BMS-986166 / BMS - LARVOL DELTA

Targeting Intracellular Pathways in Atopic Dermatitis with Small Molecule Therapeutics. (PubMed, Curr Issues Mol Biol) - "Although biologic agents such as dupilumab, tralokinumab, and lebrikizumab have revolutionized AD management, their high costs, injectable administration, and limited global accessibility highlight the need for alternative options...This review provides a comprehensive analysis of key agents including Janus kinase (JAK) inhibitors (upadacitinib, abrocitinib, baricitinib, ruxolitinib, delgocitinib), phosphodiesterase 4 (PDE4) inhibitors (crisaborole, difamilast, roflumilast, apremilast), as well as STAT6 degraders (KT621, NX3911), aryl hydrocarbon receptor modulators, histamine H4 receptor antagonists (adriforant, izuforant), and sphingosine-1-phosphate receptor modulators (etrasimod, BMS-986166). We summarize their mechanisms of action, pharmacological profiles, and pivotal clinical trial data, emphasizing their potential to address unmet therapeutic needs. Finally, we discuss safety concerns, long-term tolerability, and future directions for integrating small molecule..."

Journal • Review • Atopic Dermatitis • Dermatitis • Dermatology • Immunology • Inflammation • STAT6

Synthetic methodology development driven by the needs of medicinal chemistry efforts: Examples from the identification of S1P1 receptor modulators and RORγt inverse agonists (ACS-Fall 2023) - "For this program, the development of various synthetic approaches expedited the identification of two clinical compounds, BMS-986104 and BMS-986166.In addition, I will discuss the discovery of a photochemical decarboxylative annulation methodology developed for the retinoic acid-related orphan receptor gamma t (RORγt) inverse agonist program. This decarboxylative intramolecular arene alkylation works even with electronically poor arenes where Friedel-Craft reaction usually fails and proved enabling for the synthesis of a highly electron-deficient arene core."

S1PR1

A Study to Evaluate the Drug Levels of BMS-986166 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=7 | Completed | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Completed

Trial completion

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2 | N=17 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | Trial completion date: Jan 2024 ➔ Aug 2022

Trial completion • Trial completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2 | N=17 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting | N=150 ➔ 17 | Trial primary completion date: Nov 2023 ➔ Aug 2022

Enrollment change • Enrollment closed • Trial primary completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Feb 2023 ➔ Jan 2024 | Trial primary completion date: Jan 2023 ➔ Nov 2023

Trial completion date • Trial primary completion date • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study to Evaluate the Drug Levels of BMS-986166 in Healthy Male Participants (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial

A Study to Assess the Effect of Itraconazole, Phenytoin and Gemfibrozil on the Drug Levels of BMS-986166 in Healthy Participants (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | N=72 ➔ 15

Enrollment change • Trial completion

A Study to Assess the Effect of Itraconazole, Phenytoin and Gemfibrozil on the Drug Levels of BMS-986166 in Healthy Participants (clinicaltrials.gov) - P1 | N=72 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2022 ➔ Apr 2022 | Trial primary completion date: Jan 2022 ➔ Apr 2022

Enrollment closed • Trial completion date • Trial primary completion date

A Study to Characterize the Drug Levels of an Oral Contraceptive With and Without BMS-986166 in Healthy Female Participants of Childbearing Potential (clinicaltrials.gov) - P1 | N=25 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed

Trial completion

A Study to Evaluate the Safety, Tolerability, Drug Levels, and Drug Effects of BMS-986166 in Healthy Japanese Participants (clinicaltrials.gov) - P1 | N=23 | Completed | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Completed | Trial completion date: Nov 2021 ➔ Feb 2022 | Trial primary completion date: Nov 2021 ➔ Feb 2022

Trial completion • Trial completion date • Trial primary completion date

[VIRTUAL] BMS-986166, a novel S1PR1,4,5 modulator, is highly efficacious in a mouse model of atopic dermatitis (EADV 2021) - No abstract available

Preclinical • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study of BMS-986166 or Branebrutinib for the Treatment of Participants With Atopic Dermatitis (clinicaltrials.gov) - P2; N=150; Recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P2 trial • Atopic Dermatitis • Dermatitis • Dermatology • Immunology

A Study to Characterize the Pharmacokinetics of an Oral Contraceptive With and Without BMS-986166 in Healthy Female Participants of Childbearing Potential (clinicaltrials.gov) - P1; N=24; Recruiting; Sponsor: Bristol-Myers Squibb; Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Assess the Effect of Itraconazole, Phenytoin, and Gemfibrozil on the Drug Levels of BMS-986166 in Healthy Participants (clinicaltrials.gov) - P1; N=60; Recruiting; Sponsor: Bristol-Myers Squibb; Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Evaluate the Safety, Tolerability, Drug Levels, and Drug Effects of BMS-986166 in Healthy Japanese Participants (clinicaltrials.gov) - P1; N=20; Not yet recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P1 trial

Effect of Itraconazole, Phenytoin, and Gemfibrozil on the Pharmacokinetics of BMS-986166 (clinicaltrials.gov) - P1; N=60; Not yet recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P1 trial

A Study to Characterize the Pharmacokinetics of an Oral Contraceptive With and Without BMS-986166 in Healthy Female Participants of Childbearing Potential (clinicaltrials.gov) - P1; N=24; Not yet recruiting; Sponsor: Bristol-Myers Squibb

Clinical • New P1 trial

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - "Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo."

Clinical • Journal • PK/PD data • Immunology

The safety and pharmacokinetics of a novel, selective S1P1R modulator in healthy participants. (PubMed, Expert Opin Investig Drugs) - P1 | "Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg. BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711."

Clinical • Journal • PK/PD data

Identification and Preclinical Pharmacology of ((1R,3S)-1-amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-Phosphate (S1P1) Receptor Modulator Advanced into Clinical Trials. (PubMed, J Med Chem) - "In comparison to fingolimod (1), a full agonist of S1P currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments will be discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune disease are presented."

Journal

Aryl ether and thioether-derived bicyclic S1P1 partial agonists: Optimization of the PK, PD and safety profiles through sidechain modifications (ACS-Sp 2020) - "Our efforts towards the identification of partial agonists of S1P1 with differentiated safety profiles led to the discovery and clinical development of BMS-986104 (1) and BMS-986166 (2). In this presentation, the effects of analogs 3–6 on the levels of lymphocyte reduction in the rat (the desired pharmacology) along with pulmonary and cardiovascular-related effects (undesired pharmacology) will be detailed. The projected safety profiles of select compounds were found to be superior to that of FTY720 and comparable to what was observed for 1 and 2, with notable reductions in t1/2."

Clinical