Phase 2 Trial Overview and Primary Endpoint Results
French biotech Axoltis Pharma may have failed to meet its primary endpoint in its phase 2 trial for amyotrophic lateral sclerosis (ALS), but it highlighted secondary endpoints to continue pursuing its synthetic peptide.
The phase 2 trial included 82 ALS patients in France in a double-blind, randomized, multicenter study. Patients were given either five or 10 mg/kg of the drug, called NX210c, or a placebo three times a week for four weeks.
Blood neurofilament light chain (NfL), an indicator of leakage of NfL protein into the blood when nerve cells are damaged, did not show a statistically significant change from baseline at six weeks. While there was a trend of a decrease in NfL in the blood in 25.4% of patients in the NX210c arms of the study compared to 11.8% among the placebo-takers after four months, these results were not significant, Axoltis noted in a Sept. 15 release.
Secondary Endpoints and Impact on BBB Integrity
Patients taking 5 mg/kg NX210c experienced a 64% reduction in benefits in motor function, based on the harmonized revised amyotrophic lateral sclerosis functional rating scale, while those taking 10 mg/kg experienced a 33% reduction. The decreases indicate that a person with ALS is doing better or slowing down in their ability to use their physical and/or limb movements, Axoltis said.
There was also a significant reduction in blood claudin-5, a protein that is released into the blood when the blood-brain barrier (BBB) is damaged, indicating restoration of the BBB among patients treated with 10 mg/kg of NX210c versus those treated with the placebo, the biotech said.
According to Axoltis CEO Yann Godfrin, the observed effect of NX210c on reducing plasma claudin-5 opens new avenues for the use of NX210c to treat a wide range of indications in which blood-brain barrier dysfunction has been observed, including Alzheimer’s disease, Parkinson’s disease and multiple sclerosis.
ALS (also called Lou Gehrig’s disease) is a disease that affects the brain and spinal cord and causes the nerve cells to die. As these nerve cells are killed, they no longer communicate with muscles, resulting in loss of walking, talking, chewing, and breathing ability.
The BBB is the protective barrier of the brain that prevents toxins and other pathogens from entering the brain and allows nutrients to pass through to the brain. That barrier consists of endothelial cells extremely tightly packed together and having forbidden molecules that are unable to pass. If a molecule wishes to enter the brain, it must be small enough to pass through the densely packed cells, or it must have a transporter; one of the main gatekeepers of the brain is a tight junction protein called claudin-5.
NX210c Mechanism and Clinical Outlook
Axoltis’ NX210c has a three-pronged approach of targeting BBB restoration, protecting neurons, and enhancing intercellular communication. The therapy includes a series of sequences of the glycoprotein, called spondin, produced by the subcommissural organ (SCO) in embryonic development, which is essential for the development of neurons.
“These results are promising and contribute to generating evidence that NX210c’s properties are beneficial in neurodegenerative diseases, especially ALS,” Axoltis Chief Medical Officer Annette Janus said in the release. The research “will help move NX210c up the clinical development pipeline,” the company said in a news release.
Current ALS Treatment Landscape and Pipeline
The only ALS treatments currently available are Biogen’s genetically targeted therapy Tofersen, available for people with the SOD1 mutation. Also, there’s Mitsubishi Tanabe’s CNA drug Radicava, for which Shionogi had the rights last year, as well as the glutamate antagonist riluzole.
Other possible treatments are being developed. Last month, Coya Therapeutics got permission to begin a phase 2 trial of its IL-2 candidate, COYA 302, paired with a CTLA4-Ig, and Corcept Therapeutics announced in June that the drug candidate—its IL-2 plus a CTLA4-Ig—was showing promise in a mid-stage ALS trial despite failing to slow the disease. Eli Lilly also became a player in the space last year after it penned a $415 million deal to license Alchemab’s early-stage ALS drug program.
Axoltis and the Phase 2 ALS Study
The Axoltis SEALS trial was designed as a randomized, double-blind, placebo-controlled Phase 2 study. Patients received NX210c at either 5 mg/kg or 10 mg/kg, or placebo, through intravenous infusions three times a week for four weeks. The main assessment focused on blood neurofilament light chain and a biomarker related to blood-brain barrier integrity.
Axoltis Reports Secondary Findings
Although the primary endpoint was not achieved, Axoltis reported several positive secondary and exploratory observations. The company said clinical function measured using the ALSFRS-R showed a slower decline in the treatment groups compared with placebo in post-hoc analyses. A reduction in plasma claudin-5 was also observed, particularly at the 10 mg/kg dose.
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