OPL-0301 / Sanofi, Valo Health - LARVOL DELTA

Endothelial sphingosine 1-phosphate receptor-1 promotes inflammation-induced thrombus formation through ß-arrestin-biased signaling (ISTH 2026) - "In activated endothelium, S1P enhanced TF activity when bound to albumin, but not when bound to HDL, indicating augmentation of TF activity by S1P mediated through β -arrestin, rather than G α i. Siponimod, a β -arrestin-biased S1PR1 agonist used for treatment of multiple sclerosis, potentiated TF activity. In contrast, SAR247799, a Gα i-biased agonist, had 100-fold less prothrombotic activity...B:Knockdown of S1PR1, but not S1PR3, inhibits TNFa- stimulated FXa generation in endothelium. Page 3 DOI*10.1016/j.rpth.2026.103759"

CNS Disorders • Hematological Disorders • Infectious Disease • Inflammation • Multiple Sclerosis • Septic Shock • Thrombosis • S1PR1 • TNFA

Structural insights into subtype-specific agonist recognition by sphingosine-1-phosphate receptors. (PubMed, PLoS Biol) - "Through an integrated approach combining structural analysis, molecular dynamics simulations, and pharmacological assays, the molecular basis for the selectivity of CYM5442, HY-X-1011, Ponesimod, and SAR247799 toward S1PR1 over S1PR2-S1PR5 is uncovered. Besides, the relatively broad molecular width of the agonist sterically hinders its binding into S1PR2 and S1PR4 pocket by nonconserved residue pairs bearing bulky side chains. These findings establish a structural framework for the rational design of next-generation S1PR1 highly selective agonists with improved therapeutic potential."

Journal • S1PR1 • S1PR2 • S1PR5

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of OPL-0301 Compared to Placebo in Adults With Post-Myocardial Infarction (MI) (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Valo Health, Inc. | N=174 ➔ 0 | Not yet recruiting ➔ Withdrawn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