Lilly Wins Second Accelerated Approval for Reversible BTK Inhibitor

 Lilly Biotechnology Center in San Diego, CA

Pictured: Eli Lilly's Biotechnology Center in California/iStock, JHVEPhoto

The FDA on Friday granted accelerated approval to Eli Lilly’s reversible BTK inhibitor Jaypirca (pirtobrutinib) for the treatment of chronic lymphocytic leukemia or small lymphocytic leukemia in adult patients who have undergone at least two prior lines of therapy, including another BTK inhibitor and a BCL-2 inhibitor.

This approval comes nearly a year after Jaypirca won its first indication in January 2023, when the FDA signed off on its use to treat adults with relapsed or refractory mantle cell lymphoma. Jaypirca is the first, and still the only, FDA-approved reversible BTK inhibitor on the market, according to Lilly’s news release on Friday.

In the release, William Wierda, professor at the University of Texas MD Anderson Cancer Center, called Jaypirca a “new treatment option” for chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) patients, for whom there are few alternatives after disease progression following treatment with covalent BTK inhibitors or BCL-2 inhibitors.

Jaypirca is a small molecule inhibitor of the enzyme BTK, which under normal circumstances is key to the development, proliferation and function of B lymphocytes. BTK is a well-validated target in several leukemias and lymphomas.

BTK blockers such as J&J’s Imbruvica (ibrutinib) and AstraZeneca’s Calquence (acalabrutinib) typically form covalent bonds with the enzyme to disrupt its activity. While effective, this mode of action can have the side effect of inducing treatment resistance, which can arise from point mutations at BTK’s active site.

Jaypirca, on the other hand, establishes non-covalent links with BTK, preventing the development of resistance. Additionally, because Jaypirca does not rely on the presence of specific amino acid residues at the enzyme active site, it can exert its effects on both wildtype and mutated BTK.

Jaypirca’s latest approval is supported by data from a subset of patients in the Phase I/II BRUIN study. In 108 CLL or SLL patients, a 200-mg, once-daily Jaypirca dose elicited a 72% objective response rate, with a median time to response of 3.7 months. Treatment response, as determined by an independent review committee, lasted for a median of 12.2 months.

As for safety, 56% of patients treated with Jaypirca experienced serious side effects, the most common of which were pneumonia, COVID-19, sepsis and febrile neutropenia. Adverse events led to treatment interruptions in 42% of treated patients, and to dose reductions in 3.6%. Nine percent of patients permanently discontinued Jaypirca treatment due to toxicities.

As part of its obligations under the FDA’s accelerated pathway, and to keep Jaypirca on the market, Lilly is running the Phase III BRUIN CLL-321, an open-label Phase III randomized study, to serve as Jaypirca’s confirmatory trial. The study will pit Jaypirca against idelalisib or bentamustine combined with rituximab in CLL or SLL.

Lilly has shared topline data from BRUIN CLL-321 with the FDA and promises to make it available to the broader medical community at an upcoming congress.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at or

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