ION363 · program

Ulefnersen (ION363) for Amyotrophic lateral sclerosis

Phase 3ActiveIonis Pharmaceuticals, Inc. (IONS)

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.

Data current as of

Development timeline

Phase 3Jun 2021 – Dec 2026
  1. 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.↗
  2. Ionis announced FUSION completed enrollment: 89 participants across ~25 sites in 16 countries; estimated primary completion 2H 2026.↗
  3. 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.↗
  4. 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.↗
  5. Ionis initiated the pivotal Phase 3 FUSION trial (NCT04768972) of ION363 in FUS-ALS (randomized, double-blind, placebo-controlled).
PreclinicalJun 2019
  1. 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.).↗

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 in Amyotrophic lateral sclerosis

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)

Started Jun 2021· Primary completion Jun 2026· 📍 25 sites across 16 countries (United States, South Korea, Germany, Brazil)

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.

Mechanism of action (compound-wide)

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.

TargetActionAffinity
FUSprimaryFUSInhibitor—ⓘ

← Full ION363 compound page (identity, identifiers, all indications)

Sources

  1. 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
  2. FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in ALS Participants With FUS Mutations (NCT04768972) — ClinicalTrials.gov
  3. Ionis ALS community statement on completion of enrollment of FUSION (ulefnersen), 12 Aug 2025 — Ionis (via EUpALS)
  4. 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.
  5. Ulefnersen (ION363) — Alzforum