ATS 2021 will feature presentations of original research from accepted abstracts. Mini Symposia and Thematic Poster Sessions are abstract based sessions.
Please use the form below to browse scientific abstracts and case reports accepted for ATS 2021. Abstracts presented at the ATS 2021 will be published in the Online Abstract Issue of the American Journal of Respiratory and Critical Care Medicine, Volume 203, May 3, 2021.
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A Pharmacokinetic/Pharmacodynamic Based Rationale for Dose Selection of the TPH Inhibitor Rodatristat Ethyl in ELEVATE-2 - a Phase 2b Study in Pulmonary Arterial Hypertension
Session Title
TP82 - TP082 LET IT BE - CLINICAL ADVANCES IN PULMONARY VASCULAR DISEASE: PAH AND BEYOND
Abstract
A3604 - A Pharmacokinetic/Pharmacodynamic Based Rationale for Dose Selection of the TPH Inhibitor Rodatristat Ethyl in ELEVATE-2 - a Phase 2b Study in Pulmonary Arterial Hypertension
Author Block: B. Johnson1, M. Palacios2, J. Zhou3, V. D. Schmith3, S. Wring2; 1Sumitovant Biopharma, Durham, NC, United States, 2Altavant Sciences, Cary, NC, United States, 3Nuventra Pharma Sciences, Durham, NC, United States.
RATIONALE: Rodatristat ethyl (RE) is a prodrug of rodatristat, an inhibitor of peripheral tryptophan hydroxylase, in clinical development for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) with a new mechanism of action. Tryptophan hydroxylase is the rate-limiting enzyme for serotonin biosynthesis. Aberrant production of serotonin has been implicated in the vascular remodeling that can lead to right heart failure and death in PAH. Herein, we describe a pharmacokinetic (PK) and pharmacodynamic (PD) rationale for the doses of RE selected for ELEVATE-2, a phase 2b study in PAH. METHODS: A population PK model was developed to characterize rodatristat PK following single and 14-day repeat-dose RE from a phase 1 study in healthy subjects [n=46, 400 to 1200 mg, once (QD) or twice daily (BID)]. A rodatristat PK/PD model of reduction in urinary 5-HIAA (biomarker of total serotonin biosynthesis) from two phase 1 studies also was developed (n=89, repeat-dose placebo or 100 to 800 mg, QD or BID). Simulations (n=10,000) were then conducted to assess the probability of 300 mg or 600 mg BID RE achieving 5‑HIAA reductions associated with efficacy in rat models of PAH. RESULTS: A 40% reduction in serotonin biosynthesis resulted in significant (p<0.05) improvement in efficacy endpoints including reductions in vascular remodeling and pulmonary vascular resistance in rat models of PAH (28-day treatment). RE was generally well tolerated in phase 1 studies and there were no serious adverse events. Reductions in 5-HIAA were dose-dependent with maximal effects at doses ≥800 mg/day; at lower doses, 5-HIAA was still trending down at Day 14. The population PK model included allometric effects of body weight on clearance and volume; no other covariates were evident in this dataset. The estimated between-subject variability in rodatristat AUC was low, 28%. An inhibitory Emax model described the relationship between rodatristat AUC and 5-HIAA, with an Emax of -73% (placebo-adjusted). Simulations based on the variability in rodatristat exposure and 5-HIAA reductions indicate the probability of an individual subject achieving a 40% reduction in serotonin biosynthesis following 14 days of treatment are 61% for 300 mg and 84% for 600 mg BID RE. CONCLUSIONS: Simulations indicate that 300 mg and 600mg BID RE may have a high probability of lowering serotonin biosynthesis to extents associated with vascular remodeling and reductions in pulmonary vascular resistance in rat models of PAH and have the potential to improve exercise capacity over the 24-week treatment period of ELEVATE-2.
Author Block: B. Johnson1, M. Palacios2, J. Zhou3, V. D. Schmith3, S. Wring2; 1Sumitovant Biopharma, Durham, NC, United States, 2Altavant Sciences, Cary, NC, United States, 3Nuventra Pharma Sciences, Durham, NC, United States.
RATIONALE: Rodatristat ethyl (RE) is a prodrug of rodatristat, an inhibitor of peripheral tryptophan hydroxylase, in clinical development for the treatment of pulmonary arterial hypertension (PAH, WHO Group 1) with a new mechanism of action. Tryptophan hydroxylase is the rate-limiting enzyme for serotonin biosynthesis. Aberrant production of serotonin has been implicated in the vascular remodeling that can lead to right heart failure and death in PAH. Herein, we describe a pharmacokinetic (PK) and pharmacodynamic (PD) rationale for the doses of RE selected for ELEVATE-2, a phase 2b study in PAH. METHODS: A population PK model was developed to characterize rodatristat PK following single and 14-day repeat-dose RE from a phase 1 study in healthy subjects [n=46, 400 to 1200 mg, once (QD) or twice daily (BID)]. A rodatristat PK/PD model of reduction in urinary 5-HIAA (biomarker of total serotonin biosynthesis) from two phase 1 studies also was developed (n=89, repeat-dose placebo or 100 to 800 mg, QD or BID). Simulations (n=10,000) were then conducted to assess the probability of 300 mg or 600 mg BID RE achieving 5‑HIAA reductions associated with efficacy in rat models of PAH. RESULTS: A 40% reduction in serotonin biosynthesis resulted in significant (p<0.05) improvement in efficacy endpoints including reductions in vascular remodeling and pulmonary vascular resistance in rat models of PAH (28-day treatment). RE was generally well tolerated in phase 1 studies and there were no serious adverse events. Reductions in 5-HIAA were dose-dependent with maximal effects at doses ≥800 mg/day; at lower doses, 5-HIAA was still trending down at Day 14. The population PK model included allometric effects of body weight on clearance and volume; no other covariates were evident in this dataset. The estimated between-subject variability in rodatristat AUC was low, 28%. An inhibitory Emax model described the relationship between rodatristat AUC and 5-HIAA, with an Emax of -73% (placebo-adjusted). Simulations based on the variability in rodatristat exposure and 5-HIAA reductions indicate the probability of an individual subject achieving a 40% reduction in serotonin biosynthesis following 14 days of treatment are 61% for 300 mg and 84% for 600 mg BID RE. CONCLUSIONS: Simulations indicate that 300 mg and 600mg BID RE may have a high probability of lowering serotonin biosynthesis to extents associated with vascular remodeling and reductions in pulmonary vascular resistance in rat models of PAH and have the potential to improve exercise capacity over the 24-week treatment period of ELEVATE-2.
