Treating ALS: Multiple ALS Drugs Move to Phase 3 Trials

Amyotrophic lateral sclerosis (ALS) is a rare, incurable neurodegenerative disease affecting roughly 30,000 people in the US. It progressively attacks the nerves that control muscle movement, eroding the ability to walk, talk, eat and in the final stages, breathe. 

Now, a handful of new experimental therapies attempting to slow the disease and prolong independent function are advancing toward pivotal Phase 3 trials.

In up to 10 percent of cases, ALS is caused by a single mutation in a gene like SOD1 or C9orf72. While some companies are developing treatments specifically targeting these mutations, others are hoping their experimental treatments could help the majority of people, who have a sporadic form of the disease, where the cause is unknown. 

“Over 40 genes that are linked to ALS, some of them causative, and some of the mutations alter risk,” Robert Bowser, chief scientific officer and professor at the Barrow Neurological Institute told Being Patient. “A number of different mechanisms contribute and play a role in ALS, which makes it a challenge to develop an effective therapy.”

Protecting neurons to treat ALS 

Drugmaker QurAlis is hoping their new treatment, QRL-201, could protect motor neurons from dying. In ALS, misfolded proteins including TDP-43 build up, leading to broad molecular disruptions within cells.

“TDP-43 regulates the normal expression of thousands of genes in every cell of our body,” said Bowser, who wasn’t involved with the studies conducted by QurAlis. One of the downstream consequences of this buildup is a disruption in the cell’s ability to accurately transcribe the instructions for building a protein encoded by the STMN2 gene, lowering the levels of this protein. 

Enter QRL-201. This experimental treatment is a short strand of genetic code, called an antisense oligonucleotide, injected into the cerebrospinal fluid to counteract the effects of TDP-43 and raise the levels of STMN2 protein. In February, QurAlis shared that the drug raised the levels of this protein in its early stage Phase 1/2 trial of their drug, though it did not share or publish the data. 

In the placebo-controlled study of 69 participants with ALS, those who received the drug showed an increase in the levels of STMN2 and lower levels of inflammatory biomarkers. 

Though the study wasn’t designed to test effectiveness, the study showed signs that the drug may have slowed disease progression over six months. QurAlis has not made the data public or published it in a peer-reviewed journal. 

The company is continuing to follow participants over time and is planning a Phase 3 trial for 2027.

“The idea is if we can restore STMN2, then we might protect the motor neuron, protect the connection to the muscle, protect the functionality of that cell,” said Bowser. But it’s still “unclear” whether fixing the levels of one of the many proteins dysregulated in ALS could slow or treat the disease. 

An antibody that clears out misfolded proteins

Other companies are taking aim directly at the misfolded proteins. 

AL-S Pharma is testing an antibody called AP-1 that targets misfolded proteins, echoing the strategy of recent Alzheimer’s treatments. Rather than targeting beta-amyloid like Leqembi and Kisunla, AP-1 takes aim at misfolded SOD1 proteins, which are thought to drive the disease in people who have a genetic mutation as well as in sporadic cases.  

The 48 week long Phase 2 trial tested the drug in 73 participants, including 21 with the SOD1 mutation. 

At the 2026 Alzheimer’s & Parkinson’s Diseases Conference in Copenhagen, Dr. Angela Genge, neurologist and professor at McGill University, shared data showing that the treatment was safe and well-tolerated. 

The treatment reduced biomarkers of neuronal damage in cerebrospinal fluid and blood in the sporadic ALS group but not in those with the SOD1 gene. Across all participants in the treatment group, functional decline slowed and by the end of the safety followup, those who received the drug lived longer and were less likely to require breathing support.   

The company is now planning a confirmatory Phase 3 trial in people with both sporadic and SOD1 forms of ALS.

Targeting everything, everywhere, all at once

Rather than targeting individual problems like inflammation or specific proteins, Neurosense Therapeutics is taking a multitarget approach with their experimental treatment PrimeC.

Their therapy is a combination of the antibiotic ciprofloxacin and the anti-inflammatory drug celecoxib to target multiple pathways at once. Though it’s approved for killing off harmful bacteria, researchers discovered that ciprofloxacin has a broad range of neuroprotective and anti-inflammatory properties.

At the AD/PD 2026 conference, Christian Lunetta of Clinico Nemo Center in Italy presented the company’s Phase 2 trial of PrimeC. The trial randomized 68 participants 2:1 to receive the treatment or placebo for six months. Afterward, all the participants had the opportunity to receive the drug. 

The drug did not lead to a significant disease slowing in the first six months compared to placebo but reduced multiple biomarkers of ALS. More than three years after treatment, participants who received PrimeC survived an average of 15 months longer.

U.S. regulators have given the company the green flag to move forward with a 300-person Phase 3 trial.

The evolving treatment landscape for ALS

The current treatments for ALS are limited. The disease affects both the upper motor neurons found in the brain and the brainstem, as well as the lower motor neurons that innervate the spinal cord. There’s a lot of variation within ALS on both where it originates and how quickly it progresses, complicating the search for treatments.

Two treatments on the market, Riluzole and Radicava, are approved for treating sporadic ALS. Bowser said the effects of both these drugs lead to a modest reduction of disease progression through different biological mechanisms.

Ionis Pharmaceuticals’ Qalsody received accelerated approval in 2023 for treating people with ALS who have a SOD1 gene mutation, accounting for about two percent of cases. “That drug has had marked improvement on those particular patients,” said Bowser.

Meanwhile, Amylyx Pharmaceuticals voluntarily withdrew their ALS drug Relvyrio, after the drug which received accelerated approval in 2022 failed to show benefits in Phase 3 trials. 

Bowser is hopeful that biomarker stratification could help develop better, targeted treatments. With diseases driven by a specific protein, “a drug that targets that mechanism might work best,” he said. Ultimately, he added, this personalized approach “will become much more common as we move forward in drug development for ALS.”