Crinetics Pharmaceuticals (CRNX) Study Update summary

Study Overview and Objectives

• Atumelnant is the first oral ACTH antagonist in clinical trials, targeting CAH and ACTH-dependent Cushing's syndrome (ADCS).

• Phase II studies evaluated safety, efficacy, and pharmacokinetics in CAH and ADCS, focusing on normalizing hormone levels and reducing disease complications.

• The CAH study included 24 participants in three dose cohorts (40, 80, 120 mg) over 12 weeks, maintaining pre-trial glucocorticoid therapy.

• The ADCS study was an open-label, multiple ascending dose trial with 18 participants, assessing 80 mg and 120 mg doses over 10 days.

• The goal is to enable once-daily oral therapy that allows patients to achieve normal hormone levels and reduce or eliminate excessive glucocorticoid use.

Efficacy Results in CAH

• 100% of participants on 80 mg atumelnant maintained androstenedione (A4) below the upper limit of normal at all time points.

• Over 90% reduction in A4 and 97% reduction in 17-OHP observed from 2 weeks, sustained through 12 weeks.

• Two female participants resumed regular menstrual cycles after years of amenorrhea.

• Both 40 mg and 80 mg doses showed rapid, profound, and sustained reductions in A4 and 17-OHP.

• Phase II results support normalization of hormone levels with physiologic glucocorticoid replacement.

Efficacy Results in Cushing's Disease/ADCS

• All participants on 80 mg atumelnant achieved 24-hour urine-free cortisol below the upper limit of normal during treatment.

• Every participant experienced improvement in at least two Cushing's symptoms in a 10-day study.

• Rapid achievement of serum cortisol <5 µg/dL in all participants, with sustained control using hydrocortisone add-back.

• Clinical and laboratory improvements included normalization of neutrophilia, leukocytosis, and testosterone.

• UFC normalization aligns with FDA-recommended primary endpoint for Cushing's syndrome.