Pyrukynd
mitapivat
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“6-month and 9-month repeat-dose toxicity studies in rats and monkeys, respectively”
Why that species
Dog was hypersensitive in single-dose studies, so rat and monkey were chosen
“The dogs were a hypersensitive species, thus the applicant has preferred the use of rat and monkeys only for the repeat dose toxicity studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“A 9-Month (Twice Daily) Oral (Nasogastric) Toxicity and Toxicokinetic Study of Mitapivat in Cynomolgus Monkey”
Species: general tox
Rat (6-month) and monkey (9-month)
“6-month and 9-month repeat-dose toxicity studies in rats and monkeys, respectively”
Species: DART
Rat and rabbit (full reproductive toxicity battery)
“a full battery of reproductive toxicity studies in rats and rabbits, and 2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies.”
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (6-month)
“a full battery of reproductive toxicity studies in rats and rabbits, and 2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies.”
Surrogate used in
No surrogate used; mitapivat itself tested in rat and cynomolgus monkey
“A 9-Month (Twice Daily) Oral (Nasogastric) Toxicity and Toxicokinetic Study of Mitapivat in Cynomolgus Monkey”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“6-month and 9-month repeat-dose toxicity studies in rats and monkeys, respectively”
Pivotal GLP studies
6-month rat and 9-month cynomolgus monkey oral studies
“6-month and 9-month repeat-dose toxicity studies in rats and monkeys, respectively”
Route in tox
Oral, twice daily (nasogastric in monkeys)
“A 9-Month (Twice Daily) Oral (Nasogastric) Toxicity and Toxicokinetic Study of Mitapivat in Cynomolgus Monkey”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat bone marrow micronucleus assays
“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, or in an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
2-year rat and 26-week rasH2 mouse: not carcinogenic
“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”
Reproductive & developmental
Rat EFD: post-implantation loss, lower fetal weight and malformations at 100 mg/kg BID (63× MRHD)
“Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 times the MRHD”
Safety pharmacology
Low hERG potential (IC50 29.4 µM)
“Mitapivat inhibited hERG potassium channel current at an IC50 of 29.4µM and an IC20 of 8.6µM (Hill coefficient, 1.1), suggesting a low potential for inhibition of the hERG current at the clinical exposure”
Genotox: Ames
Negative (Ames)
“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, or in an in vivo rat bone marrow micronucleus assay.”
Genotox: in vitro mammalian
In vitro human lymphocyte micronucleus: negative
“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, or in an in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“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, or in an in vivo rat bone marrow micronucleus assay.”
Carcinogenicity model
2-year rat and 26-week Tg rasH2 mouse: not carcinogenic
“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”
Carcinogenicity timing
2-year rat and 26-week Tg rasH2 mouse studies completed and reviewed in the NDA
“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”
hERG / QT
hERG IC50 29.4 µM (IC20 8.6 µM); low potential at clinical Cmax 935.2 ng/mL
“Mitapivat inhibited hERG potassium channel current at an IC50 of 29.4µM and an IC20 of 8.6µM (Hill coefficient, 1.1), suggesting a low potential for inhibition of the hERG current at the clinical exposure (clinical Cmax: 935.2 ng/mL).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Pyrukynd don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL 25 (M) / 50 (F) mg/kg BID (1.2x / 2.2x MRHD AUC), based on subcapsular inflammation/necrosis at higher doses (FDA integrated review, p. 153)
NOAEL / key findings
NOAEL 25 (M) / 50 (F) mg/kg BID (1.2x / 2.2x MRHD AUC), based on subcapsular inflammation/necrosis at higher doses
“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Distribution to pigmented skin and uveal tract; potential melanin binding
“The distribution of [14C]mitapivat to melanin-containing tissues, such as pigmented skin and the uveal tract of the ocular system, indicates that mitapivat has the potential to bind melanin.”
Modality-specific risk
Off-target aromatase inhibition causing reproductive organ toxicity in rats
“Noteworthy nonclinical findings were observed in the reproductive organs in the rats and were likely due to mitapivat-mediated aromatase (also known as cytochrome P450 [CYP19]) inhibition”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Acute Hemolysis with Abrupt Treatment Interruption
- Hepatocellular Injury in Another Condition
Hepatotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Pyrukynd don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL 25 (M) / 50 (F) mg/kg BID (1.2x / 2.2x MRHD AUC), based on subcapsular inflammation/necrosis at higher doses (FDA integrated review, p. 153)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month cynomolgus monkey oral study; liver finding reversible (recovery length not stated)
“During the 9-month study in monkey, mitapivat increased the incidence of emesis at all doses. A reversible white area in liver was observed in females at 200 mg/kg.”
Pivotal GLP studies
6-month rat and 9-month cynomolgus monkey oral studies
“6-month and 9-month repeat-dose toxicity studies in rats and monkeys, respectively”
DART package
Species: DART
Rat and rabbit (full reproductive toxicity battery)
“a full battery of reproductive toxicity studies in rats and rabbits, and 2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies.”
Reproductive & developmental
Rat EFD: post-implantation loss, lower fetal weight and malformations at 100 mg/kg BID (63× MRHD)
“Enlarged or fused placenta and/or a distended amniotic sac, an increase in post-implantation loss (early and late resorptions), a decrease in the mean number of viable fetuses, lower mean fetal weights, and external, visceral, and skeletal malformations were observed at the high dose (100 mg/kg twice daily, 63 times the MRHD”
PPND / ePPND: when
Rat PPND completed and reviewed in the NDA
“NOAEL is 10 mg/kg/BID (3.5× MRHD) for maternal toxicity and 25 mg/kg/BID (exposure 13× MRHD, based on AUC) for postnatal development.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg.rasH2 mouse (6-month)
“a full battery of reproductive toxicity studies in rats and rabbits, and 2-year rat and 6-month Tg.rasH2 mouse carcinogenicity studies.”
Carcinogenicity model
2-year rat and 26-week Tg rasH2 mouse: not carcinogenic
“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”
Carcinogenicity timing
2-year rat and 26-week Tg rasH2 mouse studies completed and reviewed in the NDA
“Mitapivat was not carcinogenic in a 2-year rat study at doses up to 150 mg/kg/BID in males and 100 mg/kg/BID in females (47× and >100× MRHD, respectively), or in transgenic ras H2 mice up to the highest doses tested at 500 mg/kg/day in males and 250 mg/kg/day in females when given orally for 26 weeks.”
Safety marginopen answer page →
Safety margin at NOAEL
Chronic monkey NOAEL 1.2x (males) and 2.2x (females) MRHD AUC
“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”
NOAEL / key findings
NOAEL 25 (M) / 50 (F) mg/kg BID (1.2x / 2.2x MRHD AUC), based on subcapsular inflammation/necrosis at higher doses
“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”
Efficacy evidenceopen answer page →
Efficacy evidence
Hbbth3/+ β-thalassemia mouse (another hemolytic anemia), normal mice, and RBCs from PKD patients ex vivo
“The Applicant stated that in vivo studies were conducted in normal C57BL/6 mice and in the murine Hbbth3/+ model of β-thalassemia, another hemolytic anemia, because suitable animal models of PKD were not available during the early development of mitapivat.”
Why that model
No suitable animal model of PK deficiency available; β-thalassemia mouse used instead
“The Applicant stated that in vivo studies were conducted in normal C57BL/6 mice and in the murine Hbbth3/+ model of β-thalassemia, another hemolytic anemia, because suitable animal models of PKD were not available during the early development of mitapivat.”
Reviewer's view of the efficacy data
FDA: no in vivo PKD model, but thalassemia mouse, ex vivo data and mechanism give sufficient evidence of potential effectiveness
“Although a proof-of-concept from an in vivo model of PKD was not conducted, the beneficial effect of mitapivat on RBC in the mouse model of thalassemia, combined with the ex vivo studies with PK isoforms, and pharmacological rationale (i.e., allosteric activation of a deficient PK enzyme) provides sufficient evidence of potential effectiveness in treating PKD.”
Flexibilityopen answer page →
Flexibility accepted
Efficacy modelAcceptedBeyond the letter
No in vivo pyruvate kinase deficiency model; efficacy shown in a β-thalassemia mouse model, normal mice and patient RBCs ex vivo
Why: No suitable PKD animal models available; thalassemia model, ex vivo PK isoform data and mechanism give sufficient evidence · Pharmacology or kinetics · Weight of evidence
“The Applicant stated that in vivo studies were conducted in normal C57BL/6 mice and in the murine Hbbth3/+ model of β-thalassemia, another hemolytic anemia, because suitable animal models of PKD were not available during the early development of mitapivat.”
“Although a proof-of-concept from an in vivo model of PKD was not conducted, the beneficial effect of mitapivat on RBC in the mouse model of thalassemia, combined with the ex vivo studies with PK isoforms, and pharmacological rationale (i.e., allosteric activation of a deficient PK enzyme) provides sufficient evidence of potential effectiveness in treating PKD.”
Safety marginAcceptedBeyond the letter
Low exposure margins at NOAELs; chronic monkey NOAEL 1.2 times (males) MRHD AUC
Why: Findings of limited severity and mostly reversible · Other reason
“NOAEL is 25 mg/kg/BID (1.2× MRHD, based on AUC) and 50 mg/kg/BID (2.2× MRHD, based on AUC) in males and females, respectively, based on the occurrence of subcapsular inflammation/necrosis at higher doses.”
“The safety margins are acceptable even if they are low. Indeed, the severity was of relative significance and effects were reversible in most of cases.”
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