Introduction: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a relative deficiency in frataxin. Mean tissue frataxin concentrations in patients with FRDA range from 21% to 35% relative to healthy controls with 2 normal frataxin gene alleles, while in asymptomatic heterozygous carriers, mean tissue frataxin concentrations are approximately 50% of controls. Increases in tissue frataxin concentrations were observed in adults with FRDA who received 25 mg to 100 mg nomlabofusp in short term Phase 1 and Phase 2 studies. The objective of this study was to predict the potential increase in tissue frataxin concentrations after long term administration of 25 mg to 100 mg nomlabofusp.
Methods: Plasma nomlabofusp concentrations and skin frataxin concentrations from adults with Friedreich’s ataxia (FRDA) before and after short term (< 30 days) subcutaneous administration of 25, 50, 75, and 100 mg nomlabofusp in Phase 1 and 2 clinical studies were used to construct an exposure-response model. Simulations of a population of virtual FRDA patients receiving daily doses of 25, 50, 75 or 100 mg of nomlabofusp were performed (n=100, 100 trials) and skin frataxin profiles over time at each dose were predicted.
Results: The simulations predicted that skin frataxin concentrations should reach steady state at approximately 28 days after daily administrations across all doses. Daily administration of 25, 50, 75, and 100 mg nomlabofusp was predicted to attain a median maximum skin frataxin concentration of 6.22, 9.06, 11.9, and 14.7pcg/mcg, respectively.
Discussion: In a separate study, the mean skin frataxin concentration in healthy controls with 2 normal frataxin alleles was 16.35 pcg/mcg. Prior published studies indicate that the mean frataxin concentration in asymptomatic heterozygous carriers is 50% of healthy controls. In relation to these findings, 59% of patients with FRDA receiving daily 50 mg nomlabofusp are predicted to achieve skin frataxin concentrations that are equal or above 50% of the concentrations found in healthy controls.
Conclusion: Modeling and simulation using data from short term studies of nomlabofusp administration can be used to predict a potential long term therapeutic dose. Daily administration of 50 mg nomlabofusp is predicted to result in skin frataxin concentrations that are > 50% of concentrations found in healthy controls.