Ayala Pharmaceuticals expects to initiate Phase II trials in triple-negative breast cancer (TNBC) and T-cell acute lymphoblastic lymphoma (T-ALL) with AL101 as well as in desmoid tumours with AL102 in 2020, said CEO Roni Mamluk.

The clinical-stage candidates AL101 and AL102 inhibit gamma secretase, a protease complex, which is involved in the activation of the Notch signalling pathway. The Notch signalling pathway is a cell signalling system present in most animals. 

The Phase II AL-101 TNBC study will begin in the first half of 2020, said Mamluk, adding that the company is currently finalizing design plans. Ayala is close to locking in a CRO to manage the study, she noted.

The company — with offices in Wilmington, Delaware and Rehovot, Israel — is fresh off a presentation at the European Society for Medical Oncology (ESMO) meeting, where it announced data from the Phase II ACCURACY (NCT03691207) study with AL101 in patients with adenoid cystic carcinoma (ACC), a type of malignant neoplasm commonly found in the major and minor salivary glands of the head and neck.

Ayala previously announced plans to initiate a TNBC study when it raised USD 30m in a Series B round in May. In addition to the aforementioned TNBC trial, it also plans to initiate Phase II studies with AL101 in patients with T-ALL, and its second candidate, AL102, in desmoid tumours by YE20, said Mamluk. The Series B funds will support plans of continuing the ACCURACY study and initiating the planned Phase II studies, which should take the company through 2H20, noted Mamluk.

Considering the incidences of the mutations in the given indications, it is unlikely that the Phase II studies will recruit several hundred patients like other all-comer studies, said Mamluk. But she added it was too early to share the designs of the upcoming studies and declined to comment further.

Notch-activating mutations are found in 35% of patients with ACC, and approximately 10% of TNBC patients, said Mamluk. The company is developing a companion diagnostic test for cancers bearing Notch-activating mutations and fusions with the Boulder, Colorado-based molecular technology company ArcherDx, as per an 8 July press release. Approximately 50% of T-ALL patients carry Notch-activating mutations, so while the indication is very rare, the incidence of the mutations is very high, said Mamluk.

The Phase II AL102 study in patients with desmoid tumours—another rare condition—will also begin in 2020, said Mamluk. Unlike the other indications, activating mutations are not the disease drivers in desmoid tumours, but the Notch signalling pathway itself is oncogenic in them, said Mamluk. Due to this, the Phase II desmoid tumour study will not be screening patients for mutations in the Notch pathway, she added.

Based on the incidences of Notch-activating mutations in the aforementioned indications, Ayala estimates AL101 and AL102 to have a market of approximately 8,000 patients globally, per year, said Mamluk.

In addition to its own AL102 development plans, Ayala also has an ongoing deal with Novartis wherein the latter plans to conduct studies with AL102 in combination with its B-cell maturation antigen therapies in multiple myeloma, as per a 20 December 2018 press release. The Series B round was led by Novartis and investors including The Israeli venture capital fund SBI JI and existing investors like Israel Biotech Fund, a Moon and Harel Insurance and Finance group, according to a 28 May announcement.

The company previously raised $17m in a Series A round, added Mamluk. Ayala will continue to finance the development of AL101 and AL102, but Mamluk did not elaborate on the fundraising plans.

In the ESMO update, among 18 evaluable recurrent or metastatic ACC patients, four and seven patients recorded a partial response and stable disease, respectively, as per a 30 September press release. AL101 has an orphan drug designation for its use as a potential treatment for ACC. The company will continue enrolling patients as per the trial’s design, said Mamluk. The design calls for accruing 36 patients, according to ClinicalTrials.gov. Ayala will decide its registrational plans for the drug based on the data, especially the durability of recorded responses, said Mamluk. When the time is right, the company will pursue an orphan drug designation in T-ALL and TNBC as well, she added.

by Manasi Vaidya in New York

Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalData’s investigative journalism team. A version of this article originally appeared on the Insights module of GlobalData’s Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.