A Randomized, Double-Blind and Nested Crossover (For Placebo and Moxifloxacin) Thorough QT Study to Evaluate the Effect of Rodatristat Ethyl, Rodatristat, and Its Major Metabolites on Cardiac Repolarization in Healthy Volunteers

To evaluate whether Rodatristat Ethyl prolongs the QTc interval when orally administered to healthy volunteers.

Start Date12 May 2023

Sponsor / Collaborator

Altavant Sciences, Inc.Startup

NCT05684640 / CompletedPhase 1

A Single and Multiple Dose Study of Rodatristat Ethyl in Healthy Subjects to Evaluate the Effect of Food, and the Safety, Tolerability, and Pharmacokinetics of a Supratherapeutic Dose of Rodatristat Ethyl

This is a single and multiple dose food effect study of rodatristat ethyl in healthy subjects

Start Date29 Sep 2022

Sponsor / Collaborator

Altavant Sciences, Inc.Startup

[+1]

NCT05065359 / CompletedPhase 1

A Randomized, Double-Blinded, Placebo-Controlled, MultipleAscending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Rodatristat Ethyl in Healthy Japanese and Caucasian Subjects

This study is a randomized, placebo-controlled, multiple-ascending dose study in healthy Japanese and Caucasian subjects.

Start Date01 Oct 2021

Sponsor / Collaborator

Altavant Sciences, Inc.Startup

[+2]

100 Clinical Results associated with Rodatristat ethyl

100 Translational Medicine associated with Rodatristat ethyl

100 Patents (Medical) associated with Rodatristat ethyl

Literatures (Medical) associated with Rodatristat ethyl

01 Nov 2024·The Lancet Respiratory Medicine

Safety and efficacy of rodatristat ethyl for the treatment of pulmonary arterial hypertension (ELEVATE-2): a dose-ranging, randomised, multicentre, phase 2b trial

Article

Author: Grewal, Ravi ; Parsley, Ed ; Marmon, Tonya ; Lazarus, Howard M ; Humbert, Marc ; Kamau-Kelley, Watiri ; McLaughlin, Vallerie ; Denning, Jill ; Palacios, Michelle ; Jones, Renee ; Feldman, Jeremy ; Langleben, David ; Sitbon, Olivier ; Wring, Steve ; Skride, Andris ; Naik, Himanshu ; Shlobin, Oksana A ; Ghofrani, Hossein-Ardeschir ; Sahay, Sandeep ; D'Souza, Gwyn

BACKGROUNDThe role of serotonin in pulmonary arterial hypertension has been extensively studied in recent decades, with preclinical data strongly indicating involvement in disease pathogenesis; however, clinical studies have yielded mixed results.METHODSELEVATE-2 was a phase 2b dose-ranging, randomised, double-blind, placebo-controlled, multicentre trial investigating rodatristat ethyl as a treatment for patients with pulmonary arterial hypertension. The study was conducted at 64 sites across 16 countries in Europe and North America. Eligible participants were aged 18 years or older, had pulmonary arterial hypertension with WHO functional class II or III symptom severity, and had received a stable dose and regimen of one or more pulmonary arterial hypertension treatments for at least 12 weeks. Participants were randomly assigned 1:1:1 to receive two placebo tablets, one placebo and one rodatristat ethyl 300 mg tablet, or two rodatristat ethyl 300 mg tablets twice daily using an interactive response system. Participants, investigators, site personnel, and sponsors were masked to treatment allocation. Participants who completed the 24 week treatment period were invited to continue in an open-label extension. The primary endpoint was percent change in pulmonary vascular resistance (PVR) from baseline to week 24. Primary efficacy analyses were conducted on the intention-to-treat population and analyses of harms were conducted in the safety population, which included all patients who received any amount of the study drug. This trial is registered with ClinicalTrials.gov, NCT04712669, and is now complete.FINDINGSBetween March 18, 2021 and Dec 13, 2022, 108 participants were enrolled and randomly assigned. 36 participants received placebo, 36 received rodatristat ethyl 300 mg, and 36 received rodatristat ethyl 600 mg twice daily. Overall, 85 (79%) of participants were female and 23 (21%) were male. The mean age was 52·8 years (SD 14·7) in the full analysis set. In the open-label extension phase, 62 (82%) of participants were female and 14 (18%) were male, and the mean age was 52·8 years (SD 14·7); this phase was terminated following sponsor review of unmasked main study results. Least-squares mean percent change in PVR from baseline to week 24 favoured placebo and was 5·8% (SE 18·1) for the placebo group, 63·1% (18·5) for the rodatristat ethyl 300 mg group, and 64·2% (18·0) for the rodatristat ethyl 600 mg group. Treatment-emergent adverse events (TEAE) were reported for 29 (81%) patients in the placebo group, 33 (92%) patients in the rodatristat ethyl 300 mg group, and all 36 (100%) patients in the rodatristat ethyl 600 mg group. TEAE leading to study discontinuation were reported for three (8%) patients in the placebo group, four (11%) patients in the rodatristat ethyl 300 mg group, and four (11%) in the rodatristat ethyl 600 mg group. There was one (3%) TEAE leading to death in the rodatristat ethyl 300 mg group.INTERPRETATIONOur results indicate that reducing peripheral serotonin concentrations via rodatristat ethyl has a negative effect on pulmonary haemodynamics and cardiac function in patients with pulmonary arterial hypertension. This finding suggests that manipulating this pathway might not be a suitable option for pulmonary arterial hypertension therapy.FUNDINGEnzyvant Therapeutics (now Sumitomo Pharma America).

01 Apr 2022·ChestQ1 · MEDICINE

Novel Mechanisms Targeted by Drug Trials in Pulmonary Arterial Hypertension

Q1 · MEDICINE

Review

Author: Vazquez, Rocio ; Zamanian, Roham T ; Chakraborty, Ananya ; Patel, Hiral ; Auer, Natasha ; de Jesus Perez, Vinicio A ; Condon, David F ; Agarwal, Stuti

Pulmonary arterial hypertension (PAH) is a rare disease associated with abnormally elevated pulmonary pressures and right heart failure resulting in high morbidity and mortality. Although the prognosis for patients with PAH has improved with the introduction of pulmonary vasodilators, disease progression remains a major problem. Given that available therapies are inadequate for preventing small-vessel loss and obstruction, there is active interest in identifying drugs capable of targeting angiogenesis and mechanisms involved in the regulation of cell growth and fibrosis. Among the mechanisms linked to PAH pathogenesis, preclinical studies have identified promising compounds that are currently being tested in clinical trials. These drugs target seven of the major mechanisms associated with PAH pathogenesis: bone morphogenetic protein signaling, tyrosine kinase receptors, estrogen metabolism, extracellular matrix, angiogenesis, epigenetics, and serotonin metabolism. In this review, we discuss the preclinical studies that led to prioritization of these mechanisms, and discuss completed and ongoing phase 2/3 trials using novel interventions such as sotatercept, anastrozole, rodatristat ethyl, tyrosine kinase inhibitors, and endothelial progenitor cells, among others. We anticipate that the next generation of compounds will build on the success of the current standard of care and improve clinical outcomes and quality of life for patients with PAH.

01 Apr 2022·Pulmonary Circulation

A trial design to maximize knowledge of the effects of rodatristat ethyl in the treatment of pulmonary arterial hypertension (ELEVATE 2)

Article

Author: Feldman, Jeremy ; Lazarus, Howard M. ; Hoffman, Sidra ; Symonds, William ; Wring, Stephen ; Denning, Jill ; Crizer, Katelyn ; Kamau‐Kelley, Watiri ; Palacios, Michelle

AbstractSerotonin plays a key role in the development and maintenance of the pathobiology associated with pulmonary arterial hypertension (PAH). Platelet‐driven and locally produced serotonin from lung tissue and arterial endothelial cells induce excessive growth of pulmonary artery smooth muscle cells. The unchecked growth of these cells is a major driver of PAH including the remodeling of pulmonary arteries that dramatically reduces the diameter and flexibility of the arterial lumen. Tryptophan hydroxylase 1 (TPH1) is the rate‐limiting enzyme for biosynthesis of serotonin and is upregulated in PAH arterial endothelial cells, supporting TPH1 inhibition to treat PAH. Targeting the serotonin pathway via inhibition of peripheral serotonin and local production in diseased tissues, rather than individual receptor‐mediated or receptor‐independent mechanisms, may result in the ability to halt or reverse pulmonary vascular remodeling. Rodatristat ethyl, a prodrug for rodatristat, a potent, peripheral inhibitor of TPH1, has demonstrated efficacy in monocrotaline and SUGEN hypoxia nonclinical models of PAH and robust dose‐dependent reductions of 5‐hydroxyindoleacetic acid, the major metabolite of serotonin in plasma and urine of healthy human subjects. ELEVATE 2 (NCT04712669) is a Phase 2b, double‐blind, multicenter trial where patients with PAH are randomized to placebo, 300 or 600 mg twice daily of rodatristat ethyl. The trial incorporates endpoints to generate essential clinical efficacy, safety, pharmacokinetic, and pharmacodynamic data needed to evaluate the ability of rodatristat ethyl to ameliorate PAH by halting or reversing pulmonary vascular remodeling through its unique mechanism of TPH1 inhibition. Herein we describe the experimental design highlighting the trial's unique features.

News (Medical) associated with Rodatristat ethyl

08 Dec 2022

·www.pmlive.com

Enzyvant and Altavant announce merger to accelerate rare disease therapies

Enzyvant Therapeutics (Enzyvant) and Altavant Sciences (Altavant) have announced a merger to form a biopharmaceutical company focused on accelerating the development of therapies for patients with rare diseases. The combined company, which retains the name Enzyvant, will have a full range of capabilities required to advance 'bold science' for rare diseases in immunology and cardiopulmonology. This includes the development of an in-house regenerative medicine manufacturing facility to serve the company’s commercial and clinical research needs for regenerative medicines. Financial terms of the deal have not yet been disclosed. Myrtle Potter, chief executive officer of Sumitovant Biopharma, of which both individual companies are wholly owned subsidiaries of, said: “There is an immense human need for rare disease therapies, but innovation in this field is complex. Enzyvant has a proven track record of bringing unique expertise to tackle some of the greatest unmet needs in the space. “We believe the combined company will be better positioned to deliver breakthroughs in a way that wouldn’t have been possible separately.” Enzyvant received approval from the US Food and Drug Administration in October 2021 for its first commercial product, Rethymic (allogeneic processed thymus tissue-agdc), a one-time regenerative tissue-based therapy for immune reconstitution in paediatric patients with congenital athymia, a disease characterised by the absence of a functioning thymus. The thymus is an organ that sits on top of the heart and helps the body produce T-cells. Children with congenital athymia can face repeated infections and may also be affected by autoimmune conditions, both of which can be fatal. Rethymic, which has been studied across ten clinical trials for over 25 years, is engineered human thymus tissue designed to regenerate the thymic function children with congenital athymia are missing and does not require donor-recipient matching. The company is also currently evaluating an investigational product, rodatristat ethyl, which is designed to address a root cause of pulmonary arterial hypertension. Also commenting on the merger, Dr Bill Symonds, current chief executive officer of both Enzyvant and Altavant, who will also lead the merged company, said: “Together, our combined team has the proven expertise to take a product from early clinical development through commercialisation, and the passion and focus to drive accelerated development of urgently needed rare disease medicines in immunology and cardiopulmonology. “Patients and families facing very serious and difficult-to-treat rare conditions are the inspiration for our work and vital partners in moving our programs forward.”

Drug ApprovalAcquisition

100 Deals associated with Rodatristat ethyl

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Phase 2	CA	Altavant Sciences, Inc.Startup	01 Aug 2019
Pulmonary Arterial Hypertension	Phase 2	US	Altavant Sciences, Inc.Startup	01 Aug 2019
Idiopathic Pulmonary Fibrosis	Phase 1	-	Roivant Sciences Ltd.	-
Sarcoidosis	Phase 1	-	Roivant Sciences Ltd.	-

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04712669 (ELEVATE 2, ATS2023)	Phase 2	Pulmonary Arterial Hypertension Tryptophan Hydroxylase 1 (TPH1)	90	Placebo	(osblzizfsm) = wpapcegxcu sjildtrvyx (pquniwuqzx ) View more	Positive	21 May 2023
				Rodatristat ethyl 300 mg BID	(osblzizfsm) = ravxpcqous sjildtrvyx (pquniwuqzx ) View more

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