scholarly journals 24-Hour Profiles of 11-Oxygenated C19 Steroids and Δ5-Steroid Sulfates during Oral and Continuous Subcutaneous Glucocorticoids in 21-Hydroxylase Deficiency

2021 ◽  
Vol 12 ◽  
Author(s):  
Adina F. Turcu ◽  
Ashwini Mallappa ◽  
Aikaterini A. Nella ◽  
Xuan Chen ◽  
Lili Zhao ◽  
...  
Keyword(s):  
Disease Control ◽  
Early Morning ◽  
Response To Treatment ◽  
Consistent Difference ◽  
Serum Samples ◽  
Open Label ◽  
Hydroxylase Deficiency ◽  
Diurnal Variability ◽  
Open Label Phase ◽  
21 Hydroxylase Deficiency

BackgroundOptimal management of androgen excess in 21-hydroxylase deficiency (21OHD) remains challenging. 11-oxygenated-C19 steroids (11-oxyandrogens) have emerged as promising biomarkers of disease control, but data regarding their response to treatment are lacking.ObjectiveTo compare the dynamic response of a broad set of steroids to both conventional oral glucocorticoids (OG) and circadian cortisol replacement via continuous subcutaneous hydrocortisone infusion (CSHI) in patients with 21OHD based on 24-hour serial sampling.Participants and MethodsWe studied 8 adults (5 women), ages 19-43 years, with poorly controlled classic 21OHD who participated in a single-center open-label phase I–II study comparing OG with CSHI. We used mass spectrometry to measure 15 steroids (including 11-oxyandrogens and Δ5 steroid sulfates) in serum samples obtained every 2 h for 24 h after 3 months of stable OG, and 6 months into ongoing CSHI.ResultsIn response to OG therapy, androstenedione, testosterone (T), and their four 11-oxyandrogen metabolites:11β-hydroxyandrostenedione, 11-ketoandrostenedione, 11β-hydroxytestosterone and 11-ketotestosterone (11KT) demonstrated a delayed decline in serum concentrations, and they achieved a nadir between 0100-0300. Unlike DHEAS, which had little diurnal variation, pregnenolone sulfate (PregS) and 17-hydoxypregnenolone sulfate peaked in early morning and declined progressively throughout the day. CSHI dampened the early ACTH and androgen rise, allowing the ACTH-driven adrenal steroids to return closer to baseline before mid-day. 11KT concentrations displayed the most consistent difference between OG and CSHI across all time segments. While T was lowered by CSHI as compared with OG in women, T increased in men, suggesting an improvement of the testicular function in parallel with 21OHD control in men.Conclusion11-oxyandrogens and PregS could serve as biomarkers of disease control in 21OHD. The development of normative data for these promising novel biomarkers must consider their diurnal variability.

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

2021 ◽  
Author(s):  
Richard J Auchus ◽  
Kyriakie Sarafoglou ◽  
Patricia Y Fechner ◽  
Maria G  Vogiatzi ◽  
Erik A Imel ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Adrenal Hyperplasia ◽  
Open Label ◽  
Adrenal Androgen ◽  
Hydroxylase Deficiency ◽  
Clinical Endpoints ◽  
Phase 2 Study ◽  
Open Label Phase ◽  
Factor Type ◽  
21 Hydroxylase Deficiency

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.

scholarly journals SUN-037 Discordant Serum 17-hydroxyprogesterone and Androstenedione in the Management of Congenital Adrenal Hyperplasia: Are 11-oxygenated Androgens Useful?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Smita Jha ◽  
Adina F Turcu ◽  
Ninet Sinaii ◽  
Brittany Brookner ◽  
Padmasree Veeraraghavan ◽  
...  
Keyword(s):  
Disease Control ◽  
Good Control ◽  
Tanner Stage ◽  
Poor Control ◽  
Serum Samples ◽  
Hydroxylase Deficiency ◽  
Monitoring Therapy ◽  
Clinical Control ◽  
Good Disease Control ◽  
21 Hydroxylase Deficiency

Abstract Background 21-hydroxylase-deficiency (21OHD) accounts for more than 95% of CAH cases. Serum 17-hydroxyprogesteron (17OHP) and androstenedione (A4) are traditional biomarkers for monitoring therapy. While generally there is good linear correlation between 17OHP and A4, physicians are likely to encounter scenarios where 17OHP is within “acceptable range” while A4 is elevated and vice versa. Mildly elevated 17OHP is considered acceptable, as normalization of 17OHP is likely to result in overtreatment. 11-ketotestosterone (11KT) is a potent agonist of the androgen receptor with androgenic activity equivalent to testosterone. We hypothesized that patients with high 17OHP would be more likely than those with high A4 to be in good disease control. We speculated that A4 would correlate more strongly with 11-oxygenated C19 steroids (11oxyandrogens) than 17OHP and that patients in poor clinical control would have higher median fold-elevation of 11oxyandrogens, especially 11-KT, compared to controls. Methods We performed retrospective analysis of patients seen at NIH from 2006 to 2019 and identified discordant 17OHP and A4 (17-OHP ≥1200 ng/dL with A4 normal for age/sex or tanner stage and vice-versa). Good or poor clinical control was based on abnormal growth, precocious puberty, irregular menses, hypogonadotrophic hypogonadism and A4/T. Quantitation of 15 steroids in stored peripheral sera was performed by LC-MS/ MS and compared to age- and sex-matched controls. Data between groups were compared using t-tests or non-parametric Wilcoxon rank sum tests. Correlation analyses utilized the Pearson and Spearman’s rho. Results We identified 122 of 789 (15%) discordant laboratory assessments among adults [84 with high 17OHP (69%)] and 347 of 1,949 (18%) among children [319 with high 17OHP (92%)]. Of these, 50 patients with available serum samples were identified (44 with high 17OHP). Twenty-five patients (50%) appeared to have good disease control. There was no difference in the frequency of patients in good or poor control between patients with high 17OHP or those with high A4 (p=0.7). Median fold elevation of 11KT relative to controls was higher in patients in poor control (2.87 fold, IQR 1.87-5.42, range 0.31-10.69) but with wide ranges and substantial overlap compared to those in good control (1.71 fold, IQR 1.06-2.92, range 0.35-16.59, p=0.068). 17OHP correlated with 21-deoxycortisol (rs=0.67, p<.001) while A4 correlated strongly with 11oxyandrogens (rs range 0.42-0.71, p<.003 for all). However, we did not find any substantial difference in the level of 11oxyandrogens between patients with high 17OHP and those with high A4. Conclusion: Discordance between 17OHP and A4 is common in the management of CAH and patients with elevation of either of these biomarkers are equally likely to have poor disease control. Limited evidence suggests a role for 11KT, as a discriminator for disease control.

Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: A phase Ib/II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 312-312
Author(s):  
Mitesh J. Borad ◽  
Li-Yuan Bai ◽  
Ming-Huang Chen ◽  
Joleen M. Hubbard ◽  
Kabir Mody ◽  
...  
Keyword(s):  
Phase Ii ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Preliminary Evidence ◽  
Phase Iii ◽  
Response To Treatment ◽  
Open Label ◽  
Phase Ib ◽  
Open Label Phase ◽  
Almost All

312 Background: Silmitasertib (CX-4945), an oral small molecule inhibitor of casein kinase 2 (CK2), has exhibited preclinical antitumor activity and strong synergism with gemcitabine + cisplatin. We investigated the safety and efficacy of silmitasertib in combination with gemcitabine + cisplatin in patients with unresectable cholangiocarcinoma (CCA). Methods: S4-13-001 is a multicenter, open-label, phase Ib/II study of silmitasertib in combination with gemcitabine + cisplatin in patients with locally advanced or metastatic CCA. The phase Ib portion included dose-escalation, expansion, and exploratory cohorts of silmitasertib with doses ranging from 200 to 1000 mg bid (6 days for the escalation/expansion cohorts and 10 and 21 days’ continuous dosing for the exploratory cohorts). In the phase II portion patients received silmitasertib 1000 mg bid for 10 days in combination with gemcitabine + cisplatin on days 1 & 8 over a 21-day cycle. In this interim analysis, we present findings from the combined population of patients from the phase Ib and II portions of the study. Response to treatment was assessed by RECIST v1.1 every 6 weeks. Primary efficacy outcome measure was progression-free survival (PFS). ClinicalTrials.gov (NCT02128282). Results: A total of 87 patients were enrolled and received silmitasertib in the phase Ib (n=50) and phase II (n=37) portions of the study. Of these, 55 patients were evaluable for efficacy with details as follows: median PFS 11.1 (95% CI 7.6–14.7) months; median overall survival (OS) 17.4 (95% CI 13.4–25.7) months; overall response rate (ORR) 32.1%; and disease control rate (DCR) 79.3%. Almost all patients (79/87; 90.8%) evaluable for safety reported ≥1 treatment-related adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib were diarrhea (65.5%), nausea (50.6%), vomiting (33.3%), fatigue (31.0%), and anemia (21.8%). The most common grade ≥3 TEAEs were diarrhea (13.8%), neutropenia (11.5%), nausea (9.2%), anemia (8.0%), and thrombocytopenia (8.0%). Eleven patients (12.6%) discontinued treatment due to TEAEs. Conclusions: Silmitasertib in combination with gemcitabine + cisplatin yields promising preliminary evidence of efficacy in patients with locally advanced or metastatic CCA. Based on these data a randomized phase III trial is planned. Clinical trial information: NCT02128282.

A randomized, open label, prospective study comparing the association between sorafenib (So) and interleukin-2 (IL-2) versus So alone in advanced untreated renal cell cancer (RCC): Rosorc Trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5099-5099
Author(s):  
G. Procopio ◽  
E. Verzoni ◽  
S. Bracarda ◽  
S. Ricci ◽  
C. Sacco ◽  
...  
Keyword(s):  
Disease Control ◽  
Cell Cancer ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
Antitumoral Activity ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
Open Label Phase ◽  
Hand Foot Syndrome ◽  
Tumour Shrinkage

5099 Background: So is an orally active multikinase inhibitor with a well documented activity in advanced RCC. IL-2 is a pleiotropic cytokine with antitumoral activity depending on dose and schedule. The aim of the study is to evaluate the activity and the safety of So and IL-2 association compared to So alone. Methods: In this multicenter, randomized, open label, phase II study, 128 previously untreated metastatic RCC patients (pts) were randomized to receive 400 mg of So, orally given twice daily continuously, in combination with IL-2, 4.5 MIU administered subcutaneously, five times a week for six consecutive weeks any eight weeks (arm A), or So alone (arm B) at the same dose. Therapy continued until progression of disease or unacceptable toxicity. The primary end point was progression free survival (PFS) and the secondary endpoints were response rate, safety and overall survival. Eligible pts had histological diagnosis of RCC, ECOG 0–2, no brain metastases, measurable disease and any Motzer's score. Pts were stratified according to different histotypes and Motzer's score. Results: All pts were enrolled from October 2006 to February 2008. Response rates (all partial responses, PR) were 23 % and 10 % in arm A and B respectively. Overall disease control rates (PR + stable disease SD) were 81 % versus 74 %. Tumour shrinkage was reported in 52 % and 34 % of arm A and B therapies respectively. Median PFS was 38 weeks (range 6–104+) for So + IL-2 and 30 weeks (range 6–102+) for So alone. PFS at 1 year was 31% in the combination therapy versus 22% in arm B. The most common adverse events (AEs) were asthenia, hand foot syndrome, hypertension, fever, diarrhoea and mucositis. AE were usually low or moderate in severity and always reversible and manageable. Grade 3–4 AE were reported in 33% and 22% in arm A and B, respectively. Conclusions: The safety and efficacy data suggest that the association So + IL-2 is safe and feasible and, compared to So alone, improves tumour shrinkage, disease control rate and PFS. [Table: see text]

scholarly journals 11-oxygenated androgens useful in the setting of discrepant conventional biomarkers in 21-hydroxylase deficiency

2020 ◽  
Author(s):  
Smita Jha ◽  
Adina F Turcu ◽  
Ninet Sinaii ◽  
Brittany Brookner ◽  
Richard J Auchus ◽  
...  
Keyword(s):  
Disease Control ◽  
Good Control ◽  
Signs And Symptoms ◽  
Bone Age ◽  
Menstrual Irregularity ◽  
Hydroxylase Deficiency ◽  
Natural History Study ◽  
Clinical Center ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

Abstract Context Serum 17-hydroxyprogesterone (17OHP) and androstenedione (A4) are the conventional biomarkers used to assess disease control in patients with 21-hydroxylase deficiency (21OHD). However, discrepancy between the two is not uncommon, limiting interpretation. Objective To evaluate 11-oxyandrogens in discriminating good versus poor disease control in 21OHD in the setting of discrepant 17OHP and A4. Setting and Participants Retrospective analysis of 2,738 laboratory assessments obtained as part of Natural History Study of CAH at the NIH Clinical Center. Patients with discrepant 17OHP and A4 and available sera were selected. Methods A 15-steroid mass-spectrometry panel was performed in sera from patients with 21OHD and age- and sex-matched controls. Patients were categorized in “good” or “poor” control based on clinical assessment (bone age advancement, signs and symptoms of precocious puberty, menstrual irregularity, hirsutism, or hypogonadotrophic hypogonadism). Results Discrepant 17OHP and A4 was found in 469 (17%) laboratory assessments. Of these, 403 (86%) had elevated 17OHP with A4 in reference range. Of 46 patients with available sera, 30 (65%) were in good control. Median fold elevation relative to controls was higher in patients with poor versus good control for 11OHT (median [interquartile range], 2.82 [1.25-5.43] vs. 0.91 [0.49- 2.07], P= 0.003), and 11KT (3.57 [2.11-7.41] vs. 1.76 [1.24-4.00], P = 0.047). Fold elevation of 11OHT between 3.48 (sensitivity 97%, specificity 47%) and 3.88 (sensitivity 100%, specificity 40%) provided the best discrimination between poor vs. good control. Conclusion 11-oxyandrogens, especially 11OHT, may be useful in the management of CAH when conventional biomarkers are inconclusive.

A randomized, controlled, open label phase II study of erlotinib (E) with or without the MET antibody emibetuzumab (Emi) as first-line treatment for EGFRmt non-small cell lung cancer (NSCLC) patients who have disease control after an 8-week lead-in treatment with erlotinib.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9019-9019 ◽  
Author(s):  
Giorgio V. Scagliotti ◽  
Denis Moro-Sibilot ◽  
Jens Kollmeier ◽  
Adolfo G. Favaretto ◽  
Eun Kyung Cho ◽  
...  
Keyword(s):  
Disease Control ◽  
Single Agent ◽  
Stage Iv ◽  
Exploratory Analysis ◽  
Clinical Activity ◽  
Open Label ◽  
Egfr Inhibition ◽  
Significant Difference ◽  
Open Label Phase ◽  
Ecog Ps

9019 Background: MET expression is a mechanism of resistance to EGFR inhibition in EGFRmt NSCLC and correlated with poor prognosis. Emi (LY2875358) is a humanized IgG4 monoclonal bivalent MET antibody that blocks ligand dependent and independent HGF/MET signaling. This Phase 2 study compared the clinical activity of Emi + E versus single agent E in 1st line EGFRmt metastatic NSCLC. Methods: Stage IV, EGFRmt NSCLC pts with disease control following an 8-week lead-in E (150 mg PO QD) treatment were randomized 1:1 to receive Emi (750 mg IV Q2W) + E or E alone. Pts were stratified by ECOG PS, ethnicity, MET expression status, and response at the end of the lead-in. The primary endpoint was PFS from randomization. Additional endpoints included safety, OS, PK, and exploratory analysis of MET-expressing populations. Results: Out of181 pts enrolled, 141 pts were randomized (Emi+E: 71; E: 70). In the ITT population, median PFS for EMI+E was 9.3 months (m) compared with 9.5 m for E (HR = 0.89: 90% CI 0.64-1.23; p = 0.534). Exploratory analysis of MET-high expressing pts (MET 3+ expression in ≥90% of tumor cells; n = 24 pts) showed a 15.3 m improvement in PFS (EMI+E: 20.7 m; E: 5.4 m [HR: 0.39; 90% CI: 0.17-0.91]). No difference in PFS was observed in the complementary population (HR: 1.1 [90% CI: 0.7-1.7]). Similar frequencies of related AEs were reported for both treatment arms. Drug-related TEAEs that were more frequent ( > 10%) for Emi+E were peripheral edema and fatigue (all grade 1 or 2). Emi serum concentrations were consistent with previously obtained PK results, and no apparent exposure-response was observed. Median OS in the ITT population was not achieved (NA) for either arm. In MET-high expressing pts, median OS was 20.6 m for E (90% CI: 8.87, NA) whereas it was not achieved for Emi+E (90% CI: NA, NA). Conclusions: No statistically significant difference in PFS was noted in the ITT population.Exploratory analysis confirmed that high MET expression is a negative prognostic marker for pts treated with E and indicated that these pts may receive clinically meaningful benefit from Emi+E. Clinical trial information: NCT01897480.

Bortezomib With or Without Irinotecan in Relapsed or Refractory Colorectal Cancer: Results From a Randomized Phase II Study

2008 ◽  
Vol 26 (14) ◽  
pp. 2320-2326 ◽  
Author(s):  
Peter S. Kozuch ◽  
Caio Max Rocha-Lima ◽  
Tomislav Dragovich ◽  
Howard Hochster ◽  
Bert H. O'Neil ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Sensory Neuropathy ◽  
Primary Objective ◽  
Response To Treatment ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

PurposeTo evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC).Patients and MethodsPatients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m2(arm A) or bortezomib 1.3 mg/m2plus irinotecan 125 mg/m2(arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability.ResultsA preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade ≥ 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B.ConclusionBortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.

scholarly journals Adrenal-derived 11-oxygenated 19-carbon steroids are the dominant androgens in classic 21-hydroxylase deficiency

2016 ◽  
Vol 174 (5) ◽  
pp. 601-609 ◽  
Author(s):  
Adina F Turcu ◽  
Aya T Nanba ◽  
Robert Chomic ◽  
Sunil K Upadhyay ◽  
Thomas J Giordano ◽  
...  
Keyword(s):  
Adrenal Insufficiency ◽  
Cytochrome B5 ◽  
Vena Cava ◽  
Adrenal Vein ◽  
Serum Samples ◽  
Hydroxylase Deficiency ◽  
Men And Women ◽  
Liquid Chromatography Tandem Mass ◽  
21 Hydroxylase Deficiency ◽  
Immunohistochemical Studies

Abstract Objective To comprehensively characterize androgens and androgen precursors in classic 21-hydroxylase deficiency (21OHD) and to gain insights into the mechanisms of their formation. Design Serum samples were obtained from 38 patients (19 men) with classic 21OHD, aged 3–59, and 38 sex- and age-matched controls; 3 patients with 11β-hydroxylase deficiency; 4 patients with adrenal insufficiency; and 16 patients (8 men) undergoing adrenal vein sampling. Paraffin-embedded normal (n = 5) and 21OHD adrenal tissues (n = 3) were used for immunohistochemical studies. Methods We measured 11 steroids in all sera by liquid chromatography-tandem mass spectrometry. Immunofluroescence localized 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) within the normal and 21OHD adrenals. Results Four 11-oxygenated 19-carbon (11oxC19) steroids were significantly higher in male and female 21OHD patients than in controls: 11β-hydroxyandrostenedione, 11-ketoandrostenedione 11β-hydroxytestosterone, and 11-ketotestosterone (3–4-fold, P < 0.0001). For 21OHD patients, testosterone and 11-ketotestosterone were positively correlated in females, but inversely correlated in males. All 11oxC19 steroids were higher in the adrenal vein than in the inferior vena cava samples from men and women and rose with cosyntropin stimulation. Only trace amounts of 11oxC19 steroids were found in the sera of patients with 11β-hydroxylase deficiency and adrenal insufficiency, confirming their adrenal origin. HSD3B2 and CYB5A immunoreactivities were sharply segregated in the normal adrenal glands, whereas areas of overlapping expression were identified in the 21OHD adrenals. Conclusions All four 11oxC19 steroids are elevated in both men and women with classic 21OHD. Our data suggest that 11oxC19 steroids are specific biomarkers of adrenal-derived androgen excess.

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

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 &gt;2x ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results In Study 1, evaluable participants with baseline A4 &gt;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 &gt;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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