Biologic · ION363
Ulefnersen (ION363)
Ionis Pharmaceuticals' investigational antisense oligonucleotide (ASO) designed to lower production of the FUS (Fused in Sarcoma) protein in people with ALS caused by FUS mutations (FUS-ALS), a rare, aggressive, often juvenile-/young-onset form. Administered by intrathecal injection. Originally given under compassionate use as 'jacifusen' (named for the first patient, Jaci Hermstad); now in pivotal Phase 3 (FUSION). Otsuka holds an exclusive worldwide license (Nov 2024).
Also known as: ION363, ION-363, Jacifusen, Ulefnersen, 2589926-25-3
- Modality
- Biologic
- Chemical class
- antisense oligonucleotide, 2'-MOE gapmer, phosphorothioate oligonucleotide
- Mechanism
- FUS inhibitor
- Highest phase
- Phase 3
- Lead indication
- Amyotrophic lateral sclerosis
- Developer
- Ionis Pharmaceuticals, Inc. (IONS)
- Trials
- 1 tracked · 25 sites
- Next catalyst
- second half 2026 — Topline data (Amyotrophic lateral sclerosis)
Mechanism of action
Ulefnersen is an antisense oligonucleotide that binds FUS pre-mRNA (reported to target intron 6 of the FUS transcript) and reduces FUS expression in a non-allele-selective manner, lowering production of the mutated, neurotoxic FUS protein that drives motor-neuron degeneration in FUS-ALS. As an ASO it has no receptor pharmacology, so no Ki/EC50 affinity applies; action is captured as gene/mRNA inhibition. In the investigator-initiated case series, treatment reduced CSF neurofilament light chain (a marker of neuronal injury) by up to 82.8% at 6 months and reduced FUS protein and pathology on post-mortem analysis.
| Target | Action | Affinity |
|---|---|---|
| FUSprimaryFUS | Inhibitor | —ⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Ulefnersen intrathecal injectionlumbar intrathecal bolus injection 120 mg by lumbar intrathecal injection every 12 weeks, with an additional loading dose at week 4 (Phase 3 FUSION regimen; compassionate-use dosing was titrated from 20 mg to a 120 mg maximum) | Intrathecal | — | — |
Development timeline
- UpcomingFUSION Phase 3 (ulefnersen vs placebo in FUS-ALS) — estimated primary completion in 2H 2026; would be the first controlled readout for a FUS-ALS therapy.↗
- Ionis announced FUSION completed enrollment: 89 participants across ~25 sites in 16 countries; estimated primary completion 2H 2026.↗
- mixedLancet case series (n=12, investigator-initiated): jacifusen reduced CSF neurofilament light chain by up to 82.8% at 6 months; one participant showed objective functional recovery, another remained asymptomatic — but two deaths (deemed unrelated) and uncontrolled design temper interpretation.↗
- Otsuka obtained exclusive worldwide license from Ionis to develop and commercialize ulefnersen ($10M upfront plus milestones/royalties); Ionis continues FUSION with Otsuka cost reimbursement from 2025.↗
- Ionis initiated the pivotal Phase 3 FUSION trial (NCT04768972) of ION363 in FUS-ALS (randomized, double-blind, placebo-controlled).
- First human dosing as 'jacifusen' under FDA compassionate/expanded access (single patient, Jaci Hermstad, FUS P525L), expanding into an investigator-initiated case series (Columbia; Shneider et al.).↗
Ulefnersen (ION363) for Amyotrophic lateral sclerosis
Phase 3ActiveAmyotrophic lateral sclerosis indication →
Pivotal Phase 3 FUSION trial (NCT04768972), an Ionis-sponsored randomized, double-blind, placebo-controlled study of intrathecal ulefnersen in FUS-ALS, is active and not recruiting: enrollment completed 12 Aug 2025 with 89 participants across ~25 sites in 16 countries; estimated primary completion in 2H 2026. Otsuka holds an exclusive worldwide license (Nov 2024). Supportive open-label evidence comes from an investigator-initiated 12-patient case series (Lancet 2025) showing CSF NfL reduction up to 82.8% at 6 months and rare functional recovery. No FDA designation (orphan/fast-track/breakthrough) for ulefnersen is cleanly citable from a primary source.
Readouts
- second half 2026AnticipatedTopline dataNCT04768972
FUSION Phase 3 (ulefnersen vs placebo in FUS-ALS) — estimated primary completion in 2H 2026; would be the first controlled readout for a FUS-ALS therapy. ↗
- 2025-06-07ReportedFull resultsmixed
Lancet case series (n=12, investigator-initiated): jacifusen reduced CSF neurofilament light chain by up to 82.8% at 6 months; one participant showed objective functional recovery, another remained asymptomatic — but two deaths (deemed unrelated) and uncontrolled design temper interpretation. ↗
Clinical trials
NCT04768972FUSION (ION363-CS2)Phase 3Activen=89
FUSION: A Phase 1-3 Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION363 in ALS Participants With Fused in Sarcoma Mutations (FUS-ALS)
pendingprimaryEfficacy/safety of intrathecal ION363 vs placebo in FUS-ALS (Part 1 double-blind, then open-label Part 2)
Pivotal Phase 3; enrollment completed 12 Aug 2025 (89 participants, ~25 sites, 16 countries). Active, not recruiting. Primary completion estimated 2H 2026; topline not yet reported.
Identifiers
Sources
- Antisense oligonucleotide jacifusen for FUS-ALS: an investigator-initiated, multicentre, open-label case series (Shneider et al., Lancet 2025;405:2075-2086) — The Lancet / PubMed
- FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in ALS Participants With FUS Mutations (NCT04768972) — ClinicalTrials.gov
- Ionis ALS community statement on completion of enrollment of FUSION (ulefnersen), 12 Aug 2025 — Ionis (via EUpALS)
- Otsuka Obtains Exclusive Global Licensing Rights from Ionis to Ulefnersen, a Potential Treatment for Amyotrophic Lateral Sclerosis Caused by Mutations in the Fused in Sarcoma Gene (FUS-ALS) — Otsuka Pharmaceutical Co., Ltd.
- Ulefnersen (ION363) — Alzforum