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”
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”
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”