Landmark 289 · Trial in people
ION464 / BIIB101 (synuclein antisense)
Tested only in MSA, a related disease. The company dropped it in 2025, so it will not give an answer for Parkinson's.
In short
The first synuclein-lowering drug given to patients, an antisense injected into the spinal fluid, was safe in the first 22 people, but it is being tested in multiple system atrophy (MSA), not Parkinson's, and Biogen dropped it in 2025.
- What it is
- Trial in people
- Outcome
- Did not work
- When
- 2022–2027
- Size
- 40 people · Phase 1
- Approach
- Clear the bad protein
- Research lane
- Synuclein lowering
- Trial registry
- NCT04165486
- Last checked
- 22 Oct 2026
The research record
This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".
Who
Ionis Pharmaceuticals, with Biogen until 12 February 2025, when Biogen announced it would stop developing it. Ionis kept listing it in its own pipeline.
What happened
- Drug. An antisense oligonucleotide (a short strand of DNA-like material that blocks one messenger RNA) against alpha-synuclein, given into the spinal fluid. It was first aimed at Parkinson's and related diseases.
- HORIZON (NCT04165486). Phase 1 in about 40 adults with MSA, a faster, related disease with synuclein clumps in glial cells. Started 21 July 2022 at sites in Europe; recruiting; estimated completion September 2027. Part 1: rising doses or placebo for 12 weeks. Part 2: open-label extension to 72 weeks of treatment. Primary: safety. Secondary: spinal-fluid alpha-synuclein.
- Interim (MDS congress, September 2024). First 22 people: no drug-related serious adverse events or deaths. Common events were falls (25), urinary infections (12) and headache (6). No spinal-fluid synuclein or efficacy numbers were shown.
Why it moved us toward a cure
It is the earliest human test of lowering synuclein at its source, the idea from landmark 14, and shows the safety record of an approach that mouse knockouts predicted (landmark 201). It relies on the spinal-fluid antisense route proven by landmark 256. Its MSA setting means it cannot show benefit in Parkinson's. Siblings: landmark 287, landmark 288; overview in landmark 29.
Outcome
Dead end for Parkinson's. Biogen dropped the programme in 2025, the trial runs in multiple system atrophy only, and no target-engagement or efficacy data have been shown. Label changed from pending on 22 Oct 2026 because no Parkinson's readout is expected.
Sources
- ClinicalTrials.gov NCT04165486 (API read 19 Oct 2026)
- Alzforum ION464 (last updated 13 Mar 2025; cites the Biogen discontinuation)
- NeurologyLive on the MDS 2024 poster
- Ionis pipeline
- Not yet verified: Biogen's own statement; current Ionis plans for Parkinson's; whether HORIZON is still on schedule.
How it connects
Built on
- builds on Synuclein knockout mice are viable · 2000
- tests Extra copies of the synuclein gene cause Parkinson's · 2003
- uses Nusinersen: intrathecal antisense works · 2016
Led to
None recorded.