AL101 / Immunome - LARVOL DELTA

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

Ayala Pharmaceuticals to Accelerate Development of AL102 for the Treatment of Desmoid Tumors in Pivotal Phase 2/3 Study (GlobeNewswire) - "Ayala Pharmaceuticals, Inc...announced the completion of its end-of-Phase 1 meeting with the U.S. Food and Drug Administration (FDA) on AL102, a potent, selective, oral gamma secretase inhibitor (GSI), for the treatment of desmoid tumors. The FDA has agreed, based on data from AL101 and AL102 studies including durable responses observed in patients with Desmoid tumors, to proceed with a Phase 2/3 pivotal study, which can potentially be used as a registrational study. Ayala expects to initiate the pivotal Phase 2/3 RINGSIDE study in adult and adolescent patients with desmoid tumors in the first half of 2021....initial interim data read-out from part 1 and dose selection expected by mid-2022 with part 2 of the study to commence immediately thereafter."

FDA event • P2/3 data • Trial status • Desmoid Tumors • Oncology

AL101 Before Surgery for the Treatment of Notch Activated Adenoid Cystic Cancer (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: M.D. Anderson Cancer Center | Active, not recruiting ➔ Completed | Trial completion date: Dec 2028 ➔ Jun 2026 | Trial primary completion date: Dec 2028 ➔ Jun 2026

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

Window of opportunity study of the Notch inhibitor AL101 in Notch1 activated adenoid cystic carcinoma (ACC): Biological effects and biomarker correlates. (ASCO 2026) - P1 | "In this first window-of-opportunity study in ACC, AL101 demonstrated biological target modulation. Importantly, MYB overexpression and NOTCH signaling activity rather than NICD1 modulation or NOTCH1 mutation correlated with tumor shrinkage. These findings provide translational insights and support biomarker-driven development of rational combination strategies in NOTCH1-activated ACC."

Biomarker • Adenoid Cystic Carcinoma • Oncology • NFIB • NOTCH1

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 | Trial completion date: Dec 2025 ➔ Dec 2028 | Trial primary completion date: Dec 2025 ➔ Dec 2028

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

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

Reprogramming the Tumor Microenvironment in TNBC: A Novel Strategy Combining Notch Inhibition with Radiotherapy and Checkpoint Blockade (SABCS 2025) - "Notch inhibition reprograms the radiation-altered TME to enhance responsiveness to checkpoint blockade in this TNBC model. Triple therapy prolongs survival and reduces metastasis by restoring CD103⁺ dendritic cells, activating CD8⁺ T cells, and suppressing immunosuppressive cell populations. These data support the translational potential of integrating Notch inhibition into breast cancer immuno-radiotherapy regimens."

Biomarker • Checkpoint block • Checkpoint inhibition • Tumor microenvironment • Breast Cancer • Oncology • Triple Negative Breast Cancer • CD8 • ITGAE

Advances in the molecular pathogenesis of lacrimal gland adenoid cystic carcinoma and associated targeted therapies (PubMed, Zhonghua Yan Ke Za Zhi) - "Emerging breakthroughs in targeted therapies warrant attention, including antisense oligonucleotides targeting MYB-NFIB fusion genes, clinical trial data of NOTCH inhibitors (e.g., AL101), and PARP inhibitor-based combinatorial regimens leveraging DNA damage repair mechanisms. By integrating fundamental research and clinical translational evidence, this review provides a theoretical framework for optimizing LGACC diagnosis and treatment paradigms."

Journal • Review • Adenoid Cystic Carcinoma • Eye Cancer • Oncology • Solid Tumor • BRCA • NFIB

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

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