BMS-986449 / BMS - LARVOL DELTA

Discovery of BMS-986449: A Potent, Selective Degrader of the Transcription Factors IKZF2 (Helios) and IKZF4 (Eos) to Target Regulatory T Cells in Solid Tumors. (PubMed, J Med Chem) - "Nonhuman primates administered daily with BMS-986449 show sustained IKZF2 degradation in Treg cells providing confidence in human clinical doses. Collectively, these findings establish BMS-986449 as a promising clinical candidate for cancer immunotherapy."

Journal • Oncology • Solid Tumor • Targeted Protein Degradation • CRBN • IKZF1 • IKZF2 • IKZF3

Identification and optimization of pyridylbenzylamine analog 1 as potent and selective Helios degrader (AACR 2026) - "We recently disclosed the discovery of a potent and selective IKZF2 degrader, BMS-986449, derived from lenalidomide/pomalidomide scaffolds. Herein, we report SAR optimization studies leading to the identification of a pyridylbenzylamine appended lenalidomide analog (compound 1) with excellent Helios degradation activity and improved selectivity over related neosubstrates (e.g. IKZF1, IKZF3, and CK1α). In addition, 1 also exhibited favorable ADME properties and robust in vivo pharmacodynamic effects in a mouse syngeneic model."

IO biomarker • Oncology • CRBN • FOXP3 • IKZF1 • IKZF2 • IKZF3 • IL2

The discovery of BMS-986449, a highly potent and selective degrader of the transcription factors Helios (IKZF2) and Eos (IKZF4) for the treatment of solid tumors (AACR 2025) - "Regulatory T (Treg) cell abundance in the tumor microenvironment is associated with poor responses to immunotherapies, such as nivolumab. In cynomolgus monkeys, oral administration of BMS-986449 (0.3 mg/kg, QD) was well-tolerated and maintained ≥80% degradation of Helios in circulating Treg cells over 24h. Given the positive outcomes from these pre-clinical studies and an acceptable safety profile, BMS-986449 was advanced into Phase I/II clinical trials for patients with advanced solid tumors."

Oncology • Solid Tumor • CRBN • IKZF1 • IKZF2

Selective degradation of Helios induces Treg cell reprogramming and enhanced antitumor immunity (AACR 2025) - "In tumor bearing hCRBN-KI mice, BMS-986449 daily dosing induced monotherapy activity in the CT26, MB49, and MC38 tumor models with TGI values of up to 75%, 62%, and 42%, respectively; in combination with anti-PD-1 immune checkpoint blockade more robust efficacy was achieved with TGI values of 95%, 97%, and 92%, respectively. Additionally, in cynomolgus monkeys, daily dosing of BMS-986449 (0.1 mg/kg) maintained greater than 80% degradation of Helios in circulating Treg cells, supporting the advancement of BMS-986449 into Phase 1/2 clinical trials for patients with advanced solid tumors."

IO biomarker • Oncology • Solid Tumor • CRBN • FOXP3 • GZMB • IKZF2

A Study of BMS-986449 With and Without Nivolumab in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1/2 | N=100 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2027 ➔ Sep 2026 | Trial primary completion date: May 2025 ➔ Sep 2026

Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • Triple Negative Breast Cancer