Summary Basis of Decision for Jaypirca

Clinical Pharmacology

Pirtobrutinib, the medicinal ingredient in Jaypirca, is a reversible, small molecule inhibitor that binds non-covalently to Bruton tyrosine kinase (BTK), a key member of the TEC (tyrosine kinase expressed in hepatocellular carcinoma) family of non-receptor tyrosine kinases. Bruton tyrosine kinase plays a critical role in the B-cell receptor signalling pathway, which is essential for B-cell proliferation, differentiation, and survival. As such, the inhibition of BTK can reduce oncogenic signaling in a variety of B-cell malignancies.

For further details, please refer to the Product Monograph for Jaypirca, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Jaypirca as a monotherapy treatment for adult patients with mantle cell lymphoma (MCL), as well as for adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) was demonstrated in the pivotal study, LOXO-BTK-18001, hereafter referred to as Study 18001.

Study 18001 was an open-label, international, multicentre, multi-cohort, single-arm study conducted in two stages, Phase I and Phase II. Phase I was a dose-escalation stage that assessed Jaypirca as a monotherapy, with doses ranging from 25 mg to 300 mg administered once daily. Based on the efficacy, pharmacokinetic, and clinical results from the Phase I, a recommended dose regimen of 200 mg once daily was established for Phase II. The aim of the Phase II stage was to assess the anti-tumour activity of Jaypirca. Patients received Jaypirca at a does of 200 mg orally once daily until disease progression or the occurrence of unacceptable toxicity. Disease response for MCL patients was evaluated by an independent review committee (IRC) and the study investigator according to the 2014 Lugano criteria for malignant lymphoma. Disease response for CLL/SLL patients was based on evaluations conducted by both the independent review committee and the study investigator according to the 2018 iwCLL criteria for CLL/SLL.

Mantle Cell Lymphoma

The efficacy of Jaypirca was evaluated in 74 patients with MCL who had previously received treatment with a BTK inhibitor. These patients received one or more doses of Jaypirca as monotherapy, starting at 200 mg once daily without dose escalation, prior to disease progression being assessed by an IRC.

The baseline characteristics of the patients were as follows: median age was 71 years old (range: 46 to 87 years old); 82.4% were male; race distribution was 82.4% White, 8.1% Asian, 1.4% Black or African American, and 8.1% Other. The baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1 in 98.6% of patients. The simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) score was low in 17.6%, intermediate in 60.8% and high in 21.6% of patients.

Patients had received a median of three prior lines of therapy (range: 1 to 8). All patients had received at least one prior line of BTK inhibitor therapy. Among them, 94.6% had previously received anti-CD20 monoclonal antibody therapy, 85.1% had received chemotherapy, 21.6% had undergone a stem cell transplantation, 23% had received an immunomodulator, 14.9% had received a B-cell lymphoma 2 inhibitor, 5.4% had received chimeric antigen receptor T-cell therapy, and 4.1% had received a phosphoinositide 3-kinase inhibitor. Of those who discontinued BTK therapy, 83.8% did so because of disease progression, 12.2% due to toxicity, and 4.1% for other reasons. At baseline, 31.1% of patients had tumor bulk greater than or equal to 5 cm, 41.9% had extranodal disease, and 51.4% had bone marrow involvement. Additionally, 75.7% were classified as Ann Arbor Stage IV. Regarding histology, 78.4% had classic or leukemic morphology, while 12.2% had pleomorphic and 9.5% had blastoid MCL histology.

The primary endpoint to measure the efficacy of Jaypirca was overall response rate (ORR) as determined by an IRC. Secondary endpoints, such as duration of response (DoR) were also included to further characterize clinical efficacy. These two endpoints are commonly used to demonstrate efficacy in oncology settings with a high unmet need. In high-grade malignant lymphomas, the primary endpoint, ORR, has been shown to serve as an early surrogate for clinical benefit, correlating with progression-free survival and overall survival. An IRC was used to assess ORR in order to minimize biases and variability when evaluating clinical data. The ORR was determined by evaluating images obtained through computed tomography scans, with or without fluorodeoxyglucose-positron emission tomography images, along with relevant clinical data.

A sample size of 65 patients was estimated to provide approximately 92% power to ensure that the lower bound of the two-sided 95% confidence interval (CI) for the estimated ORR exceeded 20%. An ORR greater than 20% was considered a clinically meaningful response for MCL patients who had discontinued prior BTK inhibitor therapy.

The efficacy results from Study 18001 met the primary endpoint and were considered clinically meaningful. The lower bound of the two-sided 95% CI for IRC-assessed ORR far exceeded the prespecified 20% threshold. The ORR, as assessed by an IRC, was 56.8% (95% CI: 44.7, 68.2%). This included 18.9% of patients who achieved a complete response (CR) and 37.8% patients who achieved a partial response (PR).

The secondary endpoint of DoR was defined as the time (i.e., number of months) from the first documented response (complete or partial) to the earliest date of disease progression or death from any cause based on IRC assessment. In the patient analysis set, a DoR of nine months is generally considered clinically meaningful because patients with MCL who progress after BTK inhibitor therapy generally have poor outcomes, with a median overall survival of 2.5 months to 8.4 months. In Study 18001, the median DoR for MCL patients was 21.6 months (95% CI: 6.9, not estimable). The estimated median follow-up among responders was 7.85 months (range: 5.6 to 20.3 months). The Kaplan-Meier estimate DoR rate at 6 months was 76.2% (95% CI: 58.9, 86.9) and 54% (95% CI: 33.2, 70.9) for 18 months or longer, respectively.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

The efficacy of Jaypirca in patients with CLL/SLL was evaluated in 110 patients with CLL/SLL who previously had been treated with a BTK inhibitor and a BCL-2 inhibitor. Jaypirca was administered orally at a dose of 200 mg once daily and continued until disease progression or unacceptable toxicity occurred. Patients with active central nervous system lymphoma or allogeneic hematopoietic stem cell transplantation (HSCT) within 60 days were excluded.

The median age of patients was 68 years (range: 41 to 88 years). Most of the patients were male (67%) and White (89%), with 4.5% of patients being Black or African American, and 1.8% Asian. Baseline ECOG performance status was 0 or 1 in 91% of patients, and 47% of patients had Rai stage III or IV disease. Among those patients with a suitable sample for testing, 41% (37 of 90 patients) had a C481 BTK mutation, 54% (43 of 80 patients) had 17p deletion and/or tumour protein 53 mutation, 93% (78 of 84 patients) had an unmutated immunoglobulin heavy chain variable region, and 22% (16 of 73 patients) had an 11q deletion. Patients had received a median of five prior lines of therapy (range: 1 to 11). All patients received at least one line of therapy containing a BTK inhibitor and at least one line containing a prior BCL-2 inhibitor. The most common prior BTK inhibitors received were ibrutinib (96%), acalabrutinib (9%), and zanubrutinib (1.8%). Some patients may have received more than one prior BTK inhibitor. Of these, 76% discontinued their most recent BTK inhibitor due to refractory or progressive disease, 14% due to toxicity, and 10% for other reasons.

The primary endpoint to measure the efficacy of Jaypirca was ORR, based on the evaluations conducted by an IRC. Secondary endpoints, such as DoR were also included to further characterize clinical efficacy. A sample size of approximately 68 patients was estimated to provide approximately 91% power to ensure that the lower bound of the two-sided 95% confidence interval (CI) for the estimated ORR exceeded 30%. The analysis set included patients with CLL/SLL who had previously received both a BTK inhibitor and a BCL-2 inhibitor and who received one or more monotherapy doses of Jaypirca at a starting dose of 200 mg once daily without dose escalation.

The efficacy results from Study 18001 in patients with CLL/SLL met the primary endpoint and were clinically meaningful. The ORR, as assessed by an IRC, was 72.7% (95% CI: 63.4, 80.8). The lower bound of the two-sided 95% CI for IRC-assessed ORR far exceeded the prespecified 30% threshold, which was considered a clinically meaningful response.

For the secondary endpoint, the median DoR was 12.45 months (95% CI: 9.33, 14.69) based on the IRC assessment, with a median follow-up duration of 15.74 months. According to the investigator assessment, the median DoR was 12.91 months (95% CI: 9.23, 14.72), with a median follow-up duration of 16.59 months.

Median progression-free survival, as estimated by the IRC was 16.59 months (95% CI: 13.83, 18.73). The Kaplan-Meier estimate of median overall survival was not reached. The Kaplan-Meier estimates for the overall survival rate were 78.8% (95% CI: 69.90, 85.41) at 12 months and 69.2% (95% CI: 59.20, 77.18) at 18 months.

Efficacy conclusion

Although the benefit-harm-uncertainty profile for Jaypirca was favorable for the approved indications, Study 18001 was an open-label, single-arm trial by design (i.e., non-randomized and without a comparator group). As such, Study 18001 lacked robust primary endpoints, such as progression-free survival or overall survival, which would have enabled a direct comparison between Jaypirca and standard care. The study endpoints, ORR and DoR, were based on a relatively small patient population (74 with MCL and 110 patients with CLL/SLL) and a limited followed-up period (median of 7.85 and 15.7 months, respectively). Therefore, a Notice of Compliance with Conditions-Qualifying Notice was recommended in accordance with the Guidance Document: Notice of Compliance with Conditions (NOC/c). The sponsor was also requested to confirm the benefit of Jaypirca through additional confirmatory studies.

Indication

The New Drug Submission for Jaypirca was filed by the sponsor with the following proposed indication:

Jaypirca (pirtobrutinib) is indicated for the treatment of adult patients with:

• mantle cell lymphoma (MCL) who have been previously treated with a Bruton tyrosine kinase (BTK) inhibitor.

• chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have been previously treated with a BTK inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor.

To align with the MCL and CLL/SLL patient populations used to establish the efficacy and safety of Jaypirca, Health Canada revised the sponsor’s proposed indication. Accordingly, Health Canada approved the following indication:

Jaypirca (pirtobrutinib) is indicated as monotherapy for the treatment of adult patients with:

• mantle cell lymphoma (MCL) relapsed or refractory in patients who have previously received at least two lines of systemic therapy including a Bruton tyrosine kinase (BTK) inhibitor.

• chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy including a BTK inhibitor and a B-cell lymphoma 2 (BCL-2) inhibitor.

For more information, refer to the Product Monograph for Jaypirca, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The overall monotherapy treatment safety analysis set included all patients enrolled in Phase I or Phase II of Study 18001 who received Jaypirca monotherapy at a starting dose of 200 mg once daily, without subsequent dose escalation. This group was used as the primary analysis set for evaluating and interpreting safety data.

Compared to patients younger than 65 years, patients 65 years of age and older experienced higher rates of Grade 3 or 4 adverse events, adverse events leading to dose interruptions, and serious adverse events.

The most frequently reported adverse events for Jaypirca were decreased neutrophil count, decreased hemoglobin, fatigue, decreased lymphocyte count, musculosketetal pain, decreased platelet count, diarrhea, coronavirus disease 2019 (COVID-19), bruising, and cough. Adverse events leading to death were observed in 45 (6.2%) patients. Adverse events leading to death that were assessed as being related to study treatment occurred in four (0.6%) patients. Most adverse events leading to fatal outcome were due to infections. Adverse events that were Grade 3 or higher occurred in 53.5% of patients receiving Jaypirca. Grade 3 or higher adverse events occurring in 5% or more of patients included decreased neutrophil count, anemia, neutropenia, pneumonia and decreased platelet count.

Serious adverse events occurred in 44.5% of patients receiving Jaypirca. The most frequently reported events, occurring in 1% or more of patients, included pneumonia, COVID-19, febrile neutropenia and sepsis, anemia, acute kidney injury, pyrexia, respiratory failure, dyspnea, atrial fibrillation, bacteremia, pleural effusion, and septic shock.

Adverse events resulting in treatment discontinuation occurred in 9.3% of patients. They also led to a dose reduction in 5.2% of patients and a dose interruption in 40.8% of patients.

Five adverse events of special interest were identified for Jaypirca, based on the known safety profile of BTK inhibitors. These included COVID-19 infection, infection, bleeding, cytopenia, and atrial fibrillation/flutter. There were also five adverse events of potential clinical significance identified for Jaypirca. These included rash, cardiovascular events second primary malignancy, lymphocytosis, and tumor lysis syndrome.

Data from an ongoing signal assessment for hepatotoxicity including drug induced liver disease associated with BTK inhibitors identified cases of severe hepatotoxicity possibly caused by all three marketed BTK inhibitors. Data from other pre-market BTK inhibitors also support a class-wide effect of severe hepatotoxicity.

Safety conclusion

Overall, the demonstrated safety profile of Jaypirca in Study 18001 was consistent with that reported for other BTK inhibitors. Most of the adverse events related to treatment could be mitigated by dose modification/interruption or best supportive care (such as, antibiotic, anti-fungal, and antiviral therapy, and close monitoring). In view of these findings, the safety of Jaypirca is deemed acceptable. The Risk Management Plan review was also found to be acceptable.

For more information, refer to the Product Monograph for Jaypirca, approved by Health Canada and available through the Drug Product Database.

The non-clinical evaluation of Jaypirca included in vitro and in vivo pharmacodynamic, pharmacokinetic, and toxicological assessments. These studies were conducted to characterize the compound’s mechanism of action, assess systemic distribution, and identify potential adverse effects.

Pirtobrutinib, the medicinal ingredient in Jaypirca, is a non-covalent, selective inhibitor of Bruton’s tyrosine kinase (BTK) that, demonstrates activity against both wild-type and C418S mutant forms. In vitro assays revealed antiproliferative effects in mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma cell lines. In vivo, efficacy was confirmed though dose-dependent tumour growth inhibition in human lymphoma xenograft mouse models.

Following oral administration, pirtobrutinib showed rapid absorption. In rat models, pirtobrutinib distributed extensively and showed association with melanin. Despite this distribution profile, no significant ocular toxicity was observed in human safety datasets.

Non-clinical studies in rats and dogs identified immune system effects consistent with BTK inhibition. These included decreased B-lymphocytes and suppressed T-cell-dependent antibody responses.

Pulmonary vascular necrosis and inflammation were observed in male rats at doses exceeding clinical exposure. In canine studies, corneal toxicity was noted in a 3-month study but was not replicated in a subsequent 9-month study. These ocular findings were not associated with irreversible systemic toxicity, and the corneal effects can be monitored clinically.

Embryofetal toxicity, including fetal malformations and increased mortality, was observed in rats at maternal exposures approximately three-fold higher than that of human dose exposures. These findings support a warning against use of Jaypirca during pregnancy and the need for effective contraception for both males and females.

These non-clinical findings have been appropriately included in the Product Monograph for Jaypirca through contraindications, warnings, and non-clinical toxicology disclosures.

For more information, refer to the Product Monograph for Jaypirca, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Jaypirca has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations.