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    DRUG:

    AL101

    i
    Other names: AL101, BMS-906024, AL 101, BMS 906024
    Company:
    Immunome
    Drug class:
    γ-secretase inhibitor, Notch inhibitor, Notch-2 receptor inhibitor, Notch-3 receptor inhibitor, Notch-4 receptor inhibitor
    Related drugs:
    13d
    Structural basis of human γ-secretase inhibition by anticancer clinical compounds. (PubMed, Nat Struct Mol Biol)
    Here we report the cryo-electron microscopy structures of human γ-secretase bound individually to five clinically tested GSIs (RO4929097, crenigacestat, BMS906024, nirogacestat and MK-0752) at overall resolutions of 2.4-3.0 Å. The size and shape of the binding pocket are induced by the bound GSI. Analysis of these structural features suggest strategies for modification of the GSI with improved inhibition potency.
    Journal
    |
    NICD (NOTCH1 intracellular domain)
    |
    Ogsiveo (nirogacestat) • AL101 • RG4733 • MK-0752 • crenigacestat (LY3039478)
    2ms
    AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov)
    P1, N=14, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    AL101
    7ms
    AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov)
    P1, N=14, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025
    Trial completion date • Trial primary completion date
    |
    AL101
    10ms
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=18, Terminated, Ayala Pharmaceuticals, Inc, | N=67 --> 18 | Active, not recruiting --> Terminated; Sponsor's decision
    Enrollment change • Trial termination
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101
    11ms
    ACCURACY: A Study Of AL101In Patients With Adenoid Cystic Carcinoma (ACC) Bearing Activating Notch Mutations (clinicaltrials.gov)
    P2, N=87, Completed, Ayala Pharmaceuticals, Inc, | Active, not recruiting --> Completed
    Trial completion
    |
    AL101
    over1year
    Efficacy of NOTCH inhibitors (Ni) relative to prior systemic therapy or observation in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) (ESMO 2023)
    Ni included AL101, a gamma-secretase inhibitor, or OMP-52M51, an antibody targeting N1...The efficacy of Ni compares favorably with efficacy of systemic therapies administered prior to Ni. The limited PFS and high rate of tumor progression on non-target lesions suggests Ni combination therapy may be necessary to address ACC heterogeneity.
    Clinical • Metastases
    |
    NOTCH1 (Notch 1)
    |
    AL101 • brontictuzumab (OMP-52M51)
    over1year
    AL101 therapy in patients with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC): Final ACCURACY trial results and meta-analysis of clinical outcomes (ESMO 2023)
    *Inverse variance method, no transformation, 0.5 continuity correction. ORR: CR + PR; DCR: CR + PR + SD Conclusions AL101 showed acceptable safety and tolerability in ACC pts with Notchmut and a response rate comparable to pooled estimates for available therapies in pts regardless of Notch status.
    Clinical data • Retrospective data • Metastases
    |
    NOTCH1 (Notch 1)
    |
    NOTCH mutation
    |
    AL101
    over2years
    AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling. (PubMed, Cell Death Dis)
    Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.
    Journal
    |
    NOTCH1 (Notch 1)
    |
    NOTCH1 mutation • NOTCH mutation
    |
    AL101
    over2years
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=67, Active, not recruiting, Ayala Pharmaceuticals, Inc, | Recruiting --> Active, not recruiting
    Enrollment closed
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101
    over2years
    Genetic heterogeneity and therapeutic target detection through microdissection in solid-type adenoid cystic carcinoma. (PubMed, Pathology)
    Guided by the genetic profiles, the preclinical efficiency of the gamma-secretase inhibitor BMS-906024 was evaluated in patient derived xenograft models (PDXs) with activating NOTCH1 mutations and demonstrated robust antitumour effects...In contrast to cribriform/tubular ACCs, solid-type ACCs should be approached with a distinct therapeutic strategy, particularly targeting NOTCH1. Microdissecting the highest grade component guided by histology is a highly recommended tumour sampling strategy and facilitates the detection of key molecular targets.
    Journal • BRCA Biomarker
    |
    BRCA2 (Breast cancer 2, early onset) • FGFR2 (Fibroblast growth factor receptor 2) • NOTCH1 (Notch 1) • NOTCH2 (Notch 2) • BCOR (BCL6 Corepressor) • NICD (NOTCH1 intracellular domain)
    |
    BRCA2 mutation • FGFR2 mutation • NOTCH1 mutation • BCOR mutation • NICD expression
    |
    AL101
    3years
    Activity of the Gamma Secretase Inhibitor AL101 in Desmoid Tumors: A Case Report of 2 Adult Cases. (PubMed, Curr Oncol)
    Also, in a phase 1 study of AL102, a potent orally administered gamma secretase inhibitor that shares structural features with AL101, a patient with a desmoid tumor was noted to have tumor shrinkage. Formal clinical testing of AL102 for the treatment of patients with desmoid tumors that are not amenable to surgery or are refractory to/recurrent from other prior therapies is currently underway.
    Clinical • Journal
    |
    CTNNB1 (Catenin (cadherin-associated protein), beta 1)
    |
    AL101 • varegacestat (AL102)
    4years
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=67, Recruiting, Ayala Pharmaceuticals, Inc, | Not yet recruiting --> Recruiting
    Clinical • Enrollment open
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101
    over4years
    Precision medicine for human cancers with Notch signaling dysregulation (Review). (PubMed, Int J Mol Med)
    Small‑molecule γ‑secretase inhibitors (AL101, MRK‑560, nirogacestat and others) and antibody‑based biologics targeting Notch ligands or receptors [ABT‑165, AMG 119, rovalpituzumab tesirine (Rova‑T) and others] have been developed as investigational drugs...Phase III clinical trials of Rova‑T for patients with small‑cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch‑related knowledge‑base and optimize Notch‑targeted therapy for patients with cancer.
    Journal
    |
    HER-2 (Human epidermal growth factor receptor 2) • FLT3 (Fms-related tyrosine kinase 3) • MET (MET proto-oncogene, receptor tyrosine kinase) • FGFR2 (Fibroblast growth factor receptor 2) • FGFR3 (Fibroblast growth factor receptor 3) • NOTCH1 (Notch 1) • FGFR (Fibroblast Growth Factor Receptor) • CD19 (CD19 Molecule) • TNFRSF8 (TNF Receptor Superfamily Member 8) • CCND1 (Cyclin D1) • CD79B (CD79b Molecule) • HGF (Hepatocyte growth factor) • ROR1 (Receptor Tyrosine Kinase Like Orphan Receptor 1) • TNFA (Tumor Necrosis Factor-Alpha) • TNFRSF17 (TNF Receptor Superfamily Member 17) • NOTCH2 (Notch 2) • DLL3 (Delta Like Canonical Notch Ligand 3) • CD44 (CD44 Molecule) • NOTCH3 (Notch Receptor 3) • NOTCH4 (Notch 4) • RAC1 (Rac Family Small GTPase 1) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • FGF (Fibroblast Growth Factor) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
    |
    NOTCH1 mutation
    |
    Rova-T (rovalpituzumab tesirine) • Ogsiveo (nirogacestat) • AL101 • AMG 119 • dilpacimab (ABT-165)
    over4years
    TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov)
    P2, N=67, Not yet recruiting, Ayala Pharmaceuticals, Inc,
    Clinical • New P2 trial
    |
    HER-2 (Human epidermal growth factor receptor 2) • PGR (Progesterone receptor)
    |
    HER-2 negative
    |
    AL101