Larimar Therapeutics presented encouraging data on nomlabofusp, a potential treatment for Friedreich's ataxia (FA), at the International Congress for Ataxia Research (ICAR) in London. The data encompasses findings from Phase 1 studies, a Phase 2 dose exploration study, and initial results from an ongoing open-label extension (OLE) study, suggesting improvements in frataxin (FXN) levels, gene expression, and lipid profiles in FA patients. These findings support the continued development of nomlabofusp as a potential disease-modifying therapy for this rare neurodegenerative disorder.
Nomlabofusp Impact on FXN Levels and Metabolic Pathways
Data presented at ICAR highlighted that treatment with nomlabofusp not only increased FXN levels but also modified gene expression and lipid profiles in study participants. According to Carole Ben-Maimon, MD, President and CEO of Larimar, modeling and simulation data predict that a daily 50 mg dose of nomlabofusp could achieve FXN levels comparable to those observed in asymptomatic heterozygous carriers, typically around 50% of healthy control levels. This increase in FXN is crucial, as FA is characterized by a deficiency in this mitochondrial protein due to GAA repeat expansions in the FXN gene.
Representativeness of Study Participants
The study participants in the nomlabofusp trials were found to be representative of the broader adult FA population. Lower tissue FXN levels correlated with earlier disease onset and more severe, rapidly progressive disease, aligning with previously published studies. This consistency strengthens the applicability of the trial results to the wider FA patient community.
Prediction of FXN Levels with Nomlabofusp
Modeling based on Phase 1 and Phase 2 data suggests that daily administration of 50 mg nomlabofusp could achieve skin FXN levels above 50% of those seen in healthy controls for most patients. This target is significant, as it mirrors the mean tissue FXN levels observed in asymptomatic heterozygous carriers. The prediction model is set to be refined with long-term administration data from the ongoing OLE study and upcoming data from pediatric trials.
Effects on Gene Expression and Lipid Profiles
An exploratory analysis revealed that nomlabofusp administration influenced gene expression and lipid profiles in FA patients. Specifically, improvements were observed in gene expression and triglyceride levels, with post-treatment values trending towards those of healthy controls. This suggests that nomlabofusp may impact downstream metabolic pathways disrupted in FA, potentially addressing the metabolic dysfunction associated with FXN deficiency.
Open Label Extension Study
Initial data from the ongoing long-term OLE study evaluating daily subcutaneous injections of 25 mg of nomlabofusp showed that the drug was generally well tolerated. Tissue FXN levels showed a mean change from baseline of 1.32 pg/undefined in buccal cells and 9.28 pg/undefined in skin cells at Day 90. 25 mg of nomlabofusp increased and maintained tissue FXN levels over time, increasing from a mean level of 15% of HV at baseline to 30% in buccal cells and from 16% to 72% in skin cells at Day 90. Decreased values indicating early trends towards improvement were observed in modified Friedreich Ataxia Rating Scale, FARS-Activities of Daily Living, Modified Fatigue Impact Scale, and 9 Hole Peg Test at Day 90 relative to baseline.
Future Directions
Larimar Therapeutics anticipates providing a nomlabofusp program update in mid-December 2024 and plans to submit a Biologics License Application (BLA) in the second half of 2025. The company is also screening adolescents for a pediatric pharmacokinetic (PK) run-in study, with dosing expected to begin early next year. These steps are crucial for expanding the potential use of nomlabofusp to a broader patient population, including children and adolescents with FA.
