OPL-0301 / Sanofi, Valo Health - LARVOL DELTA

S1PR1-biased activation drives the resolution of endothelial dysfunction-associated inflammatory diseases by maintaining endothelial integrity. (PubMed, Nat Commun) - "Cryo-electron microscopy structure of S1PR1-Gi signaling complex bound to SAR247799 with a resolution of 3.47 Å revealed the recognition mode for the biased ligand. With the efficacy of SAR247799 in treating other endothelial dysfunction-associated inflammatory diseases, our study offers mechanistic insights into the Gi-biased S1PR1 agonist and represents a strategy for endothelial dysfunction-associated disease treatment."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • S1PR1

RESTORE: Efficacy and Safety of OPL-0301 Compared to Placebo in Adults With Post-Myocardial Infarction (MI) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Valo Health, Inc. | N=174 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Cardiovascular • Heart Failure • Myocardial Infarction

RESTORE: Efficacy and Safety of OPL-0301 Compared to Placebo in Adults With Post-Myocardial Infarction (MI) (clinicaltrials.gov) - P2 | N=174 | Not yet recruiting | Sponsor: Valo Health, Inc. | Initiation date: Jun 2022 ➔ Sep 2022

Trial initiation date • Cardiovascular • Heart Failure • Myocardial Infarction

RESTORE: Efficacy and Safety of OPL-0301 Compared to Placebo in Adults With Post-Myocardial Infarction (MI) (clinicaltrials.gov) - P2 | N=174 | Recruiting | Sponsor: Valo Health, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Heart Failure • Myocardial Infarction

RESTORE: Efficacy and Safety of OPL-0301 Compared to Placebo in Adults With Post-Myocardial Infarction (MI) (clinicaltrials.gov) - P2 | N=174 | Not yet recruiting | Sponsor: Valo Health, Inc.

New P2 trial • Cardiovascular • Heart Failure • Myocardial Infarction

A G-protein-biased S1P1 agonist, SAR247799, improved LVH and diastolic function in a rat model of metabolic syndrome. (PubMed, PLoS One) - "These experimental findings suggest that S1P1 activation with SAR247799 may be considered as a new therapeutic approach for LVH and diastolic dysfunction, major components of HFpEF."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Metabolic Disorders • Obesity

Endothelial-protective effects of a G-protein-biased S1P agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial. (PubMed, Br J Clin Pharmacol) - "These data provide the first human evidence suggesting endothelial-protective properties of S1P activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub-lymphocyte-reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A label-free impedance assay in endothelial cells differentiates the activation and desensitization properties of clinical S1P agonists. (PubMed, FEBS Open Bio) - "The latter is exploited in the approval and/or late-stage development of receptor-desensitizing agents targeting the S1P receptor in multiple sclerosis, such as siponimod, ozanimod and ponesimod. Thus, we show that SAR247799 is the most G protein biased S1P agonist currently characterized. This rank-order of bias amongst the most clinically advanced S1P modulators provides a new perspective on the relative potential of these clinical molecules for improving endothelial function in patients in relation to their lymphocyte-reducing (desensitization) properties."

Clinical • Journal • CNS Disorders • Multiple Sclerosis

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G-protein-biased Sphingosine-1 phosphate receptor-1 agonist for endothelial protection. (PubMed, Br J Clin Pharmacol) - "SAR247799 is suitable for exploring the biological role of endothelial S1P activation without causing receptor desensitization."

Clinical • Journal • P1 data • PK/PD data • CNS Disorders • Multiple Sclerosis

A G protein-biased S1P agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers. (PubMed, Sci Signal) - "Similarly, in a rat model of renal ischemia/reperfusion injury, SAR247799 preserved renal structure and function at doses that did not induce S1P-desensitizing effects, such as lymphopenia and lung vascular leakage. In contrast, a clinically used S1P functional antagonist, siponimod, conferred minimal renal protection and desensitized S1P These findings demonstrate that sustained S1P activation can occur pharmacologically without compromising the immune response, providing a new approach to treat diseases associated with endothelial dysfunction and vascular hyperpermeability."

Journal • CNS Disorders • Gene Therapies • Immunology • Ischemic stroke • Multiple Sclerosis • Reperfusion Injury

Pharmacodynamic Study to Assess the Effects of Repeated Dosing of SAR247799 on Endothelial Function in Patients With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P1; N=54; Completed; Sponsor: Sanofi; N=23 ➔ 54

Clinical • Enrollment change

Pharmacodynamic Study to Assess the Effects of Repeated Dosing of SAR247799 on Endothelial Function in Patients With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P1; N=23; Completed; Sponsor: Sanofi; Recruiting ➔ Completed; N=108 ➔ 23

Clinical • Enrollment change • Trial completion