Friedreich Ataxia Therapy Nomlabofusp Increases Frataxin Levels in Phase 2 Study
Findings from a phase 2 study of nomlabofusp, a novel investigational therapy for Friedreich ataxia, demonstrated an increase in tissue frataxin levels and metabolic improvements.
New phase 2 clinical trial (NCT05579691) data showed that nomlabofusp (Larimar Therapeutics), an investigational therapy for Friedreich ataxia (FA), was well tolerated and led to significantly increased frataxin levels in treated patients. By increasing frataxin concentrations and improving metabolic function, the findings suggest nomlabofusp may have disease-modifying potential in FA.1
Presented at the
Presented by lead author Russell Clayton, DO, chief medical officer at Larimar Therapeutics, the study enrolled 2 cohorts of adults with FA: 13 participants in Cohort 1 (nomlabofusp, n = 9; placebo, n = 4) and 15 participants in Cohort 2 (nomlabofusp, n = 10; placebo, n = 5). Nomlabofusp was administered via subcutaneous injection, with daily dosing for the first 14 days, followed by every-other-day administration for another 14 days. Researchers measured tissue frataxin levels in buccal and skin cells and assessed metabolic function through gene expression and lipid profiling.
In addition to frataxin level increases, nomlabofusp treatment appeared to improve metabolic function. At baseline, researchers observed abnormal gene expression in multiple genes, but post treatment analysis revealed a dose-dependent normalization of these abnormalities. Similarly, lipid profiling showed abnormal levels at baseline that shifted toward normalization after nomlabofusp administration, further suggesting a metabolic benefit.
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Building on these recent findings with nomlabofusp, another new study sought to predict the potential long-term effects of daily administration on tissue frataxin levels in patients with FA. Researchers utilized data from short-term phase 1 and phase 2 clinical trials, where participants received 25 mg to 100 mg doses of nomlabofusp for less than 30 days. Plasma and skin frataxin concentrations were collected before and after treatment to create an exposure-response model that could predict the outcomes of prolonged therapy.2
The simulations based on this model suggested that skin frataxin concentrations would reach steady-state levels approximately 28 days after daily dosing across all dose groups. Specifically, the simulations predicted median maximum skin frataxin concentrations of 6.22 pg/µg, 9.06 pg/µg, 11.9 pg/µg, and 14.7 pg/µg for the 25 mg, 50 mg, 75 mg, and 100 mg doses, respectively. These findings indicated that increasing the dose of nomlabofusp leads to progressively higher frataxin concentrations in the skin, with the highest dose (100 mg) achieving levels closer to the normal range seen in healthy individuals.
In comparison, previous studies have shown that the mean skin frataxin concentration in healthy controls with 2 normal frataxin alleles is 16.35 pg/µg, while asymptomatic heterozygous carriers of the FA gene typically have frataxin concentrations about 50% of that amount. Notably, the simulations suggest that approximately 59% of patients receiving the 50 mg dose of nomlabofusp daily are expected to reach or exceed 50% of the frataxin levels seen in healthy controls, further supporting the potential therapeutic effect of this dose.
Presented at the 2025 MDA Conference by lead author Flavia De Toni, PhD, senior director of PK/PD at Larimar Therapeutics, these modeling results provide valuable insights for determining a long-term therapeutic dose of nomlabofusp. The data predicted that daily administration of 50 mg nomlabofusp could achieve significant increases in skin frataxin concentrations, potentially improving disease progression in patients with FA. Future clinical trials could be crucial in confirming these predictions and assessing the long-term efficacy and safety of sustained nomlabofusp treatment.
REFERENCES
1. Clayton R, Scherer N, Clements-Egan A, et al. Effect of nomlabofusp administration on tissue frataxin levels, gene expression, and lipid profiles in patients with Friedreich’s ataxia. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P186.
2. De Toni F, Scherer N, Schapiro E, et al. Effect of nomlabofusp administration on tissue frataxin levels, gene expression, and lipid profiles in patients with Friedreich’s ataxia. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P186.
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