Recently, Arrowhead Pharmaceuticals announced that it was able to establish a deal with big pharma Novartis relating to the development of a small interfering RNA (siRNA) candidate by the name of ARO-SNCA. The goal is to advance this preclinical candidate to help treat patients with synucleinopathies like Parkinson’s Disease (PD) and others. As part of this collaboration agreement, Arrowhead received an upfront payment of $200 million and then is eligible to earn up to $2 billion in milestone payments.
Synucleinopathies like PD are plagued with one major issue, which is the formation of abnormal alpha-synuclein. This is what causes disorders like PD and others like dementia with Lewy bodies (DLB). The reason why is because the alpha-synuclein protein itself is encoded by the gene of SNCA and is responsible for synaptic trafficking and releasing neurotransmitters in the brain itself. The aggregation of the abnormal form of this protein leads to the inclusion of Lewy bodies being formed, and thus the patients suffer from a host of symptoms. Other synucleinopathies that ARO-SNCA could eventually be used for might be DLB and multiple system atrophy (MSA).
What Novartis was getting was not just ARO-SNCA itself, but a technology that comes along with it. Small interfering RNA targets the production of proteins at the source when it is in the messenger RNA (mRNA) period. These mRNA give instructions to the ribosomes to build the protein in question, which in the case of abnormal formation or abundant formation is bad, as it causes disease. The genes in play built a faulty protein that causes the major issue at hand. The goal of siRNAs is to enter the specific target cells causing disease, and once inside, reduce the amount of mRNA for protein production. Where the TRiM platform comes into play is to act as targeted RNA interference (RNAi) molecules.
These specific RNAi molecules, TRiM, are developed by Arrowhead to target any cell in the body, thus giving the company the advantage to go after many disease targets. ARO-SNCA has a long way to go in preclinical development, but thus far, based on what the company has achieved, one subcutaneous injection is delivered in an efficient manner in the central nervous system (CNS). This is definitely not a bad deal at all for Arrowhead because all it needs to do under the agreement made is to develop these drugs in the preclinical environment and get each intended candidate ready for a clinical trial authorization (CTA) filing. Not only that, but the candidates to be selected thereafter from Novartis have to be such that they are not a part of the pipeline that exists for Arrowhead.
This preclinical work is going to take time, but the company does not solely rely on this program alone; it has an extensive pipeline. With that being said, it is gearing up for a major inflection point later this year, and this would be an FDA review. That is, a Prescription Drug User Fee Act (PDUFA) date of November 18, 2025, has been set for the FDA to decide by then whether or not its drug plozasiran should be approved for the treatment of patients with familial chylomicronemia syndrome (FCS). This specific FCS disorder occurs because there is a genetic defect in the protein (enzyme) known as lipoprotein lipase, which is responsible for breaking down fats that the body uses and stores as energy.
The problem is that when this lipoprotein lipase doesn’t work properly or is missing, it leads to a buildup of chylomicrons (fat particles) in the blood. With this being said, another factor that could cause disease is Apolipoprotein C-III (APOC3) missing, because this activates lipoprotein lipase. The reason why I brought this up is because plozasiran targets APOC3 genetic misfunction. This is why this drug candidate is also known as ARO-APOC3 in the pipeline. Hopefully positive data from the phase 3 PALISADE trial will be enough for the FDA to grant this drug U.S. marketing approval to treat these FCS patients. In the highest dose tested of 25 mg, the drug was able to help patients see an -80% reduction of triglycerides.
The beauty of plozasiran is that it can be applied to other cardiometabolic disorders beyond that of only FCS. Speaking of which, Arrowhead has an ongoing phase 3 program with several studies that could be used to support marketing approval of plozasiran to treat patients with hypertriglyceridemia. The three studies in question are SHASTA-3, SHASTA-4, and MUIR-3. It believes that the main portion of these studies is to be completed by mid-2026, and from there topline results should be released shortly thereafter.