Aqvesme

Description for Aqvesme

The active ingredient of AQVESME is mitapivat, a pyruvate kinase activator, present as mitapivat sulfate. The chemical name of mitapivat sulfate is 8-quinolinesulfonamide, N-[4-[[4-(cyclopropylmethyl)-1-piperazinyl]carbonyl]phenyl]-, sulfate, hydrate (2:1:3).

The chemical structure of mitapivat sulfate is:

The molecular formula is (C₂₄H₂₆N₄SO₃)₂ · H₂SO₄ · 3H₂O, and the molecular weight is 1053.23 for mitapivat sulfate. Mitapivat sulfate is a white to off-white solid and is slightly soluble in water.

AQVESME is available as 100 mg tablets for oral administration. Each tablet contains 100 mg mitapivat free base, provided as 117.0 mg of the sulfate hydrate salt, and the following inactive ingredients: croscarmellose sodium, mannitol, microcrystalline cellulose, and sodium stearyl fumarate. The 100 mg tablet film coating contains the inactive ingredients FD&C Blue No. 2, hypromellose, lactose monohydrate, titanium dioxide, triacetin, and macrogol/PEG. The tablets are imprinted with blue ink containing the inactive ingredients ammonium hydroxide, FD&C Blue No. 1, isopropyl alcohol, n-butyl alcohol, propylene glycol, shellac glaze, and titanium dioxide.

INDICATIONS AND USAGE

Aqvesme is a pyruvate kinase activator indicated for the treatment of anemia in adults with alpha- or beta-thalassemia.

DOSAGE AND ADMINISTRATION

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.

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.

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.

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.

HOW SUPPLIED

Dosage Forms and Strengths

100 mg tablets: oblong, blue, film-coated tablets with "M100" printed on both sides.

How Supplied

Tablet Strength Package Configuration Tablet Description Tablet Imprint NDC 100 mg Carton containing 4 blister wallets. Each blister wallet contains 14 tablets. Oblong, blue, film-coated tablets "M100" printed on both sides Carton: 71334-235-00; Blister wallet: 71334-235-14

Storage and Handling

Store in a refrigerator 2°C to 8°C (36°F to 46°F). Aqvesme may be stored at room temperature, 20°C to 25°C (68°F to 77°F) for up to 3 months. The discard date is 3 months after removal of the tablets from the refrigerator. Write the discard date in the space provided on the blister wallet and/or the carton. Discard the tablets if not used within 3 months or if the expiration date has passed, whichever occurs first. Dispense and store the blister wallets in the original carton until use.

Side Effects for Aqvesme

The following clinically significant adverse reaction is described elsewhere in labeling:

• Hepatocellular Injury [see Warnings and Precautions]

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].

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.

Drug Interactions for Aqvesme

Effect of Other Drugs on Aqvesme

Interaction Type	Clinical Impact	Prevention or Management
Strong CYP3A Inhibitors	Co-administration increased mitapivat plasma concentrations. Increased concentrations may increase the risks of adverse reactions.	Avoid co-administration of strong CYP3A inhibitors with Aqvesme.
Moderate CYP3A Inhibitors	Co-administration will increase mitapivat plasma concentrations.	Avoid co-administration of moderate CYP3A inhibitors with Aqvesme.
Strong CYP3A Inducers	Co-administration decreased mitapivat plasma concentrations, which will reduce the efficacy of Aqvesme.	Avoid co-administration of strong CYP3A inducers with Aqvesme.
Moderate CYP3A Inducers	Co-administration will decrease mitapivat plasma concentrations.	Consider alternative therapies that are not moderate CYP3A inducers. If no alternatives, monitor Hb and do not exceed the maximum dose of 100 mg twice daily.

Effect of Aqvesme on Other Drugs

Substrate Type	Clinical Impact	Prevention or Management
CYP3A Substrates	Aqvesme induces CYP3A, decreasing concentrations of sensitive substrates, including hormonal contraceptives (e.g., ethinyl estradiol).	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	Aqvesme induces these enzymes in vitro and may decrease systemic concentrations of their sensitive substrates.	Monitor patients for loss of therapeutic effect of sensitive substrates with a narrow therapeutic index.
UGT1A1 Substrates	Aqvesme induces UGT1A1 in vitro and may decrease systemic concentrations of these substrates.	Monitor patients for loss of therapeutic effect of UGT1A1 substrates with a narrow therapeutic index.
P-gp Substrates	Aqvesme inhibits the P-gp transporter in vitro and may increase systemic concentrations of these substrates.	Monitor patients for adverse reactions of P-gp substrates with narrow therapeutic index.

Warnings for Aqvesme

Included as part of the PRECAUTIONS section.

Precautions for Aqvesme

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

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.

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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

USE IN SPECIFIC POPULATIONS

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 doses up to 13 and 3 times the maximum recommended human dose (MRHD) of 50 mg twice daily, respectively. Mitapivat administered orally to pregnant rats twice daily during organogenesis through lactation did not result in adverse developmental effects at doses up to 13 times the MRHD.

The estimated background risk of major birth defects for the indicated population is unknown. Estimated frequencies for other important background risks in the population are as follows: miscarriage 18%, growth retardation 24%, preterm birth 56%. 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

Untreated PK deficiency in pregnant women may precipitate acute hemolysis, pre-term labor, miscarriage and severe anemia requiring frequent transfusion. Additionally, preeclampsia and severe hypertension have been reported.

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 the high dose 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 external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 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 (13 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 (3 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 (≥13x MRHD, based on AUC). At 100 mg/kg twice daily (63x 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 (13 times the MRHD, based on AUC).

Lactation

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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

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.

Hepatic Impairment

Avoid use of Aqvesme in patients with moderate and severe hepatic impairment. Mitapivat undergoes extensive hepatic metabolism. In patients with moderate and severe hepatic impairment, there is a potential increase in the systemic exposure of mitapivat.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of hepatocellular injury. Instruct patients to swallow tablets whole and not to split, crush, chew, or dissolve them.

Clinical Pharmacology for Aqvesme

Mechanism 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.

Pharmacodynamics

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.

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

Mitapivat Dosage	Cmax (ng/mL)	Ctrough (ng/mL)	AUC0-12 (ng*h/mL)	Accumulation Ratio
100 mg twice daily	1641.7 (12.9%)	71 (18.5%)	4835.6 (5.8%)	0.83

Absorption: Median tmax 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 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 42.5 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 m² was not significantly different compared to patients with eGFR ≥90 mL/min/1.73 m². There are limited data available in patients with eGFR 30 to <60 mL/min/1.73m² and no data available in patients with eGFR <30 mL/min/1.73 m².

Drug Interaction Studies

Effect of Strong CYP3A Inhibitors on Aqvesme

Itraconazole increased mitapivat AUCinf and Cmax by 4.9-fold and 1.7-fold, respectively, following a single Aqvesme dose of 20 mg. Ketoconazole increased mitapivat AUC0-12 and Cmax by approximately 3.9-fold and 2.4-fold, respectively, following Aqvesme 100 mg twice daily.

Effect of Moderate CYP3A Inhibitors on Aqvesme

Fluconazole increased mitapivat AUC0-12 and Cmax by 2.7-fold and 1.7-fold, respectively, following Aqvesme 100 mg twice daily.

Effect of Strong CYP3A Inducers on Aqvesme

Rifampin decreased mitapivat AUCinf and Cmax by 91% and 77%, respectively, following a single Aqvesme dose of 50 mg.

Effect of Moderate CYP3A Inducers on Aqvesme

Efavirenz decreased mitapivat AUC0-12 and Cmax by 52% and 21%, respectively, following Aqvesme 100 mg twice daily.

Effect of Aqvesme on CYP3A substrates

Midazolam (a CYP3A substrate) AUCinf and Cmax 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.

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 randomized, double-blind, placebo-controlled clinical study 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 alphaglobin 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 (β⁰/β⁰ vs non-β⁰/β⁰).

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	171	87	258
Median	9.0	8.9	8.9
(min, max)	(5.1, 11.8)	(5.1, 10.9)	(5.1, 11.8)
Thalassemia Genotype, n (%)
β0/β0	75 (44)	39 (45)	114 (44)
non-β0/β0	96 (56)	48 (55)	144 (56)
Transfusion Burden (RBC units), n (%)
≤12	54 (32)	21 (24)	75 (29)
>12	117 (68)	66 (76)	183 (71)
Hepatic Iron Concentration (mg/g), n	133	74	207
Median	4.58	4.43	4.55
(min, max)	(0.37, 28.21)	(0.37, 20.47)	(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)

Endpoints	AQVESME N=171 n (%)	Placebo N=87 n (%)	Difference Adjusted Rate Difference (%) (95% CI)	p-valueb
≥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
≥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.

^b The difference is adjusted for randomization stratification factors, which included geographical region (North America and Europe vs Asia-Pacific vs Rest of World) and thalassemia genotype (ß⁰/ß⁰ vs non-ß⁰/ß⁰). The two-sided p-value is based on the Mantel-Haenszel stratum weighted method adjusting for the randomization stratification factors.

Non-Transfusion-Dependent alpha- or beta-Thalassemia

The efficacy of AQVESME was evaluated in ENERGIZE, a multinational, randomized, double-blind, placebo-controlled clinical study of 194 adults with non-transfusion-dependent alphaor beta-thalassemia, defined as having had no more than 5 RBC units transfused during the 24-week period prior to randomization and no RBC transfusions within 8 weeks prior to informed consent and during the screening period. Patients were included if they had a documented diagnosis of thalassemia (beta-thalassemia with or without alpha-globin gene mutations, HbE/beta-thalassemia, or alphathalassemia/HbH disease) and a baseline Hb concentration =10 g/dL. Randomization was stratified by baseline Hb concentrations (=9 g/dL vs 9.1-10 g/dL) and thalassemia genotype (alphathalassemia/HbH disease vs beta-thalassemia).

Among the 194 patients with non-transfusion-dependent alpha- or beta-thalassemia, 130 patients were randomized to receive 100 mg of AQVESME twice daily during the 24-week double-blind period.

The median duration of treatment with AQVESME was 24.1 weeks (range: 1.1 to 28.1 weeks). Overall, 97 (75%) patients were exposed to AQVESME for >24 weeks. Among the 194 randomized patients, the median age was 41 years (range: 18 to 69) and 36.6% were male; race was reported in 99% of patients: 56.2% White, 39.2% Asian, 1.0% Black or African American, 0.5% Multiracial, and 2.1% unknown.

The baseline disease characteristics are shown in Table 6.

Table 6: Baseline Disease Characteristics in Patients with Non-Transfusion-Dependent Thalassemia (ENERGIZE)

Baseline Disease Characteristicsa	AQVESME N=130	Placebo N=64	Total N=194
Hemoglobin (g/dL), n	130	64	194
Median	8.4	8.4	8.4
(min, max)	(5.3, 10.4)	(5.9, 10.7)	(5.3, 10.7)
Thalassemia Genotype, n (%)
alpha-thalassemia/HbH disease	42 (32)	20 (31)	62 (32)
beta-thalassemia	88 (68)	44 (69)	132 (68)
Transfusion Burden (RBC units), n (%)b
0	114 (87.7)	54 (84.4)	168 (86.6)
1-2	10 (7.7)	7 (10.9)	17 (8.8)
3-5	6 (4.6)	3 (4.7)	9 (4.6)
Reticulocyte (Fraction of 1), n	122	58	180
Median	0.04	0.05	0.05
(min, max)	(0.00, 0.22)	(0.00, 0.30)	(0.00, 0.30)
Indirect Bilirubin (mg/dL), n	130	62	192
Median	1.37	1.32	1.34
(min, max)	(0.13, 9.11)	(0.15, 4.77)	(0.13, 19.11)
LDH (U/L), n	130	64	194
Median	264	267	265
(min, max)	(108, 1208)	(110, 1009)	(108, 1208)
Hepatic Iron Concentration (mg/g), n	98	52	150
Median	3.93	2.76	3.64
(min, max)	(0.75, 27.19)	(0.75, 18.53)	(0.75, 27.19)
Prior History of Splenectomy, n (%)	47 (36)	25 (39)	72 (37)
Prior History of Cholecystectomy, n (%)	45 (35)	16 (25)	61 (31)
Prior History of Iron Chelation, n (%)	46 (35)	22 (34)	68 (35)
Prior History of Hydroxyurea, n (%)	11 (8.5)	6 (9.4)	17 (8.8)

Hb: hemoglobin, LDH: lactate dehydrogenase, RBC: red blood cell

^a n is the number of patients with non-missing data.

^b Total number of RBC units transfused in the 24-week period before randomization.

Table 7: Efficacy Results in Patients with Non-Transfusion-Dependent Thalassemia (ENERGIZE)

Endpoint	AQVESME N=130 n (%)	Placebo N=64 n (%)	Difference Adjusted Rate Difference (%) (95% CI)	p-value
Hb Responseb	55 (42.3)	1 (1.6)	40.9 (32.0, 49.8)	<0.0001
Endpoint	AQVESME N=130 LS mean (95% CI)	Placebo N=64 LS mean (95% CI)	LS mean difference (95% CI)	p-value
Hemoglobin (g/dL)c	0.86 (0.73, 0.99)	-0.11 (-0.28, 0.07)	0.96 (0.78, 1.15)	<0.0001
FACIT-Fatigued	4.85 (3.41, 6.30)	1.46 (-0.43, 3.34)	3.40 (1.21, 5.59)	0.0026

CI: confidence interval, Hb: hemoglobin, LS: least squares

^a All p-values are 2-sided and all results are statistically significant.

^b For Hb response, the difference is adjusted for randomization stratification factors, which included Hb concentrations (=9.0 g/dL vs 9.1-10.0 g/dL) and thalassemia genotype (alpha-thalassemia/HbH disease vs beta-thalassemia). The two-sided p-value is based on the Mantel-Haenszel stratum weighted method adjusting for the randomization stratification factors.

^c Change from baseline in average Hb concentration from Week 12 through Week 24.

^d Change from baseline in average FACIT-Fatigue score from Week 12 through Week 24. FACIT-Fatigue total scores range from 0 to 52 with higher scores indicating less fatigue. At baseline, patients reported a mean FACIT-Fatigue score of approximately 36 in both the AQVESME and placebo arms.

Note: For the endpoints of change from baseline in average Hb concentration from Week 12 through Week 24 and change from baseline in average FACIT-Fatigue score from Week 12 through Week 24, the 95% CIs and the two-sided p-values are based on an analysis of covariance (ANCOVA) model, which included change from baseline as the dependent variable, treatment group as the independent variable, and baseline and the randomization stratification factors as covariates. The results are based on observed cases.

Eighty-seven percent of patients in the AQVESME arm experienced an increase from baseline in average Hb from Weeks 12 through 24 (see Figure 1). Figure 2 depicts change from baseline in hemoglobin over time.

Figure 1: Average Change from Baseline in Hemoglobin from Week 12 through Week 24 by Patient - All Randomized Patients (ENERGIZE)

Figure 2: Change from Baseline in Hemoglobin Over Time - All Randomized Patients (ENERGIZE)

Of the 55 patients with Hb response in the AQVESME arm, the average increase in Hb was 1.6 g/dL and the median duration of response was 19.6 weeks (range: 4.0 to 23.4+ weeks) during the 24-week double-blind period.

Patients in the AQVESME arm experienced an improvement compared to placebo in the change from baseline to Week 24 for 2 markers of hemolysis (indirect bilirubin [-0.62 mg/dL (95% CI: -0.80, -0.44)] and lactate dehydrogenase [-24.28 U/L (95% CI: -45.40, -3.15)]).

Patient Information for Aqvesme

What is the most important information I should know about Aqvesme?

Aqvesme can cause serious side effects, including:

Liver injury. Aqvesme can cause serious liver injury. Liver injury has happened in people with thalassemia within the first 6 months of treatment with Aqvesme. Your healthcare provider will do blood tests to check your liver before you start treatment with Aqvesme, every 4 weeks for the first 24 weeks of treatment, and as needed. Your healthcare provider may temporarily or permanently stop your treatment with Aqvesme if you have abnormal liver blood tests.

Tell your healthcare provider right away if you develop any new or worsening signs or symptoms of liver problems including:

• loss of appetite
• nausea
• pain in the upper right side of your stomach area
• vomiting
• yellowing of the skin or white part of your eyes (jaundice)
• dark-colored urine

Because of the risk of liver injury, Aqvesme is only available through a restricted program called the Aqvesme Risk Evaluation and Mitigation Strategy (REMS).

• Your healthcare provider must be enrolled in the Aqvesme REMS for you to be prescribed Aqvesme.
• Before you start treatment with Aqvesme, you must enroll in the Aqvesme REMS. Talk to your healthcare provider about how to enroll in the Aqvesme REMS.
• Before you take Aqvesme, your healthcare provider will make sure you understand how to take Aqvesme safely, which will include liver tests when advised by your healthcare provider. Your healthcare provider will counsel you on the risk of liver injury and the REMS requirements.
• Aqvesme can only be dispensed by a certified pharmacy that participates in the Aqvesme REMS. Your healthcare provider can give you information on how to find a certified pharmacy.
• If you have any questions about the Aqvesme REMS, ask your healthcare provider, go to www.aqvesmerems.com or call 1-800-625-9951.

See "What are the possible side effects of Aqvesme?" for more information about side effects.

What is Aqvesme?

• Aqvesme is a prescription medicine used to treat anemia (low red blood cells) in adults with alpha- or beta-thalassemia.
• It is not known if Aqvesme is safe and effective in children.

Before taking Aqvesme, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems, such as cirrhosis.
• are pregnant or plan to become pregnant. It is not known if Aqvesme will harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with Aqvesme.
• are breastfeeding or plan to breastfeed. It is not known if Aqvesme passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with Aqvesme.

Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

• Make sure to tell your healthcare provider if you take or use hormonal birth control (contraceptives). If you take or use hormonal birth control (except for intrauterine systems containing levonorgestrel), it may not work as well during treatment with Aqvesme. Use a different type of birth control or use an additional nonhormonal birth control method (such as condoms) during treatment with Aqvesme and for 28 days after stopping treatment with Aqvesme.

Aqvesme and certain other medicines may affect each other and cause side effects. Aqvesme may affect the way other medicines work, and other medicines may affect how Aqvesme works.

Know the medicines you take. Keep a list of them to show your healthcare provider or pharmacist when you get a new medicine.

How should I take Aqvesme?

• Take Aqvesme exactly as your healthcare provider tells you to take it.
• Take Aqvesme with or without food.
• Swallow Aqvesme tablets whole. Do not split, crush, chew, or dissolve the tablets.
• If you miss a dose of Aqvesme by 4 hours or less, take your dose as soon as possible. If more than 4 hours have passed since your regularly scheduled dose, do not take the missed dose and wait for the next dose. Return to your normal schedule at the next dose.

What are the possible side effects of Aqvesme?

Aqvesme can cause serious side effects:

• See "What is the most important information I should know about Aqvesme?"

The most common side effects of Aqvesme include headache and trouble sleeping (insomnia).

These are not all of the possible side effects of Aqvesme. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Aqvesme?

• Store Aqvesme in a refrigerator between 36°F to 46°F (2°C to 8°C).
• You may also store Aqvesme at room temperature between 68°F to 77°F (20°C to 25°C) for up to 3 months. If you remove Aqvesme from the refrigerator, store Aqvesme at room temperature.
• Write the discard (throw away) date in the space provided on the blister wallet and the carton. The discard date is 3 months after you remove the tablets from the refrigerator.
• Throw away Aqvesme if not used by the written discard date or by the expiration date, whichever happens first.
• Store the blister wallets in the original carton until use.

Keep Aqvesme and all medicines out of the reach of children.

General information about the safe and effective use of Aqvesme.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Aqvesme for a condition for which it was not prescribed. Do not give Aqvesme to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about Aqvesme that is written for health professionals.

What are the ingredients in Aqvesme?

Active ingredients: mitapivat

Inactive ingredients: croscarmellose sodium, mannitol, microcrystalline cellulose, and sodium stearyl fumarate.

The tablet film-coating contains: FD&C Blue No. 2, hypromellose, lactose monohydrate, titanium dioxide, triacetin, and macrogol/PEG.

The tablet printed with blue ink contains: ammonium hydroxide, FD&C Blue No. 1, isopropyl alcohol, n-butyl alcohol, propylene glycol, shellac glaze, and titanium dioxide.