Pirtobrutinib Granted FDA Accelerated Approval for CLL, SLL Based on BRUIN Trial Results

Pirtobrutinib (Jaypirca) is a next-generation, highly selected, non-covalent BTK inhibitor that has shown nanomolar potency against wild-type and C481-mutant BTK in cell and enzyme assays.

The FDA has granted Jaypirca (pirtobrutinib) with accelerated approval to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who were previously administered least two prior lines of therapy that included a Bruton tyrosine kinase (BTK) inhibitor and a BCL2 inhibitor.1 Jaypirca is a next-generation, highly selected, non-covalent BTK inhibitor that has shown nanomolar potency against wild-type and C481-mutant BTK in cell and enzyme assays.

“Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients,” said William G. Wierda, MD, PhD, of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, in a news release.1 “Jaypirca offers a new treatment option and different approach to targeting BTK, providing clinical benefit for a high proportion of patients with CLL or SLL in the BRUIN phase 1/2 trial whose disease progressed following treatment with a covalent BTK inhibitor and with a BCL2 inhibitor.”

Jaypirca is the first medication that offers non-covalent, reversible binding, which allows greater BTK inhibition and a higher selectivity, reducing any off-target adverse effects (AEs).2 The drug’s favorable pharmacologic properties allow sustained BTK inhibition throughout dosing intervals. As a third generation BTK inhibitor, Jaypirca does not rely on binding to Cys-481 in the active site, which prevents resistance. As the body synthesizes new amounts of BTK, the drug remains in the body and causes ongoing inhibition, differing from other BTK inhibitors, which lack long half-lives, causing gaps in inhibition.2

The FDA action was based on overall response rate (ORR) and duration of response (DOR) findings from the phase 1/2 BRUIN trial (NCT03740529), an open-label, single-arm, multicohort study. Among 108 patients with CLL/SLL enrolled in the trial, ORR was 72%, which were all partial responses. Median time to response was observed at 3.7 months, with a median DOR of 12.2 months.

In January, the FDA approved Jaypirca to treat adults with relapsed or refractory mantle cell lymphoma (MCL) following at least 2 lines of systemic therapy, including a BTK inhibitor.3

“This FDA approval—the second for Jaypirca in 2023—underscores the impactful clinical benefit of continuing to leverage the BTK pathway with Jaypirca for patients with CLL or SLL as seen in the BRUIN trial,” Jacob Van Naarden, chief executive officer, Loxo@Lilly, added.1 “These first two indications for Jaypirca represent the beginning of the eventual impact that we hope Jaypirca can have for patients, and we look forward to seeing the results of the comprehensive phase 3 development program across CLL, SLL and MCL.”

In terms of safety, AEs that caused permanent discontinuation of treatment in more than 1% of patients included second primary malignancy, COVID-19, and sepsis. Serious AEs were observed in 56% of patients administered Jaypirca. Serious AEs observed in at least 5% of patients included pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%).

As part of the FDA’s accelerated approval, continued approval for this indication may be dependent on confirmation of clinical benefit in confirmatory trials.

“The treatment landscape for CLL has been dramatically improved by the introduction of covalent BTK inhibitors and BCL2 inhibitors. However, most patients will unfortunately relapse eventually,” Brian Koffman, MD, chief medical officer and executive vice president at the CLL Society, said in a press release.1 “[Jaypirca’s] approval gives patients a much-needed option and brings forward new possibilities as they continue their treatment journey.”


1. Jaypirca® (pirtobrutinib) Now Approved by U.S. FDA for the Treatment of Adult Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Who Have Received at Least Two Lines of Therapy, Including a BTK Inhibitor and a BCL-2 Inhibitor. Eli Lilly and Company. News release. December 1, 2023. Accessed December 4, 2023. https://investor.lilly.com/news-releases/news-release-details/jaypircar-pirtobrutinib-now-approved-us-fda-treatment-adult

2. Shirley M. Bruton Tyrosine Kinase Inhibitors in B-Cell Malignancies: Their Use and Differential Features [published correction appears in Target Oncol. 2021 Dec 24;:]. Target Oncol. 2022;17(1):69-84. doi:10.1007/s11523-021-00857-8

3. US FDA approves Jaypirca (pirtobrutinib), the first and only non-covalent (reversible) BTK inhibitor, for adult patients with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. News release. Loxo@Lilly. January 27, 2023. Accessed December 4, 2023.

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