AQVESME

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) ] .

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS 5.1 Hepatocellular Injury AQVESME can cause hepatocellular injury. Avoid use of AQVESME in patients with cirrhosis. In patients with thalassemia treated with AQVESME, liver injury with and without jaundice has been observed within the first 6 months of exposure. Obtain liver tests (including ALT, AST, alkaline phosphatase, total bilirubin with fractionation) prior to the initiation of AQVESME, then every 4 weeks for the first 24 weeks, and as clinically indicated thereafter. Interrupt AQVESME if clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the upper limit of normal (ULN). Complete a comprehensive evaluation to rule out other causes of liver injury when drug-induced liver injury (DILI) is suspected. Discontinue AQVESME if hepatocellular injury due to AQVESME is suspected [see Dosage and Administration (2.3) ] . Symptoms and signs of early liver injury may mimic those of thalassemia. Advise patients to report new or worsening symptoms of loss of appetite, nausea, right upper quadrant abdominal pain, vomiting, scleral icterus, jaundice, or dark urine while on AQVESME treatment. During the double-blind period, 2 of 301 patients (0.66%) with thalassemia treated with AQVESME experienced adverse reactions suggestive of hepatocellular injury. Three additional patients experienced adverse reactions suggestive of hepatocellular injury during the open-label extension periods after switching from placebo to AQVESME. Of these 5 patients, two had serious liver injury and were hospitalized including 1 patient who developed jaundice (peak bilirubin 32 mg/dL). Another patient developed jaundice (peak bilirubin 4 mg/dL) without being hospitalized. These reactions were characterized by a time to onset within the first 6 months of treatment with peak elevations of alanine aminotransferase of >5×ULN with or without jaundice. All patients discontinued treatment with AQVESME, and these reactions improved upon treatment discontinuation. AQVESME is available only through a restricted program under a REMS [see Warnings and Precautions (5.2) ] . 5.2 AQVESME REMS AQVESME is available only through a restricted program under a REMS called the AQVESME REMS because of the risk of hepatocellular injury. Notable requirements of the AQVESME REMS include the following: Prescribers must be certified by enrolling in the REMS and completing training. Prescribers must counsel patients receiving AQVESME about the risk of hepatocellular injury. Prescribers must monitor liver tests (including ALT, AST, alkaline phosphatase, total bilirubin with fractionation, and other tests as clinically indicated) to determine if the patient is appropriate to receive AQVESME treatment. Patients must enroll in the REMS and comply with the monitoring requirements. Pharmacies must be certified by enrolling in the REMS and must only dispense to patients who are authorized to receive AQVESME. Further information is available at www.aqvesmerems.com or 1-800-625-9951.

7 DRUG INTERACTIONS Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. ( 7.1 ) Moderate CYP3A Inhibitors: Avoid concomitant use. ( 7.1 ) Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, see Full Prescribing Information for recommended dosage for drug interactions with moderate CYP3A inducers. ( 2.4 , 7.1 ) Sensitive CYP3A substrates including hormonal contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. ( 7.2 ) CYP2B6, CYP2C and UGT1A1 Substrates: Monitor patients for efficacy of the substrates with narrow therapeutic index. ( 7.2 ) P-gp Substrates: Monitor patients for adverse reactions of the substrates with narrow therapeutic index. ( 7.2 ) 7.1 Effect of Other Drugs on AQVESME Strong CYP3A Inhibitors Clinical Impact Co-administration of AQVESME with strong CYP3A inhibitors increased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Increased mitapivat plasma concentrations may increase the risks of adverse reactions of AQVESME. Prevention or Management Avoid co-administration of strong CYP3A inhibitors with AQVESME [see Dosage and Administration (2.4) ] . Moderate CYP3A Inhibitors Clinical Impact Co-administration of AQVESME with moderate CYP3A inhibitors will increase mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid co-administration of moderate CYP3A inhibitors with AQVESME [see Dosage and Administration (2.4) ] . Strong CYP3A Inducers Clinical Impact Co-administration of AQVESME with strong CYP3A inducers decreased mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Decreased mitapivat plasma concentrations will reduce the efficacy of AQVESME. Prevention or Management Avoid co-administration of strong CYP3A inducers with AQVESME [see Dosage and Administration (2.4) ] . Moderate CYP3A Inducers Clinical Impact Co-administration of AQVESME with moderate CYP3A inducers will decrease mitapivat plasma concentrations [see Clinical Pharmacology (12.3) ] . Prevention or Management 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 twice daily [see Dosage and Administration (2.4) ] . 7.2 Effect of AQVESME on Other Drugs CYP3A Substrates Clinical Impact AQVESME induces CYP3A. Co-administration of AQVESME will decrease systemic concentrations of drugs that are sensitive CYP3A substrates, including hormonal contraceptives (e.g., ethinyl estradiol) [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid co-administration of AQVESME with sensitive CYP3A substrates that have narrow therapeutic index when co-administered with AQVESME. Avoid concomitant use with hormonal contraceptives except for intrauterine systems containing levonorgestrel. If contraception is desired or needed, use an alternative contraceptive that is not affected by enzyme inducers. If concomitant use is unavoidable, use additional nonhormonal contraception during concomitant use and for 28 days after discontinuation of AQVESME. CYP2B6 and CYP2C Substrates Clinical Impact AQVESME induces CYP2B6, CYP2C8, CYP2C9, and CYP2C19 enzymes in vitro , and may decrease systemic concentrations of drugs that are sensitive substrates of these enzymes [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of sensitive substrates of these enzymes with narrow therapeutic index when co-administered with AQVESME. UGT1A1 Substrates Clinical Impact AQVESME induces UGT1A1 in vitro and may decrease systemic concentrations of drugs that are UGT1A1 substrates [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for loss of therapeutic effect of UGT1A1 substrates with narrow therapeutic index when co-administered with AQVESME. P-gp Substrates Clinical Impact AQVESME inhibits the P-gp transporter in vitro and may increase systemic concentrations of drugs that are P-gp substrates [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor patients for adverse reactions of P-gp substrates with narrow therapeutic index when co-administered with AQVESME.

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.

8.1 Pregnancy Risk Summary Available data from clinical trials of AQVESME are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. In animal reproduction studies, mitapivat orally administered twice daily to pregnant rats and rabbits during organogenesis was not teratogenic at exposures up to 9.9- and 2.4‑fold the human exposure associated with the MRHD, respectively. Mitapivat administered orally to pregnant rats twice daily during organogenesis through lactation did not result in adverse developmental effects at doses up to 9.9 times the MRHD ( see Data) . The estimated background risk of major birth defects for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal Risk Transfusion requirements in thalassemia patients are increased during pregnancy. Pregnant women with transfusion-dependent thalassemia are considered high risk, with their major complications being cardiac in origin, including cardiac dysrhythmia, right ventricular dysfunction, and cardiac failure, reported in 1.1% to 15.6%. Pregnant women with non-transfusion-dependent thalassemia need to be monitored and treated for risk of thrombosis, especially those who are splenectomized or infrequently transfused. Patients with non-transfusion-dependent thalassemia may develop a need for regular transfusions during pregnancy, and in such patients the risk of alloimmunization should be carefully evaluated. All pregnant women with thalassemia should be closely monitored for iron overload. Data Animal Data In an embryo-fetal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 6 to 17). There was a statistically significant 14% decrease in maternal net body weight gain at 100 mg/kg twice daily with associated decrease in food consumption. Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and fetal external, visceral, and skeletal malformations were observed at 100 mg/kg twice daily, (48 times the MRHD, based on area under the plasma drug concentration-time curve [AUC]). No maternal or embryo-fetal toxicity was observed up to 25 mg/kg twice daily (9.9 times the MRHD, based on AUC). In an embryo-fetal development study in rabbits, mitapivat was administered at doses of 12.5, 30, and 62.5 mg/kg twice daily by oral gavage during the period of organogenesis (gestation days 7 to 20). Lower fetal weight was observed at 62.5 mg/kg twice daily (2.4 times MRHD, based on AUC) and correlated with reduced maternal body weight gain. No effects on fetal morphology were observed. In a pre- and post-natal development study in rats, mitapivat was administered at doses of 5, 10, 25, and 100 mg/kg twice daily by oral gavage during the period of organogenesis and continuing to weaning (gestation day 7 to lactation day 20). Dystocia was observed at ≥25 mg/kg twice daily (≥9.9 times MRHD, based on AUC). At 100 mg/kg twice daily (48 times MRHD, based on AUC) decreased maternal body weight gain, prolonged parturition, and dystocia occurred and resulted in maternal mortality, complete litter loss, decreased pup viability and decreased pup body weight. No adverse effects on pup growth and development, and reproductive performance were observed up to 50 mg/kg (9.9 times the MRHD, based on AUC).