ALS Just Broke Another Heart. This Time It Was Novartis.
Novartis killed its ALS drug lifonebart after a Phase 2 trial missed every endpoint, adding to a decades-long streak of industry failures against one of neuroscience's most stubborn diseases. But the company's next move tells a different story.
The Graveyard Gets Another Headstone
If drug development for ALS were a batting average, it wouldn't even get you into Little League. Over 60 molecules have been tested. The overwhelming majority have struck out. And now Novartis has joined the lineup of pharma giants who swung big and missed.
The company announced it's pulling the plug on lifonebart (also called VHB937), its experimental ALS drug, after a Phase 2 trial called ASTRALS failed to show any meaningful benefit over placebo. The drug didn't hit its primary endpoint. It didn't hit its secondary endpoints either. Novartis is walking away from ALS entirely, at least with this molecule.
For the roughly 90–95% of ALS patients whose disease has no known genetic cause, it's another door closing in a hallway that's running out of doors.
What Lifonebart Was Supposed to Do
ALS (amyotrophic lateral sclerosis) destroys motor neurons, the nerve cells that control movement, speech, and eventually breathing. Most patients die within a few years of diagnosis. It's fast, it's brutal, and we still don't fully understand why it happens.
Lifonebart was a monoclonal antibody (a lab-made protein designed to work with the immune system) that targeted something called TREM2, a receptor on brain immune cells called microglia. Think of microglia as the brain's cleanup crew. They clear out damaged cells and calm inflammation. The idea was that by stabilizing TREM2, you could supercharge this cleanup crew and protect neurons from the damage that spirals out of control in ALS.
It's a clever theory. The problem is that ALS doesn't care about clever theories.
The ASTRALS trial enrolled 251 patients with early-stage ALS, all within about two years of their first symptoms. The primary endpoint was a combined measure: could the drug keep patients alive without permanent ventilator support and slow the decline in daily functioning over 40 weeks? Secondary endpoints tracked respiratory function and a blood biomarker called neurofilament light (NfL), which rises as neurons die.
Get tomorrow's biotech intelligence before your competitors.
Join thousands of biotech professionals who start their day with our free, daily briefing.
None of it moved. Not the survival measure, not the functional scores, not the biomarkers. The drug simply didn't outperform a sugar pill.
A Pattern That Won't Quit
This isn't just a Novartis problem. ALS has humbled the entire pharmaceutical industry for decades.
Consider the recent track record. In 2021, AstraZeneca killed its Phase 3 CHAMPION-ALS trial of ravulizumab after an interim look showed it wasn't working. In 2022, Amylyx got accelerated approval for Relyvrio, which briefly looked like a breakthrough; then the confirmatory trial flopped, and the drug was pulled from the market in 2024. That same year, Sanofi and Denali watched their Phase 2 candidate SAR443820 miss its primary endpoint, and Ferrer's FAB122 failed in Phase 3.
Now Novartis in 2026. The pattern is relentless.
To this day, riluzole remains the longest-standing ALS drug approved by both the FDA and EMA, and it offers only a modest survival benefit. "Modest" in clinical terms means months, not years. ALS remains, by any honest measure, incurable.
Why This Disease Keeps Winning
The fundamental challenge is that ALS isn't really one disease. It's more like a syndrome: a collection of overlapping conditions that all end in motor neuron death but get there through different biological routes.
Protein clumping, RNA processing errors, mitochondrial breakdowns, runaway inflammation, problems with cellular recycling: researchers have identified at least half a dozen mechanisms that seem to play a role. A drug that targets one of these pathways might help a subset of patients while doing nothing for the rest. But current trials typically lump everyone together, making it nearly impossible to detect a signal.
Then there's the blood-brain barrier, the biological bouncer that keeps most drugs from reaching the central nervous system. Getting a large molecule like a monoclonal antibody into the brain in sufficient quantities is like trying to sneak a refrigerator through a cat door. It's a delivery problem layered on top of a biology problem.
Late diagnosis makes things worse. By the time most patients are enrolled in trials, significant neuron loss has already occurred. You're essentially trying to save a house that's already half-burned.
A Rough Year for Novartis, Period
The ALS failure doesn't exist in a vacuum. Novartis has had a genuinely rough stretch in the lab. Its cardiovascular hopeful pelacarsen failed a pivotal Phase 3 outcomes study. Its late-stage candidate del-desiran missed the primary endpoint in myotonic dystrophy, sparking a sharp stock selloff. And the company paused eight of ten studies in its CAR-T (a type of engineered immune cell therapy) program after three patient deaths.
By some analyst accounts, Novartis missed on two of its three key pipeline readouts in 2025. The lifonebart failure in 2026 adds another tally mark to an increasingly uncomfortable scorecard. Investors are starting to ask whether these setbacks reflect deeper problems with how Novartis picks its bets.
But Novartis Isn't Abandoning the Brain
Interestingly, even as it retreats from ALS, Novartis is doubling down on getting drugs into the brain. The company has been quietly assembling a toolkit of CNS delivery platforms through a series of deals.
In July 2025, it struck an option deal with Sironax for a brain delivery platform, then exercised that option in September 2026 for $125 million. A month after the Sironax deal, it signed an agreement with BioArctic for its BrainTransporter technology, with potential payments up to $772 million. And in September 2025, it licensed Arrowhead's preclinical Parkinson's program ARO-SNCA, which uses a specialized platform for CNS delivery.
The strategy is clear: instead of one massive acquisition, Novartis is building a reusable delivery stack piece by piece. If the blood-brain barrier is the cat door, they're investing in better tools to get the refrigerator through it.
Notably, lifonebart itself isn't completely dead. Reports indicate the molecule is still being developed for Alzheimer's disease, suggesting Novartis sees the TREM2 approach as potentially viable in a different neurological context. The ALS biology was just too hostile.
The Uncomfortable Bottom Line
For ALS patients and their families, none of this corporate strategy talk matters much. What matters is that another potential treatment has failed, and the options remain painfully thin.
The disease affects a relatively small population, which limits commercial incentive. The biology is fiendishly complex, which limits scientific confidence. And the diagnostic timeline is slow, which limits the window for intervention. It's a perfect storm of obstacles that has defeated some of the smartest drug developers on the planet for over 30 years.
Novartis says it will release fuller trial data later. Maybe those results will contain clues about subgroups or dosing that keep the broader field moving forward. But for now, ALS remains what it has been for far too long: a disease where hope goes to be tested, and usually fails.
Deals & M&A4 min read
$315M for a Drug That Doesn't Exist Yet
SK Biopharmaceuticals just dropped $315 million on a Parkinson's drug that hasn't even picked its final molecule yet. The dual-target approach is scientifically intriguing, but the timing, right after the field's biggest clinical failure, makes this one of 2026's boldest preclinical bets.
