Prediction of tissue frataxin levels with long term administration of nomlabofusp in adults with Friedreich's ataxia using modeling and simulations
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Determining the optimal dose of an investigational product prior to the conduct of a pivotal Phase 3 study is typically achieved via the performance of a number of Phase 2 dose determination studies. However, in rare genetic disease populations, it is not feasible to conduct multiple Phase 2 studies. As an alternative, prediction of optimal doses of an investigational product can be performed using pharmacokinetic (PK) and pharmacodynamic (PD) data from prior Phase 1 and Phase 2 studies. Friedreich’s ataxia (FRDA) is a rare autosomal recessive disease in which guanine adenine adenine (GAA) repeat expansions result in partial gene silencing and decreased production of the protein frataxin (FXN). Nomlabofusp is being developed as a therapy to increase tissue FXN concentrations in patients with FRDA. Prior published studies indicate that the mean frataxin concentration in asymptomatic heterozygous carriers is approximately 50% of healthy controls. This information suggests that increasing tissue FXN concentrations in patients with FRDA to levels that approximate 50% of concentrations observed in healthy controls may potentially decrease the rate of disease progression.
Methods:
Plasma nomlabofusp concentrations and skin frataxin concentrations from adults with 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 subcutaneous 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. In a separate study, the mean skin frataxin concentration in healthy controls with 2 normal frataxin alleles was observed to be 16.35 pcg/mcg.
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. 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 simulations using PK and PD data from short term studies can be used to predict a potential long term therapeutic dose. In the majority of patients with FRDA, daily administration of 50 mg nomlabofusp is predicted to result in skin frataxin concentrations that are > 50% of concentrations observed in healthy controls.
Determining the optimal dose of an investigational product prior to the conduct of a pivotal Phase 3 study is typically achieved via the performance of a number of Phase 2 dose determination studies. However, in rare genetic disease populations, it is not feasible to conduct multiple Phase 2 studies. As an alternative, prediction of optimal doses of an investigational product can be performed using pharmacokinetic (PK) and pharmacodynamic (PD) data from prior Phase 1 and Phase 2 studies. Friedreich’s ataxia (FRDA) is a rare autosomal recessive disease in which guanine adenine adenine (GAA) repeat expansions result in partial gene silencing and decreased production of the protein frataxin (FXN). Nomlabofusp is being developed as a therapy to increase tissue FXN concentrations in patients with FRDA. Prior published studies indicate that the mean frataxin concentration in asymptomatic heterozygous carriers is approximately 50% of healthy controls. This information suggests that increasing tissue FXN concentrations in patients with FRDA to levels that approximate 50% of concentrations observed in healthy controls may potentially decrease the rate of disease progression.
Methods:
Plasma nomlabofusp concentrations and skin frataxin concentrations from adults with 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 subcutaneous 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. In a separate study, the mean skin frataxin concentration in healthy controls with 2 normal frataxin alleles was observed to be 16.35 pcg/mcg.
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. 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 simulations using PK and PD data from short term studies can be used to predict a potential long term therapeutic dose. In the majority of patients with FRDA, daily administration of 50 mg nomlabofusp is predicted to result in skin frataxin concentrations that are > 50% of concentrations observed in healthy controls.