Aqvesme mitapivat 100 mg Tablet, Film Coated — NDC 71334-235-00 (Billing 71334-0235-00)

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. Imbalances in globin chain production during erythropoiesis result in increased oxidative stress, which leads to ineffective erythropoiesis and hemolysis. In nonclinical models of beta-thalassemia, mitapivat improved energy homeostasis, RBC longevity, ineffective erythropoiesis, and hemolysis by increasing PK activity.

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

12.3Pharmacokinetics The population pharmacokinetic model simulated C max , C trough , AUC 0-12 and accumulation ratio of mitapivat at the recommended dosage is listed in Table 3. Table 3: Steady State Mitapivat Exposure at the Recommended Dosage a Mitapivat Dosage C max (ng/mL) C trough (ng/mL) AUC 0-12 (ng*h/mL) Accumulation Ratio 100 mg twice daily b 1641.7 (12.9%) 71 (18.5%) 4835.6 (5.8%) 0.83 a Pharmacokinetic parameters are presented as geometric mean (CV%). The interval of the last 12 hours was selected for steady state PK parameters calculation.

Residual error was not included during simulation. b The simulations were performed at steady state. Absorption Median t max values at steady state were 0.5 to 1.0 hour post-dose at 100 mg twice daily. The absolute bioavailability after a single dose was approximately 73%.

Effect of Food Following administration of a single dose of AQVESME 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 (V ss ) was

42.5L. Elimination Population pharmacokinetics derived median CL/F at steady state was

17.7L/h at 100 mg twice daily. 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 pharmacokineti… [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. Imbalances in globin chain production during erythropoiesis result in increased oxidative stress, which leads to ineffective erythropoiesis and hemolysis. In nonclinical models of beta-thalassemia, mitapivat improved energy homeostasis, RBC longevity, ineffective erythropoiesis, and hemolysis by increasing PK activity.

12.3Pharmacokinetics The population pharmacokinetic model simulated C max , C trough , AUC 0-12 and accumulation ratio of mitapivat at the recommended dosage is listed in Table 3. Table 3: Steady State Mitapivat Exposure at the Recommended Dosage a Mitapivat Dosage C max (ng/mL) C trough (ng/mL) AUC 0-12 (ng*h/mL) Accumulation Ratio 100 mg twice daily b 1641.7 (12.9%) 71 (18.5%) 4835.6 (5.8%) 0.83 a Pharmacokinetic parameters are presented as geometric mean (CV%). The interval of the last 12 hours was selected for steady state PK parameters calculation.

Residual error was not included during simulation. b The simulations were performed at steady state. Absorption Median t max values at steady state were 0.5 to 1.0 hour post-dose at 100 mg twice daily. The absolute bioavailability after a single dose was approximately 73%.

Effect of Food Following administration of a single dose of AQVESME 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 (V ss ) was

42.5L. Elimination Population pharmacokinetics derived median CL/F at steady state was

17.7L/h at 100 mg twice daily. 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 and no data available in patients with eGFR <30 mL/min/1.73 m 2 .

Drug Interaction Studies Clinical Studies and Model-Based Approaches Effect of Strong CYP3A Inhibitors on AQVESME Itraconazole (a strong CYP3A inhibitor) increased mitapivat AUC inf and C max by 4.9-fold and 1.7-fold, respectively, following a single AQVESME dose of 20 mg. Itraconazole increased mitapivat AUC 0-12 and C max by 1.9‑fold and 1.6-fold, respectively, following AQVESME 100 mg twice daily. Ketoconazole (a strong CYP3A inhibitor) increased mitapivat AUC 0-12 and C max by approximat… [Excerpted — this section continues on DailyMed.]

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

14 CLINICAL STUDIES Patients with Transfusion-Dependent and Non-Transfusion-Dependent alpha- or beta-Thalassemia Transfusion-Dependent alpha- or beta-Thalassemia The efficacy of AQVESME was evaluated in ENERGIZE-T, a multinational, randomized, double-blind, placebo-controlled clinical study (NCT04770779) of 258 adult patients with transfusion-dependent alpha- or beta-thalassemia, defined as having had 6 to 20 RBC units transfused and no longer than a 6-week transfusion-free period during the 24 weeks prior to randomization.

Patients were included if they had a documented diagnosis of thalassemia (beta-thalassemia with or without alpha-globin gene mutations, HbE/beta-thalassemia, or alpha-thalassemia/HbH disease). Randomization was stratified by geographical region (North America and Europe vs Asia-Pacific vs Rest of World) and thalassemia genotype (β 0 /β 0 vs non-β 0 /β 0 ). Among the 258 patients with transfusion-dependent alpha- or beta-thalassemia, 171 patients were randomized to receive 100 mg of AQVESME twice daily during the 48-week double-blind period.

The median duration of treatment with AQVESME was 48.1 weeks (range: 0.3 to 59.9 weeks). Overall, 104 (60.5%) patients were exposed to AQVESME for >48 weeks. Among the 258 randomized patients, the median age was 33.5 years (range: 18 to 67) and 47.3% were male; 62.0% were from North America and Europe, 18.2% were from Asia-Pacific, and 19.8% were from the rest of the world; race was reported in 95.7% of patients: 60.1% White, 30.2% Asian, 0.8% Black or African American, 0.8% Multiracial, and 3.9% unknown.

The baseline disease characteristics are shown in Table 4. Table 4: Baseline Disease Characteristics in Patients with Transfusion-Dependent Thalassemia (ENERGIZE-T) Baseline Disease Characteristics AQVESME N=171 Placebo N=87 Total N=258 Hemoglobin (g/dL) , n a Median (min, max) 9.0 (5.1, 11.8) 8.9 (5.1, 10.9) 8.9 (5.1, 11.8) Thalassemia Genotype , n (%) beta 0 / beta 0 non-beta 0 / beta 0 75 (44) 96 (56) 39 (45) 48 (55) 114 (44) 144 (56) Transfusion Burden (RBC units) , n (%) b ≤12 >12 54 (32) 117 (68) 21 (24) 66 (76) 75 (29) 183 (71) Hepatic Iron Concentration (mg/g) , n Median (min, max) 133 4.58 (0.37, 28.21) 74 4.43 (0.37, 20.47) 207 4.55 (0.37, 28.21) Prior History of Splenectomy, n (%) 92 (54) 49 (56) 141 (55) Prior History of Cholecystectomy, n (%) 42 (25) 24 (28) 66 (26) Prior History of Iron Chelation, n (%) 165 (96) 87 (100) 252 (98) Prior History of Hydroxyurea, n (%) 7 (4.1) 3 (3.4) 10 (3.9) Hb: hemoglobin, RBC: red blood cells a Pretransfusion Hb threshold is the mean of all pretransfusion Hb concentrations for the RBC transfusions administered during the 24-week period before randomization. b Total number of RBC units transfused in the 24-week period before randomization.

Efficacy was based upon transfusion reduction response, defined as ≥50% reduction in the number of red blood cell units transfused with a reduction of at least 2 units of RBCs transfused in any consecutive 12-week period through Week 48 compared with baseline. The efficacy results are shown in Table 5. Table 5: Efficacy Results in Patients with Transfusion-Dependent Thalassemia (ENERGIZE T) AQVESME N= 171 Placebo N=87 Difference Endpoints n (%) n (%) Adjusted Rate Difference a (%) (95% CI) p-value b ≥50% reduction from baseline in RBC units transfused in any consecutive 12 weeks, with a reduction of at least 2 units 52 (30.4) 11 (12.6) 17.6 (8.0, 27.2) 0.0003 Endpoints n (%) n (%) Adjusted Rate Difference b (%) (95% CI) p-value a ≥50% reduction from baseline in RBC units transfused in any consecutive 24 weeks 23 (13.5) 2 (2.3) 11.1 (5.1, 17.0) 0.0003 ≥33% reduction from baseline in RBC units from Week 13 through Week 48 25 (14.6) 1 (1.1) 13.4 (7.7, 19.1) <0.0001 ≥50% reduction from baseline in RBC units from Week 13 through Week 48 13 (7.6) 1 (1.1) 6.4 (1.9, 10.9) 0.0056 CI: confidence interval, RBC: red blood cell a All p-values are 2-sided and all results are statistically significant.… [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 35 times and >86 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 34 times the MRHD of 100 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 37 times the MRHD of 100 mg twice daily, based on AUC, did not result in adverse effects on fertility or reproductive function.