Idalopirdine: another disappointment for people with dementiaBMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k753 (Published 21 February 2018) Cite this as: BMJ 2018;360:k753
- David G Le Couteur, professor of geriatric medicine1,
- Brace Bateman, living with dementia and dementia advocate2,
- Carol Brayne, professor of public health3
- 1Centre for Education and Research on Ageing, Concord Hospital and University of Sydney, Sydney, Australia
- 2Dementia Australia, Melbourne, Australia
- 3Cambridge Institute of Public Health, Cambridge, UK
This has already been a disheartening year for research into drug treatments for dementia and Alzheimer’s disease, especially for people affected by dementia. Negative results have been posted for phase III clinical trials of two 5-hydroxytryptamine-6 receptor (5-HT6) antagonists for the symptomatic treatment of moderate dementia,12 as well as for a trial of an amyloid β antibody as a disease modifying treatment in mild dementia.3 Pfizer announced that it will end its neuroscience and related dementia investments in drug development, removing a major industry partner from the field.4
Negative drug trials
These developments follow a long period of negative drug trials in dementia. In recent decades the failure rate has been nearly 100%,5 and the only registered medicines are the cholinesterase inhibitors and memantine, which at best generate modest symptomatic improvement in cognitive testing among some patients and for only a limited period.
Drug development has often been associated with great excitement generated by the so called breakthroughs seen in animal models of dementia, followed by uncertain results in early human studies and then the certainty of negative results from phase III studies. But it has been a rollercoaster of hype and disappointment for people with dementia and their families, who are understandably dismayed, and may even grieve, when a promising new treatment fails in high profile clinical trials.
The major focus of research in dementia has been on the “magic bullet” of an effective disease modifying drug. However, an estimated 47 million people in the world have dementia, and improvement in distressing symptoms is a priority for them.6 Much hope was therefore pinned on 5-HT6 antagonists providing a new effective class of drugs for symptomatic treatment.
Phase II human studies found that idalopirdine led to a small improvement in cognition in a subgroup of participants taking donepezil.7 Subgroup analyses should always be treated with caution, and previous trials based on hopeful hints in subgroups of early phase studies have failed.8 Even so, plausible biological mechanisms may explain why acting on both neurotransmitter systems might be effective,9 although it was also noted that idalopirdine, as a cytochrome P450 inhibitor, may simply be increasing the blood levels of co-administered donepezil.10
Phase III clinical trials were undertaken to determine whether idalopirdine can improve cognition in people with Alzheimer’s disease who are currently taking cholinesterase inhibitors, mostly donepezil.1 These multicentre, multinational studies—STARSHINE, STARBEAM, and STARBRIGHT—enrolled 2525 participants with mild to moderate Alzheimer’s dementia and compared three doses of idalopirdine and placebo over 24 weeks.
The results of these high quality, definitive studies were recently published and were entirely negative.1 The authors noted that the positive results from the phase II subgroup analysis had been achieved with a higher dose but, even so, they concluded that idalopirdine was ineffective. Likewise, negative results have been posted from a similar trial with another 5-HT6 antagonist, intepirdine. Together, these trials indicate that 5-HT6 antagonism is yet another blind alley in treating dementia.
Despite the long line of drug trial failures, including most recently idalopirdine, people affected by dementia confirm (through peak bodies such as Dementia Australia) that they are still willing to be involved as participants and co-designers in clinical trials, understanding that progress depends entirely on their voluntary and altruistic contribution. Collaborative research organisations are harnessing this willingness to establish “trial-ready” or “readiness” cohorts: registries of people who have undergone investigations such as cognitive testing and biomarkers, who may be at higher risk of developing dementia in years to come and are willing to take part in clinical trials. This will facilitate clinical trials, but it raises substantial ethical issues such as the status of consent obtained well in advance of any trial, when disease progression might later change participants’ or their carers’ wishes.11
Participants in this long list of previous negative trials deserve great recognition, reward, and respect for their contribution; and people with dementia make it very clear that they should be actively included in the design and implementation of future trials. There should also be a greater incentive for them to be involved as participants. But everyone must be represented in this endeavour, including older people with comorbidities and frailty—the overwhelming majority of people with dementia.
Current fault lines in the research agenda will need careful navigation—for example, the tension between those people with early dementia or genetic susceptibility who are willing to face uncertainty and possible harm from evaluating long term disease modifying treatments that may not work; and the wider public, in whom most future dementia will arise. These different priorities must also be balanced against those of older people with more advanced dementia and their carers, who may be more interested in developing symptomatic treatments.
Either way, clinical trials to date suggest that any therapeutic advances in dementia are likely to be hard won and incremental.11 The expectations of people affected by dementia, carers, doctors, and the wider public must remain realistic while we conduct an open debate on the ethical issues that accompany progress, including the disclosure to asymptomatic individuals of a possible but uncertain risk of dementia.
We thank the Ageing and Alzheimers Institute, the Sydney Medical School Foundation, and Dementia Australia for their support.
The Alzheimer’s Society has published its Dementia Research Roadmap for Prevention, Diagnosis, Intervention and Care by 2025 (Jan 2018), which is available at https://www.alzheimers.org.uk/researchroadmap
Competing interests: none.