ALS Drug Development Shifts Beyond Survival to ‘Disease Biology’

Drug development for amyotrophic lateral sclerosis (ALS) is moving away from a focus on survival and the ALS Functional Rating Scale-Revised (ALSFRS-R) toward approaches based on disease biology.

According to Fierce Biotech on the 21st (local time), most people with ALS die within 2~5 years of diagnosis, and no treatment has yet meaningfully changed that period.

The U.S. Centers for Disease Control and Prevention (CDC) presented these statistics, and regulators’ approval of tofersen based on reductions in neurofilament light chain (NfL) has given drugmakers a concrete biomarker to use in trial design and participant stratification.

Robert Bowser, chief scientific officer (CSO) of the Barrow Neurological Institute, said, “ALS drug development is at a very exciting point right now.”

Dr. Bowser explained that ALS can begin in the limbs or the bulbar region, and that patients vary in age and rate of progression, making it difficult to show a clear signal in a mixed population with a single mechanism or dose.

He also challenged the view that ALS is inherently diagnosed “late.” He said the problem is the delay between the onset of the first symptoms and seeing a neuromuscular specialist.

Primary care physicians rarely encounter ALS cases, so they spend months ruling out more common conditions and sometimes recommend surgery that does not help, he said.

Stacey Seidel, an ALS consultant to Neurizon Therapeutics, drawing on her experience watching her father receive an ALS diagnosis, said, “Many people see several doctors and undergo testing for other conditions before ALS is seriously considered.”

He added that because ALS trials typically recruit participants within 24 months of symptom onset, delayed diagnosis can leave some patients ineligible.

NfL, measured in blood or cerebrospinal fluid, rises as motor neurons degenerate and falls when a drug protects them, establishing it as an early pharmacodynamic measure that complements survival curves and the ALSFRS-R.

Seidel said, “A biomarker package is now a key component of a strong regulatory package,” citing tofersen’s NfL data as early evidence.

Martin Engel, head of scientific and commercial partnerships at Neurizon Therapeutics, said, “Biomarker strategies are evolving to integrate different types of measures and provide a broader range of information.”

Developers are assembling panels to track nerve damage, inflammation, protein clearance, mitochondrial function and muscle health, using them to define subgroups, monitor progression and confirm drug target engagement.

Trial design is also changing. Rather than tailoring a single drug to all patients, developers are increasingly matching existing treatments or combination therapies to biological subtypes identified by biomarkers.

Some drugmakers are shifting to platform trials that test multiple treatments simultaneously, and unequal randomization, with three participants assigned to a treatment group for every one assigned to placebo, is also becoming more common.

Seidel said biomarker-rich trial protocols face practical constraints, noting that consistent sample collection and testing can be an operational burden.

He advised managing this by aligning sample collection with existing visit schedules and working with centralized, experienced laboratories.

People with ALS and advocacy groups are also no longer passively accepting outcomes. Seidel said, “The ALS field is very different from what it was 10 years ago, and the impact of biomarkers is drawing attention.”

Families now routinely ask about biomarker plans and how they have affected eligibility requirements and access, he said.

Biomarkers are also changing how clinical trial participants are selected. By monitoring biological disease progression alongside physiological measures, researchers can identify and recruit suitable patients who may be difficult to find based on clinical presentation alone.

Dr. Bowser and Seidel said disease-specific biomarkers could ultimately develop into diagnostic tools and help detect ALS earlier if their role in screening is demonstrated.

Seidel explained that an enhanced biomarker package could support an accelerated approval pathway, while ALSFRS-R and survival data would remain essential for full approval.

Collected biofluid samples are being accumulated in shared repositories such as Target ALS, NEALS, ALL ALS and Answer ALS, extending their value beyond individual studies.

Dr. Bowser identified funding cloud-based infrastructure, agreeing on common data standards and building tools to analyze large-scale multimodal data as remaining challenges.

He cautioned that biology-based drug development is not a shortcut to ALS treatment. However, he predicted that combination therapies and precision-based treatments would become a reality in the coming years.

Seidel said, “In a terminal disease like ALS, every clinical trial that uses biomarkers makes each participant’s contribution meaningful.”

This approach is also being applied in clinical practice. The ALS drug candidate NUZ-001 is being evaluated in an adaptive Phase 2/3 platform trial, where biomarker monitoring alongside physiological measures is being used to track participants’ biological responses.