PrimeC Safe, Lowers ALS Disease Biomarkers in Phase 2 Clinical Study
The trial is testing the safety of the combination antibiotic, anti-inflammatory
PrimeC, an experimental combination treatment for amyotrophic lateral sclerosis (ALS) being developed by NeuroSense Therapeutics, was well tolerated and lowered disease biomarkers in an open-label Phase 2 clinical trial.
That’s according to the study, “Combination of ciprofloxacin/celecoxib as a novel therapeutic strategy for ALS,” published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. The work was funded by NeuroSense.
“We are very pleased to have our Phase IIa findings of PrimeC published in a leading ALS journal,” Alon Ben-Noon, CEO of NeuroSense, said in a company press release.
“This study, as well as previously published preclinical work, provides strong encouragement for the continued development of Prime C. We need more treatments for ALS, and PrimeC is an exciting candidate,” Jeremy Shefner, MD, PhD, a professor at Barrow Neurological Institute and co-author of the paper, said.
PrimeC contains a fixed-dose combination of two medicines already approved for other indications: ciprofloxacin (an antibiotic) and celecoxib (an anti-inflammatory therapy). It’s thought that the combination therapy may reduce neuroinflammation and other biological processes that help drive ALS progression.
This Phase 2 study, called NST002 (NCT04165850), was conducted in Israel between 2019 and 2020 and enrolled 15 people with ALS who had a disease duration of three years or shorter. They were mostly male (73%), median age of 59, and 80% were on a stable regimen of approved therapies.
All the participants were treated with PrimeC, taken by mouth three times a day for a total dosage of 909 mg/day. The study’s main goal was to determine the safety and tolerability profile after a year.
“The safety profiles of each of the components of PrimeC are well known, as these drugs have been in clinical use for many years. However, the safety of their combination has never been assessed,” the researchers wrote.
Side effects, slower deterioration rates
One participant was withdrawn from the study early due to issues taking the therapy as directed. Two patients died during the study, but neither death was deemed related to PrimeC treatment and in prognostic models both were at high risk of ALS-related mortality. The remaining 12 patients completed the yearlong study.
Side effects related to treatment were reported by four patients. Most affected the digestive tract, and included indigestion, flatulence, nausea, abdominal pain, and constipation. None were unexpected and most (69%) were mild or moderate in severity.
Despite the commonality of digestive symptoms, no participant had major weight loss.
“As expected, a few AEs [adverse events] affecting the gastrointestinal system were seen. No unexpected AEs arose from the use of the combination of both drugs chronically,” the researchers concluded.
At the start of the study, the average score on the revised ALS Functional Rating Scale (ALSFRS-R) was 37 points and the average forced vital capacity (FVC) was 89%. The ALSFRS-R measures patients’ ability to function in daily life, while FVC measures lung function.
Over the course of the study, ALSFRS-R scores decreased (worsened) at an average rate of 0.84 points per month while FVC worsened by 2.09% per month. Comparisons with data from the PRO-ACT database showed the decline was slower overall than rates of decline among historical ALS patients, though differences were not statistically significant.
“Trial participants showed a nonsignificant trend toward more moderate rates of deterioration on ALSFRS-R and FVC than records matched from the PRO-ACT database,” the researchers wrote. While the team emphasized that the study was not designed to test the therapy’s effectiveness, they said these trends are “reassuring.”
PrimeC alters disease biomarkers
Biomarker analysis showed PrimeC treatment led to a marked decline in levels of the ALS-associated protein TDP-43 in neuron-derived exosomes (NDEs), which are packets of cellular cargo released by nerve cells that can be isolated in blood and other bodily fluids.
Levels of another protein called LC3, a marker of a cellular recycling process called autophagy that’s usually lower in the NDEs of ALS patients were increased with PrimeC treatment. These NDE analyses were performed using technology developed by NeuroDex.
“When we discovered that TDP43, a major ALS biomarker, and LC3, an autophagy biomarker, can be measured in NDEs and are different in ALS patients, we hoped this would help to advance therapeutic development,” Erez Eitan, PhD, chief scientific officer at NeuroDex and co-author of the study, said. “We are thankful to NeuroSense for providing us with the opportunity to test the biomarkers in their clinical trials.”
NeuroSense is running a Phase 2b study called PARADIGM (NCT05357950) to compare PrimeC against a placebo in roughly 69 ALS patients. The trial is recruiting participants at a single site in Israel, with additional locations in the U.S. and Italy to open in the future.
Participants diagnosed up to 30 months before enrollment will be randomly assigned to an optimized version of PrimeC or a placebo given as four daily capsules for six months. An open-label extension, wherein all will receive the medication for another six months, will be available for those who complete the trial.