Pyrukynd is indicated for the treatment of adult patients with non-transfusion-dependent and
transfusion-dependent alpha- or beta-thalassaemia.

Posology
The recommended dose is 100 mg taken orally twice daily.
Treatment with Pyrukynd is intended to be long-term. Pyrukynd should be discontinued if a patient
does not experience an improvement of haemolytic anaemia based on the totality of laboratory results
and clinical status of the patient, unless there is another explanation for response failure (eg, bleeding,
surgery, other concomitant illnesses).
Interruption or discontinuation
If a patient needs to interrupt or discontinue Pyrukynd for any reason, a dose taper is not necessary.
Missed dose
If a dose of Pyrukynd is missed by 4 hours or less, the dose should be administered as soon as
possible. If a dose is missed by more than 4 hours, a replacement dose should not be administered, and
the patient should wait until the next scheduled dose. Subsequently, the patient should return to their
normal dosing schedule.

Recommended dosage for drug interactions
Strong CYP3A4 Inhibitors
Co-administration of strong CYP3A4 inhibitors with Pyrukynd should be avoided (see section 4.5).
Strong CYP3A4 Inducers
Co-administration of strong CYP3A4 inducers with Pyrukynd should be avoided (see section 4.5).
Moderate CYP3A4 Inhibitors
If concomitant use of a moderate CYP3A4 inhibitor is unavoidable, the dose of Pyrukynd should be
100 mg once daily and patients should be monitored for increased risk of adverse reactions. When
used with a moderate CYP3A4 inhibitor, patients should not exceed a dose of 100 mg once daily (see
section 4.5).
Moderate CYP3A4 Inducers
Patients should be monitored for reduced activity of Pyrukynd when co-administered with a moderate
CYP3A4 inducer. When used with a moderate CYP3A4 inducer, patients should not exceed the
recommended dose of 100 mg twice daily (see section 4.5).
Special populations
Elderly
There were 7 patients in the clinical studies for thalassaemia who were 65 years of age or older. No
differences in the pharmacokinetics or other reported clinical experiences were observed in these
patients compared to younger patients. No dose modifications are recommended in elderly patients
(see section 5.2).
Hepatic impairment
The pharmacokinetics of mitapivat were studied in adult subjects with moderate hepatic impairment.
No dose modifications are recommended in patients with mild or moderate hepatic impairment.
Mitapivat has not been studied in patients with severe hepatic impairment.
Renal impairment
The effects of renal impairment on mitapivat pharmacokinetics were assessed as part of the population
pharmacokinetic analyses. No dose modifications 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.
Paediatric population
The safety and efficacy of Pyrukynd in children and adolescents (<18 years old) have not been
established. Non-clinical studies in juvenile animals have been conducted (see section 5.3).
Method of administration
For oral use.
Pyrukynd may be taken with or without food. The tablets should be swallowed whole. The tablets
should not be split, crushed, chewed or dissolved.

Hepatocellular Injury
Liver injury has been observed in patients with thalassaemia treated with Pyrukynd within the first
6 months of exposure (see section 4.8). Obtain liver tests prior to the initiation of Pyrukynd and
monthly thereafter for the first 6 months and as clinically indicated. Pyrukynd should be interrupted if
clinically significant increases in liver tests are observed or alanine aminotransferase is >5 times the
upper limit of normal (ULN). Pyrukynd should be discontinued if hepatic injury due to Pyrukynd is
suspected.
Lactose
Pyrukynd contains lactose. Patients with rare hereditary problems of galactose intolerance, total
lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Sodium
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially
‘sodium-free’.

Effects of other medicinal products on Pyrukynd (from clinical studies and model-based approaches)
Strong CYP3A Inducers
Rifampicin (a strong CYP3A inducer) decreased mitapivat AUC0-12hr and Cmax by approximately 93%
and 82%, respectively, following Pyrukynd 100 mg twice daily. Decreased mitapivat plasma
exposures may reduce the efficacy of Pyrukynd. The concomitant use of strong CYP3A4 inducers
with Pyrukynd should be avoided (see section 4.2).
Strong CYP3A Inhibitors
Itraconazole (a strong CYP3A inhibitor) increased mitapivat AUC0-12hr and Cmax by 1.9-fold and
1.6-fold, respectively, following Pyrukynd 100 mg twice daily. Ketoconazole (a strong CYP3A
inhibitor) increased mitapivat AUC0-12hr and Cmax by approximately 3.9-fold and 2.4-fold, respectively,
following Pyrukynd 100 mg twice daily. Increased mitapivat plasma exposures may increase the risk
of adverse reactions. The concomitant use of strong CYP3A4 inhibitors with Pyrukynd should be
avoided (see section 4.2).
Moderate CYP3A Inducers
Efavirenz (a moderate CYP3A inducer) decreased mitapivat AUC0-12hr and Cmax by approximately 52%
and 21%, respectively, following Pyrukynd 100 mg twice daily. Decreased mitapivat plasma
exposures may reduce the efficacy of Pyrukynd. Alternative therapies that are not moderate CYP3A4
inducers should be considered during treatment with Pyrukynd. If concomitant use of a moderate
CYP3A4 inducer is unavoidable, patients should be monitored for reduced activity of mitapivat.
Patients should not exceed the recommended dose of 100 mg twice daily (see section 4.2).
Moderate CYP3A Inhibitors
Fluconazole (a moderate CYP3A inhibitor) increased mitapivat AUC0-12hr and Cmax by approximately
2.7-fold and 1.7-fold, respectively, following Pyrukynd 100 mg twice daily. Increased mitapivat
plasma exposures may increase the risk of adverse reactions. Alternative therapies that are not
moderate CYP3A4 inhibitors should be considered during treatment with Pyrukynd. If concomitant
use of a moderate CYP3A4 inhibitor is unavoidable, the dose of Pyrukynd should be 100 mg once
daily and patients should be monitored for increased risk of adverse reactions. When used with a
moderate CYP3A4 inhibitor, patients should not exceed a dose of 100 mg once daily (see section 4.2).

Gastric acid-reducing agents
Concomitant use of Pyrukynd with drugs that elevate gastric pH was not evaluated in a clinical drugdrug
interaction study; however, there were no clinically meaningful changes in steady-state AUC and
Cmax with concomitant administration of proton pump inhibitors in thalassaemia patients based on
population PK analysis.
Effect of Pyrukynd on other medicinal products
CYP3A substrates
Midazolam (a CYP3A substrate) AUCinf and Cmax decreased by 65% and 59%, respectively, with
Pyrukynd 100 mg twice daily. Pyrukynd induces CYP3A4 and co-administration with sensitive
CYP3A4 substrates (eg, midazolam) may decrease systemic exposure of these medicinal products.
Alternative therapies that are not sensitive substrates of CYP3A4 should be considered during
treatment with Pyrukynd. If concomitant use of Pyrukynd with sensitive CYP3A4 substrates is
unavoidable, patients should be carefully monitored for loss of therapeutic effect.
Hormonal contraceptives
Mitapivat may decrease the systemic concentrations of hormonal contraceptives that are sensitive
substrates of CYP3A4 (eg, ethinyl estradiol) (see section 4.6).
UGT1A1
Based on in vitro data, mitapivat may induce uridine diphosphate glucuronosyltransferase 1A1
(UGT1A1) and may decrease systemic exposure to substrates of this enzyme (see section 5.2). Patients
should be monitored for loss of therapeutic effect of UGT1A1 substrates with a narrow therapeutic
index when co-administered with Pyrukynd.

Women of childbearing potential/Contraception in females
Women of childbearing potential should avoid becoming pregnant while receiving Pyrukynd.
Women of childbearing potential should use contraception during treatment with Pyrukynd and for at
least 28 days after the last dose. Mitapivat may decrease the systemic concentrations of hormonal
contraceptives that are sensitive substrates of CYP3A4 (see section 4.5). For patients using hormonal
contraceptives, concomitant use of a barrier method of contraception or an alternative non-hormonal
contraceptive method is recommended.
Pregnancy
There are no or limited amount of data from the use of mitapivat in pregnant women. Studies in
animals have shown reproductive toxicity (see section 5.3).
Pyrukynd is not recommended during pregnancy.
Breastfeeding
It is unknown whether mitapivat and/or its metabolites are excreted in human milk. A risk to
newborns/infants cannot be excluded.
A decision must be made whether to discontinue breastfeeding or to abstain from Pyrukynd therapy,
taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Fertility
There are no human data on the effect of mitapivat on fertility. Based on findings in animals, there
were no adverse effects in fertility or reproductive function in male or female animals (see
section 5.3).

Pyrukynd has no or negligible influence on the ability to drive and use machines.

4.8.1 Adverse reactions:
Summary of the safety profile
In Phase 3 clinical studies, 301 patients with thalassaemia received Pyrukynd for up to 59.9 weeks.
The safety evaluation of Pyrukynd is based on experience from 2 randomized, double-blind, placebocontrolled
clinical studies: 1 in adult patients with non-transfusion-dependent alpha- or betathalassaemia
(ENERGIZE) and 1 in adult patients with transfusion-dependent alpha- or betathalassaemia
(ENERGIZE-T).
The most common adverse reactions across both studies were headache (24.9%) and insomnia
(24.3%) and the most common laboratory abnormalities observed were blood testosterone increased
(males) (32.0%), free testosterone increased (males) (48.8%), oestrone decreased (males) (51.2%), and
oestradiol decreased (males) (13.6%).
Tabulated list of adverse reactions
The adverse reactions associated with Pyrukynd as identified in clinical studies of patients with
thalassaemia 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 (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare
(<1/10000); not known (cannot be estimated from the available data). Within each frequency
grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 1: Adverse reactions
System organ class Very common
Psychiatric disorders Insomnia
Nervous system disorders Headache
Investigations Blood testosterone increased (males)
Free testosterone increased (males)
Oestrone decreased (males)
Oestradiol decreased (males)
Description of selected adverse reactions
Hepatocellular Injury
Liver injury has been observed in patients with thalassaemia treated with Pyrukynd. For guidance on
how to interrupt or discontinue treatment (see section 4.2).
In ENERGIZE and ENERGIZE-T, 2 of 301 patients (0.66%) treated with Pyrukynd experienced
adverse events suggestive of hepatocellular injury during the double-blind period. Three additional
patients experienced adverse events suggestive of hepatocellular injury during the open-label
extension periods after switching from placebo to Pyrukynd. For 2 of the 5 patients, the events were
serious (requiring hospitalization) and for the remaining 3 the events were nonserious. These events
were characterized by a time to onset within the first 6 months of treatment with peak elevations of
alanine aminotransferase of >5×ULN. All patients discontinued treatment with Pyrukynd and these
events improved upon treatment discontinuation. None of the events resulted in liver failure, liver
transplant, or death.

Change in sex hormone levels
Pyrukynd is a weak aromatase inhibitor in vitro. In ENERGIZE, 15 of 46 (32.6%) males experienced
increases in testosterone to above normal levels and 18 of 46 (39.1%) and 2 of 46 (4.3%) males
experienced decreases in oestrone and oestradiol below the lower limit of normal, respectively. In
ENERGIZE-T, 25 of 79 males (31.6%) experienced increases in testosterone to above normal levels
and 46 of 79 (58.2%) and 15 of 79 (19.0%) males experienced decreases in oestrone and oestradiol
below the lower limit of normal, respectively. These changes in hormone levels were maintained
during treatment with Pyrukynd. In patients who discontinued Pyrukynd, the hormone changes were
reversible. Sex hormone analysis in female patients was limited due to physiologic variations in
hormone levels expected throughout the normal menstrual cycle and the various types of hormonal
contraceptives used by patients.
Insomnia
In ENERGIZE, insomnia was reported in 35 of 129 (27.1%) patients who received Pyrukynd and 5 of
63 (7.9%) patients who received placebo. In ENERGIZE-T, insomnia was reported in 38 of
172 (22.1%) patients who received Pyrukynd and 8 of 85 (9.4%) patients who received placebo.
To report any side effect(s):

Kingdom of Saudi Arabia
The National Pharmacovigilance Centre (NPC):
SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa
Website: https://ade.sfda.gov.sa/

There is no information on overdose with Pyrukynd.
In case of overdose, patients should be treated symptomatically and provided with appropriate
supportive measures as required.

Pharmacotherapeutic group: Other haematological agents, ATC code: B06AX04
Mechanism of action
Mitapivat is a pyruvate kinase activator and acts by directly binding to the pyruvate kinase tetramer.

In thalassaemia, imbalances in globin chain production during erythropoiesis result in increased
oxidative stress, which leads to ineffective erythropoiesis and haemolysis. Mitapivat improves energy
homeostasis, RBC longevity, ineffective erythropoiesis, and haemolysis by increasing PK activity.
Pharmacodynamic effects
In healthy volunteers and patients with thalassaemia, decreases in 2,3 diphosphoglycerate and
increases of ATP concentrations were observed after dosing mitapivat to steady state.
Clinical efficacy and safety
The efficacy of Pyrukynd was evaluated in 2 multinational Phase 3 clinical studies in patients with
alpha- and beta-thalassaemia: ENERGIZE and ENERGIZE-T.
Patients with non-transfusion-dependent Thalassaemia (ENERGIZE)
The efficacy of Pyrukynd was evaluated in a multinational, randomized, double-blind, placebocontrolled
clinical study (ENERGIZE) of 194 adult patients with non-transfusion-dependent alpha- or
beta-thalassaemia, defined as having had no more than 5 RBC units transfused during the 24-week
period prior to randomization and no RBC transfusions within 8 weeks prior to informed consent and
during the screening period. Patients were included if they had a documented diagnosis of
thalassaemia (beta-thalassaemia with or without alpha-globin gene mutations, HbE/beta-thalassaemia,
or alpha-thalassaemia/HbH disease) and a baseline Hb concentration ≤100 g/L. Randomization was
stratified by baseline Hb concentrations (≤90 g/L vs 91-100 g/L) and thalassaemia genotype (alphathalassaemia/
HbH disease vs beta-thalassaemia).
Among the 194 patients with non-transfusion-dependent alpha- or beta-thalassaemia, 130 patients
were randomized to receive 100 mg of Pyrukynd twice daily during the 24-week double-blind period.
The median duration of treatment with Pyrukynd was 24.1 weeks (range 1.1 to 28.1 weeks). Overall,
97 (75%) patients were exposed to Pyrukynd for >24 weeks. Among the 194 randomized patients, the
median age was 41.0 years (range 18 to 69) and 36.6% were male; race was reported in 99% of
patients including 56.2% White, 39.2% Asian, 1.0% Black or African American, 0.5% Multiracial,
and 2.1% unknown.
The baseline disease characteristics are shown in Table 2.
Table 2: Baseline Disease Characteristics in Patients with Non-Transfusion-Dependent
Thalassaemia (ENERGIZE)
Baseline Disease Characteristics1
Pyrukynd
N=130
Placebo
N=64
Total
N=194
Haemoglobin (g/L), n
Median
(min, max)
130
83.88
(53.0, 104.0)
64
84.17
(58.5, 107.0)
194
84.00
(53.0,107.0)
Thalassaemia Genotype, n (%)
alpha-thalassaemia/HbH disease
beta-thalassaemia
42 (32.3)
88 (67.7)
20 (31.3)
44 (68.8)
62 (32.0)
132 (68.0)
Transfusion Burden (RBC units)2, n (%)
0
1-2
3-5
114 (87.7)
10 (7.7)
6 (4.6)
54 (84.4)
7 (10.9)
3 (4.7)
168 (86.6)
17 (8.8)
9 (4.6)
Reticulocyte (Fraction of 1), n
Median
(min, max)
122
0.05
(0.003, 0.298)
58
0.04
(0.000, 0.219)
180
0.05
(0.000, 0.298)
Indirect Bilirubin (μmol/L), n
Median
(min, max)
130
23.38
(2.2, 155.8)
62
22.63
(2.7, 81.6)
192
23.00
(2.2, 155.8)

9
Baseline Disease Characteristics1
Pyrukynd
N=130
Placebo
N=64
Total
N=194
LDH (U/L), n
Median
(min, max)
130
263.50
(107.5, 1207.5)
64
267.25
(110.0, 1009.0)
194
265.00
(107.5, 1207.5)
Hepatic Iron Concentration (mg/g), n
Median
(min, max)
98
3.93
(0.75, 27.19)
52
2.76
(0.75, 18.53)
150
3.64
(0.75, 27.19)
Prior History of Splenectomy, n (%) 47 (36.2) 25 (39.1) 72 (37.1)
Prior History of Cholecystectomy, n (%) 45 (34.6) 16 (25.0) 61 (31.4)
Prior History of Iron Chelation, n (%) 46 (35.4) 22 (34.4) 68 (35.1)
Prior History of Hydroxyurea, n (%) 11 (8.5) 6 (9.4) 17 (8.8)
Hb: haemoglobin, LDH: lactate dehydrogenase, RBC: red blood cell
1 n is the number of patients with non-missing data.
2 Total number of RBC units transfused in the 24-week period before randomization.
The primary endpoint of Hb response was defined as a ≥10 g/L increase in average Hb concentration
from Week 12 through Week 24 compared with baseline. The efficacy results are shown in Table 3.
Table 3: Efficacy Results in Patients with Non-Transfusion-Dependent Thalassaemia
(ENERGIZE)
Pyrukynd
N= 130
Placebo
N=64
Difference
Primary Endpoint n (%) n (%)
Adjusted Difference (%)
(95% CI)
p-value1
Hb Response2 55 (42.3) 1 (1.6)
40.9
(32.0, 49.8)
<0.0001
Secondary Endpoints
LS mean
(95% CI)
LS mean
(95% CI)
LS mean difference
(95% CI)
p-value1
Haemoglobin (g/L)3
8.57
(7.26, 9.88)
-1.06
(-2.77, 0.65)
9.63
(7.80, 11.46)
<0.0001
FACIT-Fatigue4
4.85
(3.41, 6.30)
1.46
(-0.43, 3.34)
3.40
(1.21, 5.59)
0.0026
CI: confidence interval, Hb: haemoglobin, LS: least squares
1 All p-values are 2-sided and all results are statistically significant.
2 For Hb response, the difference is adjusted for randomization stratification factors, which included Hb
concentrations (≤9.0 g/dL vs 9.1-10.0 g/dL) and thalassaemia genotype (alpha-thalassaemia/HbH disease vs
beta-thalassaemia). The two-sided p-value is based on the Mantel-Haenszel stratum weighted method adjusting
for the randomization stratification factors.
3 Change from baseline in average Hb concentration from Week 12 through Week 24.
4 Change from baseline in average Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue score
from Week 12 through Week 24. The FACIT-Fatigue total score ranges from 0 to 52, with a higher score
indicating better health-related quality of life.
Note: For the endpoints of change from baseline in average Hb concentration from Week 12 through Week 24
and change from baseline in average FACIT–Fatigue score from Week 12 through Week 24, the 95% CIs and
the two-sided p-values are based on an analysis of covariance (ANCOVA) model, which included change from
baseline as the dependent variable, treatment group as the independent variable, and baseline and the
randomization stratification factors as covariates.
The majority of patients in the Pyrukynd arm experienced an increase from baseline in average Hb
from Weeks 12 through 24 (Figure 1). Dosing with Pyrukynd led to early and sustained increases in
Hb (Figure 2).

Figure 1: Average Change from Baseline in Haemoglobin from Week 12 through Week 24 by
Patient – All Randomized Patients (ENERGIZE)
Figure 2: Change from Baseline in Haemoglobin Over Time – All Randomized Patients
(ENERGIZE)
Of the 55 patients with Hb response in the Pyrukynd arm, the average increase in Hb was 15.55 g/L
and the median duration of response was 19.6 weeks (range 4.0 to 23.4+ weeks) during the 24-week
double-blind period.
Patients in the Pyrukynd arm experienced an improvement compared to placebo in the change from
baseline to Week 24 for 2 markers of haemolysis (indirect bilirubin and lactate dehydrogenase) and
1 marker of erythropoiesis (reticulocytes [fraction of 1]); no improvements for patients in the
Pyrukynd arm compared to placebo were observed for haptoglobin or erythropoietin.
Patients were fatigued at baseline reflected by a mean FACIT-Fatigue score of approximately 36 in
both the Pyrukynd and placebo arms. The proportion of patients who achieved the meaningful within-
Subject with missing baseline or with no assessments from Week 12 through Week 24
IXRS-Thalassemia Genotype: α-thalassemia/IXRS-Baseline Hb Category: 9.1-10 g/dL α HbH disease
α α α α α α α α α α α α
α α α α α α α
α α α α α α αααα α α α α α αα α ααα α α α αα αααααααα α
α ααα
α α αα
-15
-10
0
10
20
30
from Week 12 Through Week 24 (g/L)
Average Change from Baseline in Hb Concentration
PYRUKYND (N=130) Placebo (N=64)
130 114 115 118 119 119 117
64 58 56 55 54 54 54
Baseline 4 8 12 16 20 24
Week
-5

Of the 55 patients with Hb response in the Pyrukynd arm, the average increase in Hb was 15.55 g/L
and the median duration of response was 19.6 weeks (range 4.0 to 23.4+ weeks) during the 24-week
double-blind period.
Patients in the Pyrukynd arm experienced an improvement compared to placebo in the change from
baseline to Week 24 for 2 markers of haemolysis (indirect bilirubin and lactate dehydrogenase) and
1 marker of erythropoiesis (reticulocytes [fraction of 1]); no improvements for patients in the
Pyrukynd arm compared to placebo were observed for haptoglobin or erythropoietin.
Patients were fatigued at baseline reflected by a mean FACIT-Fatigue score of approximately 36 in
both the Pyrukynd and placebo arms. The proportion of patients who achieved the meaningful within- person change threshold for the FACIT-Fatigue score, defined as ≥4.5-point improvement from
baseline in average score from Week 12 through 24, was higher in the Pyrukynd arm (36.2%) than in
the placebo arm (21.9%) (Figure 3).
Figure 3: Average Change from Baseline in FACIT-Fatigue Score from Week 12 through
Week 24 by Patient – All Randomized Patients (ENERGIZE)
Note: The dotted line represents the meaningful within-person change threshold for FACIT-Fatigue score,
defined as ≥4.5-point improvement from baseline in average score from Week 12 through 24.
At baseline, the mean 6-minute walk test (6MWT) distance was 422 meters in the Pyrukynd arm and
412 meters in the placebo arm. Patients in the Pyrukynd arm experienced improved walking capacity
compared to placebo as assessed by change from baseline to Week 24 in 6MWT distance. The LS
mean (SE) change was 30.48 meters (5.651) in the Pyrukynd arm and 7.11 meters (7.346) in the
placebo arm. The LS mean (SE) difference was 23.36 meters (8.337) (95% CI: 6.90, 39.83).
Patients with transfusion-dependent Thalassaemia (ENERGIZE-T)
The efficacy of Pyrukynd was studied in a multinational, randomized, double-blind, placebocontrolled
clinical study (ENERGIZE-T) of 258 adult patients with transfusion-dependent alpha- or
beta-thalassaemia, defined as having had 6 to 20 RBC units transfused and no longer than a 6-week
transfusion-free period during the 24 weeks prior to randomization. Patients were included if they had
a documented diagnosis of thalassaemia (beta-thalassaemia with or without alpha-globin gene
mutations, HbE/beta-thalassaemia, or alpha-thalassaemia/HbH disease). Randomization was stratified
by geographical region (North America and Europe vs Asia-Pacific vs Rest of World) and
thalassaemia genotype (β0/β0 vs non-β0/β0).
Among the 258 patients with transfusion-dependent alpha- or beta-thalassaemia, 171 patients were
randomized to receive 100 mg of Pyrukynd twice daily during the 48-week double-blind period. The
median duration of treatment with Pyrukynd was 48.1 weeks (range 0.3 to 59.9 weeks). Overall,
104 (60.5%) patients were exposed to Pyrukynd for >48 weeks. Among the 258 randomized patients,
the median age was 33.5 years (range 18 to 67) and 47.3% were male; 62.0% were from North
America and Europe, 18.2% were from Asia-Pacific, and 19.8% were from the rest of the world; race was reported in 95.7% of patients: 60.1% White, 30.2% Asian, 0.8% Black or African American,
0.8% Multiracial, and 3.9% unknown.
The baseline disease characteristics are shown in Table 4.
Table 4: Baseline Disease Characteristics in Patients with Transfusion-Dependent
Thalassaemia (ENERGIZE-T)
Baseline Disease Characteristics
Pyrukynd
N=171
Placebo
N=87
Total
N=258
Haemoglobin (g/L), n1
Median
(min, max)
89.60
(51.00, 118.40)
89.20
(51.20, 109.10)
89.35
(51.00, 118.40)
Thalassaemia Genotype, n (%)
beta0/ beta0
non-beta0/ beta0
75 (43.9)
96 (56.1)
39 (44.8)
48 (55.2)
114 (44.2)
144 (55.8)
Transfusion Burden (RBC units), n (%)2
≤12
>12
54 (31.6)
117 (68.4)
21 (24.1)
66 (75.9)
75 (29.1)
183 (70.9)
Hepatic Iron Concentration (mg/g), n
Median
(min, max)
133
4.58
(0.37, 28.21)
74
4.43
(0.37, 20.47)
207
4.55
(0.37, 28.21)
Prior History of Splenectomy, n (%) 92 (53.8) 49 (56.3) 141 (54.7)
Prior History of Cholecystectomy, n (%) 42 (24.6) 24 (27.6) 66 (25.6)
Prior History of Iron Chelation, n (%) 165 (96.5) 87 (100) 252 (97.7)
Prior History of Hydroxyurea, n (%) 7 (4.1) 3 (3.4) 10 (3.9)
Hb: haemoglobin, RBC: red blood cells
1 Pretransfusion Hb threshold is the mean of all pretransfusion Hb concentrations for the RBC transfusions
administered during the 24-week period before randomization.
2 Total number of RBC units transfused in the 24-week period before randomization.
The primary endpoint of transfusion reduction response (TRR) was defined as ≥50% reduction in the
number of red blood cell (RBC) units transfused with a reduction of at least 2 units of RBCs
transfused in any consecutive 12-week period through Week 48 compared with baseline. The efficacy
results, including secondary endpoints that characterize the durability of the effect of Pyrukynd versus
placebo on transfusion burden, are shown in Table 5.
Table 5: Efficacy Results in Patients with Transfusion-Dependent Thalassaemia
(ENERGIZE-T)
Pyrukynd
N= 171
Placebo
N=87
Difference
Primary Endpoint n (%) n (%)
Adjusted Difference2 (%)
(95% CI)
p-value1
≥50% reduction from baseline
in RBC units transfused in any
consecutive 12 weeks, with a
reduction of at least 2 units
52 (30.4) 11 (12.6)
17.6
(8.0, 27.2)
0.0003
Secondary Endpoints n (%) n (%)
Adjusted Difference2 (%)
(95% CI)
p-value1
≥50% reduction from baseline
in RBC units transfused in any
consecutive 24 weeks
23 (13.5) 2 (2.3)
11.1
(5.1, 17.0)
0.0003
≥33% reduction from baseline
in RBC units from Week 13
through Week 48
25 (14.6) 1 (1.1)
13.4
(7.7, 19.1)
<0.0001

Pyrukynd
N= 171
Placebo
N=87
Difference
≥50% reduction from baseline
in RBC units from Week 13
through Week 48
13 (7.6) 1 (1.1)
6.4
(1.9, 10.9)
0.0056
CI: confidence interval, RBC: red blood cell
1 All p-values are 2-sided and all results are statistically significant.
2 The difference is adjusted for randomization stratification factors, which included geographical region (North
America and Europe vs Asia-Pacific vs Rest of World) and thalassaemia genotype (β0/β0 vs non-β0/β0). The
two-sided p-value is based on the Mantel-Haenszel stratum weighted method adjusting for the randomization
stratification factors.
During the double-blind period, 17 (9.9%) patients in the Pyrukynd arm and 1 (1.1%) patient in the
placebo arm achieved transfusion independence, defined as transfusion-free for at least 8 consecutive
weeks through Week 48. Three patients in the Pyrukynd arm did not receive any transfusions during
the 48-week double-blind period. At the end of the double-blind period, 4 patients in the Pyrukynd
arm had remained transfusion free for >40 weeks, including 1 patient for 59.9 weeks (Figure 4).
Figure 4: Duration of Transfusion Independence (ENERGIZE-T)
Note: Sorted by the longest duration of transfusion-free period.

General Introduction
The pharmacokinetics of mitapivat have been characterized in healthy adults and patients with
thalassaemia. 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.
Absorption
Mitapivat was readily absorbed after single and multiple doses in healthy subjects and patients with
thalassaemia. 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%.

Effect of food
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.
Distribution
Mitapivat is highly protein bound (97.7%) in plasma with low RBC distribution. The mean volume of
distribution (Vz) was 135 L.
Biotransformation
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.
In vitro drug interaction studies
Metabolic pathways
Mitapivat induces CYP3A4 and may also induce CYP2B6, CYP2C8, CYP2C9, CYP2C19 and
UGT1A1.
Drug transporter systems
Mitapivat is a substrate for P-gp.
Elimination
Mitapivat has a mean t1/2 ranging from 16.2 to 79.3 hours following single oral dose administrations

(5 to 2500 mg) under fasted conditions to healthy subjects. Population pharmacokinetics derived
median CL/F at steady state was 17.7 L/h for the 100 mg twice daily regimen.
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).
Linearity/non-linearity
The AUC and Cmax of mitapivat increased in a less than dose proportional manner over the dose range
of 5 to 100 mg twice daily in healthy subjects, patients with PK deficiency, and patients with
thalassaemia.
Special populations
No clinically meaningful effects on the pharmacokinetics of mitapivat were observed based on age,
sex, race or body weight.
Elderly
There were 7 patients 65 years of age or older who received mitapivat in the clinical studies
ENERGIZE and ENERGIZE-T. No differences in the pharmacokinetics or other reported clinical
experiences were observed in these patients compared to younger patients.
Hepatic impairment
The pharmacokinetics of mitapivat were studied in adult subjects with moderate hepatic impairment
(Child-Pugh Class B). After a single oral administration of 50 mg mitapivat, subjects with moderate hepatic impairment demonstrated 36% greater exposure (AUC∞) to mitapivat, compared to subjects
with normal hepatic function. Geometric mean Cmax values were similar between the groups. There
were no major changes to plasma protein binding or elimination half-life in subjects with moderate
hepatic impairment relative to healthy controls. The physiologically based pharmacokinetic model
simulated plasma concentrations following 50 mg or 100 mg doses twice daily in adults with mild
(Child-Pugh Class A) or moderate hepatic impairment. In adults with mild hepatic impairment, no
change in drug exposure (AUCtau) was observed at either dose, while adults with moderate hepatic
impairment showed a 47% increase in AUCtau at both doses compared to adults with normal hepatic
function. This difference in exposure is not considered to be clinically meaningful. Mitapivat has not
been studied in subjects with severe hepatic impairment (Child-Pugh Class C).
Renal impairment
The effects of renal impairment on mitapivat pharmacokinetics were assessed as part of the population
pharmacokinetic analyses. There were 12 patients with mild (estimated glomerular filtration rate
[eGFR] ≥60 to ˂90 mL/min/1.73 m2) and 5 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.
Paediatric population
The pharmacokinetics of mitapivat in children and adolescent patients (<18 years old) have not been
studied.

Carcinogenesis
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 (4.8-fold the
human exposure) and 250 mg/kg/day in female mice (1.9-fold the 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 86-fold
above the range observed in humans at the maximum recommended human dose (MRHD) of 100 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 (35-fold the human AUC0-12hr at the
MRHD). The relevance of the pancreatic findings for humans is unknown.
Mutagenesis
Mitapivat was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Mitapivat was not
clastogenic in an in vitro human lymphocyte micronucleus assay nor in an in vivo rat bone marrow
micronucleus assay.
Embryo-foetal toxicity
In embryo-foetal development studies, foetal adverse events were observed at AUC0-12 values 48-fold
(rats) and 2.4-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
(10-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 (1.1-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 (≥15-fold the human AUC0-12hr at the MRHD).
Fertility
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 ≥18-fold above the human exposure at the MRHD. In females,
decreased number of oestrus stages before cohabitation was observed at AUC0-12hr values 37-fold
above the human exposure at the MRHD, and this change resolved upon cessation of dosing.
Juvenile toxicology study
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 (1.1-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 (≥17-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 (45-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 ≥15-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 ≥1.1- and ≥15-fold the human
exposure in males and females, respectively. These changes were fully reversible in females; in males,
they were fully reversible at 1.1-fold the human exposure and partially reversible at higher exposure
levels.
Repeat-dose toxicity studies
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 ≥3.5-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
2.3-fold the human exposure. All findings were reversible.

Tablet core
Microcrystalline cellulose
Croscarmellose sodium
Mannitol (E421)
Sodium stearyl fumarate
Film-coating
Hypromellose (E464)
Titanium dioxide (E171)
Lactose monohydrate
Triacetin
Indigo carmine aluminium lake (E132)
Macrogol (polyethylene glycol) (E1521)
Printing ink
Shellac (E904)
FD&C Blue #1/Brilliant Blue FCF Aluminium Lake (E133)
Titanium dioxide (E171)
Ammonium hydroxide (E527)

Not applicable.

Store in a refrigerator (2 °C to 8 °C).
Patients may store Pyrukynd at room temperature (store below 30 °C) for up to 3 months, after which
the medication should be discarded.
Date removed from the refrigerator: _____/_____/_____.

Mitapivat tablets are supplied in PVC/PCTFE/Al blister wallets in cartons.
28-day packs:
Pyrukynd 100 mg film-coated tablets
Carton containing 56 film-coated tablets in 4 blister wallets, each containing 14 film-coated tablets.

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