Hypoaldosteronism

Neurocrine Biosciences announced on its official website that the U.S. FDA has accepted two New Drug Applications (NDA) from the company, both with priority review designation, for the treatment of classic congenital adrenal hyperplasia (CAH) in children, adolescents, and adults using crinecerfont. If approved, crinecerfont will be the first new treatment option for CAH in 70 years and represents a novel therapeutic approach, offering a new treatment method for this rare and severe endocrine disorder. Crinecerfont is an orally administered selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist currently under development for the treatment of congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency. It works through a mechanism independent of glucocorticoids to reduce and control excessive levels of adrenocorticotropic hormone (ACTH) and adrenal androgens. Antagonizing CRF1 receptors in the pituitary gland has been shown to decrease ACTH levels, thereby reducing adrenal androgen production and potentially alleviating symptoms associated with CAH. Research data on crinecerfont indicates that lowering adrenal androgen levels can result in glucocorticoid dosages that are lower and more physiologically friendly, thereby potentially reducing complications in CAH patients due to exposure to higher-than-normal doses of glucocorticoids. The NDAs submitted by Neurocrine Biosciences for crinecerfont include: (1) a capsule formulation (NDA# 218808) and (2) an oral solution formulation (NDA# 218820), both showcasing the primary efficacy and safety of crinecerfont for treating classic congenital adrenal hyperplasia (CAH). Congenital Adrenal HyperplasiaCongenital Adrenal Hyperplasia (CAH) is a genetic disorder characterized by enzyme deficiencies in the synthesis of adrenal corticosteroids, leading to insufficient production of cortisol and/or aldosterone. The most common form is 21-hydroxylase deficiency, accounting for 90%-95% of typical cases. This deficiency disrupts the conversion of adrenal precursors to cortisol, and in some cases, results in aldosterone deficiency, occasionally causing severe hyponatremia and hyperkalemia. The accumulated hormone precursors are diverted into androgen production, resulting in masculinization. CAH is an autosomal recessive genetic condition, manifesting in individuals who are homozygous for the disease-causing gene (i.e., they have two copies), while heterozygous carriers (i.e., individuals with one copy of the gene) remain asymptomatic. New treatments for 21-hydroxylase deficiency (21OHD) include the use of improved controlled-release formulations of hydrocortisone (e.g., Plenadren®, Chronocort®) or improved glucocorticoid (GC) delivery methods such as continuous subcutaneous hydrocortisone infusion (CSHI). These approaches are associated with more effective suppression of the hypothalamic-pituitary-adrenal (HPA) axis-driven adrenal androgen production. Moreover, blocking the production of adrenal androgens driven by the HPA axis can be further achieved through blocking corticotropin-releasing hormone (CRH) receptors (e.g., Tildacerfont, crinecerfont) or ACTH receptors. Adrenal androgen production can also be suppressed by adrenal steroidogenesis inhibitors (e.g., Nevanimibe, abiraterone acetate), adrenotoxic drugs (e.g., mitotane), or bilateral adrenalectomy. Inhibiting the aromatization of adrenal androgens may reduce the suppressive effect of estrogens on growth, while the (combined) use of anti-androgens may inhibit the effects of excess androgens. Gene and cell-based therapies are anticipated to restore the production of glucocorticoids and mineralocorticoids regulated by the HPA axis. Crinecerfont (SSR-125543) is a selective CRF1 receptor antagonist originally developed by Sanofi. Early preclinical studies demonstrated that this molecule exhibited antidepressant effects in animal models.  However, subsequent clinical trials, specifically Phase II studies aimed at investigating its antidepressant efficacy, ended in failure. Neurocrine Biosciences was also among the first companies globally to initiate the development of CRF1 receptor antagonists. The company partnered with Janssen Pharmaceuticals to develop CRF1 receptor antagonists for the treatment of a range of psychiatric, neurological, and gastrointestinal disorders including anxiety, depression, and irritable bowel syndrome. In 1996, Neurocrine Biosciences went public through an initial public offering and was listed on the NASDAQ stock exchange. Following the IPO, Neurocrine Biosciences embarked on clinical development collaborations with Eli Lilly and GlaxoSmithKline (GSK) to explore CRF antagonists (such as NBI-34041) for the treatment of obesity, Alzheimer's disease, and as antidepressants. Nonetheless, many of these clinical developments also ended in failure. In 2015, Neurocrine Biosciences disclosed a patent where CRF1 receptor antagonists were used to treat congenital adrenal hyperplasia (CAH). The company demonstrated the potential of CRF1 receptor antagonists to directly inhibit the release of ACTH in patients with CAH, which in turn could reduce the physiological dosage of hydrocortisone necessary, normalize androgen production, and thereby reduce treatment-related side effects. It is worth mentioning that the method cited in the patent claims involves several CRF1 antagonist products reported on the market, including the original research products NBI-30775 and NBI-34041, as well as SSR-126374, SSR-125543, antalarmin, and DMP904. After nearly 30 years, the company finally published the results of its research in a study titled "Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia" in The New England Journal of Medicine in 2024. This study demonstrated the efficacy and safety of the CRF1 antagonist product Crinecerfont, originally developed by Sanofi as SSR-125543, in the treatment of congenital adrenal hyperplasia. The results show that among the total of 182 patients who participated in a 24-week trial, by week 24, there was a -27.3% change in the dosage of glucocorticoids in the Crinecerfont group compared to -10.3% in the placebo group. In the Crinecerfont group, 63% of patients reported glucocorticoid dosages within physiological levels, whereas in the placebo group, this proportion was 18%. Fatigue and headache were the most common adverse events in both trial groups. The conclusion indicates that in patients with congenital adrenal hyperplasia, the use of Crinecerfont as opposed to placebo resulted in a greater reduction in mean daily glucocorticoid dosage, including reductions to within the physiological range, following assessment of adrenal androgen levels. How to obtain the latest research advancements in the field of biopharmaceuticals? 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Post Hoc Analyses of Phase 2 Study of Crinecerfont in Adults with CAH Demonstrate Androgen Reduction Across a Broad Range of Glucocorticoid Doses Post Hoc Analyses of Phase 3 Study Demonstrate EFMODY® (hydrocortisone modified-release hard capsules) Reduced Androgen Levels Compared to Immediate-Release Hydrocortisone in Patients with CAH SAN DIEGO, May 12, 2023 /PRNewswire/ -- Neurocrine Biosciences, Inc. (Nasdaq: NBIX), a leading neuroscience-focused biopharmaceutical company, today announced that it will present new analyses of Phase 2 data of the investigational drug crinecerfont in adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) and post hoc analyses of Phase 3 data for EFMODY® (hydrocortisone modified-release hard capsules). EFMODY is approved by the European Commission for the European Economic Area (including Northern Ireland) (EEA) and by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of adults and adolescents (12 years and older) with CAH. These new data and an additional poster showing Phase 2 data of crinecerfont in adolescents with classic CAH will be presented at ECE 2023, the 25th European Congress of Endocrinology in Istanbul, Turkey from May 13–16. In previously reported Phase 2 study data, crinecerfont treatment for 14 days led to clinically meaningful reductions of 17–hydroxyprogesterone (17OHP), adrenocorticotropic hormone (ACTH), and androstenedione in adults with classic CAH due to 21-OHD. Post hoc analyses of these data released today assessed whether baseline hormone levels and glucocorticoid (GC) doses correlated with treatment response. A strong correlation was found between baseline level and change from baseline to Day 14 for 17OHP, ACTH, and androstenedione, with the greatest reductions from baseline observed in subjects with the highest baseline hormone level. These results indicate that adults with classic CAH who have more elevated baseline hormone levels have the potential for a greater response to treatment with crinecerfont. However, reductions in androgen levels were seen in patients regardless of their GC dose at baseline. See the abstract (Poster #274; Response to Crinecerfont Treatment in Adults with Classic Congenital Adrenal Hyperplasia is Correlated with Elevated Baseline Hormone Levels, but Not Glucocorticoid Dose) for more information here. "Androgen excess is a hallmark feature of classic congenital adrenal hyperplasia. These analyses demonstrate that the effectiveness of crinecerfont in reducing androgen levels in this study correlated with baseline hormone level, irrespective of GC dose. Patients with higher baseline androgens experienced greater reductions following treatment with crinecerfont, which supports the potential of crinecerfont in providing improved androgen control across a broad range of CAH patients," said Eiry W. Roberts, M.D., Chief Medical Officer at Neurocrine Biosciences. "We plan to announce top-line data from our Phase 3 CAHtalyst clinical studies of crinecerfont in children, adolescents, and adults in the fourth quarter of 2023." Treatment of adults with crinecerfont was generally well tolerated with no related serious adverse events reported. Adverse events reported in two or more participants included headache, upper respiratory tract infection, fatigue, contusion (bruising), insomnia, nasopharyngitis, pyrexia, and nausea. EFMODY has been shown to replicate the natural circadian rhythm of cortisol and reduce androgen levels in CAH patients. In a Phase 3 study, adults with classic CAH were randomized to continue standard therapy with immediate-release hydrocortisone or receive EFMODY modified-release hydrocortisone capsules (MRHC) at the same hydrocortisone dose equivalent. In the MRHC group, it was found that MRHC (which demonstrated similar bioavailability to immediate-release hydrocortisone) provided a greater reduction in 17-OHP standard deviation score 24-hour profile than was seen in the standard therapy group. The more physiological exposure pattern provided by MRHC means that patients previously on other GC therapy, experienced greater reduction in androgen levels at an equivalent dose of MRHC. These data will be part of an oral presentation (Oral Presentation, May 15, 2:20–2:30pm: Switching Patients with Congenital Adrenal Hyperplasia to Modified-Release Hydrocortisone Capsules: Relative Bioavailability and Disease Control). See more information here. "Findings of these new analyses of the EFMODY study provide prescribing physicians with dosing guidance for this alternative to immediate-release hydrocortisone, which reduces androgen levels at similar dose levels, while replicating cortisol diurnal rhythm in patients with CAH," Dr. Roberts added. In the entire EFMODY development clinical trial program, the overall most common serious adverse events were acute adrenal insufficiency (4.2 percent of patients treated with EFMODY). Other common reactions in relation to EFMODY were fatigue (11.7 percent of patients), headache (7.5 percent), increased appetite (5.8 percent), dizziness (5.8 percent) and increased weight (5.8 percent). Additional Presentation: – Selected as one of the Top 40 Posters at ECE (Poster #P1); Crinecerfont (NBI-74788), a Novel CRF1 Receptor Antagonist, Lowers Adrenal Androgens and Precursors in Adolescents with Classic Congenital Adrenal Hyperplasia Neurocrine Biosciences is developing crinecerfont, an investigational, oral, steroid-independent, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist for the treatment of classic CAH due to 21-OHD. Neurocrine has completed enrollment in Phase 3 global registrational studies of crinecerfont in adults (18 years of age and older) and children and adolescents (2 to 17 years of age) with classic CAH, called the CAHtalyst™ and CAHtalyst™ Pediatric studies, respectively. As part of the CAHtalyst clinical trial program, participants who complete these trials will be able to continue to receive crinecerfont as part of an open-label extension. Classic CAH is a rare autosomal disease caused by a genetic defect in one of the enzymes (21-OHD) involved in the production of adrenal hormones. The disorder is characterized by cortisol deficiency and often also aldosterone deficiency, elevated adrenocorticotropic (ACTH) levels, and excess production of adrenal androgens (including androstenedione). Cortisol deficiency can lead to adrenal crises, while androgen excess can lead to virilization in females, abnormalities in growth leading to short stature, early puberty, and infertility. EFMODY was developed by Diurnal Ltd. and is a preparation of hydrocortisone that has been specifically designed to replicate the natural circadian rhythm of cortisol, when given in a twice-a-day "toothbrush" regimen, (administered last thing at night before sleep and first thing in the morning on waking), to improve androgen control and chronic fatigue in patients with cortisol deficiency. It is a multi-particulate formulation presented as a capsule and is available in doses of 5 mg and 10 mg. Neurocrine Biosciences acquired Diurnal Group plc. in November 2022. About Classic Congenital Adrenal Hyperplasia (CAH) Congenital adrenal hyperplasia (CAH) refers to a group of genetic conditions that result in an enzyme deficiency that alters the production of adrenal hormones. Approximately 95 percent of CAH cases are caused by a mutation that leads to deficiency of the enzyme 21-hydroxylase (21-OHD). In classic CAH, severe deficiency of this enzyme leads to an inability of the adrenal glands to produce cortisol and, in approximately 75 percent of cases, aldosterone. If left untreated, classic CAH can result in salt wasting, dehydration, and even death. There are currently no steroid-independent treatments approved by the U.S. Food and Drug Administration (FDA) for classic CAH. Glucocorticoids, the current standard of care, are used to correct the endogenous cortisol deficiency and to try to reduce the high adrenocorticotropic hormone (ACTH) levels resulting in androgen excess. However, standard glucocorticoid treatment at dosing well above the normal physiological level for androgen control has been associated with serious and significant complications of steroid excess, including metabolic abnormalities, increased cardiovascular risk, bone loss, fractures, growth impairment, muscle weakness, and increased infection risk. Androgen excess has been associated with virilization in females, abnormalities in growth leading to short stature, early puberty, and infertility. To learn more about CAH, click here. About Crinecerfont Crinecerfont is an investigational, oral, steroid-independent, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist under evaluation for the treatment of classic CAH due to 21-hydroxylase deficiency (21-OHD). Antagonism of CRF1 receptors in the pituitary has been shown to decrease adrenocorticotropic hormone (ACTH) levels, which in turn could decrease the production of adrenal androgens and potentially the symptoms associated with classic CAH. Research also suggests that lowering androgen levels may enable lower, more physiologic dosing of glucocorticoids and thus potentially reduce the complications associated with exposure to greater than normal glucocorticoid doses in patients with classic CAH. To learn more about crinecerfont, click here. About CAHtalyst™ Studies Neurocrine Biosciences has completed enrollment in Phase 3 global registrational studies of crinecerfont in adults (18 years of age and older) and children and adolescents (ages 2 to 17 years of age) with classic CAH. As part of the CAHtalyst™ clinical trial program, participants who completed these trials will be able to continue to receive crinecerfont as part of an open-label extension. We plan to announce top-line data from our Phase 3 CAHtalyst clinical studies in the fourth quarter of 2023. Treatment with crinecerfont was generally well tolerated in adolescent and adult participants with no related serious adverse events or discontinuations due to adverse events. Treatment-emergent adverse events reported in two or more participants included headache, dizziness, upper respiratory tract infection, fatigue, contusion (bruising), insomnia, nasopharyngitis, pyrexia, and nausea. For more information about the adult CAHtalyst™ Phase 3 study, please visit cahtalyst.cahstudies.com and ClinicalTrials.gov. For more information about the pediatric CAHtalyst™ Phase 3 study, please visit cahtalystpeds.cahstudies.com and ClinicalTrials.gov. About EFMODY® EFMODY is a modified-release preparation of hydrocortisone that has been specifically designed to replicate the natural circadian rhythm of cortisol when given in a twice-a-day "toothbrush" regimen (last thing at night before sleep and first thing in the morning on waking) to reduce excess androgens and chronic fatigue in patients with diseases of cortisol deficiency. In 2021, EFMODY received marketing authorization from the Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain (England, Wales, and Scotland) and from the European Commission in the European Economic Area (including Northern Ireland). About Neurocrine Biosciences Neurocrine Biosciences is a leading neuroscience-focused, biopharmaceutical company with a simple purpose: to relieve suffering for people with great needs, but few options. We are dedicated to discovering and developing life-changing treatments for patients with under-addressed neurological, neuroendocrine, and neuropsychiatric disorders. The company's diverse portfolio includes FDA-approved treatments for tardive dyskinesia, Parkinson's disease, endometriosis* and uterine fibroids*, as well as a robust pipeline including multiple compounds in mid- to late-phase clinical development across our core therapeutic areas. For three decades, we have applied our unique insight into neuroscience and the interconnections between brain and body systems to treat complex conditions. We relentlessly pursue medicines to ease the burden of debilitating diseases and disorders, because you deserve brave science. For more information, visit neurocrine.com, and follow the company on LinkedIn, Twitter and Facebook. (*in collaboration with AbbVie) Neurocrine and the Neurocrine logo are registered trademarks and CAHtalyst is a trademark of Neurocrine Biosciences, Inc. EFMODY is a registered trademark of Diurnal Ltd. Neurocrine Biosciences Forward-Looking Statement In addition to historical facts, this press release contains forward-looking statements that involve a number of risks and uncertainties. These statements include, but are not limited to, statements regarding the potential benefits of crinecerfont to patients and future clinical development plans as well as statements regarding the potential benefits to be derived from certain of our products. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements include: our future financial and operating performance; risks and uncertainties associated with the commercialization of our products; the risk that our products and/or product candidates will not be found to be safe and/or effective or may not prove to be beneficial to patients; that development activities for our products and/or product candidates may not be completed on time or at all; risks that clinical development activities may be delayed for regulatory or other reasons, may not be successful or replicate previous and/or interim clinical trial results, or may not be predictive of real-world results or of results in subsequent clinical trials; risks that regulatory submissions for our products and/or product candidates may not occur or be submitted in a timely manner; risks that our products and/or product candidates may not obtain regulatory approvals; or that the U.S. Food and Drug Administration or regulatory authorities outside the U.S. may make adverse decisions regarding our products and/or product candidates; risks and uncertainties relating to competitive products and technological changes that may limit demand for our products; risks associated with our dependence on third parties for development and manufacturing activities related to our products and our product candidates, and our ability to manage these third parties; and other risks described in the Company's periodic reports filed with the Securities and Exchange Commission, including without limitation the Company's quarterly report on Form 10-Q for the quarter ended March 31, 2023. Neurocrine Biosciences disclaims any obligation to update the statements contained in this press release after the date hereof. SOURCE Neurocrine Biosciences, Inc.

PHOENIX, Sept. 28, 2022 /PRNewswire/ -- The Primary Aldosteronism Foundation ("Foundation"), has announced today the creation of a multistakeholder alliance to drive diagnosis and treatment of primary aldosteronism, a common cause of hypertension. Among the partners is Mineralys Therapeutics, Inc, a biopharmaceutical company developing a novel therapy for the treatment of hypertension. The initiative will facilitate the design and implementation of interventions to advance standards of care for primary aldosteronism, a highly prevalent adrenal disease and common cause of hypertension. Primary aldosteronism is neither diagnosed nor treated 95 percent of the time despite causing significant cardiovascular and renal damage along with systemic inflammation. "The Alliance was formed to highlight the unmet medical needs of millions of patients," said Marianne Leenaerts, co-founder and co-director of the Foundation. "For the first time since the discovery of the disease over 60 years ago, collaborative work will drive actions to remediate this major public health issue by addressing the factors preventing timely and adequate provision of care." This critical step precedes a much-anticipated paradigm shift in the medical treatment of primary aldosteronism with the advent of aldosterone synthase inhibitors, a new class of drugs that, for the very first time, will enable the lowering of aldosterone. "We are happy to partner with the Foundation to raise awareness for the diagnosis, treatment and management of aldosterone driven disorders such as primary aldosteronism," said Jon Congleton, chief executive officer, Mineralys Therapeutics. "Abnormal aldosterone levels are a common cause of hypertension making this a significant imperative. Together with the Foundation, we hope to address the standards of care for hypertension and primary aldosteronism and support its commitment to hypertension prescribers, patients and caregivers." Founding members of the Alliance include U.S. medical societies and stakeholders involved in care delivery, clinical research, and public health. Consensus has emerged to begin work by focusing on primary and specialized care, furthering the research agenda, and improving current guidelines. The initiative looks to grow its membership across the entire healthcare sector through 2023 and beyond. About the Primary Aldosteronism Foundation A 501(c)(3) tax-exempt charitable organization, the Primary Aldosteronism Foundation is headquartered in Phoenix, AZ. The organization is dedicated to advancing standards of care for patients by: Designing and implementing interventions with healthcare stakeholders and industry leaders to address patients' unmet medical needs; Promoting innovative ways to reach those who are undiagnosed, and to include their lived experiences in care and research processes; Advocating research funding proportional to the number of affected patients with the aim to fill the knowledge gap about excess aldosterone, and to translate such knowledge into diagnostic and therapeutic solutions. About Mineralys Therapeutics, Inc. Headquartered in Philadelphia, PA, Mineralys Therapeutics, Inc. is a private, clinical-stage biopharmaceutical company committed to developing best-in-class, novel therapy for the treatment of hypertension. The Company is driven to bring a targeted approach to the management of hypertension via the development of MLS-101. MLS-101, licensed from Mitsubishi Tanabe Pharma Corporation, is a highly selective and potent aldosterone synthase inhibitor that is being investigated for the treatment of hypertension. For more information, please visit . Contact: Marianne Leenaerts Primary Aldosteronism Foundation Phone: +1 (602) 726-0665 Email: [email protected] SOURCE Primary Aldosteronism Foundation