US FDA approves Eli Lilly’s Jaypirca to treat CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor

Eli Lilly and Company announced that the US Food and Drug Administration (FDA) approved Jaypirca (pirtobrutinib, 100 mg & 50 mg tablets) for the treatment of adult patients with chronic lymphocytic leukaemia 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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. 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.

"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 labelling for Jaypirca contains warnings and precautions for infections, haemorrhage, 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 haemoglobin, fatigue, decreased lymphocyte count, musculoskeletal pain, decreased platelet count, diarrhoea, 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.

This is the second FDA-approved indication for Jaypirca following the January 2023 Accelerated Approval for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

Loxo@Lilly is studying Jaypirca in CLL/SLL in multiple phase 3 studies.

The BRUIN phase 1/2 clinical trial is the ongoing first-in-human, global, multi-center evaluation of Jaypirca in patients with hematologic malignancies, including chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL).

The trial includes a phase 1 dose-escalation phase, a phase 1b combination arm, and a phase 2 dose-expansion phase. The primary endpoint of the phase 1 study is maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). Secondary endpoints include safety, pharmacokinetics (PK), and preliminary efficacy measured by overall response rate (ORR) for monotherapy. The primary endpoint of the Phase 1b study is safety of the drug combinations. The secondary endpoints are PK and preliminary efficacy measured by ORR for the drug combinations. The primary endpoint for the phase 2 study is ORR as determined by an independent review committee (IRC). Secondary endpoints include ORR as determined by investigator, best overall response (BOR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and PK.

Jaypirca (pirtobrutinib, formerly known as LOXO-305) (pronounced jay-pihr-kaa) is a highly selective (300 times more selective for BTK versus 98% of other kinases tested in preclinical studies), non-covalent (reversible) inhibitor of the enzyme BTK.2 BTK is a validated molecular target found across numerous B-cell leukaemias and lymphomas including mantle cell lymphoma and chronic lymphocytic leukaemia/small lymphocytic lymphoma. Jaypirca is a US FDA-approved oral prescription medicine, 100 mg or 50 mg tablets taken as a once-daily 200 mg dose with or without food until disease progression or unacceptable toxicity.

CLL and SLL are forms of slow-growing non-Hodgkin lymphoma that develop from white blood cells known as lymphocytes. CLL is one of the most common types of leukaemia in adults.5 In the US, CLL accounts for about one-quarter of the new cases of leukaemia and there are approximately 18,740 new cases of CLL diagnosed this year. SLL is identical to CLL from a pathologic and immunophenotypic standpoint, with the main difference between them being the location of the cancer cells. In CLL, the cancer cells are present in the blood, and in SLL, the cancer cells are found in the lymph nodes.

Jaypirca is a kinase inhibitor indicated for the treatment of:

Adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

Adult patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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