afimetoran (BMS-986256) / BMS - LARVOL DELTA

A Study to Assess the Effect of Famotidine on the Drug Levels of Afimetoran in Healthy Participants (clinicaltrials.gov) - P1 | N=76 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Apr 2024 ➔ Mar 2026 | Trial primary completion date: Mar 2024 ➔ Mar 2026

Trial completion date • Trial primary completion date

In Vitro and In Vivo Evidence of the Steroid-Sparing Potential of Afimetoran, an Equipotent Toll-Like Receptor 7/8 Dual Antagonist (ACR Convergence 2024) - "These translational and preclinical data further demonstrate that afimetoran can block TLR7/8 and has steroid-sparing potential in patients with SLE, lupus nephritis, and other autoimmune conditions requiring immunosuppressant therapy."

IO biomarker • Preclinical • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Renal Disease • Sjogren's Syndrome • ANXA5

A Study to Assess the Effect of Phenytoin on the Drug Levels of Afimetoran and the Effect of Afimetoran on the Drug Levels of Midazolam (clinicaltrials.gov) - P1 | N=65 | Completed | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Completed | N=50 ➔ 65 | Trial completion date: Oct 2023 ➔ Apr 2024 | Trial primary completion date: Oct 2023 ➔ Apr 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date

Design and synthesis of heteroarene-based antagonists of toll-like receptors 7 and 8 (TLR7/8) (ACS-Fall 2024) - "Our program to identify small molecule dual antagonists of TLR7/8 resulted in the discovery of afimetoran, an indole-based antagonist currently in clinical trials for lupus...In vivo performance will be described for select compounds. This presentation will also describe my personal journey of being an out, gay professional from entry level into leadership roles and my efforts to advocate for LGBTQ visibility in chemistry."

Dermatology • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Psoriasis • Rheumatoid Arthritis • Rheumatology • TLR7

Optimization of antagonists of toll-like receptors 7 and 8 (TLR7/8) leading to the discovery of afimetoran (ACS-Fall 2024) - "The successful assessment of afimetoran in patients with cutaneous lupus (CLE) marked the first clinical validation of this innovative lupus treatment approach. This positive evaluation supports the ongoing trial of afimetoran in patients with systemic lupus (SLE)."

Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7

PHARMACODYNAMIC EFFECTS AND EXPLORATORY EFFICACY OF AFIMETORAN, A TLR7/8 INHIBITOR, IN PATIENTS WITH CUTANEOUS LUPUS ERYTHEMATOSUS (EULAR 2024) - P1b | "In pts with CLE, afimetoran was safe and well tolerated compared with PBO, and demonstrated treatment efficacy and potent pharmacodynamic effects early, throughout, and beyond the treatment period. The positive impact of afimetoran on the molecular disease profile and its potent pharmacodynamic and clinical effects suggest potentially substantial therapeutic benefit for patients with CLE."

Clinical • IO biomarker • PK/PD data • Cutaneous Lupus Erythematosus • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Novel Coronavirus Disease • Systemic Lupus Erythematosus • CCL3 • IFNG • IL18 • IL6 • TLR7 • TLR8 • TNFA

A Study Evaluating the Efficacy and Safety of Afimetoran Compared With Placebo in Participants With Active Systemic Lupus Erythematosus (SLE) (clinicaltrials.gov) - P2 | N=268 | Recruiting | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Recruiting | Trial completion date: May 2026 ➔ Apr 2029 | Trial primary completion date: May 2025 ➔ Mar 2026

Enrollment open • Trial completion date • Trial primary completion date • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A Study Evaluating the Efficacy and Safety of Afimetoran Compared With Placebo in Participants With Active Systemic Lupus Erythematosus (SLE) (clinicaltrials.gov) - P2 | N=268 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Safety, Tolerability, and Exploratory Efficacy of Afimetoran, a TLR7/8 Inhibitor, in Patients with Cutaneous Lupus Erythematosus: A Phase 1b Randomized, Double-Blind, Placebo-Controlled Study (ACR Convergence 2023) - P1b, P2 | "Afimetoran demonstrated a favorable safety profile and was well tolerated vs placebo in patients with CLE. These results provide the first clinical evidence to suggest that afimetoran may offer a clinical benefit as indicated by an early and sustained clinical response vs placebo as measured by CLASI-A. As such, these results support the continued clinical investigation of afimetoran in lupus, including the ongoing phase 2b study in SLE (NCT04895696)."

Clinical • Late-breaking abstract • P1 data • Cutaneous Lupus Erythematosus • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Novel Coronavirus Disease • TLR7 • TLR8

Steroid-sparing Effects of Afimetoran (BMS-986256), an Equipotent Toll-like Receptor (TLR)7 and TLR8 Antagonist, in a Lupus Mouse Model (ACR Convergence 2023) - "Afimetoran, alone or in combination with low-dose (1mg/kg) prednisolone, showed robust efficacy in NZB/W mice with moderate disease. Bone marrow pDCs and B cells showed afimetoran-induced reversal of resistance to prednisolone-induced apoptosis. These data confirm that afimetoran has the clinical potential to be steroid sparing."

IO biomarker • Preclinical • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Renal Disease • Systemic Lupus Erythematosus • ANXA5 • LCN2 • TIMP1 • TLR8

Phenoxythiazoline (FTz)-Cobalt(II) Precatalysts Enable C(sp2)-C(sp3) Bond Formation for Key Intermediates in the Synthesis of Toll-like Receptor 7/8 Antagonists. (PubMed, Angew Chem Int Ed Engl) - "An air-stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran...Determination of the experimental rate law established a first-order dependence on the cobalt precatalyst and a saturation regime in heterogeneous potassium aryl boronate (apparent zeroth order), supporting turnover-limiting transmetalation and the origin of the observed trends in N-imine substitution. The optimized cobalt precatalyst and reaction conditions were applied to the multigram-scale synthesis of an intermediate used in both the discovery and process routes for toll-like receptor (TLR) 7/8 antagonist molecules."

Journal

A Study to Assess the Effect of Famotidine on the Drug Levels of Afimetoran in Healthy Participants (clinicaltrials.gov) - P1 | N=76 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Assess the Effect of Phenytoin on the Drug Levels of Afimetoran and the Effect of Afimetoran on the Drug Levels of Midazolam (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Bristol-Myers Squibb | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Assess the Effect of Phenytoin on the Drug Levels of Afimetoran and the Effect of Afimetoran on the Drug Levels of Midazolam (clinicaltrials.gov) - P1 | N=50 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial

In vitro evidence demonstrates that afimetoran (BMS-986256), an equipotent TLR7/8 dual antagonist, has steroid-sparing potential in the clinic (EULAR 2023) - P1 | "Conclusion WB-based data show that afimetoran is an equipotent TLR7/8-dual antagonist with sub-nM to nM potency in blocking TLR7- and TLR8-mediated functions. WB- and cell-based evidence demonstrates that afimetoran in combination with prednisolone synergistically inhibits induction of IL-6, a NFkB-dependent cytokine, and reverses TLR7-mediated resistance to prednisolone-induced pDC apoptosis, thus supporting the steroid-sparing potential of afimetoran in patients with SLE."

IO biomarker • Preclinical • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • ANXA5 • CD69 • IL6 • NF-κβ • SLAMF7 • TLR7 • TLR8

AFIMETORAN (BMS-986256), AN EQUIPOTENT TLR7/8 ANTAGONIST, DEMONSTRATES STEROID-SPARING EFFECTS IN A LUPUS MOUSE MODEL (EULAR 2023) - "It also reversed the resistance of bone marrow pDCs and B cells to prednisolone-induced apoptosis. These data confirm that afimetoran, an equipotent TLR7/8 antagonist, has the clinical potential to be steroid-sparing."

IO biomarker • Preclinical • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Renal Disease • Sjogren's Syndrome • Systemic Lupus Erythematosus • ANXA5 • ITGAX • LCN2 • NF-κβ • TIMP1 • TLR8

A Study to Assess the Effect of Famotidine on the Drug Levels of Afimetoran in Healthy Participants (clinicaltrials.gov) - P1 | N=76 | Not yet recruiting | Sponsor: Bristol-Myers Squibb

New P1 trial

A Study to Assess the Safety and Drug Levels of BMS-986256 in Participants With Active Cutaneous Lupus Erythematosus (clinicaltrials.gov) - P1b | N=13 | Completed | Sponsor: Bristol-Myers Squibb | Active, not recruiting ➔ Completed | N=24 ➔ 13 | Trial completion date: Oct 2023 ➔ Apr 2023 | Trial primary completion date: Oct 2023 ➔ Apr 2023

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

Discovery of selective small-molecule dual antagonists of toll-like receptors 7 and 8 (TLR7/8) through optimization of an indole scaffold and C-2 bicyclic heteroarene substituents (ACS-Sp 2023) - P1b, P2 | "One of the analogs discovered in our program, afimetoran, was selected as a development candidate and is currently in clinical trials for cutaneous lupus and systemic lupus (NCT04493541; NCT04895696). This poster will detail the explored SAR of the C-2 heteroarenes and C-5 piperidine substituents, and the in vivo performance for select analogs will be described."

Cutaneous Lupus Erythematosus • Dermatology • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Psoriasis • Rheumatology • Systemic Lupus Erythematosus • TLR7 • TLR8

A Study to Assess the Safety and Drug Levels of BMS-986256 in Participants With Active Cutaneous Lupus Erythematosus (clinicaltrials.gov) - P1b | N=24 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting

Enrollment closed • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

"Phase 2 RCTs are evaluating TLR 7 & TLR 8 blockade in SLE - BMS has afimetoran and Merck has enpatoran (both blocking TLR7/8) https://t.co/lSvnAkRvxB" (@RheumNow)

Inflammatory Arthritis • Lupus • TLR7 • TLR8

"Phase 2 RCTs are evaluating TLR 7 & TLR 8 blockade in SLE - BMS has afimetoran and Merck has enpatoran (both blocking TLR7/8) https://t.co/3TavS7NE99" (@RheumNow)

Inflammatory Arthritis • Lupus • TLR7 • TLR8

Exploration of carbazole-based antagonists of toll-like receptors 7 and 8 (TLR7/8) generated via structure-guided evolution of an indole series (ACS-Fall 2022) - "Our program to develop TLR7/8 selective antagonists was initially focused on our previously described indole scaffold, which led to the discovery of afimetoran, a compound in clinical evaluation for lupus...The structural refinements in our new antagonists resulted in molecules with encouraging potency, selectivity, and favorable in vitro profiles. Select compounds were advanced to in vivo studies, and their performance in mouse pharmacokinetic and pharmacodynamic assays will be described."

Dermatology • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Lupus • Psoriasis • Psoriatic Arthritis • Rheumatology • TLR7

Discovery of afimetoran, a small molecule dual antagonist of the toll-like receptors 7 and 8 (TLR7/8) advanced to clinical evaluation in patients with lupus (ACS-Fall 2022) - "Combination of afimetoran with prednisolone showed improved results relative to either monotherapy in mouse lupus models as well as in human blood assays measuring inhibition of TLR7 or TLR8 responses. With successful completion of Phase I studies revealing a favorable human pharmacokinetic and pharmacodynamic profile, afimetoran was advanced into clinical evaluation in patients with cutaneous lupus (CLE) or systemic lupus (SLE)."

Clinical • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • IRAK1 • MYD88 • TLR7 • TLR8

A Study to Assess the Safety and Drug Levels of BMS-986256 in Participants With Active Cutaneous Lupus Erythematosus (clinicaltrials.gov) - P1b | N=24 | Recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Apr 2023 ➔ Oct 2023 | Trial primary completion date: Apr 2023 ➔ Oct 2023

Trial completion date • Trial primary completion date • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus