Eli Lilly Submits First Clinical Trial Application in China for Reversible BTK Inhibitor LOXO-305, Acquired via $8 Billion Loxo Oncology Deal

The Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has recently announced that Eli Lilly and Company has submitted an Investigational New Drug (IND) application for the Class 1 novel drug LOXO-305 in China, which was accepted today. LOXO-305 is a highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor developed by Loxo Oncology, a precision medicine company. In 2019, Eli Lilly acquired Loxo Oncology for approximately $8 billion, securing a portfolio of new drugs including LOXO-305. This marks the first clinical trial application for this drug in China.

Screenshot source: 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. It exhibits high activity not only against wild-type BTK but also against BTK harboring the cysteine-481 (C481) mutation, which is the primary mechanism underlying tumor resistance to covalent BTK inhibitors.

Currently, LOXO-305 is undergoing global Phase 1/2 clinical trials. Last week, the U.S. FDA granted orphan drug designation to LOXO-305 for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). According to information published on the official website of the Center for Drug Evaluation (CDE), this marks the first clinical trial application for LOXO-305 in China.

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 LOXO-305 treatment. The trial results showed that among 13 evaluable patients with chronic lymphocytic leukemia (CLL), 10 patients responded (8 achieved partial remission and 2 achieved partial remission with lymphocytosis), resulting in an overall response rate of 77%. Among 6 evaluable patients with mantle cell lymphoma (MCL), 1 patient achieved complete remission and 2 achieved partial remission, yielding an overall response rate of 50%. Notably, two of the responding patients had previously experienced disease progression after 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 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 Sep 22, 2020, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=3

[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

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