AQVESME (mitapivat) tablet, film coated

• 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)] .

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.

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.

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)] .

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)] .

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.

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.

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.

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).

Risk Summary

There are no data on the presence of AQVESME or its metabolites in human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AQVESME and any potential adverse effects on the breastfed child from AQVESME or from the underlying maternal condition.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of AQVESME did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.

Avoid use in patients with cirrhosis (Child-Pugh Class A, B, or C) due to an increased risk of severe outcomes if hepatocellular injury occurs [see Warnings and Precautions (5.1)] . In patients with cirrhosis Child-Pugh Class B and C, there is a potential increase in AQVESME exposure [see Clinical Pharmacology (12.3)].

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.

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.

The population pharmacokinetic model simulated C _max, C _trough, AUC _0-12and accumulation ratio of mitapivat at the recommended dosage is listed in Table 3.

Absorption

Median t _maxvalues 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 _maxand a delay in t _maxof 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 vitrostudies 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 _maxvalues 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 ²was 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 ²and 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 _infand C _max by 4.9-fold and 1.7-fold, respectively, following a single AQVESME dose of 20 mg. Itraconazole increased mitapivat AUC _0-12and C _maxby 1.9‑fold and 1.6-fold, respectively, following AQVESME 100 mg twice daily. Ketoconazole (a strong CYP3A inhibitor) increased mitapivat AUC _0-12and C _maxby 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 _0-12and C _maxby 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 _infand C _maxby 91% and 77%, respectively, following a single AQVESME dose of 50 mg. Rifampin decreased mitapivat AUC _0-12and C _maxby 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 _0-12and C _maxby 52% and 21%, respectively, following AQVESME 100 mg twice daily.

Effect of AQVESME on CYP3A substrates

Midazolam (a CYP3A substrate) AUC _infand C _maxdecreased 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.

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 vitrobacterial reverse mutation (Ames) assay. Mitapivat was not clastogenic in an in vitrohuman lymphocyte micronucleus assay or in an in vivorat 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.