Continued Progress in Phase 1 Study of Antisense Oligonucleotide ION464 in MSA

Regan Fong, executive director of Clinical Development-Neurology at Ionis

Credit: LinkedIn

In an update of the HORIZON trial (NCT04165486), a phase 1/2 single- and multiple-ascending dose study of ION464 (Ionis Pharmaceuticals) in patients with multiple system atrophy (MSA), the investigational agent was shown to be safe and well tolerated thus far, with no serious adverse events (AEs) or deaths related to the study drug. ION464, also known as BIIB101, is an antisense medicine designed to inhibit the production of the alpha-synuclein protein as a potential therapy for a group of neurodegenerative disorders that include Parkinson disease (PD) and MSA.¹

Presented at the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held September 27-October 1, in Philadelphia, Pennsylvania, the poster included baseline characteristics of the first 22 participants from the study. Of these, 36% were female, 91% White, 45% with MSA-Parkinsonism, and 73% with probable MSA. To date, the treatment-emergent AEs recorded while on the study drug include falls (25), urinary tract infection (12), headache (6), contusion (5), and neck pain (3).

The study, conducted by senior author Regan Fong, executive director of Clinical Development-Neurology at Ionis, and colleagues includes approximately 40 adult patients with MSA. It is broken into 2 parts: Part 1, a multiple-ascending dose (MAD) portion, evaluates the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) properties of ION464 whereas Part 2 is an open-label, long-term extension further testing the agent’s effects. The primary outcome is safety/tolerability, and secondary outcomes include the evaluation of ION464 PK and the PD effect of ION464 on cerebrospinal fluid levels of total α-synuclein.

Part 1 of the study consists of a screening period of up to 6 weeks, a treatment period of 12 weeks, and a follow-up period of 24 weeks. The study duration for each participant in Part 2 will be approximately 96 weeks, which consists of a 72-week treatment period and a 24-week follow-up period.

To be included in the study, patients must show loss of dopamine nerve terminals in the striatum consistent with neurodegenerative parkinsonism, as assessed with qualitative, visual read. This was done through a single-photon emission computed tomography with DaTscan (ioflupane I123 inject). Coming into the trial, patients must be able to walk unassisted for at least 10 meters, have no cognitive dysfunction, and no family history of ataxia or parkinsonism and known genetic cause of ataxia or parkinsonism.

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The hypothesis is that ION464 may be able to reduce levels of SNCA mRNA and subsequently decrease synthesis of α-synuclein protein may decrease the rate of α-synuclein aggregation and spread of the α-synuclein pathology. To date, research has shown that altered and insoluble forms of α-synuclein accumulates in the brains of patients with MSA and PD and is thought to be a key driver of neurodegeneration in these diseases.

There are currently no FDA-approved therapies for patients with MSA, but there has been significant progress in the field. At the 2024 MDS Congress, several presentations showcased therapeutics in development for the disease, including the phase 2 AMULET trial (NCT05104476) of Lundbeck’s AF82422, an anti-α-synuclein antibody. Although the drug did not meet its primary end point of statistically slowing disease progression against placebo, it did show more pronounced results in treating patients with less impaired MSA. All told, the investigators concluded that the totality of evidence supports further development of the agent, which looks to enter phase 3 trials next.²

At the same conference, Alterity presented new positive 12-month data from a phase 2 trial assessing its investigational candidate ATH434 in the treatment of patients with advanced MSA. (results). ATH434 is an oral agent designed to inhibit the aggregation of pathological proteins implicated in neurodegeneration.³

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REFERENCES
1. Meilleur K, Seppi K, Krismer F, et al. SNCA Antisense Oligonucleotide for Multiple System Atrophy: HORIZON Trial Update. Presented at: 2024 MDS Congress; September 27-October 1; Philadelphia, PA. ABSTRACT 644
2. Singer W, Zanigni S, Kjaersgaard L, et al. Safety and efficacy of the anti-alpha synuclein monoclonal antibody Lu AF82422 for the treatment of patients with MSA: results from the phase 2 AMULET trial. Presented at: 2024 MDS Congress; September 27-October 1; Philadelphia, PA. ABSTRACT 20
3.