We seek to develop a pan-variant TKI targeting BCR-ABL for patients with refractory Chronic Myeloid Leukemia and newly diagnosed adults with Philadelphia Chromosome positive Acute Lymphoblastic Leukemia.
Chronic myeloid leukemia (CML) is a type of blood-cell cancer that develops from an immature version of the blood-forming myeloid cells of the bone marrow and invades the blood. About 15% of new cases of leukemia are CML. More than 95% of people with CML have what is called the Philadelphia chromosome (Ph)—a chromosome translocation which encodes the fusion gene and oncogenic driver, BCR-ABL. Treatment with BCR-ABL inhibitors is standard of care for CML patients, and the targeting of BCR-ABL has been one of the great success stories in targeted oncology. However, approximately 30-40% of patients started on any TKI will switch to an alternative TKI due to side effects or inadequate response. CML remains driven by BCR-ABL through multiple lines of TKI therapy, and patients commonly will relapse with a BCR-ABL resistance mutation. Although there are currently six BCR-ABL inhibitors approved for patients with CML, there remains a significant unmet need for a pan-variant inhibitor that optimally balances efficacy and safety in the relapsed/refractory CML setting.
Acute Lymphoblastic Leukemia (ALL) is a type of blood-cell cancer that develops from an immature form of lymphocytes (a type of white blood cell). Philadelphia Chromosome positive (Ph+) ALL is a subtype of ALL which is driven by the BCR-ABL fusion gene. Newly diagnosed patients with Ph+ ALL have historically received chemotherapy followed by allogeneic haematopoietic stem-cell transplantation (HSCT), and more recently the addition of BCR-ABL inhibitors have improved outcomes in 1L treatment, despite their lack of FDA approval. However, in newly diagnosed patients treated in combination therapy with first- or second-generation TKIs, relapse is associated with BCR-ABL resistance mutations in up to 75% of patients, with the T315I gatekeeper mutation observed most frequently. A pan-variant inhibitor with an optimized safety profile could lead to improved clinical outcomes in newly diagnosed patients, potentially turning Ph+ ALL into a chronic, transplant-free, disease with substantial duration of treatment.
A selective, well-tolerated, pan-variant BCR-ABL inhibitor could substantially improve clinical outcomes in refractory CML, and could reduce the need for HSCT in patients with Ph+ ALL when administered to newly diagnosed patients.
Theseus is developing a series of next-generation, pan-variant BCR-ABL TKI molecules for the treatment of refractory CML and newly diagnosed Ph+ ALL.