CRN04894 for Cushing's Syndrome

Overseen By Crinetics Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Crinetics Pharmaceuticals Inc.

Must not be taking: Mitotane

Disqualifiers: Pregnancy, Bilateral adrenalectomy, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 10 days

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CRN04894 for individuals with Cushing's syndrome, a condition where the body produces excess cortisol due to high levels of adrenocorticotropic hormone (ACTH). The trial aims to assess the treatment's safety, tolerability, and behavior in the body. Participants will receive the treatment over a set period to determine its effectiveness in managing symptoms. Those diagnosed with active ACTH-dependent Cushing's syndrome and who have previously used certain medications may be suitable for this trial. As a Phase 1 trial, participants will be among the first to receive this new treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

If you are taking short-acting steroidogenesis inhibitors like ketoconazole, levoketoconazole, osilodrostat, cabergoline, or metyrapone, you will need to stop them for a 14-day period before joining the trial. The protocol does not specify about other medications.

Is there any evidence suggesting that CRN04894 is likely to be safe for humans?

Research has shown that CRN04894, a drug that blocks certain hormone signals, was generally well-tolerated in earlier studies. For example, 49 healthy adults took different doses of CRN04894 without experiencing serious side effects or problems linked to the treatment. These results suggest that CRN04894 might be safe for people, but it remains under investigation. Participants in these trials contribute to gathering more information to ensure its safety for individuals with Cushing's Syndrome. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

CRN04894 is unique because it targets the CRF1 receptor, which plays a key role in the stress hormone pathway implicated in Cushing's Syndrome. Unlike current treatments that often involve surgery, radiation, or steroidogenesis inhibitors, CRN04894 offers a novel mechanism of action that directly addresses hormone imbalance. Researchers are excited about this approach because it could potentially provide a more direct and effective treatment with fewer side effects, improving the quality of life for patients with Cushing's Syndrome.

What evidence suggests that CRN04894 might be an effective treatment for Cushing's syndrome?

Research has shown that CRN04894, also known as Atumelnant, may help treat Cushing's Syndrome. This treatment lowers cortisol levels in the body. Cortisol, a hormone, causes many symptoms of Cushing's Syndrome. In studies, patients experienced a quick and lasting drop in cortisol levels in both blood and urine. This suggests that CRN04894 could help manage Cushing's Syndrome symptoms by addressing its main cause. ^{1 3 4 5 6}

Are You a Good Fit for This Trial?

This trial is for adults aged 18-75 with active ACTH-dependent Cushing's syndrome, vaccinated against COVID-19. Participants on short-term steroid inhibitors can join after a washout period. It excludes pregnant or lactating women, those with certain pituitary issues, recent unsuccessful surgery for Cushing's, and anyone with known cancer or extremely high urine cortisol levels.

Inclusion Criteria

I have been diagnosed with active Cushing's syndrome recently.

I have Cushing's syndrome and can stop my current medication for 14 days if needed.

Exclusion Criteria

I am not pregnant or breastfeeding.

I had surgery for Cushing's syndrome that didn't work within the last 6 weeks.

I have had both of my adrenal glands removed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive oral CRN04894 once daily for 10 days

10 days

Wash-out

Participants are monitored during a 4-day wash-out period after treatment

4 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CRN04894

Trial Overview The study tests CRN04894 in people with Cushing's syndrome to see how safe it is and how the body processes it. This drug blocks the action of ACTH which causes overproduction of cortisol. The trial involves increasing doses to find out what amount works best without being harmful.

How Is the Trial Designed?

Group I: Multiple Ascending Doses Experimental Treatment 1 Intervention

Sequential, open-label, 10-day or 14-day fixed-dose cohorts.

Who Is Running the Clinical Trial?

Crinetics Pharmaceuticals Inc.

Lead Sponsor

Trials

13

Recruited

760+

Published Research Related to This Trial

In a study of 82 patients with Cushing disease who underwent transsphenoidal surgery, the initial remission rate was 72.3%, and after additional treatments, the long-term remission rate was 69.7% over an average follow-up of 7.5 years.

Risk factors for tumor recurrence included undetectable tumors on MRI prior to surgery and high Ki-67 levels, indicating that careful monitoring and long-term follow-up are crucial for managing patients with Cushing disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Primary Transsphenoidal Surgery in Cushing Disease: Experience of a Tertiary Center. Keskin, FE., Ozkaya, HM., Bolayirli, M., et al.[2017]

Recent advancements in medical therapies for Cushing's syndrome include drugs that target dopamine and somatostatin receptors, which can control cortisol production in up to 40% of patients, providing a viable option when surgery is not successful.

New drug candidates like osilodrostat, levoketoconazole, and CORT125134 are being evaluated in multicenter trials, offering hope for more effective and personalized treatments for Cushing's syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in the medical treatment of Cushing's syndrome. Feelders, RA., Newell-Price, J., Pivonello, R., et al.[2022]

Cabergoline is a well-tolerated option for treating Cushing's disease, normalizing cortisol levels in about one-third of patients, making it a viable choice for those needing medical therapy after unsuccessful surgery.

Mifepristone improves clinical symptoms in most patients with Cushing's disease, but it can lead to serious side effects like adrenal insufficiency and hypokalemia, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current approaches to the pharmacological management of Cushing's disease. Molitch, ME.[2015]

A patient with Cushing's syndrome due to ectopic ACTH secretion was successfully treated with the glucocorticoid antagonist RU 486, which works by competitively blocking cortisol action at the receptor level.

The treatment led to significant improvements in symptoms and normalization of various biochemical parameters over a 9-week period, with no observed side effects, suggesting that RU 486 is a safe and effective option for managing hypercortisolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. Nieman, LK., Chrousos, GP., Kellner, C., et al.[2013]

Osilodrostat effectively normalized mean urinary free cortisol (mUFC) levels in patients with Cushing's disease, showing sustained reductions for up to 6.7 years, with over 50% of patients achieving complete or partial response.

The long-term safety profile of osilodrostat remained consistent with earlier findings, with no new safety concerns and a decrease in testosterone levels in females, indicating it is a safe option for long-term management of hypercortisolism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy and safety of osilodrostat in Cushing's disease: final results from a Phase II study with an optional extension phase (LINC 2). Fleseriu, M., Biller, BMK., Bertherat, J., et al.[2022]

Citations

1. crinetics.com crinetics.com/wp-content/uploads/2024/06/FINAL_June-3rd-Atumelnant-Investor-Call-Presentation-2.pdf

dependent Cushing's Syndrome (ADCS) Initial Phase 2 Results From Atumelnant* (CRN04894) in Congenital Adrenal Hyperplasia (CAH) and ACTH- dependent Cushing's Syndrome (ADCS).

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11455294/

12537 Once Daily Oral Atumelnant (CRN04894) Induces ... In conclusion, these data demonstrate rapid, profound, and sustained suppression of A4 and 17-OHP with 80 mg once daily, oral atumelnant. There were no serious ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05804669

NCT05804669 | A Study to Evaluate the Safety and PK of ... A Study to Evaluate the Safety and PK of CRN04894 for the Treatment of Cushing's Syndrome. ClinicalTrials.gov ID NCT05804669. Sponsor Crinetics ...

4. crinetics.com crinetics.com/crinetics-reports-topline-crn04894-phase-1-mad-results/

Crinetics Reports Top-line CRN04894 MAD Results from ... The strong, dose-dependent suppression of serum and urine free cortisol was achieved despite ACTH levels in subjects in the 60 and 80 mg cohorts ...

5. academic.oup.com academic.oup.com/jes/article/8/Supplement_1/bvae163.114/7813558

Journal of the Endocrine Society | Oxford Academic 9330 Atumelnant (crn04894) Induces Rapid And Sustained Reductions In Serum And Urine Cortisol In Patients With Acth-Dependent Cushing Syndrome ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05804669?cond=Ectopic%20cushing%20syndrome%20OR%20%22adrenocorticotropic%20hormone%20secretion%20syndrome%22%20OR%20%22%20Cushing%20syndrome%20due%20to%20ectopic%20ACTH%20secretion%22%20OR%20%22%20ectopic%20ACTH%20secreting%20tumor%22%20OR%20%22%20ectopic%20ACTH%20secreting%20tumour%22%20OR%20%22%20occult%20ectopic%20ACTH%20secretion%22%20OR%20%22%20paraneoplastic%20Cushing%20syndrome%22&aggFilters=status:not%20rec&viewType=Table&rank=1

A Study to Evaluate the Safety and PK of CRN04894 ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...