Jaypirca pirtobrutinib 100 mg Tablet, Coated, 60-count — NDC 0002-7026-60 (Billing 00002-7026-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of action Pirtobrutinib is a small molecule, noncovalent inhibitor of BTK. BTK is a signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models.

12.2Pharmacodynamics At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC 96 . BTK occupancy is maintained throughout the dosing interval, regardless of the intrinsic rate of BTK turnover. Cardiac Electrophysiology The effect of a single 900 mg dose of pirtobrutinib (equivalent to approximately 2 times higher than the concentrations achieved at steady state at the recommended dosage of 200 mg once daily) on the QTc interval was evaluated in a placebo-controlled and positive-controlled study in 30 healthy subjects.

Pirtobrutinib had no clinically meaningful effect on the change in QTcF interval (i.e., > 10 ms) and there was no relationship between pirtobrutinib exposure and change in QTc interval.

12.3Pharmacokinetics The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients with cancer. Pirtobrutinib exposure (AUC) and C max increases proportionally following single oral doses ranging from 300 mg to 800 mg (1.5 to 4 times the approved recommended dosage) and once daily doses ranging from 25 – 300 mg (0.125 to 1.5 times the recommended dosage). Steady state was achieved within 5 days of once daily dosing, and the mean (CV%) accumulation ratio was 1.63 (26.7%) based on AUC after administration of 200 mg dosages.

Following administration of the recommended dosage, the geometric mean (CV%) steady-state AUC and C max of pirtobrutinib were 92705 h*ng/mL (39%) and 6503 ng/mL (25%), respectively. The geometric mean (CV%) AUC 0-24 and C max of pirtobrutinib on Cycle 1 Day 8 were 81800 h*ng/mL (66.6%) and 3670 ng/mL (89.5%), respectively. Absorption The absolute bioavailability of pirtobrutinib after a single oral 200 mg dose is 85.5% (range 75.9% to 90.9%).

The median time (range) to reach peak plasma concentration (tmax) is approximately 2 hours (0.833 to 4.15 hours). Effect of Food No clinically significant differences in the pharmacokinetics of pirtobrutinib were observed following administration of a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) to healthy subjects. A high-fat meal decreased the C max of pirtobrutinib by 23% and delayed t max by 1 hour.

There was no effect on pirtobrutinib AUC. Distribution The mean apparent central volume of distribution of pirtobrutinib is

34.2L. Human protein binding of pirtobrutinib is 96% and is independent of concentration in vitro. Mean blood-to-plasma ratio is 0.79. Elimination The effective half-life of pirtobrutinib is approximately 20 hours and the mean (CV%) apparent clearance is

2.05L/h (35.7 %). Metabolism Pirtobrutinib is primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9, in vitro. Excretion Following a single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37% of the dose was recovered in feces (18% unchanged) and 57% in urine (10% unchanged).

Specific Populations There were no clinically significant differences in the pharmacokinetics of pirtobrutinib based on age (range 22 – 95 years), sex, race/ethnicity (White 84%, Asian 8%), body weight (range 35.7 – 152 kg), mild (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotra… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of action Pirtobrutinib is a small molecule, noncovalent inhibitor of BTK. BTK is a signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models.

12.3Pharmacokinetics The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients with cancer. Pirtobrutinib exposure (AUC) and C max increases proportionally following single oral doses ranging from 300 mg to 800 mg (1.5 to 4 times the approved recommended dosage) and once daily doses ranging from 25 – 300 mg (0.125 to 1.5 times the recommended dosage). Steady state was achieved within 5 days of once daily dosing, and the mean (CV%) accumulation ratio was 1.63 (26.7%) based on AUC after administration of 200 mg dosages.

Following administration of the recommended dosage, the geometric mean (CV%) steady-state AUC and C max of pirtobrutinib were 92705 h*ng/mL (39%) and 6503 ng/mL (25%), respectively. The geometric mean (CV%) AUC 0-24 and C max of pirtobrutinib on Cycle 1 Day 8 were 81800 h*ng/mL (66.6%) and 3670 ng/mL (89.5%), respectively. Absorption The absolute bioavailability of pirtobrutinib after a single oral 200 mg dose is 85.5% (range 75.9% to 90.9%).

The median time (range) to reach peak plasma concentration (tmax) is approximately 2 hours (0.833 to 4.15 hours). Effect of Food No clinically significant differences in the pharmacokinetics of pirtobrutinib were observed following administration of a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) to healthy subjects. A high-fat meal decreased the C max of pirtobrutinib by 23% and delayed t max by 1 hour.

There was no effect on pirtobrutinib AUC. Distribution The mean apparent central volume of distribution of pirtobrutinib is

34.2L. Human protein binding of pirtobrutinib is 96% and is independent of concentration in vitro. Mean blood-to-plasma ratio is 0.79. Elimination The effective half-life of pirtobrutinib is approximately 20 hours and the mean (CV%) apparent clearance is

2.05L/h (35.7 %). Metabolism Pirtobrutinib is primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9, in vitro. Excretion Following a single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37% of the dose was recovered in feces (18% unchanged) and 57% in urine (10% unchanged).

Specific Populations There were no clinically significant differences in the pharmacokinetics of pirtobrutinib based on age (range 22 – 95 years), sex, race/ethnicity (White 84%, Asian 8%), body weight (range 35.7 – 152 kg), mild (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST), or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment. The effect of other races/ethnicities on the pharmacokinetics of pirtobrutinib is unknown.

Patients with Renal Impairment Following a single 200 mg oral dose, the AUC of pirtobrutinib in subjects with severe renal impairment (eGFR 15-29 mL/min) increased by 62% and mean unbound AUC increased by 68% compared to healthy subjects with normal renal function. There were no clinically significant differences in the pharmacokinetics of pirtobrutinib in subjects with mild (eGFR 60-89 mL/min) or moderate renal impairment (eGFR 30-59 mL/min). The effect of renal impairment requiring dialysis on the pharmacokinetics of pirtobrutinib is unknown.

Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors: Co-administration of a single 200 mg dose of pirtobrutinib with itraconazole (strong CYP3A inhibitor) increased AUC of pirtobrutinib by 49%. Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the AUC of pirtobrutinib by 30% and 20%, respectively. Strong CYP3A inducers: Coadministration of a single 200 mg dose of pirtobrutinib with rifampin (strong CYP3A inducer) decreased the AUC of pirtobrutinib by 71%.

Moderate CYP3A Inducers: Efavirenz and bosentan (moderate CYP3A inducers… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC 96 . BTK occupancy is maintained throughout the dosing interval, regardless of the intrinsic rate of BTK turnover. Cardiac Electrophysiology The effect of a single 900 mg dose of pirtobrutinib (equivalent to approximately 2 times higher than the concentrations achieved at steady state at the recommended dosage of 200 mg once daily) on the QTc interval was evaluated in a placebo-controlled and positive-controlled study in 30 healthy subjects.

Pirtobrutinib had no clinically meaningful effect on the change in QTcF interval (i.e., > 10 ms) and there was no relationship between pirtobrutinib exposure and change in QTc interval.

14 CLINICAL STUDIES

14.1Mantle Cell Lymphoma The efficacy of JAYPIRCA in patients with MCL was evaluated in BRUIN [NCT03740529], an open-label, international, multicohort, single-arm study of JAYPIRCA as monotherapy. Efficacy was based on 120 patients with MCL treated with JAYPIRCA who were previously treated with a BTK inhibitor. JAYPIRCA was given orally at a dose of 200 mg once daily and was continued until disease progression or unacceptable toxicity.

Patients with active central nervous system lymphoma or allogeneic hematopoietic stem cell transplantation (HSCT) or CAR-T cell therapy within 60 days were excluded. The median age was 71 years (range: 46 to 88 years); 79% were male; 78% were White, 14% Asian, 1.7% Black or African American. Seventy-eight percent of patients had the classic/leukemic variant of MCL, 12% had pleomorphic MCL, and 11% had blastoid MCL.

The simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) score was low in 15%, intermediate in 59%, and high in 26% of patients. Patients received a median number of 3 prior lines of therapy (range: 1 to 9) with 93% having received 2 or more prior lines. All received 1 or more prior lines of therapy containing a BTK inhibitor; other prior therapies included chemoimmunotherapy in 88%, HSCT in 20%, lenalidomide in 18%, and CAR-T therapy in 9%.

The most common prior BTK inhibitors received were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%). Patients may have received more than one prior BTK inhibitor; 83% of patients discontinued the last BTK inhibitor for refractory or progressive disease, 10% discontinued for toxicity, and 5% discontinued for other reasons. Efficacy was based on overall response rate (ORR) and duration of response (DOR), as assessed by an independent review committee (IRC) using 2014 Lugano criteria.

Efficacy results are shown in Table 8 . Additionally, the Kaplan-Meier estimate for the DOR rate at 6 months was 65.3% (95% CI: 49.8, 77.1). Table 8: Efficacy Results per IRC in Patients with MCL Previously Treated with a BTK Inhibitor CI, confidence interval; CR, complete response; DOR, duration of response; PR, partial response; NE, not estimable. a PET-CT scans were utilized in response assessments (in 41% of patients), with the remainder being assessed by CT scans only. b ORR using CT scan-based assessments in all patients was 48% (95% CI: 38, 57) and CR rate was 13%. c Based on Kaplan-Meier estimation.

Estimated median follow-up was 7.3 months. Outcome JAYPIRCA 200 mg once daily (N = 120) Overall Response Rate a,b ORR, n 60 (50%) (95% CI, %) 41, 59 CR, n 15 (13%) PR, n 45 (38%) Time to Response Median (range), months 1.8 (0.8, 4.2) Duration of Response c Number censored, n 36 Median DOR, months (95% CI) 8.3 (5.7, NE)

14.2Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma BRUIN The efficacy of JAYPIRCA in patients with CLL/SLL was evaluated in BRUIN [NCT03740529] an open-label, international, single-arm, multicohort study of JAYPIRCA as monotherapy. 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 was given orally at a dose of 200 mg once daily and was continued until disease progression or unacceptable toxicity.

The trial required a platelet count ≥ 50 x 10 9 /L, absolute neutrophil count ≥ 0.75 x 10 9 /L, hepatic transaminases ≤ 2.5 times upper limit of normal (ULN), and an ECOG performance status of 0 to 2. The trial excluded patients with significant cardiovascular disease, major bleeding, uncontrolled or symptomatic arrhythmias, prolonged QTc interval, or need for a strong CYP3A inhibitor or inducer or strong P-gp inhibitor. Patients with active central nervous system (CNS) involvement by lymphoma or allogeneic hematopoietic stem cell transplantation (HSCT) within 60 days were excluded.

The median age was 68 years (range: 41 to 88 years); 69% were male; 89% we… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with pirtobrutinib. Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes.

Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg. Studies to assess the effects of pirtobrutinib on fertility have not been conducted. In repeat-dose toxicity studies of up to 3-months duration conducted with pirtobrutinib in rats and dogs, no effects on male or female reproductive organs were identified.