Alnylam announces updated interim results from ALN-APP study

Alnylam (ALNY) announced updated 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, or APP, in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy, or CAA. The results were presented at the 2023 Alzheimer’s Association International Conference, or AAIC, being held July 16-20 in Amsterdam, The Netherlands. ALN-APP is the first clinical-stage program using Alnylam’s proprietary C16-siRNA conjugate platform for central nervous system, or CNS, delivery and the first investigational RNAi therapeutic to demonstrate gene silencing in the human brain. ALN-APP is being developed in collaboration with Regeneron (REGN). 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, or CSF, white blood cell count and total protein levels showed no remarkable elevations from baseline. Routine laboratory assessments as well as preliminary data for the exploratory biomarker neurofilament light chain 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 APPalpha and soluble APPbeta, biomarkers of target engagement, with maximum reductions of 84% and 90%, respectively. Mean reductions in sAPPalpha of greater than 55% and sAPPbeta greater than 65% were sustained at six months after a single dose. Additional results can be seen in the presentation on Capella. 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. 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.