A Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Atumelnant in Adult Participants with Classic Congenital Adrenal Hyperplasia

The primary objective is to evaluate the efficacy of atumelnant, compared with placebo, in reducing daily glucocorticoid dosage while maintaining adrenal androgen control at the end of the 32-week treatment period in adults with classic congenital adrenal hyperplasia. This objective addresses the clinical need to minimize glucocorticoid exposure, which is associated with significant adverse metabolic and cardiovascular effects, while ensuring adequate suppression of excess adrenal androgens that characterize this condition.

The secondary objectives include:

• To evaluate the efficacy of atumelnant, compared with placebo, in reducing adrenal steroid levels and other congenital adrenal hyperplasia disease burden at Week 2.

• To evaluate the efficacy of atumelnant, compared with placebo, in reducing adrenal steroid levels and other congenital adrenal hyperplasia disease burden at the end of the 32-week treatment period.

• To evaluate the efficacy of atumelnant, compared with placebo, in reducing daily glucocorticoid dosage while maintaining adrenal androgen control at the end of the 32-week treatment period and reducing adrenal androgens over time.

The clinical trial enrolled a total of **86 participants** diagnosed with **classic congenital adrenal hyperplasia** due to **21-hydroxylase deficiency**. The study population comprised both **male and female** adults aged **18 to 74 years** at the time of enrollment. Participants were required to have confirmed classic CAH and be on a stable **glucocorticoid replacement therapy** regimen, with specific serum **androstenedione** levels that indicated either inadequate disease control or supraphysiologic glucocorticoid dosing. Eligibility criteria specified that participants must have been receiving a consistent dose of glucocorticoids for at least two months prior to screening, with doses measured in **hydrocortisone equivalents**. Those treated with **mineralocorticoids** such as **fludrocortisone** were required to maintain stable dosing for at least two months, with normal serum **sodium** and **potassium** levels and no **orthostatic hypotension**. Female participants receiving **estrogen therapy** were required to be on a stable dose for at least three months before screening. The trial excluded vulnerable populations and required participants to adhere to specific contraceptive measures throughout the study period.

This clinical trial is designed as a randomized, double-blind, multicenter, placebo-controlled study to evaluate the safety and efficacy of atumelnant in adult participants with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The trial is classified as a Phase III study. The investigational medicinal product, atumelnant, is an MC2R or ACTH receptor antagonist administered orally in tablet form at doses of 80 mg or 120 mg. The maximum daily dose is 120 mg, with a maximum total dose of 26.8 grams over the treatment period. A placebo tablet serves as the comparator. The primary objective is to evaluate the efficacy of atumelnant compared with placebo in reducing daily glucocorticoid dosage while maintaining adrenal androgen control at the end of the 32-week treatment period.

The primary endpoint is the proportion of participants with morning post-glucocorticoid androstenedione levels at or below the upper limit of normal who are on physiologic glucocorticoid replacement at Week 32. Secondary endpoints include percent change from baseline of morning androstenedione at Week 2, percent change from baseline of morning 17-hydroxyprogesterone at Week 32, proportion of participants with morning pre-glucocorticoid androstenedione at or below the upper limit of normal who are on physiologic glucocorticoid replacement at Week 32, and percent change from baseline in glucocorticoid daily dose when morning post-glucocorticoid androstenedione is at or below the upper limit of normal at Week 32.

The maximum treatment period is 32 weeks. Participant involvement includes a screening visit, a 32-week treatment period, and follow-up assessments. The estimated recruitment start date is December 2025, with an estimated study completion date in May 2027. Participants will undergo regular study visits throughout the treatment period to monitor efficacy and safety parameters, including assessments of adrenal androgen levels and glucocorticoid dosing adjustments.

Principal inclusion criteria require participants to be between 18 and 75 years of age with confirmed classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Participants must have specific morning serum androstenedione levels in relation to their current glucocorticoid replacement therapy, including those with androstenedione above the upper limit of normal on physiologic glucocorticoid doses, normal androstenedione on supraphysiologic doses, or elevated androstenedione on supraphysiologic doses. Participants must be on a stable glucocorticoid replacement regimen for at least 2 months prior to screening. If treated with mineralocorticoids such as fludrocortisone, the dose must be stable for at least 2 months without orthostatic hypotension and with normal serum sodium and potassium levels. Female participants on estrogen therapy must maintain a stable dose for at least 3 months prior to screening. Female participants of childbearing potential and male participants must agree to use appropriate contraceptive methods from screening until at least 2 weeks after the last dose of study drug.

Conditions that may lead to early termination from the study include failure to maintain protocol adherence, occurrence of significant adverse events, withdrawal of consent, pregnancy, protocol violations, or at the discretion of the investigator or sponsor for safety or administrative reasons.

The experimental medication under investigation is atumelnant, a chemical product functioning as an MC2R or ACTH receptor antagonist. Atumelnant is also identified by the sponsor product code CRN04894 and the chemical name N-[(3S)-1-Azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]-piperazin-1-yl]pyridine-2-carboxamide. The active substance is manufactured by Crinetics Pharmaceuticals, Inc. and is of chemical origin.

Atumelnant is administered in tablet form for oral use in two dosage strengths: 80 mg tablets and 120 mg tablets. The maximum daily dose is 120 mg. The maximum total dose over the treatment period is 26.8 grams. The maximum treatment period is 32 weeks.

A placebo comparator is utilized in this study. The placebo is formulated as a tablet for oral administration to maintain the double-blind design of the trial.

Efficacy will be assessed through multiple parameters focused on androgen control and glucocorticoid dose optimization in adult participants with classic congenital adrenal hyperplasia. The primary efficacy endpoint is the proportion of participants with morning post-glucocorticoid androstenedione levels at or below the upper limit of normal who are on physiologic glucocorticoid replacement at Week 32. Secondary efficacy endpoints include the percent change from baseline of morning androstenedione at Week 2, percent change from baseline of morning 17-hydroxyprogesterone at Week 32, the proportion of participants with morning pre-glucocorticoid androstenedione at or below the upper limit of normal who are on physiologic glucocorticoid replacement at Week 32, and the percent change from baseline in glucocorticoid daily dose when morning post-glucocorticoid androstenedione is at or below the upper limit of normal at Week 32. Efficacy assessments will be conducted at specified timepoints throughout the 32-week treatment period, with particular focus on Week 2 and Week 32 measurements. The evaluation involves monitoring of serum biomarker levels and glucocorticoid dosing requirements to determine the ability of atumelnant to maintain adrenal androgen control while reducing glucocorticoid dosage compared to placebo.