04 February 2019 by Steve Wring

Translational analysis of RVT-1201 Nonclinical and clinical pharmacokinetic and pharmacodynamic biomarker data to predict clinical dose of a novel tph inhibitor for treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder associated with increased pulmonary vascular resistance, remodeling and occlusion. While etiology is unknown, nonclinical and clinical data implicate a causative role for serotonin. RVT-1201 (previously KAR5585), is an oral prodrug for KAR5417 - a potent inhibitor of tryptophan hydroxylase 1, the rate-limiting enzyme in the peripheral biosynthesis of serotonin. Here we report translation of PK/PD relationships for KAR5417 exposure and serotonin biomarker pharmacodynamics, to a human dose for treatment of PAH. In rat, oral RVT-1201 at the median effective dose (100mg/kg/day; KAR5417 AUC0-24 15,300ng.h/mL) blocks or ameliorates PAH in both a monocrotaline prevention model and a SUGEN-hypoxia treatment model for established PAH. RVT-1201 (30 to 300mg/kg/day) yielded a dose-dependent reduction in rat serum serotonin (-27% to -96%) and 24h urinary output of 5-HIAA (-45% to -56%) - the metabolite that reflects total serotonin biosynthesis. Divided dose studies in rats given 75mg/kg/day (~65% serotonin reduction) demonstrated KAR5417 AUC0-24, rather than Cmax or Ctrough, correlated with lowered serotonin biomarkers. Once daily administration was comparable to BID or TID regimens. Healthy human subjects (n=~120) have received RVT-1201 across 2 studies. Treatment emergent adverse events resolved, none were serious, nor considered a dose limiting toxicity. With standard meals, AUC following single doses appeared proportional to dose (200-1200mg). At 400mg BID changes in 5-HIAA were comparable across studies. Mean change in plasma 5-HIAA was −53% from Day 1 to Day 14, whereas placebo was +26%. Change in urine 5-HIAA was −53% and placebo was +12%. Interpolation of KAR5417 AUC between 400mg and 800mg BID regimens predicts 500-600mg BID in humans will achieve the target exposure associated with efficacy in rat models. In summary, RVT-1201 was generally well tolerated in healthy subjects at doses required to achieve clinically-relevant AUC and lowering of serotonin biomarkers for treatment of PAH.

About the author

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Steve Wring

VP Research and Development


United States

Key Contributors

Stephen Wring 1*, Magdalena Alonso-Galicia 1, Katelyn Reighard Crizer 1, Eric Gaukel 2, Natalie Holman 1, Thomas Pack 1, Michelle Palacios 1, Julie Rurka 1, David Carpente r1, Melissa Rhodes 1 : 1.Altavant Sciences, Inc., 324 Blackwell Street, Suite 1104, Durham, NC, USA 2.Roivant Sciences, Inc., 320 West 37th Street, 6th Floor, New York, NY, USA All authors of this publication were all employed by either Altavant Sciences, Inc. or Roivant Sciences, Inc. at the time of the work described. Altavant Sciences, Inc. is a commonly owned affiliate of Roivant Sciences, Inc.

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