PYRUKYND mitapivat Kit — NDC 71334-230-13 (Billing 71334-0230-13)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. The red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP), shortened RBC lifespan, and chronic hemolysis.

12.2Pharmacodynamics Mitapivat decreases 2,3 diphosphoglycerate (2,3-DPG) and increases ATP in healthy volunteers. Cardiac Electrophysiology At a dose 6 times the maximum recommended dose, mitapivat did not prolong the QT interval to any clinically relevant extent.

12.3Pharmacokinetics Mitapivat exposure increased in an approximately dose proportional manner over the clinically relevant dose range of 5 mg to 50 mg twice daily. The population pharmacokinetic model simulated Cmax, Ctrough, AUC0-12 and accumulation ratio of mitapivat at recommended dosages are listed in the table below. Table 5: Steady State Mitapivat Exposure at Recommended Dosages a Mitapivat Dosage C max (ng/mL) C trough (ng/mL) AUC 0-12 (ng*h/mL) Accumulation Ratio 5 mg twice daily 101.2 (17%) 10.1 (74%) 450.4 (28%) 1.2 20 mg twice daily 389.9 (18%) 32.3 (77%) 1623.8 (28%) 1.1 50 mg twice daily 935.2 (18%) 62.1 (80%) 3591.4 (28%) 1.0 a Pharmacokinetic parameters are presented as geometric mean (CV%).

The simulations were performed until 100 days after first dose. The interval of the last 12 hours was selected for steady state PK parameters calculation. Residual error was not included during simulation.

Absorption Median t max values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily. The absolute bioavailability after a single dose was approximately 73%. Effect of Food Following administration of a single dose of PYRUKYND in healthy subjects, a high-fat meal (approximately 900 to 1,000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate, and 150 calories from protein) did not change the exposure (AUC inf ) of mitapivat, but reduced the rate of mitapivat absorption, with a 42% reduction in C max and a delay in t max of 2.3 hours when compared to dosing under fasted conditions.

Distribution Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution (RBC-to-plasma ratio of 0.37). The mean volume of distribution at steady state (Vss) was

42.5L. Elimination The mean effective half-life (t1/2) of mitapivat ranged from 3 to 5 hours following multiple dose administrations of 5 mg twice daily to 20 mg twice daily in patients with PK deficiency. Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and

14.4L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively. Metabolism In vitro studies showed that mitapivat is primarily metabolized by CYP3A4. Following a single oral dose of 120 mg of radiolabeled mitapivat to healthy subjects, unchanged mitapivat was the major circulating component.

Excretion After a single oral administration of radiolabeled mitapivat to healthy subjects, the total recovery of administered radioactive dose was 89.2%, with 49.6% in the urine (2.6% unchanged) and 39.6% in the feces (<1% unchanged). Specific Populations No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age, sex, race, or body weight. Pediatric Population The pharmacokinetics of mitapivat in children and adolescents (˂18 years old) have not been studied.

Hepatic Impairment Mitapivat undergoes extensive hepatic metabolism. The pharmacokinetics of mitapivat were studied in adult subjects with moderate hepatic impairment (Child-Pugh Class B). After a single oral administration of 50 mg mitapivat, subjects with moderate hepatic impairment demonstrated 36% greater exposure (AUC ∞ ) to mitapivat, compared to subjects with normal hepatic function.

Geometric mean C max values were similar between the groups… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. The red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP), shortened RBC lifespan, and chronic hemolysis.

12.3Pharmacokinetics Mitapivat exposure increased in an approximately dose proportional manner over the clinically relevant dose range of 5 mg to 50 mg twice daily. The population pharmacokinetic model simulated Cmax, Ctrough, AUC0-12 and accumulation ratio of mitapivat at recommended dosages are listed in the table below. Table 5: Steady State Mitapivat Exposure at Recommended Dosages a Mitapivat Dosage C max (ng/mL) C trough (ng/mL) AUC 0-12 (ng*h/mL) Accumulation Ratio 5 mg twice daily 101.2 (17%) 10.1 (74%) 450.4 (28%) 1.2 20 mg twice daily 389.9 (18%) 32.3 (77%) 1623.8 (28%) 1.1 50 mg twice daily 935.2 (18%) 62.1 (80%) 3591.4 (28%) 1.0 a Pharmacokinetic parameters are presented as geometric mean (CV%).

The simulations were performed until 100 days after first dose. The interval of the last 12 hours was selected for steady state PK parameters calculation. Residual error was not included during simulation.

Absorption Median t max values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily. The absolute bioavailability after a single dose was approximately 73%. Effect of Food Following administration of a single dose of PYRUKYND in healthy subjects, a high-fat meal (approximately 900 to 1,000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate, and 150 calories from protein) did not change the exposure (AUC inf ) of mitapivat, but reduced the rate of mitapivat absorption, with a 42% reduction in C max and a delay in t max of 2.3 hours when compared to dosing under fasted conditions.

Distribution Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution (RBC-to-plasma ratio of 0.37). The mean volume of distribution at steady state (Vss) was

42.5L. Elimination The mean effective half-life (t1/2) of mitapivat ranged from 3 to 5 hours following multiple dose administrations of 5 mg twice daily to 20 mg twice daily in patients with PK deficiency. Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and

14.4L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively. Metabolism In vitro studies showed that mitapivat is primarily metabolized by CYP3A4. Following a single oral dose of 120 mg of radiolabeled mitapivat to healthy subjects, unchanged mitapivat was the major circulating component.

Excretion After a single oral administration of radiolabeled mitapivat to healthy subjects, the total recovery of administered radioactive dose was 89.2%, with 49.6% in the urine (2.6% unchanged) and 39.6% in the feces (<1% unchanged). Specific Populations No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age, sex, race, or body weight. Pediatric Population The pharmacokinetics of mitapivat in children and adolescents (˂18 years old) have not been studied.

Hepatic Impairment Mitapivat undergoes extensive hepatic metabolism. The pharmacokinetics of mitapivat were studied in adult subjects with moderate hepatic impairment (Child-Pugh Class B). After a single oral administration of 50 mg mitapivat, subjects with moderate hepatic impairment demonstrated 36% greater exposure (AUC ∞ ) to mitapivat, compared to subjects with normal hepatic function.

Geometric mean C max values were similar between the groups. There were no major changes to plasma protein binding or elimination half-life in subjects with moderate hepatic impairment relative to healthy controls. The pharmacokinetics of mitapivat in subjects with severe hepatic impairment (Child-Pugh Class C) have not been studied.

Renal Impairment The effects of renal impairment on mitapivat pharmacokinetics were assessed with population pharmacokinetic analyses. Steady state AUC of mitapivat in patients with eGFR 60 to <90 mL/min/1.73 m 2 was not significantly different compared to patients with eGFR ≥90 mL/min/1.73 m 2 . There are limited data available in patients with eGFR 30 to <60 mL/min/1.73 m 2 a… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Mitapivat decreases 2,3 diphosphoglycerate (2,3-DPG) and increases ATP in healthy volunteers. Cardiac Electrophysiology At a dose 6 times the maximum recommended dose, mitapivat did not prolong the QT interval to any clinically relevant extent.

14 CLINICAL STUDIES Patients with PK Deficiency Patients Not Regularly Transfused The efficacy of PYRUKYND was evaluated in ACTIVATE, a multinational, randomized, double-blind, placebo-controlled clinical study (NCT03548220) of 80 adults with PK deficiency who were not regularly transfused, defined as having had no more than 4 transfusions in the 52- week period prior to treatment and no transfusions in the 3-month period prior to treatment. Patients were included if they had documented presence of at least 2 variant alleles in the pyruvate kinase liver and red blood cell (PKLR) gene, of which at least 1 was a missense variant, and Hb less than or equal to 10 g/dL.

Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded because these patients did not achieve Hb response (change from baseline in Hb ≥1.5 g/dL at >50% assessments) in the dose-ranging study. Randomization was stratified by average screening Hb (<8.5 vs ≥8.5 g/dL) and PKLR gene variant category (missense/missense vs. missense/non-missense). Among the 80 patients with PK deficiency, 40 patients were randomized to PYRUKYND.

Following a period of dose titration up to 50 mg twice daily, patients continued a fixed dose of PYRUKYND for 12 weeks. Eighty-eight percent of patients were maintained on 50 mg twice daily. The median duration of treatment with PYRUKYND was 24.1 weeks (range 23.6 to 27.4 weeks).

Overall, 30 (75%) patients were exposed to PYRUKYND for >24 weeks and <28 weeks. Among the 80 randomized patients, the median age was 33 years (range 18 to 78) and 40% were male; race was reported in 88% of patients: 75% were White, 10% Asian, 1.3% Native Hawaiian/Other Pacific Islander and 1.3% were other races. The median baseline hemoglobin was 8.5 g/dL (range: 6.4 to 10.2 g/dL).

There were 55 patients (69%) with the missense/missense PKLR gene variant category, and 25 patients (31%) with the missense/non-missense PKLR gene variant category. There were 58 patients (73%) who had a history of splenectomy. Complications and comorbidities associated with PK deficiency included iron overload with a median baseline ferritin of 479 ng/mL (range: 21 to 5890 ng/mL), chelation therapy use in the year before the first dose of study treatment in 15 patients (19%), decreased bone mineral density in 64 patients (80%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of cholecystectomy in 58 patients (73%).

Efficacy was based upon Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline sustained at 2 or more scheduled assessments (Weeks 16, 20, and 24) during the fixed dose period without transfusions. The efficacy results, including changes in markers of hemolysis are shown in Table 6. Table 6: Efficacy Results in Patients with PK Deficiency Who Were Not Regularly Transfused (ACTIVATE) Endpoint PYRUKYND N=40 Placebo N=40 Difference 1, 2 p-value Hb Response, n (%) 16 (40%) 0 39 (24, 55) <0.0001 Hemoglobin (g/dL) Baseline Mean (SD) LS Mean Change (95% CI) 8.6 (1.0) 1.7 (1.3, 2.1) 8.5 (0.8) -0.1 (-0.6, 0.3) 1.8 (1.2, 2.4) <0.0001 Indirect bilirubin (mg/dL) Baseline Mean (SD) LS Mean Change (95% CI) 4.8 (3.6) -1.2 (-1.7, -0.7) 5.2 (3.6) 0.3 (-0.2, 0.8) -1.5 (-2.2, -0.9) <0.0001 Reticulocyte (fraction of 1) Baseline Mean (SD) LS Mean Change (95% CI) 0.37 (0.24) -0.10 (-0.13, -0.07) 0.40 (0.22) 0 (-0.02, 0.03) -0.10 (-0.14, -0.06) <0.0001 LDH (U/L) Baseline Mean (SD) LS Mean Change (95% CI) 348 (276) -92 (-124, -60) 260 (140) -21 (-53, 11) -71 (-116, -26) 0.003 Haptoglobin (mg/dL) Baseline Mean (SD) LS Mean Change (95% CI) 8.2 (10.7) 16.9 (8.8, 25.1) 8.3 (13.8) 1.2 (-7.0, 9.4) 15.8 (4.3, 27.3) 0.008 CI: confidence interval, Hb: hemoglobin, LDH: lactate dehydrogenase, LS Mean Change: least square mean change from baseline, SD: standard deviation 1 All results are statistically significant.

2 For Hb response, the difference is ad… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Mitapivat was not carcinogenic in transgenic rasH2 mice up to the highest doses tested at 500 mg/kg/day in males and at 250 mg/kg/day in females when given orally for 26 weeks. Mitapivat was not carcinogenic in rats when given orally up to 300 mg/kg/day in males and 200 mg/kg/day in females, at systemic exposures 47 times and >100 times the MRHD, respectively, based on AUC. Mutagenesis Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Mitapivat was not clastogenic in an in vitro human lymphocyte micronucleus assay or in an in vivo rat bone marrow micronucleus assay. Fertility In a fertility and early embryonic development study, oral administration of mitapivat twice daily in male rats prior to and during mating at doses up to 300 mg/kg/day, which represents 45 times the MRHD of 50 mg twice daily, based on AUC, did not result in adverse effects on fertility or reproductive function. In female rats, twice daily oral administration of mitapivat prior to mating and continuing through organogenesis, at doses up to 200 mg/kg/day, which represents 48 times the MRHD of 50 mg twice daily, based on AUC, did not result in adverse effects on fertility or reproductive function.