A Business Wire Press Release on April 26, 2023, announced positive interim clinical data on an investigational RNAi therapeutic.
Alnylam Pharmaceuticals and its partner Regeneron Pharmaceuticals heralded interim results of the single ascending dose portion of the Phase 1 study of ALN-APP (amyloid precursor protein).
The study is the first RNAi therapeutic that targets central nervous system (CNS) diseases. ALN-APP was designed using 2′-O-hexadecyl (C16) conjugated (combined) siRNAs to treat diseases of the CNS, lung, and eye. Known also as short interfering RNA they are a form of double-stranded molecules that hold various roles in biology.
ALN-APP is the first RNAi to target CNS diseases. It is designed to deliver short interfering siRNA to the CNS and represents the continuance of RNAi therapeutic opportunities in tissues outside the liver (extrahepatic).
As a result of its unique targeting mechanism, ALN-APP has the potential to impact Alzheimer’s and cerebral amyloid angiopathy (CAA) which currently affect millions of people worldwide.
It has been established that genetic mutations increase the production of APP and/or alter its cleavage, causing early-onset Alzheimer’s or CAA or both.
Dr. George Yancopoulos, President of Regeneron, said that initially the idea of silencing the brain’s disease-causing genes was unheard of. However, current data gives hope to patients who suffer from neurological diseases that for the moment are incurable.
About the New Approach
The new approach is to prevent the production of amyloid protein rather than attempting to clear the amyloid plaques once they have formed.
The Phase 1 Study
Part A of the Phase 1 study enrolled 20 patients divided into three groups (cohorts). Each patient was diagnosed with early-stage Alzheimer’s disease.
Single doses of ALN-APP were administered by intrathecal injection into either the spinal canal or the subarachnoid space surrounding the spinal cord thereby reaching the cerebrospinal fluid.
To date, the dosing has been well tolerated with the data reporting mild to moderate adverse reactions. The data on cerebrospinal fluid for protein and white blood cells appeared comparable to placebo.
Patients were administered ALN-APP and exhibited a reduction of cerebrospinal fluid of 84% in soluble APPa and 90% in APPβ.
Median decreases of more than 70% remained constant for over three months when the highest dose was administered.
A New Approach
Alnylam’s early results are the first translation of the C16-siRNA platform for CNS delivery. It is also a first for demonstrating gene silencing using an RNAi therapeutic in the human brain.
Alnylam Pharmaceuticals’s CEO, Yvonne Greenstreet, emphasizes that RNAi therapeutics are poised to become the medical profession’s new class of gene silencing in CNS diseases.
Part B of the trial will include patients who participated in Part A. Regulatory approval to proceed has already been received in Canada. However, the US FDA has issued a partial hold on Part B as a result of findings from previous toxicology studies.
Ten targets have also been selected to uncover RNAi in the CNS in accordance with a 2019 collaboration by Alnyllam and Regeneron.
RNA Interference (RNAi)
RNAi is a gene-silencing cellular process representing a highly encouraging frontier in both drug development and biology. The mechanism involves harnessing the biological process of RNAi that occurs in our cells.
RNAi was awarded the 2006 Nobel Prize for Medicine and recognized as a major scientific breakthrough. This revolutionary approach potentially silences messenger RNA that encodes for disease proteins and prevents the proteins from being created.