Best-in-Class Gamma Secretase Inhibitors
At Ayala, all of our work maps back to one underlying goal: Develop and commercialize therapies that improve treatment outcomes for patients with rare and aggressive cancers. By building a pipeline of gamma secretase inhibitors (GSIs) with broad clinical utility, we’re aiming to address patient populations in need of better cancer therapies.
Ayala Pipeline Overview
Our Targeted Approach to Treating Rare Cancers
Our approach focuses on indications where Notch is a known tumorigenic driver. Using our deep understanding of the Notch pathway, we are developing precise therapies to address the underlying key drivers of tumor growth in patients where gamma secretase inhibition of Notch can lead to clinical benefit.
We believe we have built one of the largest databases of Notch-activating mutations to inform our efforts. From this database, we know that the Notch mutational landscape is diverse in cancers that can benefit from a modern screening tool.
We have developed a proprietary bioinformatics platform to analyze next generation sequencing (NGS) data and identify patients in whom Notch is a tumorigenic driver. We apply our big-data analysis capabilities to identify and confirm patients with Notch-activating mutations who are likely sensitive to GSIs.
The first step in our bioinformatics process is to gather evidence from literature and identify indications in which Notch is a known tumorigenic driver. We then confirm there are a requisite number of patients with Notch alterations in a specific indication using our proprietary database to integrate genetic information from thousands of unidentified patients. We couple these methods with our analysis of Patient-Derived Xenograft (PDX) mouse models, which allow us to assess the sensitivity of the tumors in vivo with Notch-activating mutations, for certain indications.
Our scientists continue to utilize unique capabilities in bioinformatics and functional biology to create a Notch-focused patient identification engine that we believe will result in the discovery of additional patients with currently undetected Notch-activating mutations.
Ayala currently has two product candidates in development for a variety of rare and aggressive cancers:
- Recurrent/Metastatic Adenoid Cystic Carcinoma (R/M ACC)
- Recurrent/Metastatic Triple Negative Breast Cancer (R/M TNBC)
- Relapsed/Refractory T-cell Acute Lymphoblastic Leukemia (R/R T-ALL)
- Desmoid Tumors
- Multiple Myeloma
Development of AL101
Our investigational lead candidate is a novel, injectable, potent and selective small molecule gamma secretase inhibitor (GSI). AL101 is currently being studied in Phase 2 ACCURACY clinical trial for recurrent/metastatic adenoid cystic carcinoma (R/M ACC) for patients bearing Notch-activating mutations. In addition, we intend to commence Phase 2 clinical trials of AL101 for the treatment of triple negative breast cancer (R/M TNBC) and T-cell acute lymphoblastic leukemia (R/R T-ALL).
The US Food and Drug Administration (FDA) granted Orphan Drug Designation to AL101 for the potential treatment of ACC.
Exploring the Potential of AL102
Ayala is developing AL102 for the treatment of desmoid tumors, which are rare, often debilitating and disfiguring types of soft tissue tumors. We intend to commence a Phase 2 trial of AL102.
We are also collaborating with Novartis (Novartis International Pharmaceutical Limited) to develop AL102 for the treatment of multiple myeloma (MM) in combination with Novartis’ B-cell maturation antigen (BCMA) targeting therapies. Evaluation of AL102 as an inhibitor of the Notch pathway for additional indications is ongoing.
Gamma Secretase Inhibition with AL101, AL102
The Notch pathway has been implicated in multiple solid tumor and hematological cancers, and often has been associated with more aggressive cancers. Notch receptors serve as critical facilitators in processes such as cellular proliferation, survival, migration, invasion, drug resistance and metastatic spread, which all contribute to a poorer prognosis.
See the difference between normal and tumorigenic signaling of Notch:
Normal Notch receptor signaling is initiated by the binding of a ligand expressed on an adjacent cell, which triggers a conformational change, permitting cleavage of the Notch receptor by the γ-secretase complex.
With tumorigenic Notch receptor signaling, the cleavage of the Notch receptor by γ-secretase releases the Notch intracellular domain (NICD), which then translocates to the cell nucleus, interacts with transcription complexes, and promotes the transcription of downstream target genes that regulate critical cell functions. When NICD is degraded, this pathway activation is terminated.
Activating mutations in the Notch receptor lead to accumulation of the NICD and hyper-activation of the pathway, resulting in excess NICD. Hyper-activation of the Notch pathway promotes cellular proliferation, survival, migration, invasion, drug resistance and metastatic spread, which are each hallmarks of cancer.