AL101 / Immunome - LARVOL DELTA

Clinical Outcomes With Notch Inhibitors in Notch-Activated Recurrent/Metastatic Adenoid Cystic Carcinoma. (PubMed, Cancer Med) - "NOTCH inhibitors demonstrate activity in NOTCH-activated ACC, surpassing the efficacy of observation or prior systemic therapies. However, limited PFS and progression of nontarget lesions suggest the potential need for combination therapy to address ACC heterogeneity."

Clinical data • Journal • Retrospective data • Adenoid Cystic Carcinoma • Oncology • NICD • NOTCH1

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 • Oncology • NICD

AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Recruiting ➔ Active, not recruiting

Enrollment closed • Adenoid Cystic Carcinoma • Oncology

Notch inhibitor AL101 prior to surgery in patients (pts) with Notch1 activated adenoid cystic carcinoma (ACC): Safety and efficacy in a window of opportunity study (ESMO 2024) - P1 | "Pre-operative AL101 was safe and feasible in ACC-N1 pts. Tumor NICD1 expression was not significantly reduced following AL101 treatment. Paired tissue and blood samples analyzes are ongoing."

Clinical • Surgery • Adenoid Cystic Carcinoma • Oncology • NICD • NOTCH1

Effect of RGT-61159 on inhibition of oncogene c-MYB synthesis and tumor growth inhibition in a broad range of ACC PDX models, at well tolerated doses in rodents and non-human primates. (ASCO 2024) - "Finally, we showed that the combination of RGT-M001, an analog of RGT-61159, with the NOTCH Inhibitor AL-101 resulted in significant tumor regression at well tolerated doses. Altogether, these data demonstrated that RGT-61159 efficiently and safely targets the undruggable oncogenic transcription factor c-MYB. Down-regulation of c-MYB by the RGT-61159 RNA-targeting small molecule is a very promising therapeutic strategy to treat ACC and other cancers driven by c-MYB dysregulation."

Preclinical • Adenoid Cystic Carcinoma • Oncology

AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov) - P1 | N=14 | Recruiting | Sponsor: 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 • Adenoid Cystic Carcinoma • Oncology

Immunome Reports First Quarter 2024 Financial Results and Provides Business Update (Businesswire) - "Immunome expects to report topline data for RINGSIDE Part B in the second half of 2025...Immunome anticipates submitting INDs for two preclinical candidates in the first quarter of 2025: IM-1021, a ROR1 ADC, and IM-3050, a FAP-targeted RLT....In-process research and development expenses for the quarter ended March 31, 2024 were $112.0 million. These expenses were related to Immunome’s acquisition of AL101 and AL102 from Ayala Pharmaceuticals, Inc. and the exclusive license of IM-1021 and related ADC platform technology from Zentalis Pharmaceuticals, Inc., both of which closed in the quarter ended March 31, 2024."

Commercial • IND • P2/3 data • Desmoid Tumors • Oncology • Solid Tumor

RGT-M001, a first-in-class small molecule mRNA degrader of the oncogenic transcription factor c-Myb, demonstrated remarkable single agent anti-tumor efficacy in cancer patient-derived xenograft model (AACR 2024) - "As a single agent, RGT-M001 reduced in vivo C-MYB transcript levels by >80% at peak drug exposure and induced a remarkable tumor growth inhibition response (~70% TGI) in the ACCX11 PDx mouse model, surpassing the therapeutic benchmark Lenvatinib (40% TGI)...Finally, we showed that the combination of RGT-M001 with the Notch Inhibitor AL-101 resulted in complete inhibition of tumor growth.In conclusion, these data demonstrate that small molecules targeting RNA are a safe and effective approach to address previously undruggable protein targets. Down-regulation of C-MYB by our RNA-targeting small molecules is an attractive therapeutic strategy to treat ACC and other cancers driven by C-MYB dysregulations."

Preclinical • Adenoid Cystic Carcinoma • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor

Immunome Completes Acquisition of AL102, a Phase 3 Asset for the Treatment of Desmoid Tumors, From Ayala (Businesswire) - "Immunome, Inc...announced the successful completion of its purchase of AL102 and related drug candidate AL101 from Ayala Pharmaceuticals, Inc."

M&A • Desmoid Tumors • Oncology • Solid Tumor

TENACITY: A Study of AL101 Monotherapy in Patients With Notch Activated Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=18 | Terminated | Sponsor: Ayala Pharmaceuticals, Inc, | N=67 ➔ 18 | Active, not recruiting ➔ Terminated; Sponsor's decision

Enrollment change • Monotherapy • Trial termination • Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PGR

Immunome To Acquire AL102, A Phase 3 Asset for the Treatment of Desmoid Tumors, From Ayala Pharmaceuticals (GlobeNewswire) - "Immunome, Inc...today announced that it entered into a definitive asset purchase agreement with Ayala Pharmaceuticals, Inc...to acquire AL102 and related drug candidate AL101 from Ayala. Based on the terms of the agreement, Immunome will pay Ayala $20 million in cash and $30 million in Immunome common stock (valued at 30-day VWAP as of February 1, 2024) at the closing and will pay up to an additional $37.5 million in development and commercial milestone payments. Completion of the transaction is subject to customary conditions including Ayala obtaining the requisite stockholder approval....A.G.P./Alliance Global Partners is acting as strategic advisor to Ayala Pharmaceuticals, Inc. in connection with the transaction."

Licensing / partnership • Desmoid Tumors • Oncology • Solid Tumor

ACCURACY: A Study Of AL101In Patients With Adenoid Cystic Carcinoma (ACC) Bearing Activating Notch Mutations (clinicaltrials.gov) - P2 | N=87 | Completed | Sponsor: Ayala Pharmaceuticals, Inc, | Active, not recruiting ➔ Completed

Trial completion • Adenoid Cystic Carcinoma • Oncology

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 • Adenoid Cystic Carcinoma • Oncology • NOTCH1

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) - P2 | "*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 • Metastases • Retrospective data • Adenoid Cystic Carcinoma • Oncology • NOTCH1

AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov) - P1 | N=14 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Surgery • Trial completion date • Trial primary completion date • Adenoid Cystic Carcinoma • Oncology

Ayala Pharmaceuticals Announces Second Quarter 2023 Financial Results and Provides Corporate Update (GlobeNewswire) - "Upcoming Milestones: ESMO poster presentations on AL102 and AL101: Updated results from Phase 2 of RINGSIDE evaluating AL102 in desmoid tumors and final results from the ACCURACY trial evaluating AL101 in patients with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) have been selected for presentation at the European Society for Molecular Oncology (ESMO) Congress 2023, to be held in Madrid, Spain 20-24 October 2023."

P2 data • Adenoid Cystic Carcinoma • Desmoid Tumors • Oncology • Solid Tumor

Ayala Pharmaceuticals Announces Abstracts on AL102 and AL101 Accepted for Presentation at ESMO Congress 2023 (GlobeNewswire) - "Ayala Pharmaceuticals...today announced that it will present posters on its gamma secretase inhibitors AL102 and AL101 at the European Society for Molecular Oncology (ESMO) Congress 2023, to be held in Madrid, Spain 20-24 October 2023."

P2 data • Adenoid Cystic Carcinoma • Desmoid Tumors • Oncology • Solid Tumor

Structure-activity relationship of BMS906024 derivatives for Cryptosporidium parvum growth inhibition. (PubMed, Bioorg Med Chem Lett) - "However, concomitant removal of the succinyl α-substituent and switching the primary amide with secondary amides was tolerated. For example, 32 (SH287) inhibited C. parvum growth in HCT-8 host cells with an EC = 6.4 nM and an EC = 16 nM; however, blocking C. parvum growth with BMS906024 derivatives was correlative with inhibition of Notch signaling, highlighting that additional SAR analysis will be needed to separate these two activities."

Journal

Initial results of phase II/III trial of AL102 for treatment of desmoid tumors (DT) (ESMO 2022) - P2/3 | "Table: 1488MO Summary of Treatment-emergent Adverse Events (TEAEs) by Patient *Deemed unrelated to study drug by investigator Conclusions Safety findings to date show no indication for discontinuing any of the three dosing cohorts. Efficacy, patient reported outcome and additional safety data will be presented at the conference."

P2/3 data • Desmoid Tumors • Oncology • Sarcoma

AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov) - P1 | N=12 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Apr 2023 ➔ Dec 2023 | Trial primary completion date: Apr 2023 ➔ Dec 2023

Surgery • Trial completion date • Trial primary completion date • Adenoid Cystic Carcinoma • Oncology

[VIRTUAL] The gamma secretase inhibitor AL101 combined with other drugs for dual targeting of Notch dysregulated tumors (ESMO 2021) - P2 | "Ayala is targeting Notch activated tumors with investigational small molecule pan-Notch γ-secretase inhibitors AL101 & AL102... These data support a strategy of combination therapy with AL101 in ACC tumors, regardless of mutational status. It also provides a promising approach for expansion to other cancer indications in which the Notch pathway is dysregulated."

IO biomarker • Oncology • Triple Negative Breast Cancer • BCL2 • CDK4 • FGFR • NOTCH1

INITIAL RESULTS OF PHASE 2/3 TRIAL OF AL102 FOR TREATMENT OF DESMOID TUMORS (DT) (CTOS 2022) - "Conclusions of Part A of the study will be presented at the meeting."

P2/3 data • Desmoid Tumors • Oncology • Sarcoma

Single Cell RNA-Seq Reveals Deranged Developmental Hierarchy with Coexisting Oncogenic States and Immune Evasion Programs in ETP T-ALL (ASH 2019) - P1; "These patients were enrolled on a phase I trial with the γ-secretase inhibitor (GSI) BMS-906024 (NCT01363817)... We identified deranged developmental hierarchy characterized by co-expression of stemness programs in multiple malignant cell states and ineffectual commitment to either lymphoid or myeloid lineage in ETP T-ALL. Leukemic blasts demonstrate preexisting heterogeneity of diverse oncogenic states as evidenced by opposing PI3K and Notch activity, suggesting possible novel combination therapies. Notch inhibition abolishes the Notch high state without effecting the PI3K active state."

IO Biomarker • CD8 • NOTCH1 • PD-1 • PD-L1

AL101 mediated tumor inhibition in notch-altered TNBC PDX models. (ASCO 2019) - P2; "We demonstrate that in TNBC PDX models, the presence of a Notch-on signature and Notch GOF mutations/fusions correlates with potent response to AL101. These data support the clinical development of AL101 as a targeted therapy for TNBC with Notch GOF alterations."

A phase I study of AL101, a pan-NOTCH inhibitor, in patients (pts) with locally advanced or metastatic solid tumors. (ASCO 2018) - P1; "...AL101 (formerly BMS-906024), a gamma secretase inhibitor that potently inhibits all Notch receptors, was evaluated... AL101 at the RP2D was generally well-tolerated and demonstrated sustained Notch inhibition as well as clinical activity across different tumor types. Future trials will evaluate AL101 in tumors with Notch activating mutations."

Clinical • P1 data • Non Small Cell Lung Cancer • Triple Negative Breast Cancer