CC-91633 / BMS - LARVOL DELTA

BMS-986397, a first-in-class casein kinase 1α (CK1α) degrader in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (HR-MDS): A phase 1 dose escalation study (ASH 2025) - P1 | "Two (3.8%) patients discontinued from treatment due to death fromTEAEs (not related to BMS-986458) of pneumonia and septic shock. Treatment with BMS-986397 monotherapy resulted in high response rates in R/R HR-MDS patients (CRR:57.1%) and modest activity in R/R AML (ORR: 12.1%). The most common TEAEs were grade 3/4 cytopeniasthat led to dose interruptions or reductions. The MTD was not reached."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Pneumonia • Respiratory Diseases • Septic Shock • Targeted Protein Degradation • Thrombocytopenia • GDF15 • TP53

Synergistic Activity of BMS-986397, a First-in-Class a Cereblon (CRBN) E3 Ligase Modulator (CELMoD) Targeting Casein Kinase 1α (CK1α), in Combination with Venetoclax and/or Azacitidine in Preclinical Models of Acute Myeloid Leukemia (AML) (ASH 2024) - P1 | "Conclusions : BMS-986397 combination with VEN and/or AZA unveiled preclinical efficacy improvement with tolerable safety in primary AML. These data support the use of combination-based therapies targeting different mechanism of action to achieve expanded clinical success transforming the therapeutic landscape for patients diagnosed with AML."

Combination therapy • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • CD34 • CRBN

BMS-986397, a First-in-Class Molecular Glue Degrader of Casein Kinase 1α (CK1α) for the Treatment of Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS) Harboring Functional TP53 (ASH 2024) - P1 | "Lenalidomide is a weak, but significant degrader of CK1α, and has clinical efficacy in del5q MDS relative to non-del5q MDS. Conclusions : BMS-986397 is a novel CELMoD agent with a first in class mechanism targeting CK1α degradation exhibiting strong anti-leukemic activity as a single agent in models of TP53 WT AML and HR-MDS. These data support the clinical investigation of BMS-986397 in patients with R/R AML and HR-MDS patients (NCT04951778)."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • CDKN1A • CRBN • TP53

Study to Evaluate Safety and Tolerability of CC-91633 (BMS-986397) in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=56 | Terminated | Sponsor: Celgene | N=180 ➔ 56 | Trial completion date: May 2027 ➔ Jul 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: May 2026 ➔ Jul 2025; Efficacy endpoint met; however, overall experimental dosing regimen is not considered optimal to support further clinical development in this patient population

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Study to Evaluate Safety and Tolerability of CC-91633 (BMS-986397) in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=180 | Active, not recruiting | Sponsor: Celgene | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Discovery of BMS-986397, a first-in-class molecular glue degrader of Casein Kinase 1α (CK1α) for the treatment of acute myeloid leukemia (AML) harboring functional TP53 (ACS-Fall 2024) - "Revlimid, an approved IMiD® drug, was shown to induce modest CK1α degradation, and this modest degradation likely contributes to the efficacy observed in del5q MDS patients with haploinsufficient expression of CK1α. Upon oral dosing, BMS-986397 demonstrates dose dependent PK/PD and anti-tumor efficacy in both subcutaneous and disseminated AML tumor models. BMS-986397 is currently undergoing Phase I clinical evaluation in AML patients."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Targeted Protein Degradation • CRBN • GSPT1 • IKZF1 • TP53

Study to Evaluate Safety and Tolerability of CC-91633 (BMS-986397) in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=180 | Recruiting | Sponsor: Celgene | N=120 ➔ 180

Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Study to Evaluate Safety and Tolerability of CC-91633 (BMS-986397) in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1 | N=120 | Recruiting | Sponsor: Celgene | Trial completion date: Oct 2027 ➔ May 2027 | Trial primary completion date: Nov 2025 ➔ May 2026

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Targeting cereblon in hematologic malignancies. (PubMed, Blood Rev) - "This review describes novel thalidomide analogs, immunomodulatory drugs, also known as CRBN E3 ubiquitin ligase modulators or molecular glues (avadomide, iberdomide, CC-885, CC-90009, BTX-1188, CC-92480, CC-99282, CFT7455, and CC-91633), and CRBN-based proteolysis targeting chimeras (PROTACs) with increased efficacy and potent activity for application in hematologic malignancies...Proteins that are traditionally difficult to target (transcription factors and oncoproteins) can be polyubiquitinated and degraded in this way. The competition of CRBN neosubstrates with endogenous CRBN-interacting proteins and the pharmacology and rational combination therapies of and mechanisms of resistance to CRL4 modulators or CRBN-based PROTACs are described."

Journal • Review • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Oncology • Targeted Protein Degradation • CRBN • IL17RB

"$BMY still not publicising the name of its CK1α celmod, recently into phase 1. It's CC-91633 (BMS-986397). My earlier story -> https://t.co/JBorHRy8EQ" (@JacobPlieth)

CSNK1A1

Study to Evaluate Safety and Tolerability of CC-91633 (BMS-986397) in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1; N=120; Recruiting; Sponsor: Celgene; Not yet recruiting ➔ Recruiting; Initiation date: Jul 2021 ➔ Dec 2021; Trial primary completion date: Sep 2027 ➔ Nov 2025

Clinical • Enrollment open • Trial initiation date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Study to Evaluate Safety and Tolerability of CC-91633 (BMS-986397) in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes (clinicaltrials.gov) - P1; N=120; Not yet recruiting; Sponsor: Celgene

Clinical • New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology