Otsuka, Ionis ALS drug hits primary Phase 3 endpoint, heads to FDA

Overview

Updated Sep 22

FUS-ALS patients have no approved drug targeting the cause of their disease. On September 22, an experimental therapy cleared a key hurdle: a Phase 3 trial showed ulefnersen, an RNA-targeted drug, improved function and survival versus placebo.

The results come from the first placebo-controlled study of any therapy aimed at the genetic cause of FUS-ALS, a mutation-driven subtype that hits younger people and progresses fast. Otsuka and Ionis, which discovered the compound, plan to meet the FDA to pursue accelerated approval.

Why it matters

FUS-ALS patients currently have no approved targeted therapy; ulefnersen could become the first drug to slow the disease rather than just managing symptoms.

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Key Indicators

p=0.0005

Significance of primary endpoint

Ulefnersen beat placebo on a composite measure of function and survival in FUS-ALS.

Approved targeted FUS-ALS treatments

No therapy currently targets the genetic cause of this ALS subtype.

Trial enrollment target

The global FUSION study aimed to enroll up to 95 participants with FUS-ALS.

72 weeks

Double-blind period

Patients received ulefnersen or placebo for about 72 weeks during the trial.

Voices

Curated perspectives — historical figures and your fellow readers.

Organizations Involved

Ionis Pharmaceuticals

Biotechnology company

Discovered ulefnersen; co-developing it with Otsuka

Carlsbad, California biotech focused on RNA-targeted medicines.

Otsuka Pharmaceutical

Pharmaceutical company

Leads development and commercialization of ulefnersen

Tokyo-based pharmaceutical company that licensed ulefnersen from Ionis.

U.S. Food and Drug Administration

Federal regulator

Will review ulefnersen for a potential expedited approval

The agency that decides whether ulefnersen reaches the U.S. market.

Timeline

June 2021 September 2026

2 events Latest: September 22nd, 2026 · 2 months ago

September 2026
Phase 3 results positive
Latest Clinical results

FUSION meets primary endpoint; partners plan FDA talks and open early access program.
September 22nd, 2026
June 2021
FUSION trial begins
Clinical trial

Ionis opens global Phase 1-3 study of ulefnersen in FUS-ALS, targeting 95 patients.
June 14th, 2021

Scenarios

FDA grants accelerated approval for ulefnersen

Likely Resolves by Q2 2028

Discussed by: Reuters coverage and the 2023 tofersen precedent

Otsuka and Ionis file for accelerated approval, citing the FUSION results and reduced neurofilament biomarkers. Following the tofersen template, the FDA could decide within about a year of submission. Ulefnersen would reach the U.S. market as the first FUS-ALS treatment.

FDA requests confirmatory data before deciding

Possible Resolves by Q2 2028

Discussed by: Standard agency practice for accelerated approvals

The FDA asks for longer-term data from the open-label extension or a confirmatory trial before ruling. Approval comes later, after more evidence accumulates. Patients would keep access through Otsuka's early access program in the meantime.

Regulatory setback or safety issue delays ulefnersen

Unlikely Resolves by Q2 2028

Discussed by: Longest-shot scenario; no safety signal emerged in FUSION

An unexpected safety signal, a manufacturing problem, or an advisory committee rejection stalls the program. FUSION reported a favorable safety profile, so this would surprise the market and disappoint the FUS-ALS community.

Historical Context

2 moments from history that rhyme with this story — and how they unfolded.

April 2023

Tofersen (Qalsody) for SOD1-ALS (2023)

Ionis developed tofersen, an antisense drug for SOD1-ALS, another rare genetic subtype of ALS. An FDA advisory committee voted unanimously to recommend accelerated approval, with an agency action date set for April 25, 2023.

Then

The FDA granted accelerated approval, making tofersen the first therapy for SOD1-ALS.

Now

Tofersen validated the gene-directed antisense approach for ALS and created the regulatory template ulefnersen now follows.

Why this matters now

Same company, same drug class, same disease. Ulefnersen's path mirrors the one tofersen carved.

December 2016

Nusinersen (Spinraza) for spinal muscular atrophy (2016)

Ionis discovered Spinraza, the first intrathecal antisense oligonucleotide approved for a neurodegenerative disease, treating spinal muscular atrophy. Biogen commercialized it.

Then

Spinraza became a standard-of-care therapy for SMA.

Now

It proved RNA-targeted drugs could be delivered into the spinal fluid safely over years, laying groundwork for later ALS antisense therapies.

Why this matters now

Established the delivery method and safety framework ulefnersen builds on.