Double blow to amyloid drug hopes as Roche, Lilly trial fails The two investigational candidates were unable to show benefit
A clinical trial of Roche and Eli Lilly anti-amyloid drugs in inherited forms of Alzheimer’s disease has ended in failure, in yet another setback for the class.
Lilly’s solanezumab – which failed to move the needle in phase 3 trials in non-inherited or sporadic forms of Alzheimer’s disease a few years ago – wasn’t able to do any better in patients with dominantly inherited Alzheimer's disease (DIAD) and won’t be filed for approval.
At the same time, another arm of the study testing Roche’s gantenerumab also ended in failure in DIAD – also known as autosomal dominant Alzheimer’s disease (ADAD) – which accounts for around 1% of all cases of this type of dementia.
Both companies said the results don’t have a bearing on ongoing trials of their drugs in non-inherited Alzheimer’s, but the results are another disappointment in the industry’s efforts to develop amyloid-targeting drugs for dementia.
The data comes as Biogen is planning to file its amyloid drug aducanumab for approval in the US, marking an extraordinary renaissance for the programme after it was abandoned last year following negative phase 3 results.
Further follow-up led Biogen to conclude its drug had in fact exerted a beneficial effect on cognition after all, although it remains to be seen if regulators will agree with that interpretation of the data.
DIAD is an early-onset form caused by an inherited mutation in the amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) genes. In people with this form of Alzheimer’s symptoms can emerge in the 30 to 50 years age bracket.
Both the antibodies included in the DIAN-TU-001 study conducted by Washington University School of Medicine in St. Louis, US, are designed to interrupt the process by which neurotoxic amyloid plaques are laid down in the brains of people with Alzheimer's, but work in a slightly different way.
Solanezumab works by binding to soluble amyloid beta, allowing it to be cleared from the body before amyloid plaques in the brain that characterise Alzheimer’s are formed, while gantenerumab binds to already-aggregated forms of amyloid beta.
Lilly’s drug is still in the A4 study in sporadic Alzheimer’s disease, while Roche’s drug is in two phase 3 trials (GRADUATE 1 and 2) in these patients. Both involve patients in the early stages of disease development and are due to generate results by 2022.
Ahead of the latest readout, chief scientific officer Dan Skovronsky had been playing down the chances of a positive verdict in inherited Alzheimer’s, saying the study was small and involved a very severe form of the disease.
Meanwhile, Roche’s chief medical officer Levi Garraway said the company is “unable to draw firm conclusions about the impact of gantenerumab” in DIAD due to the study’s “experimental nature”.
There’s still at least one iron in the fire for the DIAD patient community. Roche is also running a trial of another anti-amyloid antibody called crenezumab in an extended family in Colombia that are genetically predisposed to develop the disease due to PSEN1 mutations, with results due in 2022.
Last year however crenezumab failed the phase 3 CREAD 1 and CREAD 2 trials in patients with early-stage, regular Alzheimer’s.