Key highlights:
- First Clinical Study of a Central Nervous System-Administered RNAi Therapeutic Showed Rapid and Robust Target Engagement with Sustained Effect Over 6 Months with a Single Dose.
- ALN-APP Continues to Demonstrate an Encouraging Clinical Safety and Tolerability Profile.
- Multiple-dose Portion of Study, Part B, Being Initiated in Approved Regions.
Alnylam Pharmaceuticals, Inc. announced an updated positive interim results for the ongoing single ascending dose portion of the Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy (CAA). The results were presented at the 2023 Alzheimer’s Association International Conference (AAIC) being held July 16-20, 2023 in Amsterdam, The Netherlands. ALN-APP is the first clinical-stage program using Alnylam's proprietary C16-siRNA conjugate platform for central nervous system (CNS) delivery and the first investigational RNAi therapeutic to demonstrate gene silencing in the human brain.
Twenty patients with early-onset Alzheimer’s disease have been enrolled in three single-dose cohorts in Part A of the ongoing Phase 1 study. In this study to date, single doses of ALN-APP, which are administered by intrathecal injection, have been well tolerated. All adverse events were mild or moderate in severity. Cerebrospinal fluid (CSF) white blood cell count and total protein levels showed no remarkable elevations from baseline. Routine laboratory assessments (hematology, serum chemistry, liver function, urinalysis, coagulation) as well as preliminary data for the exploratory biomarker neurofilament light chain (NfL) did not reveal any significant abnormalities. Patients treated with a single dose of 75mg ALN-APP experienced a rapid and sustained reduction in cerebrospinal fluid of both soluble APPα (sAPPα) and soluble APPβ (sAPPβ), biomarkers of target engagement, with maximum reductions of 84% and 90%, respectively. Mean reductions in sAPPα of greater than 55% and sAPPβ greater than 65% were sustained at 6 months after a single dose. Additional results can be seen in the presentation on Capella.
“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,” said Dr. Sharon Cohen, MD, FRCPC, Neurologist and Medical Director, Toronto Memory Program. “These Phase 1 results show that a single dose of ALN-APP can rapidly reduce APP production and that this effect is sustained at 6 months. Given the critical need for new and better treatments for AD and CAA, these results are promising, and the approach warrants further study.”
Further exploration of single doses of ALN-APP is ongoing in Part A. In addition, the safety review committee has recommended initiation of Part B, the multiple-dose part of the study. Part B will enroll patients from Part A and has already received regulatory approval to proceed in Canada, where the majority of the Part A clinical trial patients were enrolled. The multiple dose part of the study remains on partial clinical hold in the U.S. due to findings observed in prior non-clinical chronic toxicology studies.
“The rapid, robust, and sustained target engagement that we have achieved with a single dose of ALN-APP and the encouraging interim safety data to date illustrate the potential of RNAi therapeutics to set a new standard for silencing disease-causing genes in the CNS and target diseases like AD and CAA upstream of existing therapies,” said Tim Mooney, Director, ALN-APP Program Leader at Alnylam. “We are excited to initiate the multiple dose part of the Phase 1 study and learn more about the potential of this new approach for these devastating diseases.”
ALN-APP is being developed in collaboration with Regeneron Pharmaceuticals, Inc. In addition to ALN-APP, Alnylam and Regeneron have named 10 targets in the CNS as part of their exclusive collaboration established in 2019 to discover RNAi therapeutics for eye and CNS diseases.