Roche Therapy for Rare Form of Alzheimer's Falls Short in Phase III
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The trial was evaluating crenezumab’s ability to slow or prevent Alzheimer’s disease in cognitively unimpaired people who carry a specific gene mutation that causes early-onset Alzheimer’s disease. The medicine is a monoclonal antibody engineered to neutralize neurotoxic oligomers, a form of beta-amyloid. Swiss company AC Immune initially discovered the drug.
The trial aimed to treat autosomal dominant Alzheimer’s Disease (ADAD), a rare, inherited form of the disease caused by a single gene mutation in the APP, PSEN1 or PSEN2 genes. It accounts for less than 1% of all Alzheimer’s cases globally.
ADAD has a much earlier onset than other forms of Alzheimer's, typically targeting people in their 30s to 60s. It has an average age of onset of 44, causing dementia at 49 years old, on average.
The study, dubbed the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) Colombia Trial, follows two previous Phase III failures, CREAD 1 and 2. Those 2019 studies included patients with early (prodromal to mild) sporadic Alzheimer’s disease. The company halted those studies after a pre-planned interim analysis indicated the drug was unlikely to meet the primary endpoint, which was a change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score.
In the latest trial, the drug failed to hit the co-primary endpoints, missing statistically significant clinical benefit in the rate of change in cognitive abilities or episodic memory function. These were measured via the API ADAD composite cognitive score and the Free and Cued Selective Reminding Test (FCSRT) Cueing Index.
Trial investgiators did observe small numerical differences in favor of crenezumab, but none were statistically significant.
“We’re disappointed that the treatment did not demonstrate a statistically significant clinical benefit,” Eric M. Reiman, M.D., Banner Alzheimer’s Institute executive director and one of the study leaders, said in a statement. “At the same time, we’re proud of the impact that this precedent-setting trial has had in shaping a new era in Alzheimer’s prevention research and we’re extremely grateful to our research participants and their families. This trial, the data, samples and findings that we’ll share with the research community, and the related work that we and others are doing promise to further accelerate the evaluation and approval of future prevention therapies.”
The study enrolled 252 people in Colombia, all members of the largest extended family with ADAD in the world. Of them, 94% completed the trial. A full two-thirds of participants had the Presenilin 1 E280A mutation, which generally results in cognitive impairment from Alzheimer’s by age 44. Participants received either the drug or a placebo over five to eight years. Dosage was increased as a better understanding of the treatment for Alzheimer’s disease grew.
Excluding the controversial approval of Biogen’s Aduhelm (aducanumab) in 2021, this is a familiar story in Alzheimer’s drug development, with hundreds of compounds having failed mid- and late-stage trials over the last decade. Perhaps one of the most tragic aspects of Biogen’s Aduhelm approval was its effect on the entire industry. In early April, the U.S. Centers for Medicare and Medicaid Service (CMS) issued its guidance for the drug, which significantly limited its availability.
The guidance restricted the drug to reimbursement only if used in a clinical trial, an unprecedented move by CMS for a drug approved by the FDA. The agency also applied the guidance to an entire class of beta-amyloid-clearing therapies that have yet to be submitted for approval. This likely will affect crenezumab if the company continues to pursue development.
Genentech also has another drug in its pipeline for ADAD, gantenerumab. It is also in development for sporadic Alzheimer’s and treatment of early Alzheimer’s. The company is expecting data in the fourth quarter from the Phase III GRADUATE trial of gantenerumab in early Alzheimer’s.