ASCO: Ayala's ex-BMS drug shows promise in triple-negative breast cancer

Breast Cancer Cells
Ayala Pharmaceuticals' pan-Notch, gamma secretase inhibitor AL101 showed promise in preclinical testing in triple-negative breast cancer. (National Cancer Institute)

Israeli biotech Ayala Pharmaceuticals has just added $30 million in a Novartis-backed series B round. As preclinical results have shown, the money could be used on clinical testing of its lead drug AL101 in triple-negative breast cancer (TNBC).

AL101, a former Bristol-Myers Squibb candidate, is designed for tumors with Notch-activated mutations. In preclinical studies in TNBC patient-derived xenograft mouse models, the drug showed a response correlated with Notch-related mutations, according to data presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago on Sunday.

TNBC is notoriously hard to treat. It’s associated with poor prognosis and has no available targeted therapies because patients lack common markers. AL101, if successful, could serve as an option for some of those patients with Notch-activating genetic alterations.

The Notch pathway is activated during breast development as it participates in cell proliferation and death. But its upregulation has also been identified as a driver behind about 10% of TNBCs, according to the study.

AL101 works by inhibiting gamma secretase, an enzyme that helps the activation of the Notch signaling pathway by releasing a Notch intracellular form that acts as a transcriptional activator.

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In the preclinical study, researchers picked nine models of TNBC. Among them, four models had Notch-activating mutations or fusions, two were wild-type Notch and the rest had mutations that were not expected to induce activation.

Significant inhibition of tumor growth was observed only in models with Notch-on signatures, the scientists reported. Specifically, AL101 achieved tumor growth inhibition of 103%, 62%, 75% and 147% in the four models bearing Notch-on features, while the two wild-type Notch models had 43% and 64% (with a p value of 0.13).

“These data support the clinical development of AL101 as a targeted therapy for TNBC with Notch [gain of function] alterations,” the researchers wrote.

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Few treatment options are available for TNBC. Earlier this year, Roche’s Tecentriq became the first immuno-oncology drug approved for the indication. Merck & Co.’s rival PD-1 Keytruda, however, failed to extend lives of previously treated patients with this cancer form. A team led by University of Chicago scientists recently found a possible new way by combining Type 2 diabetes med metformin and hemin, which is used to treat the rare disorder porphyria.

For the Notch approach, OncoMed and Roche have both previously abandoned their candidates after midstage trial failures.

On the back of the positive preclinical results and the recent $30 million financing round, Ayala is ready to start a phase 2 study of AL101 in TNBC. Separately, the drug is in a phase 2 trial in adenoid cystic carcinoma, with an FDA orphan drug designation. To increase its chances of success, Ayala will focus its clinical development specifically on Notch alterations that are expected to respond to AL101, the company’s chairman David Sidransky has previously said.