Strong CYP3A Inhibitors

Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)] .

Moderate CYP3A Inhibitors

Monitor Hb and for increased risks of adverse reactions from PYRUKYND. When used with a moderate CYP3A inhibitor, do not titrate PYRUKYND beyond 20 mg twice daily [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)] .

Strong CYP3A Inducers

Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)] .

Moderate CYP3A Inducers

Consider alternative therapies that are not moderate CYP3A inducers during treatment with PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond the 50 mg twice daily dose, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)] .

ACTIVATE Trial

In the ACTIVATE trial patients with PK deficiency who were not regularly transfused received PYRUKYND in incremental doses up to 50 mg twice daily (N=40) or placebo (N=39).

Serious adverse reactions occurred in 10% of patients receiving PYRUKYND in the ACTIVATE Trial, including atrial fibrillation, gastroenteritis, rib fracture, and musculoskeletal pain, which each occurred in 1 patient.

In the ACTIVATE trial, the most common adverse reactions including laboratory abnormalities (≥ 10%) in patients with PK deficiency were estrone decreased (males), increased urate, back pain, estradiol decreased (males), and arthralgia.

Table 3 summarizes the adverse reactions in the ACTIVATE trial.

Laboratory abnormalities of PYRUKYND included increased urate (15%).

ACTIVATE-T Trial

The adverse reactions reported in the population of patients who were regularly transfused (ACTIVATE-T) were consistent with that seen in ACTIVATE.

Risk Summary

Available data from clinical trials of PYRUKYND 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 ( see Data).

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

Data

Risk Summary

There are no data on the presence of PYRUKYND 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 PYRUKYND and any potential adverse effects on the breastfed child from PYRUKYND or from the underlying maternal condition.

Cardiac Electrophysiology

At a dose 6 times the maximum recommended dose, mitapivat did not prolong the QT interval to any clinically relevant extent.

Absorption

Median t maxvalues at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily.

The absolute bioavailability after a single dose was approximately 73%.

Effect of Food

Following administration of a single dose of PYRUKYND 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

The mean effective half-life (t 1/2) of mitapivat ranged from 3 to 5 hours following multiple dose administrations of 5 mg twice daily to 20 mg twice daily in patients with PK deficiency. Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and 14.4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively.

Specific Populations

No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age, sex, race, or body weight.

Drug Interaction Studies

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 47 times and > 100 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 45 times the MRHD of 50 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 48 times the MRHD of 50 mg twice daily, based on AUC, did not result in adverse effects on fertility or reproductive function.

Patients Not Regularly Transfused

The efficacy of PYRUKYND was evaluated in ACTIVATE, a multinational, randomized, double-blind, placebo-controlled clinical study (NCT03548220) of 80 adults with PK deficiency who were not regularly transfused, defined as having had no more than 4 transfusions in the 52- week period prior to treatment and no transfusions in the 3-month period prior to treatment. Patients were included if they had documented presence of at least 2 variant alleles in the pyruvate kinase liver and red blood cell (PKLR) gene, of which at least 1 was a missense variant, and Hb less than or equal to 10 g/dL. Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded because these patients did not achieve Hb response (change from baseline in Hb ≥1.5 g/dL at >50% assessments) in the dose-ranging study. Randomization was stratified by average screening Hb (<8.5 vs ≥8.5 g/dL) and PKLR gene variant category (missense/missense vs. missense/non-missense).

Among the 80 patients with PK deficiency, 40 patients were randomized to PYRUKYND. Following a period of dose titration up to 50 mg twice daily, patients continued a fixed dose of PYRUKYND for 12 weeks. Eighty-eight percent of patients were maintained on 50 mg twice daily.

The median duration of treatment with PYRUKYND was 24.1 weeks (range 23.6 to 27.4 weeks). Overall, 30 (75%) patients were exposed to PYRUKYND for >24 weeks and <28 weeks. Among the 80 randomized patients, the median age was 33 years (range 18 to 78) and 40% were male; race was reported in 88% of patients: 75% were White, 10% Asian, 1.3% Native Hawaiian/Other Pacific Islander and 1.3% were other races. The median baseline hemoglobin was 8.5 g/dL (range: 6.4 to 10.2 g/dL). There were 55 patients (69%) with the missense/missense PKLR gene variant category, and 25 patients (31%) with the missense/non-missense PKLR gene variant category. There were 58 patients (73%) who had a history of splenectomy. Complications and comorbidities associated with PK deficiency included iron overload with a median baseline ferritin of 479 ng/mL (range: 21 to 5890 ng/mL), chelation therapy use in the year before the first dose of study treatment in 15 patients (19%), decreased bone mineral density in 64 patients (80%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of cholecystectomy in 58 patients (73%).

Efficacy was based upon Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline sustained at 2 or more scheduled assessments (Weeks 16, 20, and 24) during the fixed dose period without transfusions. The efficacy results, including changes in markers of hemolysis are shown in Table 6.

In ACTIVATE, the LS Mean change from baseline with PYRUKYND compared to placebo was -0.4 (standard error [SE] 0.1) for jaundice (scale: 0-4), -1.1 (SE 0.4) for tiredness (scale: 0-10), and -0.3 (SE 0.3) for shortness of breath (scale: 0-10), assessed with the daily Pyruvate Kinase Deficiency Diary (PKDD) where lower scores represent less sign/symptom severity.

In ACTIVATE, the majority of PYRUKYND-treated patients experienced an increase in Hb, while the majority of patients in the placebo arm experienced a decrease in Hb as measured by average change from baseline at weeks 16, 20, and 24 (Figure 1).

Fifteen of the 16 patients with a Hb response in ACTIVATE continued in a long-term extension study and were evaluable for maintenance of response. Thirteen maintained increases in Hb concentration from baseline above the response threshold of ≥1.5 g/dL at the last available Hb assessment without requiring any transfusions. The median duration of response for the 16 patients with Hb response was 6.9 months (range: 3.3, 18.4+).

Patients Who Were Regularly Transfused

The efficacy of PYRUKYND in patients with PK deficiency who were regularly transfused was evaluated in ACTIVATE-T, a multinational single-arm clinical trial (NCT03559699) of 27 adults with PK deficiency who had a minimum of 6 transfusion episodes in the 52-week period prior to informed consent. Patients were included if they had documented presence of at least 2 variant alleles in the PKLR gene, of which at least 1 was a missense variant. Patients who were homozygous for the c.1436G>A (p.R479H) variant or had 2 non-missense variants (without the presence of another missense variant) in the PKLR gene were excluded. Following a period of dose titration up to 50 mg twice daily, patients continued on a fixed dose of PYRUKYND for 24 weeks.

The median duration of treatment with PYRUKYND was 40.3 weeks (range 16.3 to 46.3 weeks). Overall, 20 (74%) patients were exposed to PYRUKYND for >40 weeks and <47 weeks. The median age was 36 years (range 18 to 68) and 26% were male; race was reported in 85% of patients: 74% were White and 11% Asian. The median baseline hemoglobin was 9.1 g/dL (range: 7.4 to 10.9 g/dL). Patients had a median of 9 transfusion episodes (range: 6 to 17 episodes) in the 52 weeks before the first dose of study treatment and a median of 7 red blood cell units transfused (range: 3 to 20 units) standardized to 24 weeks. There were 20 patients (74%) with the missense/missense PKLR gene variant category, and 7 patients (26%) with the missense/non-missense PKLR gene variant category. There were 21 patients (78%) who had a history of splenectomy. Patients had evidence of complications and comorbidities associated with PK deficiency including iron overload (median baseline ferritin was 1324 ug/L; range: 163 to 5357 ng/mL), chelation therapy use in the year before the first dose of study treatment in 24 patients (89%), decreased bone mineral density in 20 patients (74%) who had a baseline femoral neck T-score or lumbar spine T-score <-1.0, and history of cholecystectomy in 23 patients (85%).

Efficacy was based on transfusion reduction response and was defined as ≥33% reduction in the number of red blood cell (RBC) units transfused during the fixed dose period compared with the patient's historical transfusion burden.

Efficacy results for patients with PK deficiency who were regularly transfused are presented in Table 7.

All 6 (22%) patients who were transfusion free in ACTIVATE-T remained transfusion free in a long-term extension study. The median duration of response for the 6 patients was 17 months (range: 11.5+, 21.8+).