15 February 2020

Do plasma metabolomic profiles differentiate responders from non-responders to oral treprostinil? Results from the FREEDOM phase 3 Clinical Development Program

Introduction: Oral treprostinil (TRE) improves exercise capacity and delays disease progression in patients with pulmonary arterial hypertension (PAH). However, the tolerance and response to TRE varies between subjects. The objective of this study was to profile plasma of subjects with PAH who were treated with TRE or placebo to identify a metabolic signature that could predict TRE responders and provide insight into the metabolic changes induced by treatment.

Methods: FREEDOM-C2 (TDE-PH-308/NCT00887978) was a 16-week, placebo-controlled, efficacy and safety study of oral treprostinil in PAH that measured change in median 6-minute walk distance (6MWD). FREEDOM-EV (TDE-PH-310/NCT01560624) was an event-driven, placebo-controlled study of oral treprostinil in PAH that assessed time to clinical worsening. Subjects consented to participate in an optional biomarker substudy. Plasma was collected at Baseline and Week 16 for TDE-PH-308 (N=187) and at Last Visit for TDE-PH-310 (N=74). Based on improvement in 6MWD, subjects were classified as either responders or nonresponders. Samples were evaluated using a comprehensive metabolomic platform (Metabolon) with the potential to identify up to 4000 chemically and structurally diverse metabolites across a variety of classes.

Results: Metabolomic profiling detected 1346 distinct biochemicals. Responders from FREEDOM-C2 had altered metabolites associated with hypoxia, glycemic health, microbiome, and redox status; changes in the microbiome and redox status occurred post-treatment. For FREEDOM-EV, metabolites classes included clotting factors, xanthine metabolites, microbial products, and homoarginine decreased in responders versus nonresponders while metabolite classes that increased in responders included acetoacetate, fatty acids, and homocitrulline.

Conclusions: These results revealed metabolites that distinguished between TRE responders and nonresponders. Metabolites involved in hypoxia, glycemic control, lipid metabolism, and microbial activity were generally correlated with improved clinical response. Subjects treated with TRE had distinct metabolic signatures associated with microbial architecture, activity, and host redox status.

Key Contributors

Christopher Rhodes, PhD; Derek Solum, PhD; Andrew Nelsen, PharmD; Sudarshan Rajagopal, MD, PhD Imperial College London, London, UK; United Therapeutics Corporation, RTP, NC, USA; Duke University Hospital, Durham, NC, USA

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