A Phase 2/3 Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Atumelnant Treatment in Pediatric Participants with Congenital Adrenal Hyperplasia Including a Long-Term Extension

This Phase 2/3 study evaluates the safety, efficacy, and pharmacokinetics of atumelnant, an MC2R or ACTH receptor antagonist, in pediatric participants with classic congenital adrenal hyperplasia (CAH). The primary objectives are structured across three study parts. In Part A, the study aims to evaluate the safety and tolerability of atumelnant in pediatric participants with CAH and to assess efficacy measured by change from baseline in serum androstenedione (A4). Part B focuses on evaluating the efficacy of atumelnant in reducing daily glucocorticoid (GC) dose while maintaining adrenal androgen normalization. Part C evaluates the efficacy of atumelnant measured by change from baseline in A4. These objectives address the clinical need for improved disease control in pediatric CAH patients while potentially reducing glucocorticoid exposure and its associated adverse effects.

The secondary objectives include multiple assessments across the three study parts. In Part A, the study evaluates efficacy of atumelnant measured by change from baseline in serum 17-hydroxyprogesterone (17-OHP) and measures the pharmacokinetic profile of atumelnant. Part B secondary objectives include evaluating the efficacy of atumelnant to reduce A4 levels, changes in 17-OHP, and reduce GC dosing. Part C assesses efficacy of atumelnant measured by change from baseline in serum 17-OHP and evaluates efficacy as assessed by GC need. These secondary endpoints provide comprehensive evaluation of biochemical control and potential for glucocorticoid dose optimization in pediatric CAH management.

This clinical trial enrolled a total of **95 participants** diagnosed with **classic congenital adrenal hyperplasia** due to **21-hydroxylase deficiency**. The study population consisted of both male and female participants, ranging in **chronological age from 1 to less than 18 years** at the time of enrollment. Participants were required to have a medically confirmed diagnosis of classic congenital adrenal hyperplasia based on standard criteria such as elevated **17-hydroxyprogesterone** levels, confirmed **CYP21A2 genetic testing**, positive newborn screening with confirmatory testing, or **cosyntropin stimulation** testing. All participants demonstrated elevated morning serum **androstenedione** levels above the upper limit of normal during screening, obtained prior to morning **glucocorticoid** administration. The trial population was selected from individuals who had been maintained on stable supraphysiologic glucocorticoid replacement therapy, including **hydrocortisone**, **prednisolone**, **prednisone**, **methylprednisolone**, or **dexamethasone**, for at least one month prior to screening. Participants were also required to demonstrate compliance with their glucocorticoid and **mineralocorticoid** replacement regimens, as assessed by the investigator during the screening period. Additionally, participants were required to have normal **thyroid-stimulating hormone** and **thyroxine** levels within three months of screening, appropriate for their age range.

This clinical trial is designed as a Phase 2/3 study to evaluate the safety, efficacy, and pharmacokinetics of atumelnant in pediatric participants with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The study comprises three distinct parts: Part A, Part B, and Part C, which includes a long-term extension phase. The investigational medicinal product atumelnant is administered as oral tablets in three dose strengths: 20 mg, 40 mg, and 80 mg. A placebo tablet is also utilized in the study design. Atumelnant is a chemical product classified as an MC2R or ACTH receptor antagonist. The maximum daily dose of atumelnant is 80 mg, with a maximum total dose of 161.68 g over a maximum treatment period of 67 weeks. The trial is categorized as a Category Two clinical trial in accordance with Regulation EU No 536/2014 and is not classified as a low-intervention clinical trial. The estimated recruitment start date is November 26, 2025, with an estimated end date of February 1, 2030.

The primary objectives of Part A are to evaluate the safety and tolerability of atumelnant in pediatric participants with congenital adrenal hyperplasia and to assess its efficacy measured by change from baseline in serum androstenedione (A4). Part B aims to evaluate the efficacy of atumelnant in reducing daily glucocorticoid dose while maintaining adrenal androgen normalization. Part C focuses on evaluating the efficacy of atumelnant measured by change from baseline in A4 over an extended treatment period. The primary endpoints for Part A include the incidence of treatment-emergent adverse events, including treatment-emergent serious adverse events and any adverse events leading to discontinuation, as well as change from baseline in morning A4 at Week 8. For Part B, the primary endpoint is the percent change from baseline in glucocorticoid daily dose at Week 28 while serum early morning A4 remains at or below the upper limit of normal. In Part C, the primary endpoint is the change from baseline in morning A4 over time.

Secondary endpoints in Part A include change from baseline in morning serum 17-hydroxyprogesterone (17-OHP) at Week 8 and plasma and blood concentrations of atumelnant to assess pharmacokinetics. Part B secondary endpoints comprise change from baseline in morning A4 at Week 4, change from baseline in morning 17-OHP at Week 4, and the proportion of participants achieving a physiologic glucocorticoid dose while maintaining morning A4 levels. Part C secondary endpoints include change from baseline in morning 17-OHP over time, percent change from baseline in glucocorticoid daily dose over time, and the proportion of participants with physiologic glucocorticoid dose while morning A4 levels are controlled.

Eligible participants for Parts A and B must be male or female at birth, between 1 to less than 18 years of chronological age at the time of signing the informed consent form. Participants must have a medically confirmed diagnosis of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency based on standard medically accepted criteria such as elevated 17-OHP level, confirmed CYP21A2 genetic testing, positive newborn screening with confirmatory second-tier testing, or cosyntropin stimulation. An elevated morning serum A4 level above the upper limit of normal during screening, obtained prior to morning glucocorticoid administration, is required. Participants must be on stable supraphysiologic glucocorticoid replacement therapy (hydrocortisone, prednisolone, prednisone, methylprednisolone, or dexamethasone) for at least one month prior to screening. Compliance with glucocorticoid replacement and mineralocorticoid replacement regimen, if applicable, must be documented during the screening period. Normal thyroid-stimulating hormone (TSH) and thyroxine (T4) levels within three months of screening per age-appropriate range are required. Female participants who have had their first menstrual cycle and engage in heterosexual intercourse must either be of nonchildbearing potential or agree to use a highly effective method of contraception from the beginning of screening until at least two weeks after the last dose of study drug. Male participants who engage in heterosexual intercourse must agree to use a condom when sexually active with a female partner of childbearing potential, remain abstinent on a long-term and persistent basis, and not donate sperm for the duration of the study and until at least two weeks after the last dose of study drug. The participant's parent(s) or legal representative must be willing and able to give signed informed consent, and participants must be willing and able to comply with study procedures and treatment. Part C inclusion criteria require participants to complete treatment in either Part A or Part B, and in the investigator's opinion, it would benefit the participant to continue in Part C, regardless of age.

Conditions that may lead to early termination from the study include the occurrence of adverse events leading to discontinuation, lack of compliance with study procedures or treatment regimen, withdrawal of informed consent by the participant's parent(s) or legal representative, or investigator decision based on safety concerns or lack of efficacy. Participants who fail screening based on findings the investigator believes are temporary and not reflective of the usual state of the participant may be considered for rescreening after discussion with the medical monitor. The overall duration of participant involvement varies depending on the part of the study in which they are enrolled, with Part A and Part B having defined treatment periods and Part C offering a long-term extension for eligible participants who complete Parts A or B.

The investigational medicinal product **Atumelnant** is administered as an oral **tablet** formulation in three different dosage strengths: 20 mg, 40 mg, and 80 mg. Atumelnant, also known by the sponsor product code **CRN04894**, is a chemical product that functions as an **MC2R** or **ACTH receptor antagonist**. The active substance is chemically designated as 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 maximum daily dose of Atumelnant is 80 mg administered via the **oral route**. The maximum total dose that may be administered during the treatment period is 161.68 grams over a maximum treatment duration of 67 weeks. The different tablet strengths allow for flexible dosing adjustments based on individual participant requirements and treatment phase objectives.

A **placebo** tablet is utilized in this clinical trial as a comparator treatment. The placebo is formulated to match the appearance of the active Atumelnant tablets to maintain blinding integrity throughout the study. The placebo is administered via the same oral route as the investigational product to ensure consistency in administration procedures across treatment arms.

Efficacy will be assessed through multiple parameters across different study parts. In Part A, the primary efficacy endpoint is the change from baseline in morning serum androstenedione (A4) at Week 8. Secondary efficacy endpoints in Part A include the change from baseline in morning serum 17-hydroxyprogesterone (17-OHP) at Week 8. In Part B, the primary efficacy endpoint is the percent change from baseline in glucocorticoid daily dose at Week 28 while maintaining serum early morning A4 at or below the upper limit of normal. Secondary efficacy endpoints in Part B include the change from baseline in morning A4 at Week 4, the change from baseline in morning 17-OHP at Week 4, and the proportion of participants achieving physiologic glucocorticoid dose while maintaining morning A4 within the target range. In Part C, the primary efficacy endpoint is the change from baseline in morning A4 over time. Secondary efficacy endpoints in Part C include the change from baseline in morning 17-OHP over time, the percent change from baseline in glucocorticoid daily dose over time, and the proportion of participants achieving physiologic glucocorticoid dose while maintaining morning A4 within the target range. Plasma and blood concentrations of atumelnant will also be measured as part of the secondary endpoints in Part A.