Crinecerfont Lowers Elevated Hormone Markers in Adults with 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia

Abstract Context Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. Objective To evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Design Open-label, phase 2 study, with sequential cohort design (NCT03525886). Setting United States (6 centers). Participants Men and women, 18-50 years, with 21OHD. Interventions Four crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg oncedaily at bedtime (Cohorts 1 and 2, respectively); 100 mg once-daily in the evening (Cohort 3); 100 mg twice-daily (BID, Cohort 4). Participants could enroll in >1 cohort. Main Outcomes Changes from baseline to Day 14 in adrenocorticotropic hormone (ACTH), 17hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results Eighteen participants (11 women, 7 men) were enrolled: Cohort 1 (n=8), Cohort 2 (n=7), Cohort 3 (n=8), Cohort 4 (n=8). Mean age was 31 years; 94% were white. Median percent reductions were >60% for ACTH (-66%), 17OHP (64%), and androstenedione (64%) with crinecerfont 100 mg BID. In female participants, 73% (8/11) had ≥50% reduction in testosterone levels; male participants had median 26-65% decreases in androstenedione/testosterone ratios. Conclusions Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical endpoints of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

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Tildacerfont for the Treatment of Patients With Classic Congenital Adrenal Hyperplasia: Results From a 12-Week Phase 2 Clinical Trial in Adults With Classic CAH

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1011 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A494-A495

Author(s):

Richard Joseph Auchus ◽

Deborah P Merke ◽

Ivy-Joan Madu ◽

Samer Nakhle ◽

Kyriakie Sarafoglou ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Good Control ◽

Autosomal Recessive Disorder ◽

Standard Of Care ◽

Adrenal Hyperplasia ◽

Open Label ◽

Adrenal Androgen ◽

Hydroxylase Deficiency ◽

Serious Adverse Events ◽

21 Hydroxylase Deficiency

Abstract Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder characterized by insufficient cortisol production resulting in excess adrenocorticotropic hormone (ACTH) and adrenal androgen production. Standard-of-care therapy with glucocorticoids (GC) is suboptimal due to the difficulty of balancing control of the ACTH-driven androgen excess against the serious long-term side effects associated with chronic supraphysiologic GC exposure. Tildacerfont, a second-generation corticotropin-releasing factor type-1 (CRF1) receptor antagonist, lowers excess ACTH, and thus has the potential to reduce adrenal androgen production and to allow for GC dosing closer to physiologic doses. A prior study demonstrated that tildacerfont was effective in reducing ACTH, 17-hydroxyprogesterone (17-OHP) and androstenedione (A4) after 2 weeks of therapy. Here we report results from an open-label 12-week extension study. Methods: Subjects met either of the following criteria: 1) completion of prior study or 2) treatment naïve to tildacerfont with 17-OHP >800 ng/dL while on a stable GC regimen (excluding dexamethasone). Subjects were treated with oral tildacerfont at 400 mg once daily for 12 weeks. Efficacy and safety parameters were assessed at baseline through Week 12. Results: Subject characteristics (n=8) are as follows: median (range) age was 44.5 years (26-67 years; 5 females), median (range) body mass index 30.8 kg/m2 (22-41 kg/m2). In month 3, in the participants with poor control of disease at baseline (elevations in all key biomarkers: ACTH, 17-OHP, and A4) (n=5), maximum mean percentage reductions for ACTH, 17-OHP and A4 were 84%, 82%, and 79%, respectively. In this subgroup, 60% of subjects achieved ACTH normalization and 40% achieved A4 normalization during treatment. Tildacerfont treatment maintained, and did not suppress, biomarkers in participants with good control of disease at baseline (A4 below upper limit of normal) (n=3). Overall, tildacerfont was well tolerated with no serious adverse events. Conclusions: This is the first study of 12 weeks’ duration for a novel, non-steroidal mechanism-of-action agent for the treatment of 21-OHD. Results of this study show that tildacerfont was generally well-tolerated and effective in achieving meaningful reductions in ACTH and A4 in poorly controlled patients over 12 weeks. In addition, this is the first, non-steroidal therapeutic to show evidence of ACTH and A4 normalization over 12 weeks of therapy. Longer term future studies will evaluate whether treatment with tildacerfont can achieve further clinical benefits and allow reduction of GC doses while controlling relevant disease biomarkers.

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Tildacerfont in Adults with Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab438 ◽

2021 ◽

Author(s):

Kyriakie Sarafoglou ◽

Chris N Barnes ◽

Michael Huang ◽

Erik A Imel ◽

Ivy-Joan Madu ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Upper Respiratory Tract ◽

Phase 2 ◽

Adrenal Hyperplasia ◽

Open Label ◽

Hydroxylase Deficiency ◽

Two Phase ◽

Clear Dose Response ◽

17 Hydroxyprogesterone ◽

21 Hydroxylase Deficiency

Abstract Context Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective Assess tildacerfont safety and efficacy. Design and Setting Two Phase 2 open-label studies. Patients Adults with 21OHD. Intervention Oral tildacerfont 200-1000 mg once daily (QD) (n=10) or 100-200 mg twice daily (n=9 and 7) for 2 weeks (Study 1) and 400 mg QD (n=11) for 12 weeks (Study 2). Main outcome measure Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤2x upper limit of normal (ULN) or A4 >2x ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results In Study 1, evaluable participants with baseline A4 >2x ULN (n=11; 19-67 years, 55% female) had reductions from baseline in ACTH (-59.4% to -28.4%), 17-OHP (-38.3% to 0.3%), and A4 (-24.2% to -18.1%), with no clear dose response. In Study 2, participants with baseline A4 >2x ULN (n=5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤2x ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.

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MON-183 Adrenal Androgen Control and Steroidal Side Effects in Adolescents and Adults with Congenital Adrenal Hyperplasia Treated with Glucocorticoids

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.374 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Henrik Falhammar ◽

Robert Farber ◽

Jean L Chan ◽

Mallory Farrar ◽

Chuck Yonan ◽

...

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Density Lipoprotein ◽

Research Network ◽

Adrenal Hyperplasia ◽

Current Standard ◽

Adrenal Androgen ◽

Hydroxylase Deficiency ◽

Adolescents And Adults ◽

Tract Infections ◽

21 Hydroxylase Deficiency

Abstract Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a rare autosomal recessive disorder that results in little or no cortisol biosynthesis, increased production of precursor steroids, and excess production of adrenal androgens. Glucocorticoid (GC) treatment, the current standard of care for CAH, is used to correct cortisol deficiency and reduce excessive androgens. Elevated 17-hydroxyprogesterone (17OHP) is used for diagnosis and management. GC titration to achieve 17OHP <1000 ng/dL may be targeted for adrenal androgen control; however, patients with 17OHP <1000 ng/dL might be at risk for complications of long-term GC excess. This real-world study evaluated adrenal androgen levels and potential GC complications in adolescents and adults with CAH. Methods: TriNetX, a research network that includes electronic medical records from >37 million U.S. patients, was searched on 30Aug2019 for patients who met the following criteria: diagnosis code of E25.0 (ICD-10) or 255.2 (ICD-9); history of GC use; available 17OHP laboratory result; and ≥15 years of age (“grown”) at the most recent 17OHP assessment. Patients were categorized as “adequately controlled” (17OHP <1000 ng/dL) or “poorly controlled” (17OHP ≥1000 ng/dL). Assessments included: demographics; laboratory results for 17OHP, adrenocorticotropic hormone (ACTH), and androstenedione (A4); and low-density lipoprotein (LDL). Adequately vs. poorly controlled groups were compared using Chi-square tests and t-tests. Results: Of 511 grown CAH patients, 352 were adequately controlled and 159 were poorly controlled. Mean concentrations for 17OHP were 244 and 5939 ng/dL in the adequately and poorly controlled cohorts, respectively (p<0.01). Adequately controlled patients also had lower ACTH and A4 than poorly controlled patients: ACTH (72 vs 389 pg/mL, p<0.01); A4 (82 vs 256 ng/dL, p<0.01). Compared to poorly controlled patients, adequately controlled patients were more likely to be female (81% vs 57%, p<0.01) and older (mean birth year: 1981 vs 1986, p<0.01). Adequately controlled patients also had evidence of more metabolic and infection complications, including higher mean LDL (105 vs 94.3 mg/dL, p=0.02), more type 2 diabetes mellitus (9% vs 4%, p=0.08), and more respiratory tract infections (21% vs 11%, p=0.01). Conclusions: In this retrospective analysis, patients with adequately controlled CAH (17OHP <1000 ng/dL) had better adrenal androgen control (lower A4) but also higher rates of complications potentially related to excessive GC exposure. These findings highlight the current challenges of managing CAH with GC regimens alone.

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Gonadal dysfunction in adult men with congenital adrenal hyperplasia

Acta Endocrinologica ◽

10.1530/acta.0.0950185 ◽

1980 ◽

Vol 95 (2) ◽

pp. 185-193 ◽

Cited By ~ 19

Author(s):

G. W. Moore ◽

A. Lacroix ◽

D. Rabin ◽

T. J. McKenna

Keyword(s):

Congenital Adrenal Hyperplasia ◽

Adult Males ◽

Adrenal Hyperplasia ◽

Adrenal Androgen ◽

Hydroxylase Deficiency ◽

Cell Hyperplasia ◽

Gonadal Dysfunction ◽

Dexamethasone Therapy ◽

Adrenal Rest ◽

21 Hydroxylase Deficiency

Abstract. Two adult males are described with congenital adrenal hyperplasia (21-hydroxylase deficiency). Patient 1 was receiving therapy with cortisone acetate and presented with clinical features of glucocorticoid excess and uncontrolled adrenal androgen activity. It was established that the short-acting steroid which the patient was receiving was cleared so rapidly that endogenous ACTH secretion was not inhibited. Patient 2 presented with enlarged and painful testes in association with poor compliance with corticosteroid therapy. The histologic picture of the testis was compatible with 'Leydig cell hyperplasia'. However, successful response to dexamethasone therapy suggests that the testes harboured an adrenal rest. These observations highlight the need for careful follow-up and treatment of adult male patients with congenital adrenal hyperplasia.

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