Arimoclomol

Risk Summary

Based on findings from animal reproduction studies, arimoclomol may cause embryofetal harm when administered during pregnancy. There are no available data on arimoclomol use in pregnant females to evaluate a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Advise pregnant females of the potential risk to the fetus.

In animal reproduction studies, oral administration of arimoclomol to pregnant rats and rabbits during organogenesis resulted in post-implantation loss and structural abnormalities in offspring. These occurred at exposures equal to or greater than 10- and 5-fold, in rats and rabbits respectively, the human exposure at the maximum recommended human daily dose of 372 mg (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryofetal development study in pregnant rats, once daily oral doses of arimoclomol were administered throughout organogenesis from gestation day 6 to 17. Increased post-implantation loss was observed at 10-fold the human exposure, based on AUC at the MRHDD, together with increased ossification in the vertebrae and dilated brain ventricles in litters of dams dosed at equal to or greater than 8-fold the human exposure at the MRHDD.

In another embryofetal development study in pregnant rats in which arimoclomol was administered three times-daily throughout organogenesis from gestation day 6 to 17, there was an increase in postimplantation loss and reduced maternal, placental, and fetal weights at 14-fold the human exposure, based on AUC at the MRHD. In addition, fetuses of dams treated at this exposure level exhibited domed craniums, partially split sternum, hydrocephaly, dilated brain ventricles, dilated interventricular foramen, misaligned and misshapen hemicentres and misaligned ossification sites in the sternebrae, misaligned costal cartilage, increased ossification, cerebral and cerebellar hemorrhages, bipartite supraoccipital, large interparietal bone, marked enlargement of the anterior and posterior fontanelles, hyoid bone, meningocele and fusion of the jugal and maxilla.

In an embryofetal development study in pregnant rabbits, arimoclomol was administered once daily by oral gavage throughout organogenesis from gestation day 7 to 19. Increased incidences of minor skeletal variations (bent hyoid and unossified phalanx) were observed at 5-fold the human AUC at the MRHDD, coinciding with an adverse reduction of maternal body weight.

In a pre- and postnatal development study in pregnant rats, oral arimoclomol was administered from gestation day 6 to lactation day 21. Increased embryofetal lethality and reduced pup weight, with a slight reduction in maternal body weight gain, were observed at 10-fold the human AUC at the MRHDD.

There are no data on the presence of arimoclomol in human or animal milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for arimoclomol and any potential adverse effects on the breastfed infant from arimoclomol or from the underlying maternal condition.

Carcinogenesis

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.

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).

Impairment of Fertility

In a fertility and early embryonic development study in rats, once daily oral arimoclomol doses were administered to males for 4 weeks prior to and throughout mating (for a total of 10 weeks) and to females for 2 weeks prior to mating and to gestation day 6. A reduction in fertility and fecundity indices was noted for both sexes at 9-fold the human exposure, based on AUC at the MRHD. At the same dose level, a reduction in the number of corpora lutea was observed in females, and reduced sperm motility, immotile sperm, reduced sperm count and increased sperm abnormalities were observed in males. A dose-dependent increase in preimplantation loss was noted across all treated groups (equal to or greater than 5-fold the human exposure, based on AUC at the MRHD), which resulted in a reduction in the number of live embryos.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of arimoclomol was evaluated in a randomized, double-blind, placebo-controlled, 12-month trial (Trial 1), which included 50 patients 2 to 19 years old with NPC. Patients received weight-adjusted doses of arimoclomol (31 to 124 mg orally three times daily); 28 of the patients were exposed to arimoclomol for one year. In Trial 1, 78% of patients received miglustat. Forty-one out of 50 patients that were enrolled in Trial 1 continued into an open-label extension trial, which included 39 patients treated with arimoclomol for more than 1 year, 34 patients treated with arimoclomol for more than 2 years, and 17 patients treated with arimoclomol for more than 5 years.

The most common adverse reactions in Trial 1 (≥15%) in arimoclomol-treated patients who also received miglustat were upper respiratory tract infection, diarrhea, and decreased weight. Three (6%) of the arimoclomol-treated patients had the following adverse reactions that led to withdrawal from Trial 1: increased serum creatinine (one patient), and progressive urticaria and angioedema (two patients). Serious adverse reactions reported in arimoclomol-treated patients in Trial 1 were hypersensitivity reactions including urticaria and angioedema.

The following table shows common adverse reactions in Trial 1 that occurred in at least 8% of arimoclomol-treated patients who also received miglustat.

Adverse Reactions in ≥8% of Patients with NPC Treated with Arimoclomol in Trial 1 (Subgroup Who Also Received Miglustat):

^* Upper Respiratory Tract Infection: Combined incidence of upper respiratory tract infection and rhinitis.
^** Urticaria: Includes one patient in which urticaria occurred alone (3%) and two patients who had urticaria with angioedema (6%)

Decreased Weight

Adverse reactions of decreased weight were observed in four patients, who were also receiving concomitant miglustat during the trial. The decrease in weight resolved in all but one of the patients. The mean duration of the weight decrease was 33 days and ranged from 22 to 60 days. One patient had two separate instances of weight loss during the trial, lasting 22 and 24 days respectively. The mean weight loss was approximately 6% from baseline in all patients and arimoclomol administration was not interrupted in any patient.

Laboratory Findings

Thrombocytopenia

Thrombocytopenia was observed in three patients during the trial, all of whom were receiving miglustat for six months or longer at the time of enrollment. In two of these patients, the thrombocytopenia was present at baseline and persisted throughout the trial. In the other patient, the thrombocytopenia developed and resolved during the trial.

Increased Creatinine

Across clinical trials in patients with NPC, healthy subjects, and patients with other diseases, increases in serum creatinine (mean increase was 10-20%) occurred mainly within the first month of dosing and were reversible upon treatment discontinuation.