3 Neuroprotection (dietary LO-MAPT complaints or family history Hospital, Recruiting treatment supplement) of Alzheimer’s disease Toulouse

Neurotransmitter based Mild to moderate Imperial College Guanfacine NorAD Recruiting (small molecule) Alzheimer’s disease London

Neurotransmitter based Agitation in people with University of Mirtazapine SYMBAD Recruiting (small molecule) dementia Sussex

Agitation associated 17-AVP-786- Neurotransmitter based Avanir AVP-786 with dementia of the Recruiting 305 (small molecule) Pharmaceuticals Alzheimer’s type

Neurotransmitter based Dementia-related ACADIA Pimavanserin HARMONY Active, not recruiting (small molecule) psychosis Pharmaceuticals

Amyloid-related & Evidence of early ALZT-OP1 COGNITE Inflammation (small AZTherapies Active, not recruiting Alzheimer’s disease molecule)

Inflammation Mild to moderate Masitinib / AB Science Active, not recruiting (small molecule) Alzheimer’s disease

Amyloid-related BAN2401 Clarity AD Early Alzheimer’s disease Eisai Planned (immunotherapy)

10 Dementia in Europe SPECIAL SUPPLEMENT

Table 3. Phase III clinical trials open for recruitment in European countries (R: Recruiting, ANR: Active not recruiting P: Planned) GAIN NorAD SYMBAD LO-MAPT LUCIDITY GRADUATE1 GRADUATE2 Brexpiprazole 17-AVP-786-305

Belgium R P

Bulgaria R R

Croatia R

Czech Republic R

Denmark R

Finland R

France R R P R

Germany R

Hungary R R

Italy R P R

Lithuania R

Netherlands ANR

Poland R R P R

Portugal R

Russia R

Serbia R

Spain R R R P R

Sweden R

Turkey R

Ukraine R

United Kingdom R R R R R

Dementia in Europe 11 Figure 3. Phase III clinical trials open for recruitment in Europe – numbers shown per country Mechanisms of actions refer to number of trials currently open (as of 25 September 2019) As described above, the Clinical Trials Watch currently reports on 8 Phase II and 9 Phase III clinical trials recruiting research participants in Europe.

8 agents are investigated in 8 Phase II clinical trials and 8 agents in 9 Phase III clinical trials. There are 12 agents that intend to achieve disease modifi cation as they attempt to alter the pathophysiology of Alzheimer’s disease. Misfolded proteins such as Amyloid and 1 Tau are the most common specifi c targets in Phase II and Phase III studies as they can accumulate into plaques, tangles and other 1 forms in the brain and become toxic. However, 1 new compounds are being studied based on 1 other mechanisms including neuroprotec- 1 tion, anti-infl ammatory approaches, synaptic activity, metabolic and genetic interventions. 5 3 1 1 1 All 8 compounds in Phase II clinical trials are 1 disease-modifying drugs. In Phase III, there 2 are 4 symptomatic agents and 4 compounds 3 1 2 2 that are targeting disease modifi cation. 1 2 Figure 4 shows a breakdown by mechanisms of 1 4 action of agents in Phase II and III clinical trials 1 recruiting research participants in Europe. The data presented here focus on agents currently reported in the Clinical Trials Watch resource.

The Clinical Trials Watch is a service bringing together up-to-date information on clinical trials investigating drugs for the treatment and prevention of Alzheimer’s and other dementias, in an accessible format.”

Figure 4. Mechanism of action of agents in Phase II and III clinical trials “ Disease-modifying therapies 56% Epigenetic Cognition (11%) (12.5%) Tau (11%)

Tau (25%)

Neuroprotection (12.5%)

8 Phase II 9 Phase III trials Agitation (33%) trials Amyloid (22%)

Neuroprotection & Infl ammation (12.5%) Amyloid (37.5%)

Symptomatic drugs Neuroprotection Disease-modifying therapies 44% (11%) 100% Infl ammation (11%) 12 Dementia in Europe SPECIAL SUPPLEMENT

Lessons have been Recent failed disease-modifying learned from failed and treatment trials discontinued clinical trials offering opportunities to Although there are four compounds on the to the recent report published by the Biotech- “improve the development of new market that treat symptoms of Alzheim- nology Innovation Organization, the clinical disease-modifying therapies.” er’s disease, there are currently no approved development success rates for Alzheimer’s disease-modifying drugs that stop the pro- disease programmes is among the lowest inhibitors (encenicline), agonists and antag- gression of the disease. found in any therapeutic area. onists of neurotransmitter receptors (idalopirdine, azeliragon, intepirdine), mole- No new disease-modifying treatments have Most Phase II clinical trials ending with a cules acting on neuronal pathways (ITI-007), been successful in Phase III clinical trials positive outcome do not succeed in Phase agents related to mitochondria and metabolic for Alzheimer’s disease underlying the very III, often due to adverse effects or failure to function (AC-1204), β-secretase inhibitors high rate of failures in Alzheimer’s disease meet pre-specified primary endpoints. Table (verubecestat, lanabecestat, atabecestat, drug development programmes which is 4 provides an overview of phase III clinical CNP520, elenbecestat) and vaccines or anti- estimated at a 99.6% failure rate during trials investigating drugs for Alzheimer’s dis- bodies targeting Aβ clearance (crenezumab, 2002–2012 (Cummings et al, 2014). According ease that have recently failed along with their gantenerumab, solanezumab, aducanumab). sponsor and the indication of why the clinical trial failed. Over the last decade, advances have been Clinical development made in understanding the biological mech- success rates for There have been many failures in attempts to anisms underlying Alzheimer’s disease. Alzheimer’s disease programmes develop new drugs for Alzheimer’s disease Furthermore, lessons have been learned from targeting the neuropathological findings of failed and discontinued clinical trials offering are among the lowest found in the disease. These investigations that have opportunities to improve the development of “any therapeutic area.” failed to date include acetylcholinesterase new Alzheimer’s disease–modifying therapies.

Most Phase II clinical trials ending with a positive outcome do not succeed in Phase III, often due to adverse effects or failure to meet pre-specified primary endpoints.” “ Dementia in Europe 13 Table 4. Overview of Phase III failures over the past years in Alzheimer’s disease-drug development

Name of the drug Name of the study Target Condition Study sponsor Results MISSIONAD1 September 2019 - Discontinuation based on data safety monitoring board recommendation due to an unfavourable risk- Elenbecestat Amyloid-related (small molecule) Early Alzheimer’s disease Eisai MISSIONAD2 benefit ratio. Generation S1 Risk to develop clinical symptoms of Alzheimer’s July 2019 – Discontinuation based on a planned analysis. The review of unblinded data reported that participants receiving CNP520 Amyloid-related (small molecule) Novartis Generation S2 disease the experimental drug worsened in some measures of cognitive function. EMERGE March 2019 – Halt based on results from a futility analysis conducted by an independent data monitoring committee, Aducanumab Amyloid-related (immunotherapy) Early Alzheimer’s disease Biogen ENGAGE which reported that the trials were unlikely to meet their primary endpoint upon completion. CREAD1 January 2019 – Discontinuation based on the results from a pre-planned interim analysis. An independent data Crenezumab Amyloid-related (immunotherapy) Prodromal to mild Alzheimer’s disease Roche CREAD2 monitoring committee reported that crenezumab was not expected to meet its primary endpoint. Neurotransmitter based December 2018 – Discontinuation based on a data monitoring committee who recommended to stop the trial for futility. ITI-007 ITI-007-201 Agitation in patients with dementia Intra-Cellular Therapies (small molecule) The study was not likely to meet its primary endpoint upon completion. AMARANTH Early Alzheimer’s disease June 2018 – Discontinuation based on an independent data monitoring committee who reported that lanabecestat was Lanabecestat Amyloid-related (small molecule) Eli Lilly DAYBREAK-ALZ Mild Alzheimer’s disease dementia unlikely to meet its primary endpoints. May 2018 – Discontinuation due to serious elevations of liver enzymes observed in some research participants who received Atabecestat EARLY Amyloid-related (small molecule) Risk for developing Alzheimer’s dementia Janssen atabecestat. The company concluded that the benefit-risk ratio is no longer supported to continue the development of the study. Amyloid-related & Inflammation Azeliragon STEADFAST Mild Alzheimer’s disease vTv Therapeutics April 2018 –Failure to meet the co-primary endpoints. (small molecule) February 2018 – Discontinuation based on recommendation by the external data monitoring Committee reporting that Verubecestat APECS Amyloid-related (small molecule) Prodromal Alzheimer’s disease Merck verubecestat was unlikely to demonstrate a positive clinical effect if the trial continued. Risk of mild cognitive impairment due to January 2018 – Discontinuation based on a planned interim futility analysis showing an inadequate treatment effect with Pioglitazone TOMMORROW Inflammation (small molecule) Takeda Alzheimer’s disease pioglitazone in delaying the onset of mild cognitive impairment due to Alzheimer’s disease. Neurotransmitter based September 2017 –Failure in demonstrating a statistically significant improvement in cognition and measures in daily Intepirdine MINDSET Mild to moderate Alzheimer’s disease Axovant Sciences (small molecule) activities (co-primary endpoints). Mitochondrial metabolism AC-1204 NOURISH AD Mild to moderate Alzheimer’s disease Accera February 2017 – Failure in demonstrating a statistically significant improvement at 26 weeks (primary endpoint). (dietary supplement) February 2017 – Discontinuation based on recommendation of an external data monitoring committee who determined Verubecestat EPOCH Amyloid-related (small molecule) Mild to moderate Alzheimer’s disease Merck no chance of a positive result and recommended ending the study. STARBEAM Neurotransmitter based Idalopirdine Mild to moderate Alzheimer’s disease Lundbeck February 2017 – Failure in demonstrating efficacy. STARBRIGHT (small molecule) November 2016 – Failure to meet primary endpoint. Solanezumab did not experience a statistically significant slowing in Solanezumab EXPEDITION-3 Amyloid-related (immunotherapy) Mild Alzheimer’s disease Eli Lilly cognitive decline. October 2016 – Discontinuation based on a planned futility interim analysis showing low probability of meeting the Gantenerumab MARGUERITE RoAD Amyloid-related (immunotherapy) Mild dementia due to Alzheimer’s Roche primary outcome measure with the doses studied. Neurotransmitter based Idalopirdine STARSHINE Mild to moderate Alzheimer’s disease Lundbeck September 2016 – Failure in showing efficacy and significant improvements. (small molecule)

Encenicline COGNITIV AD Cholinergic system (small molecule) Mild to moderate Alzheimer’s disease FORUM Pharmaceuticals January 2016 – Discontinuation following reports on gastrointestinal side effects.

December 2014 – Discontinuation based on an interim futility analysis made by an independent data monitoring Gantenerumab SCarlet RoAD Amyloid-related (immunotherapy) Prodromal Alzheimer’s disease Roche committee. The company noted that no new safety signal arose.

Timeline of failed drug trials

December 2014 September 2016 November 2016 February 2017 September 2017 Gantenerumab Idalopirdine Solanezumab Idalopirdine Intepirdine

January 2016 October 2016 February 2017 February 2017 Encenicline Gantenerumab Verubecestat AC-1204

14 Dementia in Europe SPECIAL SUPPLEMENT

Table 4. Overview of Phase III failures over the past years in Alzheimer’s disease-drug development

February 2018 May 2018 December 2018 March 2019 September 2019 Verubecestat Atabecestat ITI-007 Aducanumab Elenbecestat

January 2018 April 2018 June 2018 January 2019 July 2019 Pioglitazone Azeliragon Lanabecestat Crenezumab CNP520

Dementia in Europe 15 major impact on a person’s well being. Many The academic perspective on investigators and companies are already add- ing a new direction by looking at drugs that have a particular effect on the behavioural recent clinical trials and on the symptoms such as agitation, psychosis or sleep disturbances. Several clinical trials are future of AD research underway with agents designed to address behavioural symptoms associated with Alzheimer’s disease we see in practice. As a future as well as what to do. There will have clinician, I recognise that a lot of the chal- been a point in the course of all recent tri- lenges that people with dementia encounter als when the sponsor could have known are not just around their memory impairment and perhaps should have known that the but also on what we call neuropsychiatric intervention was highly unlikely to be suc- symptoms. New approaches for managing cessful. In that regard, the other lesson that neuropsychiatric symptoms in Alzheimer’s is very important to learn is the value of disease are needed and I think we are going adaptive trial design whereby data from to see new developments in this area both the trial is regularly reviewed. Therefore, as with pharmacological and non-pharmaco- the trial progresses, researchers and com- logical interventions. panies can actually make early decisions about whether or not there is any opportu- In terms of disease-modifying agents, the nity or any chance that the drug is going to drug development pathway is complicated be successful. If the drug is not statistically by the fact we are recognising that Alzheim- likely to be successful, they could stop that er’s disease is an incredibly complex disease trial and move the resources elsewhere and that can be initiated and driven by multiple Alzheimer Europe interviewed Professor Craig more importantly not continue to expose genetic and non-genetic factors. At a bio- Ritchie from the Centre for Dementia Preven- research participants to the risk of taking logical level it is no longer helpful to think tion (Edinburgh, Scotland) to discuss the recent a drug which is unlikely to show success. about the disease just in terms of Amyloid clinical trials’ results and the future directions and Tau pathology as there are many other of Alzheimer’s disease (AD) research. One thing I would say though is that I don’t pathological processes (both upstream and think that the targets for these drugs are downstream) that affect brain health and Recently there have been quite a few high necessarily the wrong targets. There is still which lead to the person having symptoms. profile failures of Phase III clinical trials of a lot of promise there and these approaches Researchers are now focusing on drugs disease-modifying treatments. What have like anti-amyloid therapies for instance are for a multitude of biological targets mov- we learned from these failed clinical trials? going to be useful in the future. Key though ing beyond Amyloid and Tau for instance. is to understand ‘when’ and in ‘who’ the drug Although a new breadth of approaches may One of the things we have learned over the should be tested rather than what remains a over time yield advances, we still have the past several years is that Alzheimer’s dis- little bit of a ‘one-size-fits-all’ approach too problem of when do we intervene. This can be ease starts to develop in the brain decades late in the disease course. We have funda- only informed by much better disease models before dementia symptoms appear, probably mentally reassessed how we approach clinical being developed that confirm the biology of starting in mid-life and with as yet not fully trials in Alzheimer’s disease by establishing a range of neurodegenerative brain diseases understood disease processes. Given that, projects like EPAD to find solutions to these at their earliest stages of development. recent trials have been showing us that better key challenges. targeted populations should be considered Last but in no ways least, it’s worth not- for inclusion in studies and that intervention Looking at the current compounds in the ing the value of combining therapies as a may be required before clinical symptoms Alzheimer’s disease development pipeline, method of gaining greater effectiveness in are apparent. We should of course try to tar- what is coming up next? what is after all a very complex disease with get individuals with earlier stages of disease numerous interacting biological processes. rather than those in the advanced stages of First of all, a lot of compounds that have This area has been slow to gather pace but Alzheimer’s disease. been tested recently are intended to modify is beginning to get some attention. It is the course of disease and this encompasses not without substantial challenges e.g. the It is worth mentioning of course that these the challenges mentioned above. Compa- safety of combinations of novel treatments trials, despite not being successful in achiev- nies and drug developers have recognised needs to be understood before embarking ing their primary objective, are still teaching these challenges as well as the unmet clini- on large scale trials – though the scale of us and help us develop knowledge. Maybe cal needs for people with later stage disease the problem of Alzheimer’s disease should the lesson is as much what not to do in the where other, non-cognitive, symptoms have a convince sponsors to find ways to rise to

16 Dementia in Europe SPECIAL SUPPLEMENT

these challenges. Given the complexity of knowledge and understanding of the disease agents. To be fair, I think that the priority in the disease including interactions of many processes which left alone would lead years the early stages of the disease would be life- diff erent processes, we want to consider later to the development of dementia. For style changes. the use of combination therapies to try to this, we need to have the highest quality of address these in relevant, specifi c, well char- longitudinal data including multiple diff erent What other promising research leads are acterised populations; as we do in cancer measures such as brain imaging, spinal fl uid there? interventions currently. I think personally assays, cognitive testing, genetic analysis and it would be a huge leap forward for the blood proteomics. Over time, we will generate There is a massive amount of research going Alzheimer’s disease community and may wonderful and much needed disease models on in terms of early detection, blood biomark- hold the greatest promise for disease mod- that will give us the knowledge regarding why ers, genetics, imaging and others markers. ifi cation. We still need those early disease some people develop the disease, what the There is also a number of studies in pro- models though! diseases are and what we can do to mitigate gress on the pharmacology front. Firstly, the eff ects of these dreadful brain diseases. we will defi nitely need more collaborative You are leading several programmes aiming approaches. We should find an effective to prevent the disease such as the PREVENT In my opinion, there is a consistency between mechanism to bring all the current research Dementia study and the European Preven- pharmacological and non-pharmacolog- together and engineer future research to be tion of Alzheimer’s Dementia (EPAD) project. ical interventions. We should pursue both contributing to coordinated action. It would Should we prioritise prevention over dis- strategies as at the end of the day the pre- indeed be more eff ective to use all the knowl- ease-modifying treatments? vention of Alzheimer’s dementia is going to edge and data generated to develop statistical require both. The fi rst step is always related models and methods that allow individuals I’m pleased to be part of the leadership of a to risk modifi cation and building resilience to be assessed accurately for what their risk couple of major projects working with peo- for any individual to do the best they can to of developing dementia or brain disease in ple at varying risks of dementia so together maintain their brain health from childhood the future is, so that we can intervene and we can identify risk factors for neurodegen- onwards. Public health interventions will also prevent disease taking hold. The second area erative diseases and how this is expressed play a vital role to enhance well being and I would like to highlight is that we should all and progresses decades before dementia therein brain health. If, despite this, the dis- make sure that all these research fi ndings are develops. These are the disease models I ease develops, then at that point people may rapidly implemented into clinical practice. It keep referring to. The value of the PREVENT want to consider a specifi c pharmacological is essential that this happens and researchers Dementia project and the EPAD Longitudinal intervention. It is part of the process of fi rst have to give priority and plan how to ensure Cohort Study amongst others projects across lifestyle changes, early detection and then that research rapidly, eff ectively and respon- the world is really being able to improve the intervention with or without pharmacological sibly transitions into practice.

Profi le

Prof. Craig Ritchie is the Professor of Psy- chiatry of Ageing and Director at Edinburgh Dementia Prevention, the University of Edinburgh. He is also a vis- iting Professor at Imperial College, London. Prof. Ritchie is the Chief Inves- tigator of numerous dementia research projects and these include the EPAD, PREVENT Dementia Programme and the Scottish Dementia Research Consortium. He is also the Founding Director of Brain Health Scotland. He has authored almost 200 publications in the area of dementia research.

EPAD team working with Craig Ritchie, March 2019, Centre for Dementia Prevention, Edinburgh, Scotland

Dementia in Europe 17 18 Dementia in Europe SPECIAL SUPPLEMENT

Acknowledgements

Main contributors: and update the Clinical Trials Watch, in its Special thanks to Craig Ritchie for sharing his accessible and dementia-friendly format. experiences and views for this report. yy Jean Georges (Alzheimer Europe, Luxembourg) yy Chris Robert (Vice-chair, UK-England, N. Alzheimer Europe’s Clinical Trial Watch yy Cindy Birck (Alzheimer Europe, Luxembourg) Ireland, Wales) received funding under an operating grant yy Ana Diaz (Alzheimer Europe, Luxembourg) yy Helen Rochford-Brennan (Chair, Ireland) from the European Union’s Health Pro- yy Idalina Aguiar (member, Portugal) gramme (2014–2020) We would like to thank all companies and yy Carol Hargreaves (member, UK Scotland) sponsors for their contributions to the data- yy Helga Rohra (former member, Germany) Alzheimer Europe gratefully acknowledges base. Thanks are also due to all members of yy Hilary Doxford (former member, UK the grant provided by Janssen which led to the European Working Group of People of England) the production of this report. Dementia, and in particular we are very grate- yy Agnes Houston (former member, UK ful to the members who contributed to the Scotland) development of the templates and to those yy Nina Baláčková (former member, Czech who provide help in continuing to improve Republic). Further information and references

Please note that the information provided in study. Patient Education and Counseling. Biotechnology Innovation Organization the Clinical Trials Watch service should not 84(3):303-309 (2019) The State of Innovation in Highly Preva- be interpreted as a recommendation to use lent Chronic Diseases Volume IV: Alzheimer’s a particular treatment, nor to participate in Alzheimer’s Disease Survey (2018) conducted Disease Therapeutics. a particular study. by The Harris Poll on behalf of Novartis, Amgen and Banner Alzheimer’s Institute ClinicalTrials.gov https://clinicaltrials.gov/ Further information on clinical trials and on and in association with Alzheimer’s Disease the studies appearing in the Clinical Trials International. European Union Clinical Trials Register Watch is available at: http://www.alzheim- (EudraCT) https://www.clinicaltrialsregister.eu/ er-europe.org/Research/Clinical-Trials-Watch Cummings J.L., Morstorf T., Zhong K. (2014) Alzheimer’s disease drug-development Locock L, Smith L. (2011). Personal experiences pipeline: few candidates, frequent failures. of taking part in clinical trials - a qualitative Alzheimer’s Res. Ther. 6(4):37.

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