PYRUKYND- mitapivat_tablet, film coated

Mitapivat is a pyruvate kinase activator that acts by allosterically binding to the pyruvate kinase tetramer and increasing pyruvate kinase (PK) activity. The red blood cell (RBC) form of pyruvate kinase (PK-R) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP), shortened RBC lifespan, and chronic hemolysis. Mitapivat decreases 2,3 diphosphoglycerate (2,3-DPG) and increases ATP in healthy volunteers. Cardiac Electrophysiology At a dose 6 times the maximum recommended dose, mitapivat did not prolong the QT interval to any clinically relevant extent. Mitapivat exposure increased in an approximately dose proportional manner over the clinically relevant dose range of 5 mg to 50 mg twice daily. The population pharmacokinetic model simulated Cmax, Ctrough, AUC0-12 and accumulation ratio of mitapivat at recommended dosages are listed in the table below. Table 5: Steady State Mitapivat Exposure at Recommended Dosages a Mitapivat Dosage C max (ng/mL) C trough (ng/mL) AUC 0-12 (ng*h/mL) Accumulation Ratio 5 mg twice daily 101. 1 (74%) 450. 2 20 mg twice daily 389. 3 (77%) 1623. 1 50 mg twice daily 935. 1 (80%) 3591. 0 a Absorption Median t max 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 max max Distribution Mitapivat is highly protein bound (97. 7%) in plasma with low RBC distribution (RBC-to-plasma ratio of 0. The mean volume of distribution at steady state (Vss) was 42. Elimination The mean effective half-life (t1/2) 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. 4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively. Metabolism In vitro 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. Moderate and severe hepatic impairment is expected to increase the systemic exposure of mitapivat. The pharmacokinetics of mitapivat in patients with hepatic impairment 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 2 2 2 Drug Interaction Studies Clinical Studies and Model-Based Approaches Effect of Strong CYP3A Inhibitors on PYRUKYND Itraconazole (a strong CYP3A inhibitor) increased mitapivat AUCinf and Cmax by 4. 9-fold and 1. 7-fold, respectively, following a single PYRUKYND dose of 20 mg. Itraconazole increased mitapivat AUC 0-12 max 0-12 max Effect of Moderate CYP3A Inhibitors on PYRUKYND Fluconazole (a moderate CYP3A inhibitor) increased mitapivat AUC0-12 and Cmax by approximately 2. 6-fold and 1. 6-fold, respectively, following PYRUKYND doses of 5, 20 or 50 mg twice daily. Effect of Strong CYP3A Inducers on PYRUKYND Rifampin (a strong CYP3A inducer) decreased mitapivat AUC inf max 0-12 max Effect of Moderate CYP3A Inducers on PYRUKYND Efavirenz (a moderate CYP3A4 inducer) decreased mitapivat AUC 0-12 max 0-12 max Effect of PYRUKYND on CYP3A substrates Midazolam (a CYP3A substrate) AUC inf max inf max Effect of PYRUKYND on P-gp Substrates Co-administration of PYRUKYND 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.

PYRUKYND is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.

PYRUKYND is taken orally with or without food. The tablets should be swallowed whole. Do not split, crush, chew, or dissolve the tablets. Starting dosage: 5 mg orally twice daily with or without food. 1 See Full Prescribing Information for dose titration and taper schedule. 3 The tablet should be swallowed whole. 1 PYRUKYND is taken with or without food and swallowed whole. The starting dosage for PYRUKYND is 5 mg orally twice daily. To gradually increase hemoglobin (Hb), titrate PYRUKYND from 5 mg twice daily to 20 mg twice daily, and then to the maximum recommended dose of 50 mg twice daily, with these dose increases occurring every 4 weeks (see Table 1). Assess Hb and transfusion requirement before increasing to the next dose level, as some patients may reach and maintain normal Hb at 5 mg twice daily or 20 mg twice daily. Discontinue PYRUKYND if no benefit has been observed by 24 weeks, based on the hemoglobin and hemolysis laboratory results and transfusion requirements. Table 1: Dose Titration Schedule Duration Dosage Week 1 through Week 4 5 mg twice daily Week 5 through Week 8 If Hb is below normal range or patient has required a transfusion within the last 8 weeks: Increase to 20 mg twice daily and maintain for 4 weeks. If Hb is within normal range and patient has not required a transfusion within the last 8 weeks: Maintain 5 mg twice daily. Week 9 through Week 12 If Hb is below normal range or patient has required a transfusion within the last 8 weeks: Increase to 50 mg twice daily and maintain thereafter. If Hb is within normal range and patient has not required a transfusion within the last 8 weeks: Maintain current dose (5 mg twice daily or 20 mg twice daily). Maintenance If Hb decreases, consider up-titration to the maximum of 50 mg twice daily as per the above schedule. If a dose of PYRUKYND is missed by 4 hours or less, administer the dose as soon as possible. If a dose of PYRUKYND 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. To reduce the risk of acute hemolysis, avoid abrupt interruption or abrupt discontinuation of PYRUKYND when possible [see Warnings and Precautions (5. 1) Table 2 Dose Taper Schedule Current Dose Dose Taper Schedule Day 1-7 Day 8-14 Day 15 5 mg twice daily 5 mg once Discontinue N/A 20 mg twice daily 20 mg once 5 mg once Discontinue 50 mg twice daily 50 mg once 20 mg once Discontinue Abbreviations: N/A = not applicable. Avoid use of PYRUKYND in patients with moderate or severe hepatic impairment [see Use in Special Populations (8. 6) Clinical Pharmacology (12. 3) Strong CYP3A Inhibitors Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Drug Interactions (7. 1) 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. 3) Strong CYP3A Inducers Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Drug Interactions (7. 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. 3) If a dose reduction is required because of an adverse reaction or tolerability, or for Hb above normal, the dose may be reduced to the next lower dose level, 20 mg twice daily or 5 mg twice daily. If a patient needs to discontinue PYRUKYND, the dose taper schedule (Table 2) should be followed. In situations where the risk to the patient due to the adverse reaction or Hb above normal is greater than the risk of acute hemolysis due to sudden withdrawal of the drug, treatment may be stopped without taper and patients should be monitored for signs of acute hemolysis.

The following clinically significant adverse reaction is described elsewhere in labeling: Acute Hemolysis with Abrupt Treatment Discontinuation [see Warn ings and Preca utions (5. 1) Hepatocellular Injury in Another Condition [see Warnings and Precautions (5. 2) 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. 1 To report SUSPECTED ADVERSE REACTIONS, contact Agios Pharmaceuticals at 1-833-228-8474 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. A total of 155 patients received PYRUKYND, 79% of whom were exposed for longer than 24 weeks. PYRUKYND was administered up to 50 mg orally twice daily in 67 patients with PK deficiency in the ACTIVATE trial (N=40) and the ACTIVATE-T trial (N=27) [see Clinical Studies (14) 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. Table 3: Adverse Reactions (>= 5%) in Patients Receiving PYRUKYND in ACTIVATE PYRUKYND (N=40) Placebo (N=39) Adverse Reaction All Grades (%) Grade >=3 (%) All Grades (%) Grade >=3 (%) Back pain a 15% 0 8% 0 Arthralgia b 10% 0 5% 0 Hypertriglyceridemia c 8% 5% 3% 0 Gastroenteritis 8% 3% 0 0 Hot flush d 8% 0 0 0 Oropharyngeal pain 8% 0 5% 0 Hypertension 5% 5% 0 0 Arrhythmia e 5% 0 0 0 Breast discomfort 5% 0 0 0 Constipation 5% 0 0 0 Dry mouth f 5% 0 0 0 Paresthesia 5% 0 0 0 Grades: Per the CTCAE definition. Grouped Term Definitions a b c d e f Laboratory abnormalities of PYRUKYND included increased urate (15%). Variations in Reproductive Hormones In ACTIVATE, increases in serum testosterone and decreases in serum estrone and estradiol were observed in men receiving PYRUKYND (Table 4). These changes in hormones persisted throughout the study period. In patients who discontinued PYRUKYND and had follow-up hormone measurements, the hormone changes returned close to the baseline levels 28 days after discontinuing PYRUKYND. 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 4: Laboratory Abnormalities in Reproductive Hormones in Men Receiving PYRUKYND ACTIVATE Parameter PYRUKYND (16 males) n (%) Placebo (15 males)n Reproductive hormone analyses a Estrone decreased (males) 9 (56. 3) 0 a ACTIVATE-T Trial.

None None ( 4.

Hepatic Impairment: Avoid use of PYRUKYND in patients with moderate or severe hepatic impairment. 6 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. 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). 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. Safety and effectiveness in pediatric patients have not been established. Clinical studies of PYRUKYND did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Mitapivat undergoes extensive hepatic metabolism. Moderate and severe hepatic impairment is expected to increase the systemic exposure of mitapivat. Avoid use of PYRUKYND in patients with moderate and severe hepatic impairment [see Dosage and Administration (2. 4) Warnings and Precautions (5. 2) Clinical Pharmacology (12.

Strong CYP3A Inhibitors and Inducers: Avoid concomitant use. 1 Moderate CYP3A Inhibitors: Do not titrate PYRUKYND beyond 20 mg twice daily. 1 Moderate CYP3A Inducers: Consider alternatives that are not moderate inducers. If there are no alternatives, adjust PYRUKYND dosage. 1 Sensitive CYP3A, CYP2B6, CYP2C substrates including hormonal contraceptives: Avoid concomitant use with substrates that have narrow therapeutic index. 2 UGT1A1 Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. 2 P-gp Substrates: Avoid concomitant use with substrates that have narrow therapeutic index. 2 Strong CYP3A Inhibitors Clinical Impact Co-administration of PYRUKYND 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 PYRUKYND. Prevention or Management Avoid co-administration of strong CYP3A inhibitors with PYRUKYND [see Dosage and Administration (2. 5) Moderate CYP3A Inhibitors Clinical Impact Co-administration of PYRUKYND with moderate CYP3A inhibitors will increase mitapivat plasma concentrations [see Clinical Pharmacology (12. 3) Prevention or Management Monitor Hb and for increased risks of adverse reactions with PYRUKYND. Do not titrate PYRUKYND beyond 20 mg twice daily [see Dosage and Administration (2. 5) Strong CYP3A Inducers Clinical Impact Co-administration of PYRUKYND with strong CYP3A inducers decreased mitapivat plasma concentrations [see Clinical Pharmacology (12. 3) Decreased mitapivat plasma concentrations will reduce the efficacy of PYRUKYND. Prevention or Management Avoid co-administration of strong CYP3A inducers with PYRUKYND [see Dosage and Administration (2. 5) Moderate CYP3A Inducers Clinical Impact Co-administration of PYRUKYND 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 PYRUKYND. If there are no alternative therapies, monitor Hb and titrate beyond 50 mg twice daily, if necessary, but do not exceed a maximum recommended dose of 100 mg twice daily [see Dosage and Administration (2. 5) CYP3A Substrates Clinical Impact PYRUKYND induces CYP3A. Co-administration of PYRUKYND will decrease systemic concentrations of drugs that are sensitive CYP3A substrates, including hormonal contraceptives (e. , ethinyl estradiol) [see Clinical Pharmacology (12. 3) Prevention or Management Monitor patients for loss of therapeutic effect of sensitive CYP3A substrates with narrow therapeutic index when co- administered with PYRUKYND. Advise patients using hormonal contraceptives to use an alternative non-hormonal contraceptive method or add a barrier method of contraception during treatment with PYRUKYND. CYP2B6 and CYP2C Substrates Clinical Impact PYRUKYND induces CYP2B6, CYP2C8, CYP2C9, and CYP2C19 enzymes in vitro [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 PYRUKYND. UGT1A1 Substrates Clinical Impact PYRUKYND induces UGT1A1 in vitro [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 PYRUKYND. P-gp Substrates Clinical Impact PYRUKYND inhibits the P-gp transporter in vitro [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 PYRUKYND.

How Supplied PYRUKYND 28-Day Packs Tablet Strength Description Imprint NDC 5 mg Round, blue, film-coated tablets "M5" printed on one side 71334-205-05 20 mg Round, blue, film-coated tablets "M20" printed on one side 71334-210-20 50 mg Oblong, blue, film-coated tablets "M50" printed on one side 71334-215-50 PYRUKYND Taper Packs Tablet strength(s) Blister Wallet Configuration Tablet Description Imprint NDC 5 mg 5 mg blister wallet containing 7 tablets round, blue, film-coated tablets "M5" printed on one side 71334-220-11 20 mg and 5 mg 20 mg blister wallet containing 7 tablets 5 mg blister wallet containing 7 tablets "M20" 71334-225-12 50 mg and 20 mg 50 mg blister wallet containing 7 tablets 20 mg blister wallet containing 7 tablets oblong, blue, film- coated tablets "M50" "M20" 71334-230-13 Storage [see USP Controlled Room Temperature]

NONCLINICAL TOXICOLOGY
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 vitro in vitro in vivo 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.
CLINICAL STUDIES
Patients with PK Deficiency 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. 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 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. 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. 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. Table 6: Efficacy Results in Patients with PK Deficiency Who Were Not Regularly Transfused (ACTIVATE) Endpoint PYRUKYND Placebo Difference 1, 2 p-value Hb Response, n (%) 16 (40%) 0 39 (24, 55) Hemoglobin (g/dL) 8. 4) Indirect bilirubin (mg/dL) 4. 9) Reticulocyte 0. 06) LDH (U/L) 348 (276) 260 (140) -71 (-116, -26) Haptoglobin (mg/dL) 8. 3) CI: confidence interval, Hb: hemoglobin, LDH: lactate dehydrogenase, LS Mean Change: least square mean change from baseline, SD: standard deviation 1 2 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. 4) for tiredness (scale: 0-10), and -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). a CI: confidence interval, Hb: hemoglobin, LS: least square 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. 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. 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. 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. 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. Table 7: Efficacy Results in Patients with PK Deficiency Who Were Regularly Transfused (ACTIVATE-T) Endpoints PYRUKYND Patients with Transfusion Reduction Response Patients who were Transfusion Free CI: confidence interval, RBC: red blood cell CI is based on Clopper-Pearson method. 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. Figure 1 Figure 2.

PYRUKYND- mitapivat

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