New PARADIGM Data Demonstrates PrimeC’s Impact on Iron Regulation in ALS
The data suggest that PrimeC's modulation of iron homeostasis may be a key mechanism in its therapeutic effect, supporting its advancement to phase 3 trials.
Merit Cudkowicz, MD, MSc
NeuroSense Therapeutics recently announced additional data from its pivotal phase 2b PARADIGM study (NCT05357950), highlighting the impacts of investigational PrimeC on iron regulation in patients with amyotrophic lateral sclerosis (ALS). The data, which build on previous findings of extended survival and slowed disease progression, reveal the therapy’s impact on ferritin levels and transferrin levels, both considered significant contributors to the progress of the disease.1
In the prospective, double-blind, placebo-controlled study, treatment with PrimeC, an extended-release oral formulation of ciprofloxacin and celecoxib, 2 FDA-approved treatments, resulted in a significant decrease in ferritin levels and corresponding increase in transferrin levels at 12 months. Iron levels remained stable over the 12-month treatment period, with a mean difference of 4.536 µmol (95% CI, 1.143-7.929; P = .01) compared with those who started on placebo and transitioned to PrimeC after the initial 6-month double-blind phase.
In its update, NeuroSense noted it is currently gathering additional data to share with the FDA to determine the right clinical and regulatory path forward for PrimeC. To date, treatment with the therapy has resulted in enhanced complication-free survival and a 36% slowing of disease progression (P = .009) compared with placebo. Additionally, it has also shown significant effects in patients with high-risk ALS, defined as those with a higher risk of rapid disease progression by the European Network for the Cure of ALS.
"The 12-month results from the PARADIGM Phase IIb study are encouraging, showing slowing of disease progression and improved survival outcomes," Merit Cudkowicz, MD, MSc, chair of neurology and director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, said in a statement.1 "This new analysis highlights PrimeC's ability to regulate the iron panel in people living with ALS, underscoring the drug's target engagement. These findings strongly support the proceeding to phase 3 testing of PrimeC in ALS."
According to the company, changes in iron metabolism aligned with improved clinical outcomes under PrimeC, as treated patients maintained better functionality and survival rates compared with those on placebo. Iron, as one necessary microelement of human, participates in many biological processes of human brain, such as DNA and myelin synthesis, oxygen transportation, and iron homoeostasis, and is pivotal to maintain normal brain function.
Over the years, abnormal iron metabolism has been proved to be related to several neurodegenerative disorders, including ALS. In previous research, iron serum-status indicators, including serum iron, ferritin, and transferrin, have shown potential as ALS biomarkers. A 2012 retrospective study found that serum ferritin levels were higher and serum transferrin levels were lower in patients with ALS vs controls, and the ferritin level was associated with patients’ survival time.2
Another study, published in 2020, examined the possible relationship between ALS and disturbed iron metabolism. In total, the meta-analysis included 11 studies, with 1599 patients with ALS and 1255 controls. All told, results revealed that the ferritin level was much higher in patients with ALS compared with controls (mean difference, 70.48; 95% CI, 51.41-89.55; P <.00001), and the transferrin level was decreased in patients with ALS compared with controls (standardized mean difference, –0.28; 95% CI, –0.38 to –0.18; P <.00001), while there was no statistical difference in iron levels (standardized mean difference, 0.48; 95% CI, –0.07 to 1.03; P = .09) between patients with ALS and controls.3
