Miplyffa: genotox, carcinogenicity and repro: done or skipped?

“Arimoclomol was not genotoxic in the Ames assay at up to 5,000 µg/plate, was not mutagenic in the mouse forward mutation assay at up to 1,000 µg/ml, or in the in vivo mouse micronucleus assay at doses up to 2,500 mg/kg/day.”

“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”

“In fertility and early embryonic development study (FEED) in rats, an arimoclomol dose of 1,000 mg/kg/day reduced fertility and the fecundity index in male and female rats, resulted in reduction in the number of corpora lutea, and increased pre-implantation loss in female rats. The NOAEL for the fertility study in rats is considered to be 750 mg/kg/day, which is equivalent to a 4-fold safety margin for the 600 mg/day clinical dose.”

“Additional findings in the canine 2-week repeat dose toxicity studies noted a 10% increase in the QTc interval at the end of the dosing at exposures corresponding to about 28-fold the human exposure.”

“Mutagenesis Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).”

“Mutagenesis Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).”

“Mutagenesis Arimoclomol was not mutagenic or clastogenic in a standard battery of genotoxicity tests (bacterial mutagenicity [Ames], chromosomal aberration in Chinese Hamster Ovary cells, mouse lymphoma forward mutation, mouse and rat bone marrow micronucleus).”

“In a 2-year carcinogenicity study in Han Wistar rats, and a 26-week carcinogenicity study in Transgenic rasH2 mice, oral administration of arimoclomol did not increase the incidence of tumors at systemic exposures that were approximately 8-fold and 11-fold the human exposure, based on AUC at the MRHD.”

“In their resubmission, the Applicant (Zevra) included the reports of two final carcinogenicity studies (6-month TgRas H2 transgenic mouse study and a 2-year study in rats), and additional reports of in vitro and in vivo nonclinical studies that were conducted to define a mechanism of action for arimoclomol.”

“However, arimoclomol had no effect on action potential in canine Purkinje fibers and a 16% inhibition of hERG (human Ether-a-go-go Related Gene) at 70 µM, suggestive of weak inhibitory potential at the rapidly activating delayed rectifier potassium channel (IKr).”