Crinecerfont

Available data from reports of pregnancy in clinical trials with crinecerfont are insufficient to identify a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes.

No developmental toxicity was observed in rats at 4-fold higher than human exposure at the maximum recommended human dose (MRHD) based on area under the concentration-time curve (AUC). Crinecerfont was associated with a low incidence of poly-malformations (craniofacial defects) in rabbits at 2-fold higher than human exposure at the MRHD. In a pre- and postnatal developmental toxicity study, no developmental toxicity was observed in rats at 4-fold higher than human exposure at the MRHD.

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.

There are no data on the presence of crinecerfont in human milk, the effects on the breastfed infant, or the effects on milk production. Crinecerfont is present in animal milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Infants exposed to crinecerfont through breast milk should be monitored for signs of adrenal insufficiency such as weakness, decreased feeding and weight loss.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for crinecerfont and any potential adverse effects on the breastfed child from crinecerfont or from the underlying maternal condition.

Carcinogenesis

In a 2-year carcinogenicity study, rats were administered daily crinecerfont doses of 5, 15, and 100 mg/kg/day via oral gavage. An increased incidence of thyroid follicular cell combined adenomas and carcinomas was observed in female rats at the 100 mg/kg/day dose level (approximately 4-fold higher than human exposure at the MRHD based on AUC). Thyroid follicular cell tumors can occur in rats from excessive thyroid stimulating hormone (TSH) secondary to liver enzyme induction, which is not thought to commonly occur in humans. No evidence of increased tumorigenicity was seen in male rats up to approximately 5-fold higher than human exposure at the MRHD based on AUC or in female rats up to approximately 2-fold higher than human exposure at the MRHD based on AUC.

In a 6-month study in Tg.rasH2 mice, daily crinecerfont doses of 15, 50, 500, and 1500 mg/kg/day were administered via oral gavage. Crinecerfont did not increase the incidence of tumors in male or female transgenic mice (approximately 4-fold higher than human exposure at the MRHD based on AUC).

Mutagenesis

Crinecerfont was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

There were no crinecerfont-related effects on male or female fertility or female reproductive performance in rats treated orally with up to 1000 mg/kg/day crinecerfont at 2-fold higher than human exposure at the MRHD by AUC exposure.

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.

Adults with Congenital Adrenal Hyperplasia (CAH)

The safety of crinecerfont in adults was assessed in Study 1, a randomized, double-blind, placebo-controlled study of 182 adults aged 18 to 58 years with classic CAH due to 21-hydroxylase deficiency. A total of 122 subjects received crinecerfont 100 mg twice daily and 59 subjects received placebo twice daily for up to 24 weeks.

Adverse Reactions Leading to Discontinuation of Treatment

A total of 3% of crinecerfont-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of restlessness, apathy, dyspepsia, nausea, and vomiting.

Commonly Observed Adverse Reactions

Adverse reactions that occurred in ≥4% of crinecerfont-treated subjects and more frequently than in placebo-treated subjects are presented in Table 1.

Table 1. Adverse Reactions (≥4%) in Adults with Congenital Adrenal Hyperplasia Treated with Crinecerfont and Occurring More Frequently Than in Placebo-Treated Subjects:

Suicidal Ideation and Behavior

Study 1 excluded subjects with active suicidal ideation with intent or plan within the six months prior to screening and those with a history of suicidal behavior within the past year, based on the Columbia-Suicide Severity Rating Scale (C-SSRS) administered at screening. The C-SSRS was administered to subjects at regular intervals during the study. Three of 122 (2.5%) crinecerfont-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 24-week double-blind treatment period compared to 1 of 59 (1.7%) placebo-treated subjects. One of the three subjects receiving crinecerfont and the placebo-treated subject reported a lifetime history of suicidal ideation.

One crinecerfont-treated subject without a history of suicidal ideation or behavior attempted suicide during the open-label period after 320 days of treatment.

Laboratory Findings

Neutrophil count less than 2 x 10³ cells/mcL occurred in 14% (17 of 120) of crinecerfont-treated subjects, compared to 5% (3 of 58) of subjects in the placebo group. Neutrophil count less than 1 x 10³ cells/mcL occurred in 0.8% (1 of 120) of crinecerfont-treated subjects, compared to 1.7% subjects (1 of 58) in the placebo group.

Pediatric Patients with Congenital Adrenal Hyperplasia

The safety of crinecerfont in pediatric patients was evaluated in Study 2, a randomized, double-blind placebo-controlled study of 103 pediatric subjects aged 4 to 17 years with classic CAH due to 21-hydroxylase deficiency. Pediatric subjects were randomized to receive crinecerfont twice daily (N=69) or placebo (N=34) for 28 weeks, using weight-based dosing (50 mg twice daily via oral solution for subjects 20 to <55 kg, or 100 mg twice daily via oral capsules for subjects ≥55 kg).

Adverse Reactions Leading to Discontinuation of Treatment

A total of 3% of crinecerfont-treated subjects and no placebo-treated subjects discontinued treatment because of adverse reactions of abdominal pain, myalgia, and dizziness.

Commonly Observed Adverse Reactions

Adverse reactions that occurred at an incidence of ≥4% in crinecerfont-treated pediatric subjects (50 mg twice daily or 100 mg twice daily) and greater than placebo are presented in Table 2.

Table 2. Adverse Reactions (≥4%) in Pediatric Subjects with Congenital Adrenal Hyperplasia Treated with Crinecerfont and Occurring More Frequently Than in Placebo-Treated Subjects:

¹ Abdominal pain includes: abdominal pain, abdominal pain upper and abdominal pain lower

Suicidal Ideation and Behavior

Study 2 excluded subjects with active suicidal ideation with intent or plan within six months prior to screening or those with a lifetime history of suicidal behavior based on the C-SSRS administered at screening. Four of 67 (6%) crinecerfont-treated subjects and 0 of the 31 (0%) placebo-treated subjects reported suicidal ideation without method, intent or plan on the C-SSRS during the 28-week double-blind treatment period. Two of the four crinecerfont-treated subjects reported a lifetime history of suicidal ideation. There were no completed suicides or suicide attempts.

Laboratory Findings

Neutrophil count less than 2 x 10³ cells/mcL occurred in 37% (25 of 68) of crinecerfont-treated subjects, compared to 16% (5 of 32) of subjects in the placebo group. Neutrophil count less than 1 x 10³ cells/mcL occurred in 4% (3 of 68) of crinecerfont-treated subjects, compared to no subjects (0 of 32) in the placebo group.