Mitapivat

1 INDICATIONS AND USAGE AQVESME is indicated for the treatment of anemia in adults with alpha- or beta-thalassemia. AQVESME is a pyruvate kinase activator indicated for the treatment of anemia in adults with alpha- or beta-thalassemia. ( 1.1 )

2 DOSAGE AND ADMINISTRATION The tablet should be swallowed whole. Do not split, crush, chew, or dissolve the tablets. ( 2.1 ) Recommended dose is 100 mg orally twice daily with or without food. ( 2.2 ) 2.1 Important Dosage and Administration Information AQVESME is taken with or without food. Swallow tablets whole. Do not split, crush, chew, or dissolve the tablets. If a dose of AQVESME is missed by 4 hours or less, administer the dose as soon as possible. If a dose of AQVESME is missed by more than 4 hours, do not administer a replacement dose, and wait until the next scheduled dose. Subsequently, return to the normal dosing schedule. Monitor for hepatocellular injury during treatment with AQVESME [see Dosage and Administration (2.3) ] . 2.2 Recommended Dosage The recommended dosage for adults with alpha- or beta-thalassemia is AQVESME 100 mg orally twice daily. Treatment with AQVESME is intended to be long-term. Discontinue AQVESME if no benefit in hemolytic anemia has been observed, based on the totality of laboratory results and clinical status of the patient, unless there is another explanation for response failure (e.g., bleeding, surgery, other concomitant illnesses). Interruption or Discontinuation If a patient needs to interrupt or discontinue AQVESME for any reason, a dose taper is not necessary. 2.3 Monitoring for Safety Prior to Initiating Treatment with AQVESME Check liver tests including ALT, AST, alkaline phosphatase, total bilirubin with fractionation, before first AQVESME dose. During Treatment with AQVESME After the first dose, check liver tests including ALT, AST, alkaline phosphatase, total bilirubin with fractionation every 4 weeks for 24 weeks and as clinically indicated thereafter. When Drug-Induced Liver Injury Is Suspected Interrupt AQVESME and complete a comprehensive evaluation to rule out other causes of liver injury. If AQVESME-related liver injury caused new or worsening jaundice or ALT ≥10×baseline, do NOT restart AQVESME. If AQVESME-related liver injury is not ruled out, but peak ALT is <10×baseline without elevation of bilirubin above baseline, and if AQVESME is resumed, reinitiate liver test monitoring every 4 weeks for 24 additional weeks. If AQVESME-related liver injury is ruled out, AQVESME may be restarted at provider discretion. Resume liver test monitoring schedule that existed prior to stopping AQVESME. AQVESME Interruption Due to Non-Liver Causes If AQVESME was stopped for any reason for ≤8 weeks other than suspected AQVESME-related liver injury, resume the liver test monitoring schedule that existed prior to stopping AQVESME. If AQVESME was stopped for more than 8 weeks, restart liver test monitoring every 4 weeks for 24 additional weeks upon resumption of treatment with AQVESME. If treatment is stopped for any duration after 24 weeks of monitoring and treatment, resume monitoring as clinically indicated. 2.4 Recommended Dosage for Drug Interactions Moderate CYP3A Inducers Consider alternative therapies that are not moderate CYP3A inducers during treatment with AQVESME. If there are no alternative therapies, monitor Hb and do not exceed the maximum recommended dose of 100 mg orally twice daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in labeling: Hepatocellular Injury [see Warnings and Precautions (5.1) ]. The most common adverse reactions were headache and insomnia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals, Inc. at 1-833-228-8474 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Alpha- and Beta-Thalassemia A total of 301 patients with thalassemia received AQVESME, administered at 100 mg orally twice daily, for up to 59.9 weeks in the ENERGIZE trial (N=129) and the ENERGIZE-T trial (N=172) [see Clinical Studies (14) ] . ENERGIZE Trial Patients with non-transfusion-dependent thalassemia received AQVESME (N=129) or placebo (N=63). The most common adverse reactions (≥5% and at least 5% higher in the AQVESME arm) in patients with non-transfusion-dependent thalassemia were headache and insomnia. ENERGIZE-T Trial Patients with transfusion-dependent thalassemia received AQVESME (N=172) or placebo (N=85). The most common adverse reactions (≥5% and at least 5% higher in the AQVESME arm) in patients with transfusion-dependent thalassemia were headache and insomnia. Serious adverse reactions occurred in 1.3% of patients with thalassemia treated with AQVESME, including supraventricular arrhythmia and supraventricular tachycardia. Permanent discontinuations of AQVESME due to an adverse reaction occurred in 1.3% of patients and included elevated hepatic transaminases and insomnia. Table 1 summarizes the adverse reactions in the ENERGIZE and the ENERGIZE-T trials, individually and combined. Table 1: Adverse Reactions a in Patients with Alpha- and Beta-Thalassemia Receiving AQVESME ENERGIZE (Non-transfusion-dependent) ENERGIZE-T (Transfusion-dependent) Total Adverse Reactions AQVESME (N=129) n (%) Placebo (N=63) n (%) AQVESME (N=172) n (%) Placebo (N=85) n (%) AQVESME (N=301) n (%) Placebo (N=148) n (%) Headache 29 (22.5) 6 (9.5) 46 (26.7) 10 (11.8) 75 (24.9) 16 (10.8) Insomnia b 35 (27.1) 5 (7.9) 38 (22.1) 8 (9.4) 73 (24.3) 13 (8.8) a Included adverse reactions that occurred in at least 5% of patients in the AQVESME arm and at least 5% higher than the placebo arm. b Term includes initial insomnia, middle insomnia, and terminal insomnia. Variations in Reproductive Hormones Increases in serum testosterone (T) concentrations and decreases in serum estradiol (E2) concentrations were observed in men receiving AQVESME (Table 2). These changes in hormones were maintained during treatment with AQVESME. In 3 male patients who discontinued AQVESME and in whom reproductive hormone data were available following discontinuation of AQVESME, the hormone changes were reversible. In female patients, sex hormone analysis was limited due to physiologic variations in hormones during the menstrual cycle and the use of hormonal contraceptives. Table 2: Abnormalities in Reproductive Hormones in Men with Thalassemia Receiving AQVESME ENERGIZE (Non-transfusion-dependent) ENERGIZE-T (Transfusion-dependent) Parameter AQVESME (46 males) Placebo (25 males) AQVESME (64 males) Placebo (31 males) Reproductive hormone analyses Testosterone (T) Serum T concentration (mean) Baseline Change from baseline 613 ng/dL 228 ng/dL 505 ng/dL -2.8 ng/dL 625 ng/dL 108 ng/dL 666 ng/dL 66 ng/dL Serum T increased a Baseline Change from baseline 2.2% 18.6% 4.3% 0% 3.3% 13.5% 10% 6.9% Estradiol (E2) Serum E2 concentration (mean) Baseline Change from baseline 29.6 pg/mL -8.7 pg/mL 27.3 pg/mL 0 pg/mL 26.4 pg/mL -5.0 pg/mL 28.9 pg/mL 1.6 pg/mL Serum E2 decreased b Baseline Change from baseline 0% 2.5% 9.5% 0% 10.2% 8.5% 6.9% 3.6% a Percentage of subjects with serum T concentration above the upper limit of normal (greater than 1050 ng/dL) at baseline and percentage of subjects with serum T increases from baseline to above the upper limit of normal where baseline was within normal limits. b Percentage of subjects with serum E2 concentration below the lower limit of normal at baseline and percentage of subjects with serum E2 decreases from baseline to below the lower limit of normal where baseline was within normal limits. Note: Results from the ENERGIZE-T study do not include data from patients who received concomitant testosterone replacement therapies.

12.3 Pharmacokinetics 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 42.5 L. Elimination Population pharmacokinetics derived median CL/F at steady state was 17.7 L/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 approximately 3.9-fold and 2.4-fold, respectively, following AQVESME 100 mg twice daily. Effect of Moderate CYP3A Inhibitors on AQVESME Fluconazole (a moderate CYP3A inhibitor) increased mitapivat AUC 0-12 and C max by 2.7-fold and 1.7-fold, respectively, following AQVESME 100 mg twice daily. Effect of Strong CYP3A Inducers on AQVESME Rifampin (a strong CYP3A inducer) decreased mitapivat AUC inf and C max by 91% and 77%, respectively, following a single AQVESME dose of 50 mg. Rifampin decreased mitapivat AUC 0-12 and C max by 93% and 82%, respectively, following AQVESME 100 mg twice daily. Effect of Moderate CYP3A Inducers on AQVESME Efavirenz (a moderate CYP3A4 inducer) decreased mitapivat AUC 0-12 and C max by 52% and 21%, respectively, following AQVESME 100 mg twice daily. Effect of AQVESME on CYP3A substrates Midazolam (a CYP3A substrate) AUC inf and C max decreased by 65% and 59%, respectively, with AQVESME 100 mg twice daily. Effect of AQVESME on P-gp Substrates Co-administration of AQVESME with drugs that are substrates of P-gp may result in a clinically relevant increase in plasma concentrations of these substrates. In vitro Studies CYP450 and UGT Enzymes Mitapivat induces CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UGT1A1 . Drug Transporter Systems Mitapivat is a substrate and an inhibitor of P-gp.