Browsing by Author "Fechner, Patricia Y."

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    Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia
    (Endocrine Society, 2022) Auchus, Richard J.; Sarafoglou, Kyriakie; Fechner, Patricia Y.; Vogiatzi, Maria G.; Imel, Erik A.; Davis, Shanlee M.; Giri, Nagdeep; Sturgeon, Julia; Roberts, Eiry; Chan, Jean L.; Farber, Robert H.; Medicine, School of Medicine
    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: This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Methods: This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (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 more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios. Conclusion: 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 end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.
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    Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations
    (Elsevier, 2020-01-12) Hughes, Joel J.; Alkhunaizi, Ebba; Kruszka, Paul; Pyle, Louise C.; Grange, Dorothy K.; Berger, Seth I.; Payne, Katelyn K.; Masser-Frye, Diane; Hu, Tommy; Christie, Michelle R.; Clegg, Nancy J.; Everson, Joshua L.; Martinez, Ariel F.; Walsh, Laurence E.; Bedoukian, Emma; Jones, Marilyn C.; Harris, Catharine Jean; Riedhammer, Korbinian M.; Choukair, Daniela; Fechner, Patricia Y.; Rutter, Meilan M.; Hufnagel, Sophia B.; Roifman, Maian; Kletter, Gad B.; Delot, Emmanuele; Vilain, Eric; Lipinski, Robert J.; Vezina, Chad M.; Muenke, Maximilian; Chitayat, David; Pediatrics, School of Medicine
    In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.
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    OR21-06 Growth Response Of Oral LUM-201 In OraGrowtH210 And OraGrowtH212 Trials In Idiopathic Pediatric Growth Hormone Deficiency (iPGHD): Combined Analysis Interim Analysis Data
    (The Endocrine Society, 2023-10-05) Tansey, Michael J.; Bowden, Sasigarn Arunchaiya; Dauber, Andrew Nahum; Wikiera, Beata; Pyrzak, Beata; Bossowski, Artur T.; Petriczko, Elzbieta; Stawerska, Renata; Moszczynska, Elzbieta; Cassorla, Fernando; Feldt, Matthew M.; Lunsford, Alison J.; Gottschalk, Michael Everett; Marin, Monica; Nayak, Sunil N.; Bhuvana, Sunil; Repaske, David Roy; Soyka, Leslie Ann; Fuqua, John S.; Escobar, Oscar; Bowlby, Deborah A.; Fechner, Patricia Y.; Wiltshire, Esko; Harris, Mark; Wintergerst, Kupper A.; Lafferty, Antony Richard A.; Miller, Bradley S.; Simm, Peter; Bruchey, Aleksandra; Smith, Christopher; Karpf, David B.; McKew, John C.; Thorner, Michael O.; Pediatrics, School of Medicine
    Background: LUM-201 (ibutamoren), a growth hormone (GH) secretagogue receptor 1a (GHSR1a) agonist, is a potent, long-acting investigational oral GH secretagogue currently studied in three Idiopathic Pediatric GH Deficiency (iPGHD) studies. The LUM-201 predictive enrichment marker (PEM) is used to identify patients diagnosed with iPGHD (peak stimulated GH >3<10 ng/mL) who are likely to respond to LUM-201. PEM positivity is defined as a baseline insulin-like growth factor-1 (IGF-1) level >30 ng/mL and a peak GH of ≥5 ng/mL in response to a single 0.8 mg/kg dose of LUM-201. Objectives: Report the growth response analyzing the combined interim analysis (IA) data from two Phase 2 trials studying LUM-201 at two different doses (1.6 mg/kg/day or 3.2 mg/kg/day). Methods: IA data from both studies were combined and analyzed for calculated annualized height velocity (AHV). Baseline demographics were analyzed for the two combined cohorts. Results: After 6 months of treatment with LUM-201, the calculated AHV (mean ±SD ) was 8.1±1.9 cm/year in the 1.6 mg/kg/day group and 8.0±1.5 cm/year in the 3.2 mg/kg/day group (N=15 in both groups). After 9 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.3±1.7 cm/year in the 3.2 mg/kg/day group (N=10 in both groups). After 12 months of treatment, the calculated AHV was 7.8±1.7 cm/year in the 1.6 mg/kg/day group and 7.4 ±1.2 cm/year in the 3.2 mg/kg/day group (N=6 in both groups). LUM-201 was well tolerated; no safety concerns were identified across the dose range in adverse events (AE) data, laboratory values, and ECG values. Conclusions: As the growth velocity was comparable for the two doses of oral LUM-201, this analysis of the combined IA data appears to strongly support 1.6 mg/kg/day as the optimal dose for the Phase 3 trial, as doubling the dose appeared to offer no meaningful improvement in efficacy. Final determination will await final full data set analysis of both studies.
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    Prevention of Growth Failure in Turner Syndrome: Long-Term Results of Early Growth Hormone Treatment in the “Toddler Turner” Cohort
    (Karger, 2021-07) Quigley, Charmian A.; Fechner, Patricia Y.; Geffner, Mitchell E.; Eugster, Erica A.; Ross, Judith L.; Habiby, Reema L.; Ugrasbul, Figen; Rubin, Karen; Travers, Sharon; Antalis, Caryl J.; Patel, Hiren N.; Davenport, Marsha L.; Pediatrics, School of Medicine
    Introduction: In the randomized “Toddler Turner” study, girls who received growth hormone (GH) starting at ages 9 months to 4 years (early-treated [ET] group) had marked catch-up growth and were 1.6 ± 0.6 SD taller than untreated (early-untreated [EUT]) control girls after 2 years. However, whether the early catch-up growth would result in greater near-adult height (NAH) was unknown. Therefore, this extension study examined the long-term effects of toddler-age GH treatment on height, pubertal development, and safety parameters. Methods: Toddler Turner study participants were invited to enroll in a 10-year observational extension study for annual assessments of growth, pubertal status, and safety during long-term GH treatment to NAH for both ET and EUT groups. Results: The ET group was taller than the EUT group at all time points from preschool to maturity and was significantly taller at the onset of puberty (p = 0.016), however, the difference was not significant at NAH. For the full cohort (ET + EUT combined, n = 50) mean (± SD) NAH was 151.2 ± 7.1 cm at age 15.0 ± 1.3 years. NAH standard deviation score (SDS) was within the normal range (>−2.0) for 76% of ET and 60% of EUT subjects (68% overall) and correlated strongly with height SDS at GH start (r = 0.78; p < 0.01), which in turn had a modest inverse correlation with age at GH start (i.e., height SDS declined with increasing age in untreated girls [r = −0.30; p = 0.016]). No new safety concerns arose. Conclusion: Although the ET group was taller throughout, height SDS at NAH was not significantly different between groups due to catch-down growth of ET girls during lapses in GH treatment after the Toddler study and similar long-term GH exposure overall. Early initiation of GH by age 6 years, followed by uninterrupted treatment during childhood, can prevent ongoing growth failure and enable attainment of height within the normal range during childhood, adolescence, and adulthood.
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    A View from the past into our collective future: the oncofertility consortium vision statement
    (Springer, 2021-01) Woodruff, Teresa K.; Ataman-Millhouse, Lauren; Acharya, Kelly S.; Almeida-Santos, Teresa; Anazodo, Antoinette; Anderson, Richard A.; Appiah, Leslie; Bader, Joy; Becktell, Kerri; Brannigan, Robert E.; Breech, Lesley; Bourlon, Maria T.; Bumbuliene, Žana; Burns, Karen; Campo-Engelstein, Lisa; Campos, Jacira R.; Centola, Grace M.; Chehin, Mauricio Barbour; Chen, Diane; De Vos, Michel; Duncan, Francesca E.; El-Damen, Ahmed; Fair, Douglas; Famuyiwa, Yemi; Fechner, Patricia Y.; Fontoura, Paula; Frias, Olivia; Gerkowicz, Sabrina A.; Ginsberg, Jill; Gracia, Clarisa R.; Goldman, Kara; Gomez-Lobo, Veronica; Hazelrigg, Brent; Hsieh, Michael H.; Hoyos, Luis R.; Hoyos-Martinez, Alfonso; Jach, Robert; Jassem, Jacek; Javed, Murid; Jayasinghe, Yasmin; Jeelani, Roohi; Jeruss, Jacqueline S.; Kaul-Mahajan, Nalini; Keim-Malpass, Jessica; Ketterl, Tyler G.; Khrouf, Mohamed; Kimelman, Dana; Kusuhara, Atsuko; Kutteh, William H.; Laronda, Monica M.; Lee, Jung Ryeol; Lehmann, Vicky; Letourneau, Joseph M.; McGinnis, Lynda K.; McMahon, Eileen; Meacham, Lillian R.; Velez Mijangos, Monserrat Fabiola; Moravek, Molly; Nahata, Leena; Ogweno, George Moses; Orwig, Kyle E.; Pavone, Mary Ellen; Peccatori, Fedro Alessandro; Pesce, Romina Ileana; Pulaski, Hanna; Quinn, Gwendolyn; Quintana, Ramiro; Quintana, Tomas; de Carvalho, Bruno Ramalho; Ramsey-Goldman, Rosalind; Reinecke, Joyce; Reis, Fernando M.; Rios, Julie; Rhoton-Vlasak, Alice S.; Rodriguez-Wallberg, Kenny A.; Roeca, Cassandra; Rotz, Seth J.; Rowell, Erin; Salama, Mahmoud; Saraf, Amanda J.; Scarella, Anibal; Schafer-Kalkhoff, Tara; Schmidt, Deb; Senapati, Suneeta; Shah, Divya; Shikanov, Ariella; Shnorhavorian, Margarett; Skiles, Jodi L.; Smith, James F.; Smith, Kristin; Sobral, Fabio; Stimpert, Kyle; Su, H. Irene; Sugimoto, Kouhei; Suzuki, Nao; Thakur, Mili; Victorson, David; Viale, Luz; Vitek, Wendy; Wallace, W. Hamish; Wartella, Ellen A.; Westphal, Lynn M.; Whiteside, Stacy; Wilcox, Lea H.; Wyns, Christine; Xiao, Shuo; Xu, Jing; Zelinski, Mary; Pediatrics, School of Medicine
    Purpose: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. Methods: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. Results: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. Conclusion: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.