CRN04894 for Cushing's Syndrome

Overseen By Crinetics Clinical Trials

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Crinetics Pharmaceuticals Inc.

Must not be taking: Mitotane

Disqualifiers: Pregnancy, Bilateral adrenalectomy, Malignancy, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

A Phase 1b/2a, first-in-disease, open-label, multiple-ascending dose exploratory study to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamic biomarker responses associated with CRN04894 (an adrenocorticotropic hormone \[ACTH\] receptor antagonist) in participants with ACTH-dependent Cushing's syndrome (Cushing's disease or Ectopic ACTH Syndrome \[EAS\])

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.

What data supports the effectiveness of the drug CRN04894 for Cushing's Syndrome?

While there is no direct data on CRN04894, similar drugs like RU 486, which also block cortisol (a stress hormone) receptors, have been effective in treating Cushing's Syndrome by improving symptoms and normalizing hormone levels. ^{1 2 3 4 5}

Eligibility Criteria

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 am between 18 and 75 years old.

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.

Trial Timeline

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

Treatment Details

Interventions

• CRN04894 (ACTH Receptor Antagonist)

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.

Participant Groups

Group I: Multiple Ascending Doses Experimental Treatment 1 Intervention

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

Who Is Running the Clinical Trial?

Crinetics Pharmaceuticals Inc.

Lead Sponsor

Trials

13

Recruited

760+

Findings from Research

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Outcomes of Primary Transsphenoidal Surgery in Cushing Disease: Experience of a Tertiary Center. [2017]

3. United States 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). [2022]

4. England pubmed.ncbi.nlm.nih.gov

Advances in the medical treatment of Cushing's syndrome. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

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