Eli Lilly and Company (NYSE: LLY) today announced that the U.S. Food and Drug Administration (FDA) approved Jaypirca^® (pirtobrutinib, 100 mg & 50 mg tablets) for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a Bruton's tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor. Jaypirca was approved under the FDA's Accelerated Approval pathway based on overall response rate (ORR) and duration of response (DOR) from the open-label, single-arm, multicohort, international, Phase 1/2 BRUIN trial.¹ Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.¹

Jaypirca, the first and only FDA-approved non-covalent (reversible) BTK inhibitor, is a highly selective kinase inhibitor that can extend the benefit of targeting the BTK pathway in CLL/SLL patients previously treated with a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and a BCL-2 inhibitor.^1,2 Jaypirca utilizes a novel binding mechanism and has the largest body of evidence of any targeted therapy in patients previously treated with a BTK inhibitor.^1,2

"Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 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, M.D., Ph.D., professor, medical director, and CLL section head for the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "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 BCL-2 inhibitor."

The labeling for Jaypirca contains warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, and embryo-fetal toxicity. See Important Safety Information below and full Prescribing Information for additional information, including dosing modifications.

"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," said Jacob Van Naarden, chief executive officer, Loxo@Lilly. "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."

"The treatment landscape for CLL has been dramatically improved by the introduction of covalent BTK inhibitors and BCL-2 inhibitors. However, most patients will unfortunately relapse eventually," said Brian Koffman, M.D., chief medical officer and executive vice president at the CLL Society. "Pirtobrutinib's approval gives patients a much-needed option and brings forward new possibilities as they continue their treatment journey."

The FDA approval is based on data from a subset of patients in the BRUIN Phase 1/2 trial. The assessment of efficacy was based on 108 patients with CLL/SLL treated with Jaypirca who were previously treated with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. Jaypirca 200 mg was given once daily and was continued until disease progression or unacceptable toxicity. Patients with active central nervous system (CNS) involvement by lymphoma or allogeneic hematopoietic stem cell transplantation (HSCT) within 60 days were excluded. Patients in the efficacy-eligible population had received a median of five prior lines of therapy (range: 2 to 11). The most common prior BTK inhibitors received were ibrutinib (97%), acalabrutinib (9%), and zanubrutinib (0.9%). Seventy-seven percent (77%) of patients discontinued the last BTK inhibitor for refractory or progressive disease. Efficacy was established based on ORR and DOR, as assessed by an independent review committee (IRC) using 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy results are summarized below:

The pooled safety analysis of the full BRUIN study population evaluated 593 patients with hematologic malignancies administered Jaypirca 200 mg daily as a single agent. In this pooled safety population, the most common adverse reactions (ARs) to Jaypirca therapy, occurring in 20% of patients or more, including laboratory abnormalities, were decreased neutrophil count, decreased hemoglobin, fatigue, decreased lymphocyte count, musculoskeletal pain, decreased platelet count, diarrhea, COVID-19, bruising, and cough.

The safety of Jaypirca was evaluated in the BRUIN trial in 110 patients with CLL/SLL, with 98% receiving at least two prior lines of systemic therapy, including a BTK inhibitor and a BCL-2 inhibitor. Sixty percent (60%) of these patients were exposed to Jaypirca for at least one year, and 14% were exposed for at least two years. ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs that resulted in permanent discontinuation of Jaypirca in more than 1% of patients included second primary malignancy, COVID-19, and sepsis. Serious ARs occurred in 56% of patients who received Jaypirca. Serious ARs occurring in greater than or equal to 5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%).

Lilly is committed to delivering on the requirements of the FDA's Accelerated Approval pathway, including the completion of confirmatory studies supporting traditional approval as soon as possible. The Phase 3 randomized confirmatory trial intended to convert this approval to traditional approval is BRUIN CLL-321, which reached its target number of progression-free survival (PFS) events and met its primary endpoint. Topline results were shared with the FDA in November 2023, although these data have not yet been formally reviewed. BRUIN CLL-321 is a randomized Phase 3 trial comparing pirtobrutinib monotherapy versus the investigator's choice of either idelalisib in combination with rituximab or bendamustine in combination with rituximab in patients with CLL/SLL who have been treated with at least a BTK inhibitor. These data will be presented at an upcoming medical meeting. Jaypirca is not approved for use in the BRUIN CLL-321 population.