By Neurizon Therapeutics and Robert Bowser, Ph.D
After decades of hard-won progress, ALS drug development is entering a new era, building on established efficacy measures like survival and ALSFRS-R with biology-driven science that captures the full heterogeneity of the disease. The stakes are stark: Most people diagnosed with ALS die within 2 to 5 years, according to the CDC, and no treatment has meaningfully changed that timeline. Regulators’ decision to approve tofersen based on reductions in neurofilament light (NfL) gave sponsors a concrete biomarker for designing trials, stratifying study participants and interpreting outcomes across diverse ALS study populations. Now the field is expanding into panels that track neuronal injury, inflammation and muscle health across distinct ALS subtypes.
“ALS drug development today is actually at a very exciting time,” said Robert Bowser, Ph.D., Chief Scientific Officer at Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center in Phoenix, where he also chairs the Department of Translational Neuroscience and directs the Gregory W. Fulton ALS and Neuromuscular Disease Research Center. Bowser co-directs national ALS biofluid and post-mortem tissue repositories and has helped pioneer diagnostic and prognostic biomarkers now used across the field.
Few diseases test the limits of trial design like ALS, where onset, age and progression speed can vary widely from person to person, requiring criteria calibrated to each drug’s specific profile and regulatory requirements. Onset can start in the limbs or the bulbar region, people living with ALS span decades of age, and progression speeds vary widely, making it hard for a single mechanism or dose to show a clear signal in a mixed population. Bowser also pushes back on the idea that ALS is inherently diagnosed “late.” The real problem, he said, is the lag between first symptoms and reaching a neuromuscular specialist: Primary care physicians rarely see an ALS case, so they spend months ruling out more common conditions, sometimes sending people for surgeries that don’t help and may even worsen progression. By the time someone reaches a neurologist that specializes in ALS, symptoms have further progressed and a definitive clinical diagnosis if often not difficult for the specialist. So reducing the time from initial symptom onset to visiting a neurologist that specializes in ALS is the real challenge for reducing diagnostic delay.
Stacie Seidel, an ALS consultant and patient advocate at Neurizon Therapeutics with two decades of biotech experience, offers another perspective on that diagnostic odyssey—one informed by her experience supporting her father following his ALS diagnosis: Many people pass through multiple physicians and workups for other conditions before seriously considering ALS. Because ALS trials generally enroll within 24 months of symptom onset, diagnostic delays can leave some study participants too advanced in their disease to qualify by the time they’re identified. And while survival and ALSFRS-R capture meaningful, real-world areas of daily life, they weren’t designed to account for the heterogeneity of ALS populations on their own.
Redesigning trials around biology
Those constraints are exactly why ALS researchers have spent two decades building a biomarker toolkit. NfL, measured in blood or cerebrospinal fluid, has become the workhorse marker of axonal injury. Bowser explains that NfL rises as motor neurons degenerate and falls when a drug genuinely protects them, giving sponsors a pharmacodynamic readout that complements survival curves and ALSFRS-R with an earlier, more direct window into disease biology.
Seidel no longer sees biomarkers as scientific “nice to have,” but a threshold expectation. “The biomarker package is now a critical component, alongside clinical readouts, for a strong regulatory package,” she said, pointing to tofersen’s NfL data as an early proof point. “These readouts may add a more quantitative layer alongside clinical readouts,” she added, noting that ALS advocacy groups are pushing in the same direction becausea stronger data packages may help drugs reach more people living with ALS sooner.
That shift is also reshaping biomarker strategy overall. “Often a biomarker strategy will incorporate a variety of different types of biomarkers for a breadth of information and data,” said Martin Engel, Ph.D., Head of Scientific and Commercial Partnerships at Neurizon Therapeutics, who noted that TDP‑43 is now being evaluated as both a pharmacodynamic and a surrogate marker. Rather than relying on one marker, developers are assembling panels that track neuronal injury, inflammation, protein clearance, mitochondrial function and muscle health, then using them to define subgroups, follow progression and confirm drugs are engaging their intended targets.
One trial doesn’t fit all
That same biology-driven thinking is reshaping trial design itself. Rather than searching for a single drug to fit every person living with ALS, sponsors are increasingly matching existing therapies or combinations of them to the biological subtype a person’s biomarkers reveal.
That shift shows up in how trials are structured. Some sponsors are moving toward platform trials that test multiple treatments and speeding readouts across programs. Unbalanced randomization, such as three study participants on active therapy for every one on placebo, is also becoming more common. Biomarkers sit at the center of these designs, Engel said. They stratify study participants so true responders are less diluted in a heterogeneous cohort. They also show whether a drug is engaging its target, a signal that complements ALSFRS-R and other clinical measures rather than replacing them.
Seidel cautions that ambitious, biomarker-rich protocols run into real-world constraints. Keeping sample collection and testing consistent across trial sites remains an operational burden, best managed by aligning sample collection with visits study participants already make and working with centralized, experienced lab partners.
What this means for the ALS community
People living with ALS and their advocates no longer passively accept results, Seidel said; they now expect to see the biomarker logic behind a program. “The ALS field is in a very different place than it was 10 years ago, with the impact of biomarkers now in the spotlight,” she said. Families now routinely ask about a biomarker plan and how it shaped eligibility and access.
Biomarkers are also reshaping how trials screen and select participants. By monitoring biological disease progression in parallel with physiological measures, sponsors can identify and enroll people whose disease biology fits a given trial’s profile, rather than relying on clinical presentation alone. Bowser and Seidel both point to a longer-term possibility: As disease-specific biomarkers prove themselves in this screening role, they could eventually become diagnostic tools in their own right, helping identify ALS earlier in the disease course.
Biomarker packages can also support accelerated approval pathways, Seidel said, while ALSFRS‑R and survival data remain essential for full approval. Biofluid samples collected along the way frequently go into shared repositories such as Target ALS, NEALS, ALL ALS, and Answer ALS, extending the value of each participant’s contribution beyond a single study. Bowser points to active collaborative efforts across groups actively collecting prospective samples such as ALL ALS and Target ALS to harmonize collection procedures. The remaining hurdles, Bowser said, are funding cloud‑based infrastructure, agreeing on common data standards and building analytical tools for increasingly large, multimodal data sets.
Biology‑driven drug development isn’t a shortcut to an ALS cure; ALS has a long history of mechanisms that looked promising early and failed at scale. Bowser instead points to a realistic win over the next few years: combination regimens and genuinely precision‑based care, made possible by the same biomarker-driven approach to screening, monitoring and trial design already reshaping ALS drug development. For Seidel, the measure stays simple: in a terminal disease like ALS, every trial that uses biomarkers makes each participant’s contribution count.
That same biomarker-driven approach is now being put into practice. NUZ-001, an investigational treatment for ALS, is currently being evaluated as part of an adaptive phase 2/3 platform trial, incorporating biomarker monitoring alongside physiological measures to track each participant’s biological response as the trial progresses. For a field built on decades of incremental progress, that kind of biology-first design offers real momentum: not a shortcut to a cure, but a more precise path toward treatments that meet people living with ALS where their disease actually is.
The editorial staff had no role in this post's creation.