CRN04894 for Congenital Adrenal Hyperplasia

Recruiting at 23 trial locations

Overseen By Crinetics Clinical Trials

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Crinetics Pharmaceuticals Inc.

Must be taking: Glucocorticoids

Must not be taking: Dexamethasone, Antiandrogens, Testosterone

Disqualifiers: Other CAH, Diabetes, Cancer, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called CRN04894 in people with a genetic condition called classic congenital adrenal hyperplasia (CAH). The condition affects hormone production, and current treatments may not work well. The study will see if CRN04894 can safely and effectively help manage hormone levels by targeting the underlying cause of CAH.

Do I have to stop taking my current medications for this trial?

The trial requires participants to stay on a stable regimen of glucocorticoid replacement. If you are on estrogen therapy, the dose must be stable for at least 3 months before screening. Dexamethasone use is not allowed within 30 days of screening for Cohorts 1-3, but is permitted in Cohort 4. Antiandrogen therapy and certain other medications must not have been used in the past 3 months.

Do I need to stop my current medications to join the trial?

The trial requires participants to be on a stable regimen of glucocorticoid replacement, so you won't need to stop those medications. However, you must not have used dexamethasone within 30 days of screening for most cohorts, and you should not have used antiandrogen therapy in the past 3 months.

What data supports the idea that CRN04894 for Congenital Adrenal Hyperplasia is an effective drug?

The available research does not provide any data on CRN04894 for Congenital Adrenal Hyperplasia. The studies mentioned focus on other conditions like biliary atresia and Crohn's disease, and do not include information about CRN04894 or its effectiveness for Congenital Adrenal Hyperplasia. ^{1 2 3 4 5}

What safety data is available for CRN04894 in treating congenital adrenal hyperplasia?

The provided research does not contain specific safety data for CRN04894, Atumelnant, or its other names. The studies focus on other treatments like Nevanimibe and modified-release hydrocortisone for congenital adrenal hyperplasia, but do not mention CRN04894 or its safety profile. ^{6 7 8 9 10}

Is the drug CRN04894 a promising treatment for Congenital Adrenal Hyperplasia?

The information provided does not directly mention CRN04894 or its effectiveness, so we cannot determine if it is a promising treatment for Congenital Adrenal Hyperplasia based on the given articles. ^{8 9 11 12 13}

How is the drug CRN04894 different from other treatments for congenital adrenal hyperplasia?

CRN04894 is a novel drug for congenital adrenal hyperplasia that may offer a different mechanism of action compared to traditional glucocorticoid treatments, which often have suboptimal effects and can lead to side effects like osteoporosis and metabolic issues. While existing treatments focus on replacing cortisol and controlling androgen excess, CRN04894 might provide a more targeted approach, potentially improving treatment outcomes and reducing side effects. ^{8 9 11 12 13}

Eligibility Criteria

Adults aged 18-75 with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency can join. They must be on stable glucocorticoid and, if needed, mineralocorticoid replacement therapy. Exclusions include major recent surgery, unstable heart conditions, certain drug use including testosterone or insulin changes for diabetes within the last six weeks.

Inclusion Criteria

I am between 18 and 75 years old, or over 16 in the US.

I have been diagnosed with classic 21-hydroxylase deficiency.

I have followed my prescribed steroid replacement therapy.

Exclusion Criteria

I have a condition that requires me to take steroids regularly.

My hypothyroidism is not well-controlled with my current medication.

Pregnant or lactating

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CRN04894 in sequential, open-label, 12-week fixed-dose cohorts

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• CRN04894

Trial Overview The trial is testing CRN04894's safety and effectiveness in managing CAH symptoms and how the body processes it. It's an open-label study where all participants know they're receiving CRN04894 at various doses to find the right balance between benefits and side effects.

Participant Groups

Group I: Sequential Dose Experimental Treatment 1 Intervention

Sequential, open-label, 12-week fixed-dose cohorts.

Who Is Running the Clinical Trial?

Crinetics Pharmaceuticals Inc.

Lead Sponsor

Trials

13

Recruited

760+

Findings from Research

In a pilot study of 49 biliary atresia patients, high-dose steroid treatment after the Kasai procedure did not improve jaundice-free survival compared to a control group, with overall survival rates of 63% at 6 months and 31% at 2 years.

The study identified that a bilirubin level of less than 20 micromol/L at 6 months post-surgery is a strong predictor of jaundice-free survival, suggesting that future research should focus on alternative steroid protocols and their effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative high-dose steroids do not improve mid-term survival with native liver in biliary atresia. Petersen, C., Harder, D., Melter, M., et al.[2013]

In a study of 104 children who underwent hepatoportoenterostomy (HPE) for biliary atresia, those with a total bilirubin level below 2 mg/dL at 3 months post-surgery had a significantly better survival rate without needing a liver transplant (84% vs 16%).

The presence of congenital anomalies, particularly biliary atresia splenic malformation syndrome, was associated with worse outcomes, highlighting the importance of early diagnosis and management strategies in improving prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. Shneider, BL., Brown, MB., Haber, B., et al.[2022]

In a study of 41 patients with Crohn's disease on home parenteral nutrition (HPN) for an average of 1,083 days, HPN did not reduce the number of surgical procedures needed for Crohn's disease, but it significantly decreased the use of prednisone and improved nutritional markers like serum albumin and transferrin levels.

Despite some complications associated with HPN, including catheter-related issues, the treatment led to a perceived improvement in quality of life for patients, suggesting that HPN is beneficial for managing nutritional needs in Crohn's disease, potentially preventing severe malnutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A century of home parenteral nutrition for Crohn's disease. Galandiuk, S., O'Neill, M., McDonald, P., et al.[2019]

In a study of 17 pediatric patients with severe Crohn's disease, home parenteral nutrition (HPN) successfully induced remission in 12 patients after just one course, demonstrating its efficacy as a treatment option when other therapies failed.

HPN was found to be safe, with minimal complications (only one episode of sepsis reported), and it significantly improved patients' nutritional status and growth, with many experiencing 'catch-up' growth during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Home parenteral nutrition in children with Crohn's disease: an effective management alternative. Strobel, CT., Byrne, WJ., Ament, ME.[2013]

In a study of 204 very low birth weight infants (VLBWIs) receiving parenteral nutrition, 22.5% developed parenteral nutrition-associated cholestasis (PNAC), highlighting the prevalence of this complication.

Key risk factors for PNAC included longer fasting durations and higher intake of amino acids and lipids, suggesting that early enteral nutrition and minimizing parenteral nutrition duration could help prevent PNAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[High-risk factors for parenteral nutrition-associated cholestasis in very low birth weight infants]. Zhu, MY., Gu, MZ.[2012]

In a study involving 10 adults with classic congenital adrenal hyperplasia (CAH), nevanimibe hydrochloride (ATR-101) effectively reduced levels of 17-hydroxyprogesterone (17-OHP) within 2 weeks, indicating its potential to manage androgen excess.

The treatment allowed for significant decreases in 17-OHP levels (27% to 72% in some subjects) without a dose-related increase in adverse events, although gastrointestinal side effects were common.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia. El-Maouche, D., Merke, DP., Vogiatzi, MG., et al.[2021]

In a 6-month study involving 122 adult patients with congenital adrenal hyperplasia (CAH), modified-release hydrocortisone (MR-HC) showed improved biochemical control of androgen levels compared to standard glucocorticoid therapy, with a significant increase in the percentage of patients achieving controlled serum 17-hydroxyprogesterone levels.

MR-HC not only reduced the need for higher steroid doses over time but also led to positive patient-reported outcomes, including restoration of menstrual cycles and successful pregnancies, highlighting its potential benefits beyond just biochemical control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. Merke, DP., Mallappa, A., Arlt, W., et al.[2021]

Modified-release hydrocortisone (MR-HC) provides a more physiological cortisol profile compared to conventional hydrocortisone (HC), with lower cortisol levels in the afternoon and night, which may improve treatment for congenital adrenal hyperplasia (CAH).

In a study of 14 patients, MR-HC resulted in better control of overnight adrenal androgens, but showed increased afternoon levels of certain hormones, indicating that a morning dose may be necessary for optimal management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia. Verma, S., Vanryzin, C., Sinaii, N., et al.[2022]

Individuals with congenital adrenal hyperplasia (CAH) treated with glucocorticoids show increased cardiovascular risk factors, including higher blood pressure and insulin resistance, based on a meta-analysis of 20 studies involving 416 patients.

Despite these findings, there were no significant differences in fasting blood glucose or lipid levels, indicating that while CAH patients may have cardiovascular risks, the direct metabolic effects of glucocorticoid therapy need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular and Metabolic Outcomes in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. Tamhane, S., Rodriguez-Gutierrez, R., Iqbal, AM., et al.[2019]

Children with congenital adrenal hyperplasia (CAH) show significantly higher levels of insulin resistance and glucose intolerance compared to healthy controls, indicating a heightened risk for metabolic issues.

The study found increased carotid intima media thickness (CIMT) in CAH patients, suggesting early signs of atherosclerosis and cardiovascular disease, highlighting the need for early screening in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carotid intima media thickness and other cardiovascular risk factors in children with congenital adrenal hyperplasia. Amr, NH., Ahmed, AY., Ibrahim, YA.[2021]

Children with congenital adrenal hyperplasia (CAH), particularly those with the salt-wasting subtype, have a higher incidence of hypertension (58%) compared to those with simple virilizing CAH (35%), indicating a significant risk factor associated with the condition.

The use of fludrocortisone in CAH patients is linked to a higher rate of hypertension (55% vs 31% in those not on fludrocortisone), especially in children who are oversuppressed, as indicated by multiple readings of 17-OHP < 400 ng/dl.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypertension in children with congenital adrenal hyperplasia. Maccabee-Ryaboy, N., Thomas, W., Kyllo, J., et al.[2017]

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to significant hormonal imbalances, requiring lifelong monitoring and treatment with glucocorticosteroids to manage symptoms and prevent complications like metabolic syndrome and osteoporosis.

The treatment goals for adults with classic CAH include improving quality of life, maintaining fertility, and minimizing the side effects of glucocorticosteroid therapy, with specialized care from a multidisciplinary team being essential for effective management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency - management in adults. Ambroziak, U., Bednarczuk, T., Ginalska-Malinowska, M., et al.[2017]

In a study involving 10 patients with congenital adrenal hyperplasia, switching from standard glucocorticoid treatment to dexamethasone did not achieve adequate control with any single dosage regimen.

The study suggests starting with a dose of 5 micrograms/kg/day, but emphasizes that the optimal timing and dosage must be personalized for each patient to effectively manage their condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone treatment for congenital adrenal hyperplasia. Young, MC., Hughes, IA.[2019]

References

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

Postoperative high-dose steroids do not improve mid-term survival with native liver in biliary atresia. [2013]

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

A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. [2022]

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

A century of home parenteral nutrition for Crohn's disease. [2019]

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

Home parenteral nutrition in children with Crohn's disease: an effective management alternative. [2013]

5. China pubmed.ncbi.nlm.nih.gov

[High-risk factors for parenteral nutrition-associated cholestasis in very low birth weight infants]. [2012]

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

A Phase 2, Multicenter Study of Nevanimibe for the Treatment of Congenital Adrenal Hyperplasia. [2021]

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

Modified-Release Hydrocortisone in Congenital Adrenal Hyperplasia. [2021]

8. England pubmed.ncbi.nlm.nih.gov

A pharmacokinetic and pharmacodynamic study of delayed- and extended-release hydrocortisone (Chronocort) vs. conventional hydrocortisone (Cortef) in the treatment of congenital adrenal hyperplasia. [2022]

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

Cardiovascular and Metabolic Outcomes in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis. [2019]

10. Italy pubmed.ncbi.nlm.nih.gov

Carotid intima media thickness and other cardiovascular risk factors in children with congenital adrenal hyperplasia. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Hypertension in children with congenital adrenal hyperplasia. [2017]

12. Poland pubmed.ncbi.nlm.nih.gov

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency - management in adults. [2017]

13. England pubmed.ncbi.nlm.nih.gov

Dexamethasone treatment for congenital adrenal hyperplasia. [2019]