Alnylam's RNAi approach to Alzheimer's reaches biomarker target

Alnylam’s RNAi approach to Alzheimer’s disease has reached its target, quickly reducing production of a biomarker linked to the cascade of issues in the brains of people with the neurodegenerative disease.

In early interim data from a phase 1 trial with 20 patients reporting, ALN-APP showed rapid and robust target engagement, Alnylam said in a Monday release from the Alzheimer’s Association International Conference in Amsterdam.

These results are the first time Alnylam has presented its RNAi approach for central nervous system delivery. It also represents a different approach to Alzheimer’s than the leading monoclonal antibody meds that have been spurring buzz across the long-stagnant drug discovery scene.

But it’s still the early days, and Alzheimer’s is one of the toughest indications out there. Alnylam has enrolled 20 patients so far in three single-dose cohorts in part A of the early-stage trial. So far, single doses of ALN-APP have been administered, and Alnylam said they were well tolerated with mild to moderate adverse events.

Testing showed that the patients had a “rapid and sustained reduction” in amyloid precursor protein levels in the cerebrospinal fluid. This protein is known to cause an overproduction of beta amyloid in the brain, which leads to the plaque buildups that are a hallmark of the disease. ALN-APP led 84% and 90% reductions of soluble APPα and soluble APPβ, respectively. Alnylam said this was a confirmation of target engagement, which was sustained at six months post dosing.

Sharon Cohen, M.D., a neurologist and medical director at the Toronto Memory Program, said the results warrant further study.

Alnylam is doing just that, with Part A of the trial continuing single dosing of ALN-APP. The safety review committee has also cleared the multidose Part B to start. The second portion of the study will enroll patients who already participated in Part A. The total enrollment for the study is 60 patients, with a main goal assessing safety, tolerability and target engagement.

The study is being conducted in Canada but is on partial clinical hold in the U.S. “due to findings observed in prior non-clinical chronic toxicology studies,” Alnylam said.

Tim Mooney, director of the ALN-APP program at Alnylam, said the therapy could work upstream of existing Alzheimer’s drugs. In the wake of the full approval of Eisai and Biogen’s Leqembi, many Alzheimer’s advocates have been calling for the next phase of drug development to look at combination treatments to address all factors of the disease.

Alnylam is developing ALN-APP with Regeneron through a 2019 partnership that involved 10 CNS and eye disease targets.