Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Agios Netherlands B.V., Zuidplein 36, Regus Amsterdam WTC, 1077XV Amsterdam, The Netherlands
Pharmacotherapeutic group: Other haematological agents
ATC code: B06AX04
Mitapivat is a pyruvate kinase activator and acts by directly binding to the pyruvate kinase tetramer. The red blood cell (RBC) form of pyruvate kinase (PKR) is mutated in PK deficiency, which leads to reduced adenosine triphosphate (ATP) levels, shortened RBC lifespan and chronic haemolysis. Mitapivat improves RBC energy homeostasis by increasing PKR activity.
In healthy volunteers, decreases in 2,3 diphosphoglycerate and increases of ATP concentrations were observed after dosing mitapivat to steady state. Changes to these pharmacodynamic markers are not considered significant for the assessment of activity in subjects with PK deficiency that should rely on clinical parameters only.
The efficacy of Pyrukynd was evaluated in 2 multinational Phase 3 clinical studies in patients with PK deficiency: ACTIVATE and ACTIVATE-T.
The efficacy of Pyrukynd was studied in a multinational, randomised, double-blind, placebocontrolled clinical study (ACTIVATE) of 80 adult patients 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 mutant alleles in the PKLR gene, of which at least 1 was a missense mutation, and a Hb concentration less than or equal to 100 g/L. Patients homozygous for the R479H mutation or with 2 non-missense mutations (without the presence of another missense mutation) 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 Phase 2 dose-ranging study. Randomisation was stratified by average of screening Hb concentrations (<85 vs ≥85 g/L) and PKLR gene mutation category (missense/missense vs missense/non-missense). Following a dose titration period with 2 sequential steps for dose level increase up to 50 mg twice daily, patients continued on a fixed dose of Pyrukynd for 12 weeks.
Among the 80 patients with PK deficiency, 40 patients were randomised to Pyrukynd. Thirty-five out of the 40 (87.5%) patients who received Pyrukynd received an optimised dose of 50 mg twice daily following the dose titration period. 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. Among the 80 randomised patients, the median age was 32.5 years (range 18 to 78) and 40% were male; race was reported in 87.5% of patients including 75% White, 10% Asian, 1.3% Native Hawaiian/Other Pacific Islander and 1.3% were other races.
The baseline disease characteristics are shown in Table 4.
Table 4. Baseline disease characteristics in patients with PK deficiency who were not regularly transfused (ACTIVATE):
| Baseline disease characteristics1 | Total N = 80 |
|---|---|
| Haemoglobin (g/l), n Median (min, max) | 80 85,08 (64,0, 102,3) |
| PKLR genotype, n (%) Missense/missense Missense/non-missense | 55 (68,8) 25 (31,3) |
| Reticulocyte (fraction of 1), n Median (min, max) | 80 0,4009 (0,038, 0,827) |
| Indirect bilirubin (µmol/l), n Median (min, max) | 76 74,647 (11,03, 294,7) |
| LDH (U/L), n Median (min, max) | 79 223,5 (101,0, 1 190,5) |
| Haptoglobin (g/L), n Median (min, max) | 80 0,030 (0,03, 0,70) |
| Ferritin (µg/L), n Median (min, max) | 77 479,420 (21,36, 5 890,25) |
| Femoral T-Score category by DXA, n (%) ≤ -2,5 > -2,5 - < -1,0 ≥ -1,0 Missing | 5 (6,3) 36 (45,0) 38 (47,5) 1 (1,3) |
| Prior history of splenectomy, n (%) | 58 (72,5) |
| Prior history of cholecystectomy, n (%) | 58 (72,5) |
| Prior chelation therapy, n (%) | 15 (18,8) |
DXA: dual-energy X-ray absorptiometry, LDH: lactate dehydrogenase.
1 n is the number of patients with non-missing data.
The primary endpoint of Hb response was defined as a ≥15 g/L increase in Hb concentration from baseline sustained at 2 or more scheduled assessments (Weeks 16, 20 and 24) during the fixed-dose period without transfusions. The efficacy results are shown in Table 5.
Table 5. Efficacy results in patients with PK deficiency who were not regularly transfused (ACTIVATE):
| Pyrukynd1 N = 40 | Placebo1 N = 40 | Difference1 | ||
|---|---|---|---|---|
| Primary endpoint | n (%) | n (%) | Adjusted difference2 (95% CI) | p-value |
| Hb response | 16 (40%) | 0 | 39,3 (24,1, 54,6) | <0,0001 |
| Secondary endpoints3 | LS mean 95% CI | LS mean 95% CI | LS mean difference (95% CI) | p-value |
| Haemoglobin (g/L) | 16,73 (12,60, 20,86) | -1,48 (-5,63, 2,67) | 18,21 (12,41, 24,01) | <0,0001 |
| Indirect bilirubin (µmol/L) | -21,16 (-29,59, -12,72) | 5,10 (-3,00, 13,21) | -26,26 (-37,82, -14,70) | <0,0001 |
| Reticulocytes (fraction of 1) | -0,0973 (-0,1252, -0,0694) | 0,0038 (-0,0239, 0,0315) | -0,1011 (-0,1391, -0,0632) | <0,0001 |
| LDH (U/L) | -91,99 (-124,47, -59,50) | -21,18 (-53,30, 10,94) | -70,81 (-115,88, -25,74) | 0,0027 |
| Haptoglobin (g/L) | 0,169 (0,088, 0,251) | 0,012 (-0,070, 0,094) | 0,158 (0,043, 0,273) | 0,0079 |
CI: confidence interval, Hb: haemoglobin, LDH: lactate dehydrogenase, LS: least square.
1 All p-values are 2-sided.
2 Difference adjusted for randomisation stratification factors.
3 Secondary endpoints are the average change from baseline at Weeks 16, 20 and 24 for Hb, indirect bilirubin, reticulocytes, LDH and haptoglobin.
During the study, 2 (5.0%) patients in the Pyrukynd arm and 7 (17.5%) patients in the placebo arm received transfusions.
Fifteen of the 16 patients with an 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 ≥15 g/L 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 to 18.4+ months).
The efficacy of Pyrukynd was studied in a multinational, single-arm clinical study (ACTIVATE-T) of 27 adult patients with PK deficiency who were regularly transfused. Patients who were regularly transfused were defined as having had a minimum of 6 transfusion episodes and a history of transfusions occurring on average no more frequently than once every 3 weeks during the 52-week period prior to informed consent. There were no limitations on the amount of RBC units received during the 52-week period prior to informed consent. Patients were included if they had documented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 was a missense mutation. Patients homozygous for the R479H mutation or with 2 non-missense mutations (without the presence of another missense mutation) 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 Phase 2 dose-ranging study. Following a dose titration period with 2 sequential steps for dose level increase up to 50 mg twice daily, patients continued on a fixed dose of Pyrukynd for 24 weeks.
Among the 27 patients treated, the median duration of treatment with Pyrukynd was 40.3 weeks (range 16.3 to 46.3 weeks). Overall, 20 (74.1%) patients were exposed to Pyrukynd for >40 weeks. Twenty-five out of the 27 (92.6%) patients who received Pyrukynd received an optimised dose of 50 mg twice daily following the dose titration period. The median age was 36 years (range 18 to 68 years), and 25.9% were male; race was reported in 85.2% of patients including 74.1% White, and 11.1% Asian. The baseline disease characteristics are shown in Table 6.
Table 6. Baseline disease characteristics in patients with PK deficiency who were regularly transfused (ACTIVATE-T):
| Baseline disease characteristics1 | Pyrukynd N = 27 |
|---|---|
| Haemoglobin (g/L), n Median (min, max) | 27 91,0 (74, 109) |
| PKLR genotype, n (%) Missense/missense Missense/non-missense | 20 (74,1) 7 (25,9) |
| Ferritin (µg/L), n Median (min, max) | 18 748,445 (163,42, 5 357,04) |
| Transfusion burden Number of transfusion episodes standardised to 24 Weeks, n Median (min, max) | 27 4,15 (2,8, 7,8) |
| Number of RBC units transfused standardised to 24 Week, n Median (min, max) | 27 6,92 (2,8, 20,3) |
| Femoral T-score category by DXA, n (%) ≤ -2,5 > -2,5 - < -1,0 ≥ -1,0 Missing | 1 (3,7) 15 (55,6) 10 (37,0) 1 (3,7) |
| Prior history of splenectomy, n (%) | 21 (77,8) |
| Prior history of cholecystectomy, n (%) | 23 (85,2) |
| Prior chelation therapy, n (%) | 24 (88,9) |
DXA: dual-energy X-ray absorptiometry, RBC: red blood cell.
1 n is the number of patients with non-missing data.
The primary endpoint of transfusion reduction response was defined as ≥33% reduction in the number of RBC units transfused during the fixed-dose period compared with the historical transfusion burden standardised to 24 weeks.
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):
| Endpoint | Pyrukynd N = 27 |
|---|---|
| Patients with transfusion reduction response, n ( % ) ΔΕ 95% | 10 (37,0) (19,4, 57,6) |
| Percent reduction in RBC units from baseline1 ≥ 33 έως < 50%, n () ≥ 50, n (%)2 | 1 (3,7) 10 (37,0) |
| Patients who were transfusion free, n ( % ) ΔΕ 95% | 6 (22,2) (8,6, 42,3) |
CI: confidence interval, RBC: red blood cell.
1 Calculated as the total number of RBC units transfused in the 52 weeks prior to informed consent standardised to 24 weeks.
2 One patient with ≥50% reduction in RBC units from baseline was a non-responder in the analysis of the primary endpoint (transfusion reduction response) since they received <12 weeks of treatment in the fixed-dose period.
All 6 (22.2%) subjects 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 17.0 months (range 11.5+ to 21.8+ months).
The European Medicines Agency has deferred the obligation to submit the results of studies with Pyrukynd in one or more subsets of the paediatric population in the treatment of PK deficiency (see section 4.2 for information on paediatric use).
Clinical studies of Pyrukynd did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients.
The pharmacokinetics of mitapivat have been characterised in healthy adults and patients with PK deficiency. Mitapivat is readily absorbed, extensively distributed and exhibits low clearance following oral administration.
Autoinduction of mitapivat clearance was evident upon repeat dosing.
The pharmacokinetics of mitapivat showed low to moderate variability in healthy adult subjects.
Mitapivat was readily absorbed after single and multiple doses both in healthy subjects and in patients with PK deficiency. Median Tmax values at steady state were 0.5 to 1 hour post dose across the dose range studied (5 mg to 700 mg twice daily).
The absolute bioavailability after a single dose was approximately 73%.
Mitapivat exhibits pH-dependent solubility. High solubility is observed up to pH 5.5, with decreasing solubility at higher pH which may decrease mitapivat absorption.
Following administration of a single dose in healthy subjects, and a high-fat meal (approximately 900 to 1000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate and 150 calories from protein) there was no change in AUCinf while mitapivat Cmax decreased by 42%. Administration of Pyrukynd with a high-fat meal had no clinically meaningful effect on mitapivat pharmacokinetics.
Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution. The mean volume of distribution (Vz) was 135 L.
In vitro studies showed that mitapivat is primarily metabolised by CYP3A4. Following a single oral dose of 120 mg of radiolabelled mitapivat to healthy subjects, unchanged mitapivat was the major circulating component.
Mitapivat induces CYP3A4 and may also induce CYP2B6, CYP2C8, CYP2C9, CYP2C19 and UGT1A1. Mitapivat may inhibit CYP3A4.
Mitapivat is a substrate for P-gp and may induce and inhibit P-gp.
Mitapivat has a mean t1/2 ranging from 16.2 to 79.3 hours following single oral dose administrations (5 to 2 500 mg) under fasted conditions to healthy subjects. 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.
After a single oral administration of radiolabelled mitapivat to healthy subjects, the total recovery of administered radioactive dose was 89.1%, with 49.6% in the urine (2.6% unchanged) and 39.6% in the faeces (less than 1% unchanged).
The AUC and Cmax of mitapivat increased in a dose-proportional manner over the clinically relevant dose range of 5 to 50 mg twice daily in healthy subjects and in patients with PK deficiency.
No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age, sex, race or body weight.
There were 5 patients 65 years of age or older who received mitapivat in the clinical studies ACTIVATE and ACTIVATE-T. No differences in the pharmacokinetics were observed in these patients compared to younger patients.
The pharmacokinetics of mitapivat in patients with mild, moderate or severe hepatic impairment have not been studied.
The effects of renal impairment on mitapivat pharmacokinetics were assessed as part of the population pharmacokinetic analyses. There were 24 patients with mild (estimated glomerular filtration rate [eGFR] ≥60 to ˂90 mL/min/1.73 m²) and 4 with moderate (eGFR ≥30 to ˂60 mL/min/1.73 m²) renal impairment. Steady-state AUC was similar between patients with normal renal function and mild renal impairment. Geometric mean for steady-state AUC from the small number of patients with moderate renal impairment was higher than that for patients with normal renal function but within the range of steady-state AUCs observed for patients with normal renal function (see section 4.2). There are no data available in patients with severe renal impairment.
The pharmacokinetics of mitapivat in children and adolescent patients less than 18 years old have not been studied.
Mitapivat was not carcinogenic in transgenic rasH2 mice when administered twice daily for a minimum of 26 weeks up to the highest total daily dose of 500 mg/kg/day in male mice (6.4-fold difference in human exposure) and 250 mg/kg/day in female mice (2.6-fold difference in human exposure).
In the 2-year rat carcinogenicity study, proliferative and neoplastic lesions were observed in the liver, thyroid, ovaries and pancreas. Findings in the liver and thyroid were attributed to CYP enzyme induction and were considered rodent-specific. In the ovaries, an increased incidence and/or severity of granulosa and/or luteal/granulosa cell hyperplasia was noted at mitapivat AUC0-12hr values >100-fold above the range observed in humans at the maximum recommended human dose (MRHD) of 50 mg twice daily. Benign acinar hyperplasia and adenoma in the exocrine pancreas were observed at an increased incidence and/or severity in males from all dose groups (30, 100 and 300 mg/kg/day): a no-effect level was not determined. The incidence of the pancreatic findings was only outside the range observed historically in the test strain at 300 mg/kg/day (47-fold the human AUC0-12hr at the MRHD). The relevance of the pancreatic findings for humans is unknown.
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 nor in an in vivo rat bone marrow micronucleus assay.
In embryo-foetal development studies, foetal adverse events were observed at AUC0-12 values 63-fold (rats) and 3.1-fold (rabbits) above the human AUC0-12hr value at the MRHD.
In a rat embryo-foetal toxicity study, oral administration of mitapivat was associated with foetal adverse events, including a decrease in the mean number and litter proportion of viable foetuses, lower mean foetal weights, and test article-related external, soft tissue and skeletal malformations. The maternal and foetal no-observed adverse effect level (NOAEL) occurred at a dose of 50 mg/kg/day (13-fold the human AUC 0-12hr at the MRHD).
In a rabbit embryo-foetal toxicity study, oral administration of mitapivat resulted in lower mean foetal body weights. No effects on foetal morphology were observed. The maternal and foetal NOAEL occurred at a dose of 60 mg/kg/day (1.5-fold the human AUC0-12hr at the MRHD).
In rats, mitapivat was shown to induce perinatal mortality in relation to drug-induced dystocia/prolonged parturition in both the pre-and post-natal development and juvenile toxicity studies at doses ≥ 50 mg/kg/day (≥ 20-fold the human AUC0-12hr at the MRHD).
In a fertility and early embryonic development study, oral administration of mitapivat twice daily at doses up to 300 mg/kg/day in male rats and 200 mg/kg/day in female rats prior to and during mating, and continuing in females through organogenesis, resulted in no adverse events on fertility in male or female animals. Reversible findings related to the reproductive organs of males and females were observed, which were considered related to aromatase inhibition. In males, reversible microscopic findings (degeneration of the seminiferous tubules, spermatid retention, atypical residual bodies in the testes, and increased incidence of cellular debris in the epididymides) correlating with abnormal sperm evaluation findings (decreased sperm motility and density, increased numbers of abnormal sperm) were observed at AUC0-12hr values ≥ 23-fold above the human exposure at the MRHD. In females, decreased number of oestrus stages before cohabitation was observed at AUC0-12hr values 49-fold above the human exposure at the MRHD, and this change resolved upon cessation of dosing.
In repeat dose toxicity studies in male and female rats, reproductive organ changes were observed and were attributable to aromatase inhibition. In males, lower accessory sex gland weights and higher testis weights, as well as microscopic findings in the testis and accessory sex glands were seen at AUC0-12hr values ≥ 4.7 fold the human exposure at the MRHD. In females, higher ovarian weights and lower uterus weights, and microscopic findings in the ovary and vagina occurred at AUC0-12hr values 3.0-fold the human exposure. All findings were reversible.
In a juvenile toxicology study initiated in rats aged 7 days and treated up to sexual maturity, most treatment-related findings were considered related to aromatase inhibition. In males, microscopic findings in the testis were observed from the low-dose level of 30 mg/kg/day (1.5-fold the human AUC0-12hr at the MRHD) and delayed sexual maturity, abnormal sperm evaluation findings, and mating and fertility changes were observed at ≥ 150 mg/kg/day (≥22-fold the human AUC0-12hr at the MRHD). In females, oestrous cycle changes were observed at the high-dose level of 200 mg/kg/day (60-fold the human AUC0-12hr at the MRHD). All evaluable reproductive changes were reversible or partially reversible. Treatment-related decrease and increase in body weights were observed in males and females, respectively, at ≥20-fold the human AUC0-12hr at the MRHD and were not reversed in females. Bone changes, including lower bone density and mass, were observed at ≥1.5- and ≥20-fold the human exposure in males and females, respectively. These changes were fully reversible in females; in males, they were fully reversible at 1.5-fold the human exposure and partially reversible at higher exposure levels.
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