Alnylam Pharmaceuticals and Regeneron Pharmaceuticals’ bid to alter the course of Alzheimer’s disease and other central nervous system conditions got a boost Wednesday from early data suggesting their experimental gene-targeting drug works as designed with manageable side effects.
The medicine, dubbed ALN-APP, uses RNA interference to quiet a gene involved in production of amyloid precursor protein, or APP. The protein is cut up by cells into smaller fragments, some of which can eventually build up as toxic plaques that are thought to play a role in the hallmark neurological degeneration seen in Alzheimer’s patients.
In a Phase 1 study of 20 patients with early-onset Alzheimer’s, researchers found the therapy could reduce levels of APP by more than 70% for a sustained period on the highest dose tested, the companies said Wednesday. Side effects were mild or moderate.
“When we entered into this collaboration, the idea that you could profoundly silence disease-causing genes in the brain was simply a bold dream,” Regeneron Chief Scientific Officer George Yancopoulos said in the companies’ statement. “The current data suggest that this dream is closer to becoming a reality, offering hope for the many patients suffering from incurable neurological diseases.”
Still, the positive news came with the disclosure of a new issue: a partial clinical hold on the next part of the trial issued by the Food and Drug Administration because of concerns stemming from preclinical studies. Alnylam and Regeneron said they will share the new results from human studies with the agency to lift the hold. Canadian regulators have already given the all-clear for Part B to begin.
The FDA issue should be resolvable in part because the concern stems from “exaggerated” dose levels in the preclinical tests, Stifel analyst Paul Matteis said in a Wednesday note to clients. The safety findings in humans from Part A of the trial “look fine” and should help allay the FDA’s concerns, he said.
While Alnylam and Regeneron still have a long road ahead to prove the value of their therapy, the results from Part A are about as good as they can get, Matteis said. The 70% reduction in APP “is impressive and seemingly unprecedented,” he said.
The early data have been eagerly anticipated by investors and the scientific community. The companies, which are also working together on a drug for liver disease, are trying to parlay an approach that’s worked well for diseases affecting that organ to the much more difficult target of the brain.
The Phase 1 results are “the first clinical demonstration of gene silencing in the human brain using an RNAi therapeutic,” the companies said. With the proof of concept in hand, the companies are speeding efforts to find new candidates for neurological diseases, Alnylam CEO Yvonne Greenstreet said.
Though the Phase 1 trial announced this week focused on Alzheimer’s, ALN-AAP is also being developed for patients with cerebral amyloid angiopathy.
Alnylam also sees opportunities to study RNAi drugs for a form of genetic ALS and for Huntington’s disease.