Positive Results Support Development Pathway of AL101 as a Targeted Therapy for Patients with Tumors That Have Activating Notch Mutations
REHOVOT, Israel & WILMINGTON, Del.–(BUSINESS WIRE)–Ayala Pharmaceuticals, a clinical stage precision oncology biopharmaceutical company dedicated to developing novel targeted therapies for genomically defined cancers in patient populations with high unmet medical needs, announced today results from the Phase 1b study of AL101 (formerly BMS-906024), a gamma secretase inhibitor that potently inhibits signaling downstream of Notch receptors (1, 2, 3 and 4). These data were accepted for a poster presentation titled, “A phase I study of AL101, a pan-Notch inhibitor, in patients with locally advanced or metastatic solid tumors,” at the 2018 American Society of Clinical Oncology Annual Meeting in Chicago. The poster was selected for a discussion session that will take place on Monday, June 4, 2018, from 3:00 p.m.-4:15 p.m. in Hall A, Room S406, McCormick Place.
The primary objective of the study was to assess the safety and tolerability of multiple IV doses of AL101, and to establish the recommended Phase 2 dose. Secondary objectives were to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of AL101 and its equally active metabolite after the first IV dose and after repeated doses. All study objectives were met.
AL101 is a best-in-class gamma secretase inhibitor that has demonstrated potent and selective inhibition downstream of all four Notch receptors in preclinical models. Based on these encouraging findings, a Phase 1 study was designed in advanced solid tumors to evaluate safety and tolerability as well as PK and PD of the compound.
Ninety-four patients were enrolled in the study and treated with one of two alternative regimens: Arm A (QW, n=83) and Arm B (Q2W, n=11) using a 3+3 design, with expansion at the maximum tolerated dose (MTD). Tumor types included adenoid cystic carcinoma (ACC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC) and selected other tumors with reported Notch activation. The defining dose-limiting toxicity (DLT) period was four weeks (4 doses QW or 2 doses Q2W). PD biomarkers of Notch activity, including HES1 mRNA, were evaluated in serial whole blood.
A MTD of 4 mg QW was established in the escalation phase and used in the expansion phase. The safety profile was consistent with that on target effects of Notch inhibition. The majority of adverse effects were low grade and manageable with protocol guidelines. Grade 3/4 events reported in >15% (all doses, Arm A) included: diarrhea 17 (20%), hypophosphatemia 31(37%), nausea 1 (1%), vomiting 4 (5%), hypokalemia 6 (7%).
Seven DLTs were reported in Arm A: four in patients receiving 6 mg, (Grade 3 vomiting, Grade 3 diarrhea, Grade 3 diarrhea /colonic ulcerations, Grade 3 diarrhea/Grade 4 dehydration) and in three patients receiving 8.4 mg (Recurrent Grade 3 infusion reaction, Grade 3 vomiting, Grade 5 hepatic failure). There were no DLTs in three DLT-evaluable patients at 6 mg QW during escalation, and once 8.4 mg QW was deemed above the MTD, 11 additional patients were enrolled at 6 mg (10 were DLT evaluable). There were no DLTs in seven DLT-evaluable patients receiving 4 mg QW.
Weekly dosing of AL101 led to continuous Notch inhibition as measured by HES 1 transcription at doses 4 mg QW and above. Clinical activity was demonstrated across different solid tumor types at the MTD as defined by RECIST v1.1: one complete response was observed in a patient with a gastroesophageal junction adenocarcinoma with two missense and one splice-site mutation in Notch 1. One partial response was observed in a patient with a desmoid tumor, and one PR was observed in a patient with an ACC, with mutated Notch 1.
“Ayala is dedicated to precision oncology, bringing forward targeted therapies for cancer patients with high unmet needs,” said Roni Mamluk, Ph.D., Chief Executive Officer at Ayala Pharmaceuticals. “As we continue our clinical development plans for Ayala’s Phase 2 study in the second half of this year, we are particularly encouraged by AL101’s clinical activity seen to date and look forward to initiating trials in our lead indication, ACC, in patients with activated Notch pathway, an indication with no approved treatment and patients in need for a therapy.”
About Ayala Pharmaceuticals
Ayala Pharmaceuticals is a clinical-stage biopharmaceutical company dedicated to developing targeted cancer therapies for people living with genetically defined cancers. The company was founded in November 2017 with an experienced global management team and a strong investor base. The management bench recently expanded with the appointment of Andrea Vergara-Silva, M.D. as Chief Medical Officer. Ayala raised $17 million in a series A financing to fund the company’s licensed product asset, Bristol-Myers Squibb BMS-906024 (now AL101), through a Phase 2 trial. The exclusive worldwide license agreement with Bristol-Myers Squibb includes two gamma secretase inhibitors, AL101 (BMS-906024) and AL102 (BMS-986115), which were previously developed by BMS as Notch inhibitors for oncology indications.
About AL101 (formerly BMS-906024)
AL101 is a gamma secretase inhibitor developed as a Notch inhibitor for oncology indications. Notch signaling pathway plays an important role in tumorigenesis in several solid and hematological malignancies. Upon ligand binding of the Notch receptor, an important step in the activation of Notch receptors is cleavage by gamma secretase, which frees the Notch intracellular signaling domain.1 Preclinical studies have shown low nM inhibitory activity for all four Notch receptors (1-4) and robust, broad-spectrum efficacy was seen in traditional and PDX (Patient Derived Xenograft) models, including T-ALL, TNBC, NSCLC, colorectal and pancreatic carcinoma.
In a set of three Phase 1b clinical studies, given once a week by intravenous injection, the molecule has shown positive PK/PD attributes and was tolerable with manageable side effects in more than 200 cancer patients.
Forward Looking Statements
This press release includes forward-looking statements. Because such statements deal with future events, they are subject to various risks and uncertainties and actual results could differ materially from Ayala’s current expectations. Forward-looking statements are identified by words such as “anticipates,” “projects,” “expects,” “plans,” “intends,” “believes,” “may,” “estimates,” “targets,” “hopes,” and other similar expressions that indicate trends and future events.
Factors that could cause Ayala’s results to differ materially from those expressed in forward-looking statements include, without limitation, delays in receiving regulatory guidance for the development of BMS-906024, uncertainties inherent in the initiation of future clinical trials, availability of data from previous clinical trials, satisfactory quantities of clinical drug product, availability of patients who meet the clinical trial enrollment criteria, availability of sufficient funding for foreseeable and unforeseeable operating expenses and capital expenditure requirements, and other matters that could affect the availability or commercial potential of BMS-906024. Ayala undertakes no obligation to revise or update forward-looking statements as a result of new information, since these statements may no longer be accurate or timely.
1. Aster JC, et al. Annu Rev Pathol. 2017;12:245-275.