ABBV-467 / AbbVie - LARVOL DELTA

Advances in the Management of Relapsed/Refractory CLL and Richter Transformation (ICML 2025) - P=N/A, P2, P3 | "BRUIN CLL-321 is a phase 3, registrational study that evaluated pirtobrutinib compared to the investigator's choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) [23]...Nemtabrutinib is now being evaluated in the registrational, phase 3 BELLWAVE-010 trial (NCT05947851) for patients with R/R CLL, comparing nemtabrutinib plus venetoclax to venetoclax plus rituximab...An ongoing, open-label, first-in-human phase 1/2 study is evaluating the BTK degrader BGB-16673 as monotherapy in patients with R/R CLL [27, 28]...NX-2127 is an investigational, first-in-class BTK degrader currently being evaluated in a phase 1 trial for patients with relapsed or refractory B-cell malignancies, CLL [29, 30]...NX-5948 is another investigational and more selective BTK degrader in an ongoing Phase 1a/1b clinical trial...This trial aims to establish lisaftoclax plus acalabrutinib as a potential alternative to venetoclax-based BTKi combination..."

IO biomarker • Acute Myelogenous Leukemia • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Leukemia • Non-Hodgkin’s Lymphoma • Oncology • Richter's Syndrome • Small Lymphocytic Lymphoma • BCL2L1 • TP53

Evaluation of the efficacy of novel ADCs as potential therapy options for colorectal cancer using a patient derived organoid model (DGHO 2025) - "This study investigates novel ADCs targeting B7-H3 (mirzotamab clezutoclax, ABBV-155) and EGFR (ABBV-637) linked to a Bcl-xL inhibitor as payload as therapeutic strategies for colorectal cancer using a PDO system. Four selected PDOs from CRC patients were maintained in long-term culture...Additionally, an internalization assay utilizing a pH-sensitive fluorescent dye (pHAb) was performed to assess drug uptake and intracellular localization of the ADCs. Untargeted inhibition of Bcl-xL with small molecule inhibitor A-1331852 caused significant cell viability loss (max reduction: 97% at 10 µM) and organoid structural disintegration, with efficacy correlating with baseline protein expression (r = 0.92)...Combinatorial targeting (ABBV-155 + Mcl-1 inhibitor ABBV-467) synergistically enhanced cell death (viability reduction: 62.6% vs. 0% monotherapy). These data provide critical insights into the use of novel ADCs as therapeutic options for CRC patients and suggest that..."

Clinical • Colorectal Cancer • Oncology • Solid Tumor • BCL2L1 • EGFR

Ex vivo Evaluation of BCL-2 Family Member Dependencies in Multiple Myeloma: Synergistic Combinations and Biomarkers of Sensitivity and Resistance (IMS 2025) - "Ex vivo data were integrated with molecular (WES, RNA-Seq) and clinical data using Fisher's Exact Test (mutations), enrichment analysis (transcriptional data), and adapted univariate Cox models to identify features associated with increased synergy or sensitivity ex vivo. ABBV-467, an MCL-1 inhibitor, was the most potent single agent, with LD50 values in the nanomolar range...The BCL-2 inhibitor venetoclax was highly effective in MM with t(11; 14), gain18q, trisomy 13, mutations in ARID2, XBP1, CYLD and HUWE1, "CD1" and "CD2" subtypes, and those overexpressing BCL2. In contrast, BCL-XL inhibition with A-1331852 showed limited single-agent activity...Interestingly, MCL-1 inhibition + Pom demonstrated increased activity in t(14; 16) samples, and consistent with preclinical data, BCL-2 inhibition synergized with panobinostat... BCL-2 and MCL-1 are the dominant anti-apoptotic BCL-2 family effectors in MM. While MCL-1 inhibition may effectively target..."

IO biomarker • Preclinical • Hematological Malignancies • Multiple Myeloma • ARID2 • BAK1 • BCL2 • BCL2L1 • CD2 • HUWE1 • PTPN11 • XBP1

Enabling, Decagram-Scale Synthesis of Macrocyclic MCL-1 Inhibitor ABBV-467. (PubMed, J Org Chem) - "Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Selective MCL-1 inhibitor ABBV-467 is efficacious in tumor models but is associated with cardiac troponin increases in patients. (PubMed, Commun Med (Lond)) - P1 | "The selectivity of ABBV-467 suggests that treatment-induced troponin release is a consequence of MCL-1 inhibition and therefore may represent a class effect of MCL-1 inhibitors in human patients."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Disorders • Leukemia • Lymphoma • Multiple Myeloma • Oncology • BCL2 • TNNI3

NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes. (PubMed, Biomed Pharmacother) - "Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax)...Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically...Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Lymphoma • Oncology • BCL2L1

A Study of the Safety and Tolerability of ABBV-467 in Adult Participants With Relapsed/Refractory (R/R) Multiple Myeloma (clinicaltrials.gov) - P1; N=8; Terminated; Sponsor: AbbVie; Trial completion date: Jun 2023 ➔ Apr 2021; Active, not recruiting ➔ Terminated; Trial primary completion date: Jun 2023 ➔ Apr 2021; Strategic considerations

Clinical • Trial completion date • Trial primary completion date • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of the Safety and Tolerability of ABBV-467 in Adult Participants With Relapsed/Refractory (R/R) Multiple Myeloma (clinicaltrials.gov) - P1; N=8; Active, not recruiting; Sponsor: AbbVie; Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of the Safety and Tolerability of ABBV-467 in Adult Participants With Relapsed/Refractory (R/R) Multiple Myeloma (clinicaltrials.gov) - P1; N=108; Recruiting; Sponsor: AbbVie; N=54 ➔ 108

Clinical • Enrollment change • Hematological Malignancies • Multiple Myeloma • Oncology • CD38

A Study of the Safety and Tolerability of ABBV-467 in Adult Participants With Relapsed/Refractory (R/R) Multiple Myeloma (clinicaltrials.gov) - P1; N=54; Recruiting; Sponsor: AbbVie; N=108 ➔ 54

Clinical • Enrollment change • Hematological Malignancies • Multiple Myeloma • Oncology

A Study of the Safety and Tolerability of ABBV-467 in Adult Participants With Relapsed/Refractory Multiple Myeloma (clinicaltrials.gov) - P1; N=108; Recruiting; Sponsor: AbbVie; Not yet recruiting ➔ Recruiting; N=54 ➔ 108; Initiation date: Nov 2019 ➔ Apr 2020

Enrollment change • Enrollment open • Trial initiation date • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Newly added product (clinicaltrials.gov) - P1, Oncology

Pipeline update