Eli Lilly Submits Rolling NDA to FDA for LOXO-305 (Pirtobrutinib) in Mantle Cell Lymphoma

On December 15, Eli Lilly announced that it had submitted a rolling New Drug Application (NDA) to the FDA for its next-generation BTK inhibitor pirtobrutinib (LOXO-305) for the treatment of mantle cell lymphoma.

Source: Eli Lilly and Company Official Website

LOXO-305 is an investigational, oral, highly selective non-covalent Bruton's tyrosine kinase (BTK) inhibitor. The drug maintains activity under acquired resistance C481 mutations by reversibly binding to BTK, providing sustained high target coverage, and avoiding complications caused by off-target effects of other non-covalent BTK inhibitors.

In January 2019, Eli Lilly acquired Loxo Oncology for approximately $8 billion, gaining a series of targeted anti-cancer drugs. LOXO-305 is one of the key products among them, and other assets include 50% rights to Vitrakvi, a pan-cancer anti-cancer drug and NTRK inhibitor, as well as RET inhibitor LOXO-292. Dr. Jacob Van Naarden, former CEO of Loxo Oncology, is now the President of Lilly Oncology.

LOXO-305 is also the fastest-progressing product among the new generation of BTK inhibitors targeting the BTKC481S mutation. Eli Lilly has great confidence in this new drug and has launched three head-to-head randomized superiority global multicenter Phase III clinical trials since 2021. In chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL), it directly competes with three marketed BTK inhibitors: Ibrutinib (by Johnson & Johnson/AbbVie), Acalabrutinib (by AstraZeneca), and Zanubrutinib (by BeiGene).

According to the Insight database, the Chinese portions of the two head-to-head clinical trials, BRUINCLL-321 and BRUINMCL-321, have also been initiated (CTR20212373, CTR20212310).

Pirtobrutinib Phase 3 Clinical Development

Source: Eli Lilly and Company Official Website

In December 2020, Eli Lilly presented the global multicenter Phase I/II clinical data of LOXO-305 (Abstract 542) at the ASH meeting. This clinical study enrolled patients with CLL/SLL or other NHL who had received at least two prior lines of therapy and had disease progression or were intolerant to standard treatment. As of September 27, 2020, a total of 323 patients participated in the study. The enrolled CLL/SLL patients had received an average of three lines of treatment, with 86% having previously been treated with other BTK inhibitors and 6% having received CAR-T therapy.

Eli Lilly LOXO-305 Clinical Data Released

Source: Insight Database (http://db.dxy.cn/v5/home/)

The results showed that among 139 evaluable patients with CLL/SLL, the overall response rate (ORR) was 63% (95% CI: 55-71). In 121 evaluable patients who had previously failed BTK inhibitor therapy, the ORR was 62% (95% CI: 53-71), and for those followed up for 10 months or longer, the ORR increased to 84% (21/25). The degree of response deepened over time. Among patients who had previously used covalent BTK inhibitors and discontinued treatment due to disease progression, toxicity, or other reasons, the ORRs were similar.

For patients with BTKC481 mutations and patients without BTKC481 mutations, the ORR was 71% (17/24) and 66% (43/65), respectively. Additionally, in patients who underwent stem cell transplantation, the ORR was 64% (9/14); both cases of disease progression after CAR-T therapy responded to LOXO-305.

Source: 2020 ASH