A disappointing June for Alzheimer’s disease signals setbacks for several products

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterised by memory loss, cognitive impairment and functional decline. With rapidly increasing worldwide prevalence, AD has been identified as a major global health threat by the international medical community. In order to keep raising awareness, June is Alzheimer’s and Brain Awareness Month. This June, however, has been a disappointing month for the AD space with several companies, including Roche, Athira, Acadia and Biogen, announcing poor results from clinical trials for products being developed for various stages of AD. 

On 16 June, Roche announced that its anti-amyloid-beta monoclonal antibody (mAb), crenezumab, had failed to slow or prevent AD in cognitively unimpaired people who carry a specific genetic mutation that causes early-onset AD in a Phase II trial (NCT01998841). This followed previous Phase III clinical trial failures for crenezumab in patients with prodromal to mild sporadic AD. Roche plans to present data from this trial in August at the Alzheimer's Association International Conference, which may provide a further indication as to whether this is the end of the road for crenezumab or if Roche will look to take the drug in a new direction. But with Phase III trial results for gantenerumab in mild cognitive impairment and mild AD expected in Q4, it is likely that this will be the focus for Roche in the near future. 

On 17 June, Acadia’s Nuplazid (pimavanserin) received a negative opinion from the US Food and Drug Administration's (FDA) advisory panel for the treatment of AD psychosis. The Psychopharmacologic Drugs Advisory Committee voted nine to three that the existing data does not support Nuplazid for the treatment of hallucinations and delusions in AD psychosis. While the FDA does not have to follow the panel’s advice, it seems unlikely it will approve the drug given that, in April last year, the FDA rejected Nuplazid for the treatment of dementia-related psychosis, which includes AD psychosis as a subgroup.  

The FDA approved Nuplazid for Parkinson’s disease psychosis in 2016, and GlobalData forecasts US peak sales of $1.04bn in 2027 for this indication. Given the large AD population, an additional approval for Nuplazid in AD psychosis would significantly increase its potential sales revenue; however, if the FDA recommends an additional Phase III trial to support the use of Nuplazid in this indication, Acadia will need to incur significant further cost if it decides to continue to pursue this approval. 

On 21 June, Biogen terminated its observational study of Aduhelm (aducanumab) (NCT05097131), designed to collect real-world data on its use in clinical practice. This is just the latest setback for Aduhelm, which has been severely limited by restricted insurance coverage, with Medicare reimbursement of Aduhelm confined to AD patients participating in randomised controlled trials. Indeed, Biogen cited this restricted coverage as the reason for trial termination, as there are not enough prescriptions of Aduhelm in clinical practice to make the trial feasible.  

This is a major setback for Biogen, as it is only through providing more data on Aduhelm that the restricted Medicare coverage policy may be revised. Biogen is now reliant on its Phase IV ENVISION trial (NCT05310071), which will take several years to provide results. In the meantime, GlobalData expects Aduhelm to generate minimal sales. 

Most recently, on 22 June, Athira Pharmaceuticals announced top-line results from its Phase II proof-of-concept study (NCT04491006) of its novel drug, fosgonimeton, for mild to moderate AD. The drug failed to meet the trial's primary endpoint, namely memory processing speed measured using event-related-potential (ERP) P300 latency (a measure of the delay between stimulus and response recorded by electroencephalography), as well as multiple secondary endpoints measuring cognition, global clinical change and functional change.  

Despite these negative findings, Athira pointed to a pre-specified subgroup analysis of patients who were administered fosgonimeton monotherapy (versus in combination with the standard of care acetylcholinesterase inhibitors) that suggests improvement in both ERP P300 latency and the Alzheimer's Disease Assessment Scale-Cognitive Subscale compared to placebo. Athira has already initiated a Phase III clinical trial (NCT04488419) for fosgonimeton in mild to moderate AD, but it remains to be seen whether the benefits of fosgonimeton as a monotherapy will be demonstrated in this larger trial. If successful, GlobalData expects the drug to achieve US sales of $824m by 2030. 

These four announcements highlight how difficult it has been to develop novel drugs for the treatment of AD, an indication for which the success rate of clinical trials is historically low. Despite this, there is still promise for the future of AD treatment, with several companies expecting to announce pivotal Phase III clinical trial results later this year and early next year. This includes Roche, Eisai/Biogen and Eli Lilly, each with their respective anti-amyloid-beta mAbs: gantenerumab, lecanemab and donanemab.  

In addition, on 27 June, Otsuka Pharmaceuticals and Lundbeck announced that in a Phase III study (NCT03548584), brexpiprazole significantly reduced agitation in patients with Alzheimer’s dementia compared with placebo. Based on the positive outcome, Otsuka and Lundbeck plan to submit a supplemental new drug application to the FDA later this year. GlobalData expects brexpiprazole to achieve US sales of $415m in this indication by 2030.