100% of Participants (n=6) With CAH Maintained Androstenedione (A4) Below the Upper Limit of Normal at all Time Points on Atumelnant (80 mg)
CAH Participants Achieved More Than a 90% Reduction of A4 and 97% Reduction of 17-OHP on Atumelnant (80 mg), Beginning at Two Weeks and Sustained Through 12 Weeks
In the ADCS Trial, Atumelnant (80 mg) Normalized 24-hr Urinary Free Cortisol Levels for 100% of Participants (n=5) During Treatment
Management to Host Investor Conference Call Today at 4:30 PM ET and Onsite KOL Event at ENDO for Investors and Analysts at 6:00 PM ET
June 03, 2024 -- Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX) today announced initial findings from the development program of its second clinical product candidate, atumelnant* (CRN04894), a novel, once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist. The results, presented at the Endocrine Society’s annual meeting (ENDO2024), include initial data from the Phase 1b/2a, open-label study in participants with ACTH-dependent Cushing’s syndrome (ADCS) conducted in collaboration with the National Institutes of Health, and the Phase 2 open-label TouCAHn study in participants with congenital adrenal hyperplasia (CAH).
“Despite knowing about ACTH’s pivotal role in the endocrine stress response for nearly a century, no other ACTH antagonist drug candidates have been developed and studied in humans. Achieving physiologically normal hormone levels is critical for people living with CAH and ADCS, and today’s data show an impressive ability of atumelnant to reduce key disease drivers like A4 or cortisol to healthy levels,” said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. “These data also reinforce the strength of our in-house discovery engine and our ability to purposefully design medicines with groundbreaking mechanisms of action like atumelnant, the second novel drug candidate in our pipeline to have demonstrated remarkable results in clinical studies.”
*Proposed international nonproprietary name under review
In this initial analysis of this Phase 2 trial (TouCAHn), people with classic CAH were treated with once-daily, oral atumelnant and assessed for safety and efficacy. The trial continues to enroll three treatment cohorts: 80 mg once daily (n=9), 40 mg once daily (n=9) and 120 mg once daily (n=6).
Data presented at ENDO (n=10) reflect a cutoff date of May 21, 2024. Available data for 80 mg includes: n=4 at 12 weeks of treatment, with two additional participant’s data up to six weeks of treatment. For 40 mg, available data was with n=4 for two weeks of treatment. The TouCAHn study is ongoing, with topline results from the complete study expected in the second half of 2024.
Baseline biomarker levels for subjects in Cohort 1 were:
Androstenedione (A4) mean: 838 ng/dL
17-hydroxyprogesterone (17-OHP) mean: 9,880 ng/dL
Initial results from Cohort 1:
Atumelnant resulted in profound, rapid and sustained reductions in key adrenal steroids that are hallmarks of CAH.
100% of participants had A4 levels below the upper limit of normal (ULN) at two weeks with atumelnant, which was sustained through 12 weeks.
A4 reductions, a potential endpoint in registrational trials, from the baseline mean were:
91% at two weeks (n=6)
93% at six weeks (n=6)
96% at 12 weeks (n=4)
17-OHP changes in serum levels from the baseline mean were:
97% at two weeks (n=6)
95% at six weeks (n=6)
94% at 12 weeks (n=4)
Two-week data from the first four patients in Cohort 2 (40 mg atumelnant once daily) are also presented at ENDO2024.
No severe or serious treatment emergent adverse events have been observed to date, and no participants have discontinued from the trial. All AEs to-date have been mild to moderate and transient. There were no significant changes in safety labs or electrocardiograms. The most common treatment-emergent adverse events included: fatigue (3), headache (2) and upper respiratory tract infection (2).
“In CAH, androgen production can go into overdrive and have a profound effect on people living with this difficult-to-manage disease,” said Dr. Umasuthan Srirangalingam, consultant physician in endocrinology and diabetes at University College London Hospitals NHS Foundation Trust and TouCAHn investigator. “Atumelnant’s unique ability to inhibit ACTH directly at its receptor sets it apart from how we’ve historically pursued controlling androgen production through supra-physiological doses of glucocorticoids. It’s compelling to see initial Phase 2 results showing atumelnant dramatically reduced A4 and 17-OHP.”
Initial data from five ACTH-dependent Cushing’s syndrome trial participants who completed 10 days of once- daily oral atumelnant treatment (80 mg) in this dose-finding study shows rapid and profound impact on cortisol:
In all participants, 24h urine free cortisol was below the upper limit of normal during the treatment period even while receiving oral hydrocortisone replacement. UFC normalization has been recommended by the U.S. Food and Drug Administration as a primary endpoint for drugs that decrease cortisol levels in Cushing’s syndrome.
All five participants (100%) experienced serum cortisol
Two or more clinical symptoms improved in all patients.
“This initial data showed atumelnant’s ability to rapidly reduce — and normalize — cortisol levels in people with ADCS,” said Dr. Lynnette Nieman, senior investigator, National Institutes of Health, and principal investigator of the Phase 1b/2a atumelnant trial. “As a clinician and investigator, I’ve witnessed the unmet needs in this patient population for 40 years. I am hopeful for further promising results as we continue our research on this drug candidate.”
Atumelnant was generally well tolerated. Adverse events were mild to moderate, with the most frequently reported being headache, nausea and decreased appetite, consistent with symptoms of adrenal insufficiency. Predefined biochemical adrenal insufficiency (morning serum cortisol
Atumelnant, our second investigational compound, is the first once-daily, oral adrenocorticotropic hormone (ACTH) receptor antagonist that acts selectively at the melanocortin type 2 receptor (MC2R) on the adrenal glands. Diseases associated with excess ACTH can have significant impact on physical and mental health. Atumelnant has exhibited strong binding affinity for MC2R in preclinical models and has demonstrated suppression of adrenally derived glucocorticoids and androgens that are under the control of ACTH. Data in a Phase 1 healthy volunteer study demonstrated pharmacologic proof-of-concept for atumelnant, with reductions in both serum cortisol levels and 24-hour urine free cortisol excretion in the presence of sustained, disease-like ACTH concentrations. Atumelnant is currently in Phase 2 studies for Congenital Adrenal Hyperplasia and ACTH-dependent Cushing’s syndrome.
TouCAHn is an open-label, global, Phase 2 study designed to evaluate the efficacy, safety, and pharmacokinetics of atumelnant when administered up to 12 weeks in participants with CAH caused by 21-hydroxylase deficiency. The study is ongoing and aims to enroll up to 30 patients, aged 18-75, with classic CAH and on a stable dose of glucocorticoid replacement for at least 6 months. Key endpoints include early morning androstenedione (A4), 17-hydroxyprogesterone (17-OHP) levels and safety.
The Phase 1b/2a, is the first-in-disease, open-label, multiple-ascending dose exploratory study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamic biomarker responses associated with atumelnant over a 10-day treatment period in participants with ACTH-dependent Cushing's syndrome. The study is being conducted in collaboration with the National Institutes of Health and led by Dr. Lynnette Nieman. Participants will receive oral atumelnant once daily for 10 days, followed by monitoring during four wash-out days. The study is ongoing and aims to enroll 18 people.
The content in this release is the sole responsibility of Crinetics Pharmaceuticals, Inc. and does not necessarily represent the official views or imply endorsement of the National Institutes of Health. For more information about the study, please visit clinicaltrials.gov (NCT05804669).
Crinetics Pharmaceuticals is a clinical stage pharmaceutical company focused on the discovery, development, and commercialization of novel therapeutics for endocrine diseases and endocrine-related tumors. Paltusotine, an investigational, first-in-class, oral somatostatin receptor type 2 (SST2) agonist, is in Phase 3 clinical development for acromegaly and in Phase 2 clinical development for carcinoid syndrome associated with neuroendocrine tumors. Crinetics is also developing atumelnant (CRN04894), an investigational, first-in-class, oral ACTH antagonist, that is currently completing Phase 2 clinical studies for the treatment of congenital adrenal hyperplasia and ACTH-dependent Cushing’s syndrome. All of the company’s drug candidates are orally delivered, small molecule new chemical entities resulting from in-house drug discovery efforts, including additional discovery programs addressing a variety of endocrine conditions such as hyperparathyroidism, polycystic kidney disease, Graves’ disease, thyroid eye disease, diabetes and obesity.
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