ALS Candidate PrimeC Meets Primary Safety and Secondary End Points in Phase 2b PARADIGM Study
Although not powered for statistical significance, results showed improvements in ALS Functional Rating Scale and slow vital capacity after treatment with PrimeC.
Merit Cudkowicz, MD
PrimeC, NeuroSense’s investigational amyotrophic lateral sclerosis (ALS) agent, achieved its primary safety and tolerability end points, along with secondary clinical efficacy end points, in newly announced 6-month data from the phase 2b PARADIGM study (NCT0535790). The company is expected to announced additional data in early 2024 assessing the therapy’s impact on ALS biomarkers TDP-43 and Prostagladin2.1
At 6 months, PrimeC-treated patients demonstrated a slowing of disease progression in comparison with placebo, explained by a 29% difference in ALS Functional Rating Scale (ALSFRS-R). In addition, investigators recorded a 13% treatment difference favoring the investigational agent on slow vital capacity (SVC), a measure of respiratory function.
"The clinical advancement of a new therapy that helps slow down the progression of ALS, with the potential to preserve quality of life, has the capacity to significantly positively impact people living with ALS and their families,” Merit Cudkowicz, MD, chair of neurology at Massachusetts General Hospital, director of the Healey & AMG Center for ALS, and member of NeuroSense’s scientific advisory board, said in a statement. "While the ALSFRS-R and SVC results are Phase 2 data and were not powered for statistical significance, the positive results support moving forward to a Phase 3 pivotal trial. The biomarker data will also be very informative, and I look forward to seeing those results in early 2024."
The multicenter, multinational, prospective, double-blind, placebo-controlled study included 69 patients with ALS who were randomly assigned 2:1 to either PrimeC or placebo for a 6-month double-blind period, followed by a 12-month open-label extension. PrimeC is a novel extended-release oral formulation composed of a unique fixed-dose combination of 2 FDA-approved drugs: ciprofloxacin and celecoxib. The therapy has received orphan drug designation by the FDA and the European Medicines Agency.
Following randomization, 1 patient was considered misdiagnosed and thus removed from the analysis. In total, 96% of the cohort completed the double-blind portion and choose to continue treatment through the 12-month OLE. All told, the safety and tolerability profile of PrimeC was considered comparable to placebo. To date, all the participants who already completed the 18-month trial have opted to continue treatment of PrimeC by joining a subsequent investigator-initiated trial.
In the study, randomization sequences were in random block sizes and stratified for ENCALS risk category (high-risk ≥ -4.5; low risk < -4.5) and for background ALS treatment (riluzole and/or edaravone and/or sodium phenylbutyrate and/or taurursodiol) vs no background ALS treatment. Entering the study, patients had a diagnosis of familial or sporadic ALS, disease duration after first symptom of less than 30 months prior to screening, and an ALSFRS-R score greater than 25 at screening.
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"The release of this portion of the top-line results of the PARADIGM trial marks an exciting milestone for NeuroSense as we take another step toward helping people suffering from this dire disease. We look forward to meeting with the FDA to determine the best path forward and to advancing discussions with strategic partners who share our vision for PrimeC to benefit people living with ALS," Alon Ben Noon, chief executive officer of NeuroSense, said in a statement. "I would like to thank my devoted team and everyone who made this possible, the trial participants, their caregivers and families, as well as the sites' principal investigators and trial coordinators for their tremendous contribution to PARADIGM."
NeuroSense completed a proof-of-concept, open-label, phase 2a study (NCT04165850) of PrimeC in 2022, with results published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. The trial featured 15 patients with ALS who were administered PrimeC thrice daily for 12 months, with safety as the primary outcome. Findings from that study further supported the safety and tolerability of the agent in ALS, as 4 patients experienced adverse events (AEs) related to the study drug.2
None of these AEs were unexpected, and most were mild or moderate (69%). Additionally, no serious AEs were related to the study drug. Biomarker analyses revealed significant changes associated with PrimeC in neural-derived exosomal TDP-43 levels and levels of LC3, a key autophagy marker. When compared with the PRO-ACT cohort, a mean difference of 0.18 points/month in ALSFRS-R progression rate (ns, 95% CI, –0.23 to 0.59) and 0.90 points/month in percentage predicted FVC (ns, 95% CI, –0.52 to 2.32) was observed, representing a difference of 18% and 30%, respectively.
