Ulefnersen Meets Phase 3 Endpoint in FUS-ALS, Offering New Hope for a Rare Form of ALS

Phase 3 FUSION Trial Shows Ulefnersen Improved Function and Survival

Ulefnersen, an investigational antisense therapy being developed for people with FUS-related amyotrophic lateral sclerosis (FUS-ALS), has met its primary endpoint in the Phase 3 FUSION trial.

The results were announced by the drug's developers, Otsuka and Ionis Pharmaceuticals.

According to the companies, ulefnersen significantly improved a combined measure of physical function and survival compared with placebo.

The study also showed supporting results across key secondary measures, while the safety profile was reported to be favorable.

Ulefnersen is not yet approved for use.

The results are important because FUS-ALS is a genetic form of ALS for which there has not previously been a treatment specifically designed to target the underlying genetic cause.

What Is FUS-ALS?

FUS-ALS is a rare genetic form of amyotrophic lateral sclerosis.

ALS is a progressive disease that damages nerve cells responsible for controlling voluntary movement. These nerve cells are found in the brain and spinal cord.

As ALS progresses, people can gradually lose the ability to move, speak and eventually breathe without assistance.

FUS-ALS is caused by changes in the FUS gene.

Although FUS-ALS is rare, it is an important cause of juvenile ALS, meaning ALS that begins at a young age.

The disease can progress quickly, particularly in younger patients.

For families affected by FUS-ALS, the lack of a treatment designed specifically for the genetic cause has been a major challenge.

FUSION Is the First Placebo-Controlled Trial to Show This Type of Result

The Phase 3 FUSION study is significant because it is the first placebo-controlled clinical trial to show that targeting the genetic cause of FUS-ALS can change the course of the disease.

The trial compared ulefnersen with placebo in people with FUS-ALS.

The primary endpoint combined measures of physical function and survival.

Ulefnersen met this primary endpoint, with the treatment group showing a statistically significant improvement compared with placebo.

The developers also reported supportive results from key secondary endpoints.

These findings will provide important information for regulators as they review the treatment.

How Ulefnersen Works

Ulefnersen is an antisense therapy.

Antisense medicines are designed to interact with specific RNA molecules inside cells.

In simple terms, RNA carries instructions that cells use to make proteins. An antisense therapy can be designed to bind to a specific RNA and change what happens to those instructions.

Ulefnersen is designed to target the FUS gene's RNA.

The goal is to reduce the production of harmful FUS protein associated with FUS-ALS.

Instead of simply treating symptoms, the approach is intended to target the genetic biology driving the disease.

Another Antisense Therapy Has Already Shown a Benefit in Genetic ALS

Ulefnersen is now the second antisense therapy to show that this type of approach can affect the course of a genetic form of ALS.

The first was Qalsody, also known as tofersen.

Qalsody targets SOD1-related ALS, another genetically defined form of the disease.

The ulefnersen results add another example of antisense technology being used to target a specific genetic cause of ALS.

Researchers are interested in whether this approach could eventually be applied to additional genetic forms of the disease.

A Rare Disease With a Major Need for Treatment

ALS is a fatal neurodegenerative disease.

The disease causes progressive loss of nerve cells that control muscles.

As more of these nerve cells are damaged, people can lose the ability to walk, use their hands, speak, swallow and breathe.

ALS usually progresses over several years, although the speed can vary considerably between individuals.

Most people with ALS die from complications of the disease, commonly involving respiratory failure.

There are only a limited number of approved treatment options, and there remains a major need for therapies that can slow disease progression.

For people with rare genetic forms such as FUS-ALS, treatment options are even more limited.

Jaci Hermstad Helped Start the Research Journey

The development story behind ulefnersen is closely connected to Jaci Hermstad, a young woman who was living with FUS-ALS.

Her advocacy helped bring attention to the need for research into this rare form of ALS.

The drug was originally known as jacifusen in recognition of her role in the effort.

Early clinical research was conducted at Columbia University.

When the research faced a shortage of resources, The ALS Association partnered with Project ALS to provide funding.

The ALS Association later supported an expanded access program led by Dr. Neil Shneider at Columbia University.

The program allowed additional people with FUS-ALS to receive the investigational treatment.

Early Patients Helped Move the Program Forward

The early clinical experience provided researchers with information that helped support further development of ulefnersen.

The ALS Association said some of the early results were encouraging.

One participant regained the ability to walk and breathe independently after treatment.

These early observations were not enough to establish the effectiveness of the therapy on their own, but they helped support continued research.

The expanded access experience eventually contributed to the development of the global Phase 3 FUSION trial.

Jaci Hermstad Died in 2020

Jaci Hermstad died in 2020.

The ALS Association has credited her advocacy and determination with helping bring attention and resources to FUS-ALS research.

Her story has remained closely connected to the development of ulefnersen.

The organization said her efforts were focused not only on her own disease but also on helping future families affected by FUS-ALS.

The ALS Association Helped Fund Early Antisense Research

The ALS Association said it began supporting antisense research in ALS roughly two decades ago.

At the time, antisense technology had not yet been widely tested in neurodegenerative diseases.

The organization decided to invest in the research despite the uncertainty around the approach.

That early support helped researchers investigate whether antisense therapies could be used to target the genetic causes of ALS.

Since then, antisense technology has become an important area of research in genetically defined forms of the disease.

Ulefnersen Has Not Yet Been Approved

Although the Phase 3 FUSION trial achieved its primary endpoint, ulefnersen remains an investigational therapy.

Regulatory authorities still need to review the clinical data before deciding whether the treatment can be approved.

The ALS Association is calling for a timely regulatory review and is advocating for priority review and broad access for people with FUS-ALS if the therapy is ultimately approved.

The organization said it will continue to provide updates as more information becomes available.

What the Phase 3 Results Could Mean for FUS-ALS

The FUSION results provide clinical evidence that targeting the genetic cause of FUS-ALS can affect measures of disease progression.

This is different from simply managing individual symptoms.

The findings could also help researchers understand how antisense therapies may work across other genetically defined forms of ALS.

However, each genetic form of ALS can have different biological characteristics.

Researchers will need to determine whether similar approaches can be successfully developed for other genetic causes of the disease.

The Safety Profile Was Reported as Favorable

Otsuka and Ionis reported that ulefnersen had a favorable safety profile in the Phase 3 study.

The companies also reported supporting results from key secondary measures.

Full regulatory review will provide a more detailed assessment of the treatment's benefits and risks.

Additional information from the FUSION trial will be important for understanding how the treatment performed across different patient groups and clinical measures.

What Happens Next for Ulefnersen?

The next major step is regulatory review of the Phase 3 FUSION results.

Ulefnersen's developers will work with regulators to determine the appropriate path toward potential approval.

If approved, ulefnersen could become a treatment specifically designed for people with FUS-ALS.

For families affected by this rare form of ALS, the availability of a therapy targeting the underlying genetic cause would represent a major change from the current treatment landscape.

The Phase 3 findings will also provide researchers with more information about the potential of antisense therapies for other forms of genetically driven ALS.

About The ALS Association

The ALS Association is a nonprofit organization that supports ALS research, patient care and advocacy.

The organization funds research collaborations around the world and supports people with ALS and their families through its network of care programs and certified clinical care centers.

It also works on public policies intended to improve support and treatment options for people living with ALS.

The organization continues to fund research aimed at making ALS a more manageable disease while supporting efforts to develop new treatments and find a cure.