Leaflet PYRUKYND 50mg film-coated tablets

Pyrukynd 5 mg film-coated tablets

Pyrukynd 20 mg film-coated tablets

Pyrukynd 50 mg film-coated tablets

Pyrukynd 5 mg film-coated tablets

Each film-coated tablet contains 5 mg of mitapivat (as sulfate).

Each film-coated tablet contains 0.3 mg of lactose (as monohydrate).

Pyrukynd 20 mg film-coated tablets

Each film-coated tablet contains 20 mg of mitapivat (as sulfate).

Each film-coated tablet contains 1.4 mg of lactose (as monohydrate).

Pyrukynd 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of mitapivat (as sulfate).

Each film-coated tablet contains 3.4 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet

Pyrukynd 5 mg film-coated tablets

Blue, round film-coated tablets of approximately 5 mm in diameter with “M5” printed in black ink onone side and plain on the reverse.

Pyrukynd 20 mg film-coated tablets

Blue, round film-coated tablets of approximately 8 mm in diameter with “M20” printed in black inkon one side and plain on the reverse.

Pyrukynd 50 mg film-coated tablets

Blue, oblong shaped film-coated tablets of approximately 16 mm x 6.8 mm size with 'M50' printed inblack ink on one side and plain on the reverse.

Pyrukynd is indicated for the treatment of pyruvate kinase deficiency (PK deficiency) in adult patients(see section 4.4).

The recommended starting dose is 5 mg taken orally twice daily.

To gradually increase haemoglobin (Hb) levels and maximise the effect, Pyrukynd should be titratedthrough sequential doses of 5 mg twice daily, 20 mg twice daily and 50 mg twice daily, withsequential dose increases occurring every 4 weeks (see Table 1). Hb level and transfusion requirementshould be assessed before increasing to the next dose level as some patients may reach and maintainnormal Hb levels at 5 mg twice daily or 20 mg twice daily. The maximum recommended dose is50 mg twice daily.

Treatment with Pyrukynd is intended to be long-term. Pyrukynd should be discontinued if a patientdoes not experience an improvement of haemolytic anaemia at the maximum recommended dose,based on the totality of laboratory results and clinical status of the patient, unless there is anotherexplanation for response failure (e.g. bleeding, surgery, other concomitant illnesses).

Table 1: Dose titration and maintenance schedule

Duration Dose titration and maintenance

Day 1 to Week 4 All patients:

* 5 mg twice daily

Week 5 to Week 8 If Hb level is below normal range or patient has required a transfusion withinthe last 8 weeks:

* Increase to 20 mg twice daily and maintain for 4 weeks.

If Hb level is within normal range and patient has not required a transfusionwithin the last 8 weeks:

* Maintain 5 mg twice daily.

Week 9 to Week 12 If Hb level is below normal range or patient has required a transfusion withinthe last 8 weeks:

* Increase to 50 mg dose twice daily and maintain thereafter.

If Hb level is within normal range and patient has not required a transfusionwithin the last 8 weeks:

* Maintain current dose (5 mg twice daily or 20 mg twice daily).

Maintenance If Hb level decreases, consider up-titration to the maximum of 50 mg twicedaily as per the above schedule.

Interruption or discontinuation

To minimise the risk of acute haemolysis, abrupt interruption or discontinuation of Pyrukynd shouldbe avoided. The dose should be tapered to gradually discontinue the medicinal product over a1-2 week period (see Table 2). Patients should be monitored for signs of acute haemolysis withworsening of anaemia (see sections 4.4 and 4.8).

Table 2: Dose taper schedule

Dose taper schedule

Current dose

Day 1-7 Day 8-14 Day 155 mg twice daily 5 mg once daily Discontinue N/A20 mg twice daily 20 mg once daily 5 mg once daily Discontinue50 mg twice daily 50 mg once daily 20 mg once daily Discontinue

N/A: not applicable.

If a dose of Pyrukynd is missed by 4 hours or less, the dose should be administered as soon aspossible. If a dose is missed by more than 4 hours, a replacement dose should not be administered, andthe patient should wait until the next scheduled dose. Subsequently, the patient should return to theirnormal dosing schedule.

Dose adjustments due to adverse events

If a dose reduction is required for adverse event management and/or tolerability, the dose may bereduced to the next lower dose level, 20 mg twice daily or 5 mg twice daily.

If a patient needs to discontinue the medicinal product due to an adverse event, the dose taper schedule(Table 2) should be followed. In situations where the risk to the patient due to the adverse event isgreater than the risk of acute haemolysis due to sudden withdrawal of the medicinal product, treatmentmay be stopped without taper and patients should be monitored for signs of acute haemolysis withworsening of anaemia.

There are limited data available in elderly patients. No dose modifications are recommended in elderlypatients (see sections 5.1 and 5.2).

There are no data available in patients with hepatic impairment. No dose recommendations can bemade.

There are limited data available in patients with mild or moderate renal impairment. No dosemodifications are recommended in patients with mild or moderate renal impairment (see section 5.2.).

There are no data available in patients with severe renal impairment. No dose recommendations can bemade.

The safety and efficacy of Pyrukynd in children and adolescents less than 18 years old have not beenestablished. No data are available. Non-clinical studies in juvenile animals have been conducted (seesection 5.3).

For oral use.

Pyrukynd may be taken with or without food. The tablets should be swallowed whole. The tabletsshould not be split, crushed, chewed or dissolved because there are no data currently available tosupport other methods of administration.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Acute haemolysis

Acute haemolysis with subsequent anaemia has been observed following abrupt interruption ordiscontinuation of Pyrukynd (see section 4.8). Abrupt interruption or discontinuation of treatment with

Pyrukynd should be avoided. A gradual reduction in dosing rather than abrupt cessation isrecommended (see section 4.2). If discontinuing treatment abruptly, patients should be monitored forsigns of acute haemolysis and anaemia which may include among other symptoms and signs: jaundice,scleral icterus and dark urine.

Efficacy across mutation types

The 2 Phase 3 clinical studies ACTIVATE and ACTIVATE-T excluded patients who werehomozygous for the R479H mutation or who had 2 non-missense mutations (without the presence ofanother missense mutation) in the PKLR gene. In the Phase 2 clinical study, there were 10 subjectswith 2 non-missense mutations (without the presence of another missense mutation) in the PKLRgene, and 5 subjects homozygous for the R479H mutation. Patients with these mutations are less likelyto respond to treatment with Pyrukynd (see section 5.1). Treatment should be discontinued if clinicalbenefit is not observed (see section 4.2).

Mitapivat may decrease the systemic exposure of hormonal contraceptives that are sensitive substratesof cytochrome P450 3A4 (CYP3A4) (e.g. ethinylestradiol) (see section 4.5). Women of childbearingpotential should be counselled regarding the use of additional or alternative contraception methods(see section 4.6).

Co-administration of specific medicinal products with mitapivat may result in increased risk ofinsomnia or changes in efficacy of mitapivat or changes in efficacy of the co-administered medicinalproducts (see section 4.5). Potential drug-drug interactions should be considered whenever beginningor discontinuing treatment with mitapivat or other medicinal products concomitantly administeredwith mitapivat.

Pyrukynd contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

Mitapivat is primarily metabolised by CYP3A4 and is a substrate for P-glycoprotein (P-gp). Mitapivatinduces CYP3A4 and may also induce CYP2B6, CYP2C8, CYP2C9, CYP2C19 and uridinediphosphate glucuronosyltransferase 1A1 (UGT1A1). Mitapivat may inhibit CYP3A4. Mitapivat mayinduce and inhibit P-gp (see section 5.2).

Effects of other medicinal products on Pyrukynd

The effect of itraconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of a single dose ofmitapivat was evaluated in a Phase 1 study. Itraconazole increased mitapivat AUC0-t, AUC∞ and Cmaxby 4.7-fold, 4.9-fold and 1.7-fold, respectively. Increased mitapivat plasma exposures may increasethe risk of insomnia. The concomitant use of CYP3A4 inhibitors with Pyrukynd should be avoided(see section 4.4). If concomitant use of a CYP3A4 inhibitor is unavoidable, patients should bemonitored for increased risk of insomnia (see section 4.2).

The effect of rifampicin (a strong CYP3A4 inducer) on the pharmacokinetics of a single dose ofmitapivat was evaluated in a Phase 1 study. Rifampicin decreased mitapivat AUC0-t, AUC∞ and Cmaxby 91%, 91% and 77%, respectively. Decreased mitapivat plasma exposures may reduce the efficacyof Pyrukynd. The concomitant use of CYP3A4 inducers with Pyrukynd should be avoided (seesection 4.4). If concomitant use of a CYP3A4 inducer is unavoidable, patients should be monitored forreduced efficacy of mitapivat.

Gastric acid-reducing agents

Mitapivat exhibits pH-dependent solubility (see section 5.2) and coadministration with gastricacid-reducing agents (e.g. famotidine) may decrease mitapivat absorption (see section 4.4).

Concomitant use of Pyrukynd with medicinal products that elevate gastric pH was not evaluated in aclinical drug-drug interaction study. If concomitant use of gastric acid-reducing agents is unavoidable,patients should be monitored for reduced efficacy of mitapivat.

Effect of Pyrukynd on other medicinal products

Mitapivat induces and may inhibit CYP3A4 (see section 5.2) and co-administration with sensitive

CYP3A4 substrates (e.g. midazolam) may alter systemic exposure of these medicinal products.

Concomitant use of Pyrukynd with substrates of this enzyme was not evaluated in a clinical drug-druginteraction study. Alternative therapies that are not sensitive substrates of CYP3A4 should beconsidered during treatment with Pyrukynd (see section 4.4). If co-administration of Pyrukynd withsensitive CYP3A4 substrates is unavoidable, patients should be carefully monitored especially forthose substrates with a narrow therapeutic index (e.g. alfentanil, carbamazepine, cyclosporine,ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus).

Mitapivat may alter the systemic exposure of hormonal contraceptives that are sensitive substrates of

CYP3A4 (e.g. ethinylestradiol) (see section 4.4) and may affect their efficacy (see section 4.6).

UGT1A1, CYP2B6 and CYP2C substrates

Based on in vitro data, mitapivat may induce UGT1A1, CYP2B6, CYP2C8, CYP2C9 and CYP2C19(see section 5.2) and may decrease systemic exposure to substrates of these enzymes (e.g. irinotecan[UGT1A1]; bupropion [CYP2B6]; omeprazole [CYP2C19]; repaglinide [CYP2C8]; warfarin[CYP2C9]). Concomitant use of Pyrukynd with substrates of these enzymes was not evaluated in aclinical drug-drug interaction study. Alternative therapies that are not UGT1A1 substrates or sensitivesubstrates of CYP2B6 or CYP2C should be considered during treatment with Pyrukynd (seesection 4.4). If co-administration is unavoidable, patients should be monitored for loss of therapeuticeffect of substates of these enzymes, especially for those with a narrow therapeutic index(e.g. irinotecan [UGT1A1]; cyclophosphamide [CYP2B6]; valproic acid [CYP2C19]; paclitaxel[CYP2C8]; warfarin, phenytoin [CYP2C9]).

Based on in vitro data, mitapivat may induce and inhibit P-gp (see section 5.2) and may alter systemicexposure of substrates (e.g. dabigatran etexilate) of this transporter. Concomitant use of Pyrukynd withsubstrates of P-gp was not evaluated in a clinical drug-drug interaction study. Alternative therapiesthat are not P-gp substrates should be considered during treatment with Pyrukynd (see section 4.4). Ifco-administration of Pyrukynd with P-gp substrates is unavoidable, patients should be carefullymonitored especially for those substrates with a narrow therapeutic index (e.g. colchicine, digoxin).

Women of childbearing potential should avoid becoming pregnant while receiving Pyrukynd.

Women of childbearing potential should use contraception during treatment with Pyrukynd and for atleast 1 month after the last dose. Mitapivat may decrease the systemic exposure of hormonalcontraceptives that are sensitive substrates of CYP3A4 (see sections 4.4 and 4.5). Additional oralternative methods of contraception should be considered.

There are no or limited amount of data from the use of mitapivat in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3).

Pyrukynd is not recommended during pregnancy and in women of childbearing potential not usingcontraception.

It is unknown whether mitapivat and/or its metabolites are excreted in human milk. A risk tonewborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to abstain from Pyrukynd therapy,taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

There are no human data on the effect of mitapivat on fertility. Animal studies have shown reversibleeffects on reproductive organs of males and females (see section 5.3). While taking mitapivat, theremay be an impact on the ability of a woman and a man to conceive.

Pyrukynd has a minor influence on the ability to drive and use machines. Patients should be advised tobe cautious when driving or using machines in case they experience insomnia during treatment with

Pyrukynd (see section 4.8).

The safety evaluation of Pyrukynd is based on experience from a randomised, double-blind, placebo-controlled clinical study of adult patients with PK deficiency who were not regularly transfused(ACTIVATE) and a single-arm clinical study of adult patients with PK deficiency who were regularlytransfused (ACTIVATE-T).

The most common adverse reaction across both studies was insomnia (19.4%) and the most commonlaboratory abnormalities observed were oestrone decreased (males) (43.5%) and oestradiol decreased(males) (8.7%).

The adverse reactions associated with Pyrukynd as identified in clinical studies of patients with PKdeficiency are tabulated below.

Adverse reactions are listed by MedDRA system organ class and frequency: very common (≥ 1/10);common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); veryrare (< 1/10 000); not known (cannot be estimated from the available data). Within each frequencygrouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3: Adverse reactions

System organ class Very common Common

Psychiatric disorders Insomnia

Gastrointestinal disorders Nausea

General disorders and Hot flushadministration site conditions

Investigations Oestrone decreased Blood testosterone increased(males) (males)

Oestradiol decreased (males)

Acute haemolysis

Abrupt interruption or discontinuation of Pyrukynd can lead to acute haemolysis (see section 4.4). Forguidance on how to interrupt or discontinue treatment see section 4.2.

In a Phase 2 study, 2 of 52 patients (3.8%) experienced haemolysis upon sudden withdrawal of

Pyrukynd, including 1 serious adverse event of acute haemolysis. In both patients who received aninitial Pyrukynd dose of 300 mg twice daily, a rapid and large Hb increase was observed during thefirst 3 weeks of treatment. This was followed by a sudden discontinuation of Pyrukynd without taper,which resulted in acute haemolysis with anaemia. Patients who missed a few doses of Pyrukynd laterin their treatment course, or for whom the dose was tapered, did not experience events of acutehaemolysis.

Changes in sex hormone levels

Mitapivat is a weak aromatase inhibitor in vitro. In ACTIVATE, 1 of 16 (6.3%) males experiencedincreases in testosterone to above normal levels and 2 of 16 (12.5%) and 9 of 16 (56.3%) malesexperienced decreases in oestradiol and oestrone below the lower limit of normal, respectively. In

ACTIVATE-T, 1 of 7 males (14.3%) experienced oestrone decrease below the lower limit of normal.

These changes in hormone levels were maintained throughout the study period. In patients whodiscontinued Pyrukynd at the end of the core period, the hormone changes were reversible. Sexhormone analysis in female patients was limited due to physiological variations in hormone levelsexpected throughout the normal menstrual cycle and the various types of hormonal contraceptivesused by patients.

Insomnia

In ACTIVATE, insomnia was reported with a similar incidence between patients who received

Pyrukynd and patients who received placebo and was reported in 6 of 27 (22.2%) patients in

ACTIVATE-T. In a Phase 2 study, 5 of 27 (18.5%) patients treated at 50 mg twice daily and 16 of 25(64%) patients treated at 300 mg twice daily experienced insomnia during the core period.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical studies in patients with PK deficiency, doses of mitapivat were assessed up to 300 mg twicedaily. Healthy volunteers received up to 2 500 mg as a single dose and 700 mg twice daily for 14 days.

One patient in a clinical study took 150 mg twice daily, a dose greater than the recommended dose inthat study (50 mg twice daily) and did not experience any associated adverse events.

Patients who received higher than the recommended maximum dose of 50 mg twice daily in clinicalstudies reported adverse events consistent with the safety profile of mitapivat in all patients.

In case of overdose, patients should be treated symptomatically and provided with appropriatesupportive measures as needed.

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 toreduced 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 wereobserved after dosing mitapivat to steady state. Changes to these pharmacodynamic markers are notconsidered significant for the assessment of activity in subjects with PK deficiency that should rely onclinical parameters only.

The efficacy of Pyrukynd was evaluated in 2 multinational Phase 3 clinical studies in patients with PKdeficiency: ACTIVATE and ACTIVATE-T.

Patients with PK deficiency who were not regularly transfused (ACTIVATE)

The efficacy of Pyrukynd was studied in a multinational, randomised, double-blind, placebo-controlled clinical study (ACTIVATE) of 80 adult patients with PK deficiency who were not regularlytransfused, defined as having had no more than 4 transfusions in the 52-week period prior to treatmentand no transfusions in the 3-month period prior to treatment. Patients were included if they haddocumented presence of at least 2 mutant alleles in the PKLR gene, of which at least 1 was a missensemutation, and a Hb concentration less than or equal to 100 g/L. Patients homozygous for the R479Hmutation 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 baselinein Hb ≥ 1.5 g/dL at > 50% assessments) in the Phase 2 dose-ranging study. Randomisation wasstratified by average of screening Hb concentrations (< 85 vs ≥ 85 g/L) and PKLR gene mutationcategory (missense/missense vs missense/non-missense). Following a dose titration period with 2sequential 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 outof the 40 (87.5%) patients who received Pyrukynd received an optimised dose of 50 mg twice dailyfollowing 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% weremale; 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 notregularly transfused (ACTIVATE)

Baseline disease characteristics1 Total

N=80

Haemoglobin (g/L), n 80

Median 85.08(min, max) (64.0, 102.3)

PKLR genotype, n (%)

Missense/missense 55 (68.8)

Missense/non-missense 25 (31.3)

Reticulocyte (fraction of 1), n 80

Median 0.4009(min, max) (0.038, 0.827)

Indirect bilirubin (µmol/L), n 76

Median 74.647(min, max) (11.03, 294.7)

LDH (U/L), n 79

Median 223.5(min, max) (101.0, 1190.5)

Haptoglobin (g/L), n 80

Median 0.030(min, max) (0.03, 0.70)

Ferritin (µg/L), n 77

Median 479.420(min, max) (21.36, 5890.25)

Femoral T-Score category by DXA, n (%)≤ -2.5 5 (6.3)> -2.5 - < -1.0 36 (45.0)≥ -1.0 38 (47.5)

Missing 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 frombaseline sustained at 2 or more scheduled assessments (Weeks 16, 20 and 24) during the fixed-doseperiod 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 Placebo1

N=40 N=40 Difference1

Adjusted

Primary endpoint n (%) n (%) difference2 p-value(95% CI)

Hb response 16 (40%) 0 39.3(24.1, 54.6) < 0.0001

Secondary LS mean LS mean LS meanendpoints3 95% CI 95% CI difference p-value(95% CI)

Haemoglobin (g/L) 16.73 -1.48 18.21(12.60, 20.86) (-5.63, 2.67) (12.41, 24.01) < 0.0001

Indirect bilirubin -21.16 5.10 -26.26(µmol/L) (-29.59, -12.72) (-3.00, 13.21) (-37.82, -14.70) < 0.0001

Reticulocytes -0.0973 0.0038 -0.1011(fraction of 1) (-0.1252, -0.0694) (-0.0239, 0.0315) (-0.1391, -0.0632) < 0.0001

LDH (U/L) -91.99 -21.18 -70.81(-124.47, -59.50) (-53.30, 10.94) (-115.88, -25.74) 0.0027

Haptoglobin (g/L) 0.169 0.012 0.158(0.088, 0.251) (-0.070, 0.094) (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 armreceived transfusions.

Fifteen of the 16 patients with an Hb response in ACTIVATE continued in a long-term extension studyand were evaluable for maintenance of response. Thirteen maintained increases in Hb concentrationfrom baseline above the response threshold of ≥ 15 g/L at the last available Hb assessment withoutrequiring any transfusions. The median duration of response for the 16 patients with Hb response was6.9 months (range 3.3 to 18.4+ months).

Patients with PK deficiency who were regularly transfused (ACTIVATE-T)

The efficacy of Pyrukynd was studied in a multinational, single-arm clinical study (ACTIVATE-T) of27 adult patients with PK deficiency who were regularly transfused. Patients who were regularlytransfused were defined as having had a minimum of 6 transfusion episodes and a history oftransfusions occurring on average no more frequently than once every 3 weeks during the 52-weekperiod prior to informed consent. There were no limitations on the amount of RBC units receivedduring the 52-week period prior to informed consent. Patients were included if they had documentedpresence 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 presenceof 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 2dose-ranging study. Following a dose titration period with 2 sequential steps for dose level increase upto 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 (range16.3 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 of50 mg twice daily following the dose titration period. The median age was 36 years (range 18 to68 years), and 25.9% were male; race was reported in 85.2% of patients including 74.1% White, and11.1% Asian. The baseline disease characteristics are shown in Table 6.

Table 6: Baseline disease characteristics in patients with PK deficiency who wereregularly transfused (ACTIVATE-T)

Baseline disease characteristics1 Pyrukynd

N=27

Haemoglobin (g/L), n 27

Median 91.0(min, max) (74, 109)

PKLR genotype, n (%)

Missense/missense 20 (74.1)

Missense/non-missense 7 (25.9)

Ferritin (µg/L), n 18

Median 748.445(min, max) (163.42, 5357.04)

Transfusion burden

Number of transfusion episodes standardised to 24 Weeks, n 27

Median 4.15(min, max) (2.8, 7.8)

Number of RBC units transfused standardised to 24 Weeks, n 27

Median 6.92(min, max) (2.8, 20.3)

Femoral T-score category by DXA, n (%)≤ -2.5 1 (3.7)> -2.5 - < -1.0 15 (55.6)≥ -1.0 10 (37.0)

Missing 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 numberof RBC units transfused during the fixed-dose period compared with the historical transfusion burdenstandardised 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 (%) 10 (37.0)95% CI (19.4, 57.6)

Percent reduction in RBC units from baseline1≥ 33 to < 50%, n (%) 1 (3.7)≥ 50%, n (%)2 10 (37.0)

Patients who were transfusion free, n (%) 6 (22.2)95% CI (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 standardisedto 24 weeks.2 One patient with ≥ 50% reduction in RBC units from baseline was a non-responder in the analysis of theprimary endpoint (transfusion reduction response) since they received < 12 weeks of treatment in the fixed-doseperiod.

All 6 (22.2%) subjects who were transfusion free in ACTIVATE-T remained transfusion free in along-term extension study. The median duration of response for the 6 patients was 17.0 months (range11.5+ 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 (seesection 4.2 for information on paediatric use).

Clinical studies of Pyrukynd did not include sufficient numbers of patients aged 65 years and over todetermine whether they respond differently from younger patients.

The pharmacokinetics of mitapivat have been characterised in healthy adults and patients with PKdeficiency. Mitapivat is readily absorbed, extensively distributed and exhibits low clearance followingoral 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 patientswith PK deficiency. Median Tmax values at steady state were 0.5 to 1 hour post dose across the doserange 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 decreasingsolubility at higher pH which may decrease mitapivat absorption.

Following administration of a single dose in healthy subjects, and a high-fat meal (approximately 900to 1 000 total calories, with 500 to 600 calories from fat, 250 calories from carbohydrate and150 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 mitapivatpharmacokinetics.

Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution. The mean volume ofdistribution (Vz) was 135 L.

In vitro studies showed that mitapivat is primarily metabolised by CYP3A4. Following a single oraldose of 120 mg of radiolabelled mitapivat to healthy subjects, unchanged mitapivat was the majorcirculating component.

In vitro drug interaction studies

Metabolic pathways

Mitapivat induces CYP3A4 and may also induce CYP2B6, CYP2C8, CYP2C9, CYP2C19 and

UGT1A1. Mitapivat may inhibit CYP3A4.

Drug transporter systems

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 derivedmedian 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 ofadministered radioactive dose was 89.1%, with 49.6% in the urine (2.6% unchanged) and 39.6% in thefaeces (less than 1% unchanged).

The AUC and Cmax of mitapivat increased in a dose-proportional manner over the clinically relevantdose 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 patientscompared to younger patients.

The pharmacokinetics of mitapivat in patients with mild, moderate or severe hepatic impairment havenot been studied.

The effects of renal impairment on mitapivat pharmacokinetics were assessed as part of the populationpharmacokinetic 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 mildrenal impairment. Geometric mean for steady-state AUC from the small number of patients withmoderate renal impairment was higher than that for patients with normal renal function but within therange of steady-state AUCs observed for patients with normal renal function (see section 4.2). Thereare no data available in patients with severe renal impairment.

The pharmacokinetics of mitapivat in children and adolescent patients less than 18 years old have notbeen studied.

Mitapivat was not carcinogenic in transgenic rasH2 mice when administered twice daily for aminimum of 26 weeks up to the highest total daily dose of 500 mg/kg/day in male mice (6.4-folddifference in human exposure) and 250 mg/kg/day in female mice (2.6-fold difference in humanexposure).

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 enzymeinduction and were considered rodent-specific. In the ovaries, an increased incidence and/or severityof 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 observedat an increased incidence and/or severity in males from all dose groups (30, 100 and 300 mg/kg/day): ano-effect level was not determined. The incidence of the pancreatic findings was only outside therange 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 notclastogenic in an in vitro human lymphocyte micronucleus assay nor in an in vivo rat bone marrowmicronucleus 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 foetaladverse events, including a decrease in the mean number and litter proportion of viable foetuses, lowermean foetal weights, and test article-related external, soft tissue and skeletal malformations. Thematernal 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 foetalbody weights. No effects on foetal morphology were observed. The maternal and foetal NOAELoccurred 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-induceddystocia/prolonged parturition in both the pre-and post-natal development and juvenile toxicity studiesat 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 atdoses 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 orfemale animals. Reversible findings related to the reproductive organs of males and females wereobserved, which were considered related to aromatase inhibition. In males, reversible microscopicfindings (degeneration of the seminiferous tubules, spermatid retention, atypical residual bodies in thetestes, and increased incidence of cellular debris in the epididymides) correlating with abnormal spermevaluation 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-foldabove 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 andwere attributable to aromatase inhibition. In males, lower accessory sex gland weights and highertestis 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 andlower uterus weights, and microscopic findings in the ovary and vagina occurred at AUC0-12hr values3.0-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, mosttreatment-related findings were considered related to aromatase inhibition. In males, microscopicfindings 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 matingand 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 orpartially reversible. Treatment-related decrease and increase in body weights were observed in malesand females, respectively, at ≥ 20-fold the human AUC0-12hr at the MRHD and were not reversed infemales. Bone changes, including lower bone density and mass, were observed at ≥ 1.5- and ≥ 20-foldthe human exposure in males and females, respectively. These changes were fully reversible infemales; in males, they were fully reversible at 1.5-fold the human exposure and partially reversible athigher exposure levels.

Microcrystalline cellulose

Croscarmellose sodium

Mannitol (E421)

Sodium stearyl fumarate

Hypromellose (E464)

Titanium dioxide (E171)

Lactose monohydrate

Triacetin

Indigo carmine aluminium lake (E132)

Shellac (E904)

Black iron oxide (E172)

Ammonium hydroxide (E527)

Not applicable.

2 years

Store below 25°C.

Mitapivat tablets are supplied in PVC/PCTFE/Al blister wallets in cartons.

Dose titration and maintenance packs:

Pyrukynd 5 mg film-coated tablets

Carton containing 56 film-coated tablets in 4 blister wallets, each containing 14 film-coated tablets.

Pyrukynd 20 mg film-coated tablets

Carton containing 56 film-coated tablets in 4 blister wallets, each containing 14 film-coated tablets.

Pyrukynd 50 mg film-coated tablets

Carton containing 56 film-coated tablets in 4 blister wallets, each containing 14 film-coated tablets.

Dose taper packs:

Pyrukynd 5 mg film-coated tablets

Carton containing 7 film-coated tablets in a blister wallet.

Pyrukynd 20 mg film-coated tablets + Pyrukynd 5 mg film-coated tablets

Each carton of 14 film-coated tablets contains:7 film-coated tablets of Pyrukynd 20 mg7 film-coated tablets of Pyrukynd 5 mg

Pyrukynd 50 mg film-coated tablets + Pyrukynd 20 mg film-coated tablets

Each carton of 14 film-coated tablets contains:7 film-coated tablets of Pyrukynd 50 mg7 film-coated tablets of Pyrukynd 20 mg

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Agios Netherlands B.V.

Zuidplein 36

Regus Amsterdam WTC1077XV Amsterdam

The Netherlands

EU/1/22/1662/001

EU/1/22/1662/002

EU/1/22/1662/003

EU/1/22/1662/004

EU/1/22/1662/005

EU/1/22/1662/006

Date of first authorisation:

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.