Eli Lilly's BTK Inhibitor LOXO-305, Acquired Through $8 Billion Loxo Oncology Deal, Granted Clinical Trial Approvals in China

Latest Announcement by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration: Eli Lilly and Company’s Investigational New Drug LOXO-305 (Class 1) Receives Implicit Approval for Two Clinical Trials, with Indications Including Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; Mantle Cell Lymphoma; and Other B-Cell Non-Hodgkin Lymphomas.

LOXO-305 is a highly selective, non-covalent BTK inhibitor developed by the precision medicine company Loxo Oncology. In 2019, Eli Lilly acquired Loxo Oncology for approximately $8 billion, securing a portfolio of new drugs including LOXO-305.

Source of screenshot: CDE official website

Bruton’s tyrosine kinase (BTK) plays a pivotal role in B-cell receptor (BCR) signaling. Upon activation, BTK responds to BCR signals, leading to B-cell survival, proliferation, differentiation, and antibody production. In the absence of BTK, BCR signaling is insufficient to induce B-cell differentiation. Furthermore, BTK mutations can result in aberrant BCR signal transduction. BTK has been identified as a molecular target in various B-cell leukemias and lymphomas.

LOXO-305 is a highly specific, non-covalent BTK inhibitor that binds reversibly to BTK. It is being developed to address the needs of cancer patients who have acquired resistance to or are intolerant of current BTK inhibitors. LOXO-305 exhibits high activity not only against wild-type BTK but also against BTK harboring the cysteine-481 (C481) mutation, which is the primary cause of tumor resistance to covalent BTK inhibitors.

Currently, LOXO-305 is undergoing global Phase 1/2 clinical trials. In September this year, the U.S. FDA granted orphan drug designation to LOXO-305 for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).

At the 2019 American Society of Hematology (ASH) Annual Meeting, Eli Lilly announced interim results from a Phase 1/2 clinical trial of LOXO-305 in patients with B-cell malignancies, including chronic lymphocytic leukemia and mantle cell lymphoma (MCL). The data demonstrated that LOXO-305 induced objective responses across multiple dose levels in patients who had received multiple prior therapies and exhibited acquired resistance.

In the Phase 1/2 clinical trial named BRUIN, a total of 28 patients received treatment with LOXO-305. The trial results demonstrated that among 13 evaluable patients with chronic lymphocytic leukemia (CLL), 10 patients responded (8 achieved partial response, and 2 achieved partial response with lymphocytosis), yielding an overall response rate of 77%. Among 6 evaluable patients with mantle cell lymphoma (MCL), 1 patient achieved complete response and 2 achieved partial response, resulting in an overall response rate of 50%; notably, two of the responding patients had previously experienced disease progression following treatment with other Bruton’s tyrosine kinase (BTK) inhibitors.

The advent of BTK inhibitors has provided therapeutic options for patients with B-cell malignancies such as leukemia and lymphoma; however, some patients still develop acquired resistance or experience intolerance. LOXO-305 holds promise as a new treatment option for these patients.

References:

[1] Center for Drug Evaluation, National Medical Products Administration of China. Retrieved Nov 24, 2020, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=25

[2]Lilly Presents Interim Clinical Data from LOXO-305 Dose Escalation Trial in B-Cell Leukemias and Lymphomas at the American Society Hematology Annual Meeting. Retrieved December 9, 2019, from https://investor.lilly.com/news-releases/news-release-details/lilly-presents-interim-clinical-data-loxo-305-dose-escalation

[3] Results from the First-in-Human, Proof-of-Concept Phase 1 BRUIN Trial in Pretreated B-Cell Malignancies for LOXO-305, a Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor. Retrieved December 9, 2019, from https://www.loxooncology.com/docs/presentations/LOXO-305-ASH2019-Phase1-8DEC2019-Final-V3.pdf

Source: Pharmaceutical Perspectives

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