Source – Alnylam Pharmaceuticals
Alnylam has presented promising preliminary clinical results for its new RNA interference candidate, ALN-APP, which targets amyloid precursor protein (APP) to potentially treat Alzheimer’s disease. A single injection of ALN-APP demonstrated the ability to reduce APP levels by up to two-thirds at six months. This marks the first clinical data for a program aiming to clear amyloid from the brains of at-risk Alzheimer’s patients using fewer doses compared to first-generation antibody-based amyloid therapies.
Moreover, this is the first instance of an RNAi drug achieving gene silencing in the human brain, making ALN-APP a significant advancement in the field. Alnylam is collaborating with Regeneron to develop ALN-APP for both Alzheimer’s and cerebral amyloid angiopathy (CAA), a related condition that can lead to brain hemorrhaging.
In a Phase I trial involving 20 subjects presented at the Alzheimer’s Association International Conference, a single 75 mg dose of ALN-APP led to a “rapid and sustained” reduction in soluble APP alpha and beta in the cerebrospinal fluid of patients, with reductions of 84% and 90%, respectively. The data, from the highest dose cohort in the single-ascending dose study, showed peak reductions at two months. The medium and low dose cohorts were also evaluated, with reductions of around 70% and little change compared to placebo, respectively.
While these initial results are promising in terms of biomarker activity, further research will be required to establish a link between these reductions and improvements in cognitive scores. The next Phase of the trial, the multiple-ascending dose portion, will involve 60 subjects and extend the follow-up to at least one year.
In the US, this stage has faced delays due to a partial clinical hold resulting from a safety signal found in animal toxicology studies. However, the trial has received approval to proceed in Canada, where most subjects from the initial phase were enrolled, and further investigation sites will be located in the UK and the Netherlands.
“We’ve known for decades that mutations that increase APP production, or alter its proteolysis, cause early-onset Alzheimer’s disease, early-onset CAA, or both. These Phase I results show that a single dose of ALN-APP can rapidly reduce APP production and that this effect is sustained for six months,” she added. “Given the critical need for new and better treatments for Alzheimer’s and CAA, these results are promising, and the approach warrants further study.”
– Dr Sharon Cohen, medical director of the Toronto Memory Programme and a lead investigator in the study
For Alnylam, these results represent a crucial endorsement of its C16-siRNA conjugate platform, which helps RNAi drugs cross the blood-brain barrier and target therapeutic sites in the central nervous system (CNS). The company’s collaboration with Regeneron involves working on ten CNS targets across various indications, including amyotrophic lateral sclerosis (ALS) and Huntington’s disease, forming a $1 billion partnership that began in 2019.
