Part B of the study, cleared to proceed in Canada, remains on hold in the U.S. due to findings from non-clinical chronic toxicology studies.
Pictured: Alnylam CEO Yvonne Greenstreet/courtesy of Alnylam Pharmaceuticals
RNAi therapeutics made clinical headway in Alzheimer’s disease Monday, as Alnylam announced data from a Phase I study of ALN-APP showing the therapy reduced levels of an Alzheimer’s-linked protein by around two-thirds.
The interim results, announced at the 2023 Alzheimer’s Association International Conference (AAIC) in Amsterdam, were from the single ascending dose portion of the study where 20 patients with early-onset Alzheimer’s disease were given 75 mg of ALN-APP. The therapy, which uses Alnylam’s C16-siRNA conjugate platform for central nervous system (CNS) delivery and is being co-developed with Regeneron Pharmaceuticals, is the first experimental RNAi therapy to demonstrate gene silencing in the human brain, according to Alnylam.
The majority of Alnylam’s RNAi therapeutics are delivered to the liver, but Alnylam CEO Yvonne Greenstreet told BioSpace in December that positive initial data from this Phase I study would “be enormously derisking with respect to the potential for a broader portfolio of neurodegenerative diseases.”
Alnylam previewed the data in April, reporting that a single round of the highest dose of ALN-APP could lower soluble amyloid precursor protein beta (sAPPβ) by as much as 90%. The breakdown of sAPPβ generates amyloid beta (Aβ), which is the primary component of the plaques characteristic of Alzheimer’s. The therapy also showed engagement with another biomarker, soluble APPα (sAPPα), reducing it by up to 84%.
At AAIC, Alnylam offered a deeper look at the data, revealing that the more than 65% reduction of sAPPβ was sustained for six months after a single dose, though the presentation—given by Sharon Cohen, medical director and principal investigator of the Toronto Memory Program—showed the numbers did begin to rise between three and six months. Mean reductions in sAPPα were greater than 55%.
Cohen called the results promising and said they warrant further study. “We’ve known for decades that mutations that increase APP production, or alter its proteolysis, cause early-onset Alzheimer’s disease, early-onset [cerebral amyloid angiopathy] or both,” she said in a prepared statement.
ALN-APP had an “encouraging clinical safety and tolerability profile,” Alnylam reported, with the study’s safety review committee recommending initiation of Part B of the study. Across three of the study’s cohorts, 15 patients experienced at least one mild adverse events (AE) and 11 had at least one moderate AE. There were no serious AEs and no deaths in the study.
Tim Mooney, director and ALN-APP program leader at Alnylam, said in a statement that the data to date “illustrate the potential of RNAi therapeutics to set a new standard for silencing disease-causing genes in the CNS.”
Part B, which will enroll patients from Part A, is approved to proceed in Canada, where most participants are located. However, the multiple-dose phase of the study remains on clinical hold in the U.S. due to findings from non-clinical chronic toxicology studies. Pushkal Garg, Alnylam’s chief medical officer, told Endpoints News that these studies were done at “very high doses and high exposures.” and that the company is “working through that” with the regulators.
Heather McKenzie is a senior editor at BioSpace, focusing on neuroscience, oncology and gene therapy. You can reach her at heather.mckenzie@biospace.com. Follow her on LinkedIn and Twitter @chicat08.
