ONCE DAILY ORAL DOSING OF RODATRISTAT ETHYL (RVT-1201) ACHIEVES REDUCTIONS IN SEROTONIN BIOSYNTHESIS COMPARABLE TO THOSE ASSOCIATED WITH REVERSAL OF VASCULAR REMODELING IN PAH ANIMAL MODELS

Abstract

SESSION TITLE: Tuesday Electronic Posters 5 SESSION TYPE: Original Inv Poster Discussion PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM PURPOSE: RVT-1201, a pro-drug for the tryptophan hydroxylase (TPH) inhibitor KAR5417, is being developed for PAH. TPH1 is the rate-limiting enzyme for peripheral biosynthesis of serotonin (5HT), which has been implicated as a causative factor in PAH. RVT-1201 decreased pulmonary vessel wall thickness in 2 PAH rodent models indicating potential to halt/reverse pulmonary remodeling in humans. The median effective dose (100 mg/kg QD) in PAH rat models yielded a ∼35% reduction in 5-HT biosynthesis (based on reduction in urinary 5-HIAA, a metabolite of 5HT). Divided-dose pharmacodynamic (PD) studies in healthy rats (QD vs BID vs TID) demonstrated KAR5417 AUC, rather than Cmax or Cmin, best correlated with lowering of 5-HT, indicating QD dosing was as effective as more frequent dosing. The purpose of this study was to compare reductions in 5-HIAA levels following QD and BID dosing in healthy subjects. METHODS: 24 healthy subjects received 800 mg total daily oral doses of RVT-1201 or placebo (PBO), either as single (800mg QD) or divided (400mg BID) doses for 14 days across two cohorts (9 active: 3 PBO per cohort). KAR5417 plasma levels and change from Baseline (BSL) PD biomarker data (plasma and urine 5-HIAA) were compared between QD and BID cohorts at Day 14. Safety and tolerability were assessed via adverse event (AE) monitoring and laboratory, vital signs and ECG assessments. RESULTS: At Day 14, KAR5417 mean (±SD) AUC0-24 at 800 mg QD (9180 ng*h/mL, ± 4280) was comparable to the mean pAUC0-24 for 400 mg BID (10400 ng*h/mL, ± 3260). 5-HT lowering was similar across both dose regimens, with 800 mg QD achieving mean (± SD) 40.0 (6.32) % and 45.8 (6.59) % reductions in plasma and urinary 5-HIAA at D14, respectively, compared to 49.9 (9.52) % and 55.5 (10.3) % reductions, respectively, with the 400 mg BID regimen. Plasma and urinary 5-HIAA levels were not reduced from BSL in the PBO arms. 5-HIAA reductions in both regimens exceeded those associated with efficacy in the rodent models. Both dose regimens were generally well-tolerated. The overall incidence of GI-related AEs was greater in the QD group (78%) compared to the divided dose group (33%); however, most AEs were mild in intensity and there were no treatment-related withdrawals in either cohort. CONCLUSIONS: Repeated QD dosing of RVT-1201, an investigational treatment for PAH, reduced 5-HT biosynthesis similarly to divided (BID) daily dosing. Reductions in 5-HIAA levels were comparable to those associated with reversal of vascular remodeling in animal PAH models. RVT-1201 was generally well-tolerated in both dose regimens. CLINICAL IMPLICATIONS: RVT-1201 has the potential to reduce serotonin production and impact vascular remodeling in PAH patients. If ultimately proven effective, the potential to dose RVT-1201 once-daily may help improve overall treatment adherence in a disease like PAH in which patients often take more than one drug in combination chronically. DISCLOSURES: Employee relationship with Altavant Sciences Please note: >$100000 Added 02/05/2019 by David Carpenter, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/15/2019 by Katelyn Crizer, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: >$100000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $1-$1000 Added 03/20/2019 by Laurence Keller, source=Web Response, value=Ownership interest Removed 03/20/2019 by Laurence Keller, source=Web Response Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Thomas Pack, source=Web Response, value=Salary Employee relationship with Altavant Sciences Please note: $20001 - $100000 Added 03/15/2019 by Michelle Palacios, source=Web Response, value=Salary No relevant relationships by Julie Rurka, source=Web Response No relevant relationships by Michele Snyder, source=Web Response Employee relationship with Altavant Sciences Inc Please note: >$100000 Added 03/18/2019 by Stephen Wring, source=Web Response, value=Salary