AMYOTROPHIC LATERAL SCLEROSIS (ALS) · White paper
Amyotrophic Lateral Sclerosis (ALS) Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About amyotrophic lateral sclerosis (als) — and why its trials are hard
Amyotrophic Lateral Sclerosis (ALS) is a progressive, fatal neurodegenerative disease that destroys upper and lower motor neurons, producing relentless muscle weakness, atrophy, and eventual respiratory failure. First described by Charcot in 1869, ALS has an incidence of roughly 1.6-2.7 per 100,000 per year and a median survival of three to five years from diagnosis. About 5-10% of cases are familial, driven by mutations in C9orf72, SOD1, TARDBP, and FUS. Despite more than a century of research there is no cure, and the therapeutic landscape offers only modest gains: riluzole and edaravone slow decline marginally, while tofersen became the first genetically targeted therapy in 2023 for SOD1-ALS. Clinical development is notoriously difficult because of disease heterogeneity, small samples, high dropout, placebo-control ethics, and the absence of fully validated biomarkers. The ALSFRS-R functional scale, survival, respiratory function, and neurofilament light chain anchor most modern trials, and adaptive, biomarker-enriched designs are increasingly used.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Riluzole (Rilutek) | 1995 | First disease-modifying therapy; inhibits glutamatergic neurotransmission | Bensimon/Lacomblez placebo-controlled trials | Survival / time to tracheostomy | Prolongs median survival by approximately 2-3 months |
| Edaravone (Radicava) | 2017 | Free-radical scavenger for a defined early, rapidly progressing subgroup | MCI186-19 (Study 19) | ALSFRS-R change over 24 weeks | 2.49-point smaller decline in ALSFRS-R vs placebo at 24 weeks |
| Tofersen (Qalsody) | 2023 | First therapy targeting a genetic cause; antisense oligonucleotide for SOD1-ALS (accelerated approval) | VALOR (NCT02623699) | Plasma neurofilament light chain reduction (surrogate) | ~55-60% reduction in plasma neurofilament light at week 28 (unverified exact value) |
| Sodium phenylbutyrate/taurursodiol (AMX0035) (Relyvrio) | 2022 | Approved 2022 based on CENTAUR; voluntarily withdrawn from the US market in 2024 after PHOENIX failed | CENTAUR (NCT03127514) | Rate of ALSFRS-R decline | ~2.3-point ALSFRS-R benefit in CENTAUR; not replicated in Phase 3 PHOENIX (withdrawn 2024) |
| Dextromethorphan/quinidine (Nuedexta) | 2010 | Symptomatic treatment of pseudobulbar affect (PBA), which is common in ALS | STAR trial | PBA episode frequency (not disease modification) | Significant reduction in frequency and severity of PBA episodes vs placebo |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in amyotrophic lateral sclerosis (als) development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Sodium phenylbutyrate/taurursodiol (AMX0035/Relyvrio) — PHOENIX (Phase 3, NCT05021536) | Failed to meet the primary ALSFRS-R endpoint; drug withdrawn from US and Canadian markets in 2024 | Small pivotal (CENTAUR) benefit not reproduced in a larger, longer confirmatory trial; illustrates risk of approving on modest single-trial data |
| Dexpramipexole — EMPOWER (Phase 3, 2013) | No benefit on the combined ALSFRS-R/survival endpoint versus placebo | Promising Phase 2 signal did not translate; disease heterogeneity and outcome-measure sensitivity |
| Diaphragm Pacing System (NeuRx) — DiPALS / RESPStim (ISRCTN53817913) | Added to non-invasive ventilation, pacing was associated with decreased survival | Harm signal in respiratory-failure patients; not recommended as routine care |
Choosing the right endpoint
Primary endpoints that matter in amyotrophic lateral sclerosis (als) trials
- ALSFRS-R (Revised ALS Functional Rating Scale) — Most common primary/co-primary endpoint; a 12-item scale tracking bulbar, motor, and respiratory function over time
- Survival / time to death or tracheostomy — Gold-standard hard endpoint but requires long follow-up and large samples to power adequately
- Respiratory function (Forced Vital Capacity, FVC) — Objective measure of respiratory-muscle decline; strongly predictive of survival
- Neurofilament light chain (NfL) — Emerging pharmacodynamic biomarker of neuronal injury; supported tofersen's accelerated approval
- Muscle strength (dynamometry) and quality of life — Secondary objective and patient-reported measures capturing functional and daily-living impact
How iNGENū runs amyotrophic lateral sclerosis (als) trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
The full white paper: approved-product analyses, pivotal endpoints and trial-design strategy. Open-access · no sign-in.
Frequently asked questions
Amyotrophic Lateral Sclerosis (ALS) clinical trials — FAQs
Which drugs are FDA-approved to modify ALS progression?
Why do so many ALS clinical trials fail?
What is the primary endpoint in most ALS trials?
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