Early PrimeC use slows ALS progression, reduces complication risk
18 months of PARADIGM trial data show benefits
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A Phase 2 clinical trial showed that early treatment with the experimental oral therapy PrimeC slowed functional decline and reduced the risk of death or ALS complications for people with amyotrophic lateral sclerosis (ALS) compared with a six-month delay in treatment.
Top-line results from the main Phase 2 PARADIGM trial (NCT05357950) were announced in 2023. Now, researchers shared 18 months of data that also cover the trial’s open-label extension.
Full results were published in JAMA Neurology in a paper titled, “Safety and Efficacy of PrimeC in Amyotrophic Lateral Sclerosis The PARADIGM Randomized Clinical Trial.” The work was funded by Neurosense Therapeutics, the company developing PrimeC.
“The publication of the PARADIGM results in the prestigious JAMA Neurology represents an important milestone for NeuroSense and for people living with ALS,” Ferenc Tracik, MD, Neurosense’s chief medical officer, said in a company press release. “This article integrates PrimeC’s safety, clinical, and biomarker data over 18 months.”
PrimeC is an extended-release combination of the antibiotic ciprofloxacin and the anti-inflammatory drug celecoxib, both of which are approved in the U.S. for other indications. The therapy aims to target several ALS-associated biological mechanisms, including reducing brain inflammation and helping normalize iron and RNA processing.
Data on safety, disease progression
In the PARADIGM trial, 68 people with ALS were randomly assigned to take PrimeC or a placebo daily for six months. All participants were then treated with PrimeC for another year in an open-label extension.
The main goals were to assess the safety of PrimeC and its impact on certain disease biomarkers, but researchers also assessed disease progression, survival, and time to certain complications and secondary measures.
Overall, safety data from PARADIGM were positive. In the main trial, side effects occurred at similar rates in people given PrimeC or a placebo.
About one in 5 patients given PrimeC experienced side effects that were considered related to the experimental drug, but these were mostly mild to moderate and temporary. The only exceptions were a serious case of pancreatitis (pancreas inflammation) and a serious case of acute coronary syndrome (reduced blood flow in the heart muscles), both of which were judged to be possibly related to PrimeC. Both these issues resolved with appropriate medical treatment.
Results from the primary biomarker analysis were not yet available.
Disease progression was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R), a standardized measure that rates a person’s ability to perform daily living tasks.
Results from the first six months showed the decline in ALSFRS-R scores tended to be slower in patients given PrimeC, though the difference between the groups wasn’t statistically significant.
After 18 months of follow-up, however, ALSFRS-R scores for patients initially given PrimeC were on average 7.92 points higher than for patients initially given a placebo — a significant difference. The researchers noted that the most dramatic improvements with PrimeC relative to the placebo were observed in subscores for mouth and throat function.
Patients initially given PrimeC also tended to have better survival outcomes at 18 months, but the difference wasn’t statistically significant. Still, analyses showed that these patients had a significant, 64% reduction in the risk of dying or experiencing complications such as serious breathing problems or hospitalization due to ALS.
Exploratory biomarker data indicated that PrimeC treatment did not reduce neurofilament light chain levels, a marker of nerve damage. Yet it altered the activity of certain iron-processing proteins, as well as small RNA molecules called microRNAs, which have been linked to ALS.
Neurosense will use the available PARADIGM data to support an application seeking expedited approval of PrimeC in Canada.
“What stands out about the PARADIGM study is the multiple clinical endpoints suggest the same level of clinical benefit and that multiple biomarkers are consistent with clinical endpoints,” said Jeremy M. Shefner, MD, PhD, co-author of the study and a neurologist at the Barrow Neurological Institute. “Together, these findings provide a strong scientific foundation for advancing PrimeC into a Phase 3 trial designed to validate its impact for patients.”
A pivotal Phase 3 trial, called PARAGON, which has been cleared by the U.S. Food and Drug Administration (FDA), is being planned to evaluate PrimeC’s efficacy in a larger patient population. The trial expects to enroll about 300 people with ALS at sites in the U.S. and Europe, who will receive PrimeC or a placebo for one year, followed by an open-label extension.
“The improved functional and biomarker signals we observed support a phase 3 study to evaluate PrimeC’s effectiveness and safety in a larger population,” Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS at Mass General Brigham and study first author, said in a press release from Mass General Brigham and Barrow. “The importance of following up on potential therapies that can slow the course of ALS is extraordinarily high for patients and families. We are determined to accelerate the development of therapies for people living with ALS.”
