Congenital Adrenal Hyperplasia Due to 21 Hydroxylase Deficiency

Company Today Also Provided Updates on R&D Portfolio and Strategy at Investor Event Crinecerfont New Drug Application Submission Planned in 2024 NBI-'770, an Oral NMDA NR2B Negative Allosteric Modulator, Entering Phase 2 for the Treatment of Major Depressive Disorder Advancing Largest Portfolio of Muscarinic Compounds in Clinical Development Top-Line Phase 2 Data Readouts for Five Programs Anticipated in 2024 Including NBI-'568, an M4 Agonist, for the Treatment of Schizophrenia SAN DIEGO, Dec. 5, 2023 /PRNewswire/ -- Neurocrine Biosciences, Inc. (Nasdaq: NBIX) today announced it received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for crinecerfont in congenital adrenal hyperplasia. The Company also provided updates on its R&D portfolio and strategy at its Analyst Day, held in New York. "We are very pleased that the FDA granted Breakthrough Therapy designation for crinecerfont, thus recognizing both the seriousness of congenital adrenal hyperplasia and the significant unmet need currently faced by patients and families living with this condition," said Eiry W. Roberts, Chief Medical Officer, Neurocrine Biosciences. "The outstanding safety and efficacy results from the Phase 3 CAHtalyst™ studies in pediatric and adult patients suggest that crinecerfont has the potential to represent a substantial improvement over current standard of care in CAH by controlling androgen levels and allowing for reduced steroid doses. We remain on track to submit the new drug application in 2024." 2023 Analyst Day R&D Portfolio and Strategy Updates At today's Analyst Day, Neurocrine Biosciences provided an update on its R&D portfolio and strategy, including the Company's focus on building breadth and depth across therapeutic areas and modalities with key focus areas in VMAT2 inhibition, CRF antagonism, muscarinic agonism to antagonism, and gene therapy. With a diversified early-stage portfolio spanning a range of modalities including small molecules and biologics, and a growing pre-clinical and development candidate portfolio, Neurocrine is uniquely positioned to advance a steady flow of innovative clinical candidates to patients across its neuroscience-focused therapeutic areas of interest. The Company remains on-track to advance two gene therapies into the clinic in 2025, and anticipates at least 20 development candidates by 2027. Other key portfolio and pipeline updates include: Valbenazine Ongoing Phase 3 study of valbenazine in adjunctive treatment of schizophrenia (ATS) will inform potential advancement of NBI-'890, a next-generation, long-acting VMAT2 inhibitor, which we anticipate will enter the clinic in 2024 No additional Phase 3 studies of valbenazine in ATS planned NBI-'770 (Oral, NMDA NR2B Negative Allosteric Modulator) Represents a potential first-in-class opportunity on a clinically validated target Program entering Phase 2 for treatment of major depressive disorder Muscarinic Compounds Validated and differentiated mechanisms of action Five programs represent largest number of muscarinic assets in human studies, including lead molecule, NBI-'568, in Phase 2 study for the treatment of schizophrenia 2024 portfolio will include four Phase 1 programs: NBI-'570 (dual M1/M4 agonist) NBI-'567 (M1-preferring agonist) NBI-'569 (M4-preferring agonist) NBI-'986 (M4 antagonist, internally discovered at Neurocrine Biosciences) Phase 2 Top-Line Clinical Data Expected in 2024 NBI-'568 (M4 agonist) for the treatment of schizophrenia Luvadaxistat (DAAO inhibitor) for cognitive impairment associated with schizophrenia NBI-'845 (AMPA potentiator) for inadequate response to treatment in major depressive disorder Efmody (long-acting glucocorticoid) for adrenal insufficiency Efmody for congenital adrenal hyperplasia About Breakthrough Therapy Designation Breakthrough Therapy designation is a process developed by the FDA to expedite development and review of drugs that are intended to treat a serious condition and where clinical evidence indicates that the potential drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s). To learn more about Breakthrough Therapy designation, click here. About Classic Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia (CAH) refers to a group of genetic conditions that result in an enzyme deficiency that alters the production of adrenal hormones which are essential for life. Approximately 95% 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% of cases, aldosterone. If left untreated, classic CAH can result in salt wasting, dehydration, and even death. There are currently no non-glucocorticoid treatments approved by the U.S. Food and Drug Administration (FDA) for classic CAH. Glucocorticoids (GCs), the current standard of care, are used not only to correct the endogenous cortisol deficiency but typically used at greater than physiologic (supraphysiologic) doses to try to suppress the high levels of corticotropin-releasing factor (CRF) and adrenocorticotropic hormone (ACTH) that result in androgen excess. However, glucocorticoid treatment at supraphysiologic doses has been associated with serious and significant complications of steroid excess, including metabolic issues such as weight gain and diabetes, cardiovascular disease, and osteoporosis. Additionally, long-term treatment with supraphysiologic GC doses may have psychological and cognitive impact such as changes in mood and memory. Androgen excess has been associated with abnormal bone growth and development in pediatric patients, female health problems such as acne, excess hair growth and menstrual irregularities, testicular rest tumors in males, and fertility issues in both sexes. To learn more about CAH, click here. About Corticotropin Releasing Factor (CRF) Corticotropin releasing factor (CRF) regulates the secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland. The neuropeptide was discovered, isolated and identified by the late Wylie W. Vale, PhD., a founder of Neurocrine Biosciences who led the Clayton Foundation Laboratories for Peptide Biology and was the Helen McLoraine Chair in Molecular Neurobiology at the Salk Institute. Dr. Vale mapped the key role CRF played in the regulation of the stress response. In the 95% of classic CAH cases caused by a mutation in the 21-hydroxylase enzyme, the severe enzyme deficiency results in little or no production of the stress hormone cortisol, which can lead to adrenal crisis. The lack of cortisol production also causes a break in the feedback loop that would normally regulate the body's secretion of CRF, and as a result ACTH, which maintains adrenal androgen production within normal ranges. About Crinecerfont Crinecerfont is an investigational, oral, selective corticotropin-releasing factor type 1 receptor (CRF1) antagonist being developed to reduce and control excess adrenal androgens through a steroid-independent mechanism for the treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). The compound was identified by Dimitri Grigoriadis, Ph.D., Chief Research Officer at Neurocrine Biosciences who conducted post-graduate research with Dr. Wylie Vale at the Salk Institute. Antagonism of CRF1 receptors in the pituitary has been shown to decrease adrenocorticotropic hormone (ACTH) levels, which in turn decreases the production of adrenal androgens and potentially the symptoms associated with classic CAH. Our data demonstrates that lowering androgen levels enables lower, more physiologic dosing of glucocorticoids and thus could potentially reduce the complications associated with exposure to greater than normal glucocorticoid doses in patients with classic CAH. Prior to receiving Breakthrough Therapy designation from the FDA, crinecerfont also received Fast Track and Rare Pediatric Disease designations in congenital adrenal hyperplasia. To learn more about crinecerfont, click here. About the CAHtalyst Phase 3 Studies The CAHtalyst Phase 3 Pediatric and Adult global registrational studies were designed to evaluate the safety, efficacy, and tolerability of crinecerfont in children and adolescents (2–17 years of age) and adults (18 years of age and older) with classic congenital adrenal hyperplasia (CAH) due to 21-OHD, respectively. The CAHtalyst Phase 3 Pediatric and Adult clinical studies met their primary and secondary endpoints. The CAHtalyst Pediatric study demonstrated a statistically significant decrease in serum androstenedione from baseline with crinecerfont at Week 4 over baseline, while both studies showed crinecerfont treatment led to statistically significant reductions in daily glucocorticoid from baseline while maintaining androgen control at Week 28 and Week 24, respectively. Crinecerfont was generally well tolerated in the CAHtalyst Phase 3 studies. The most common adverse events in the CAHtalyst Pediatric study were headache, fever, vomiting, upper respiratory tract infection, and nasopharyngitis, while the most common adverse events in the CAHtalyst Adult study were fatigue, headache, and coronavirus infection. Few serious adverse events were seen in either study, with none assessed as related to crinecerfont. Both studies achieved a >95% completion rate. Details about the Phase 3 data from the CAHtalyst Pediatric Study were reported in October 2023 and can be found here. For more information about the CAHtalyst Pediatric Phase 3 study, please visit ClinicalTrialsPediatric.gov. Details about the Phase 3 data from the CAHtalyst Adult Study were reported in September 2023 and can be found here. For more information about the CAHtalyst Phase 3 study in adults, please visit ClinicalTrialsAdult.gov. About Neurocrine Biosciences, Inc. 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, chorea associated with Huntington's disease, 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 BIOSCIENCES and NEUROCRINE are registered trademark of Neurocrine Biosciences, Inc. CAHtalyst and the Neurocrine logo are trademarks of Neurocrine Biosciences, Inc. 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 to be derived from certain of our product candidates and our future development plans. 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; 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 September 30, 2023. Neurocrine Biosciences disclaims any obligation to update the statements contained in this press release after the date hereof. SOURCE Neurocrine Biosciences, Inc.

INGREZZA® (valbenazine) Third Quarter Net Product Sales of $486 Million Representing 29% Year-Over-Year Growth INGREZZA® (valbenazine) 2023 Net Product Sales Guidance Raised to $1.82 - $1.84 Billion Crinecerfont Adult and Pediatric CAHtalystTM Studies Met Primary Endpoint and Key Secondary Endpoints for the Treatment of Congenital Adrenal Hyperplasia Analyst Day on December 5th Focused on R&D Portfolio and Strategy SAN DIEGO, Oct. 31, 2023 /PRNewswire/ -- Neurocrine Biosciences, Inc. (Nasdaq: NBIX) today announced its financial results for the third quarter ended September 30, 2023, raised 2023 net sales guidance for INGREZZA, and announced an Analyst Day to be held in New York City on December 5th. "With INGREZZA sales continuing to grow, an expanded indication to treat chorea associated with Huntington's disease, and positive Phase 3 results in congenital adrenal hyperplasia, Neurocrine remains well positioned to build a leading neuroscience-focused company," said Kevin Gorman, Ph.D., Chief Executive Officer of Neurocrine Biosciences. "We look forward to sharing more insight into our R&D portfolio and strategy at our December Analyst Day." Third Quarter INGREZZA Net Product Sales Highlights: INGREZZA third quarter 2023 net product sales were $486 million and grew 29% vs. the third quarter 2022 driven by prescription demand Continued high level of new patient scripts generated in the third quarter of 2023 Third Quarter Financial Highlights: Third quarter 2023 GAAP net income and earnings per share of $83 million and $0.82, respectively, compared with $69 million and $0.69, respectively, for third quarter 2022 Third quarter 2023 non-GAAP net income and earnings per share of $156 million and $1.54, respectively, compared with $107 million and $1.08, respectively, for third quarter 2022 Differences in third quarter 2023 GAAP and non-GAAP operating expenses compared with third quarter 2022 driven by: Increased R&D expense in support of an expanded and advancing clinical portfolio including preclinical investments in VMAT2, crinecerfont, and our muscarinic compounds Increased SG&A expense primarily due to ongoing commercial initiatives supporting INGREZZA growth including the expanded indication to treat chorea associated with Huntington's disease At September 30, 2023, the Company had cash, cash equivalents and marketable securities of approximately $1.5 billion A reconciliation of GAAP to non-GAAP financial results can be found in Table 3 and Table 4 at the end of this earnings release. Recent Events: In August 2023, the FDA approved INGREZZA for the treatment of adults with chorea associated with Huntington's disease. In September 2023, the Company announced the FDA accepted its New Drug Application (NDA) for INGREZZA oral granules, a new sprinkle formulation of INGREZZA capsules for oral administration. The agency set a Prescription Drug User Fee Act (PDUFA) target action date of April 30, 2024. In September 2023, the Company announced positive top-line data from the Phase 3 CAHtalyst™ clinical study of crinecerfont in adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). The study met its primary as well as important key secondary endpoints. In October 2023, the Company announced positive top-line data from the Phase 3 CAHtalyst clinical study of crinecerfont in pediatrics with CAH due to 21-hydroxylase deficiency (21-OHD). The study met both its primary and key secondary endpoint. Updated 2023 INGREZZA Sales Guidance and Operating Expense Guidance: Conference Call and Webcast Today at 8:00 AM Eastern Time Neurocrine Biosciences will hold a live conference call and webcast today at 8:00 a.m. Eastern Time (5:00 a.m. Pacific Time). Participants can access the live conference call by dialing 800-895-3361 (US) or 785-424-1062 (International) using the conference ID: NBIX. The webcast can also be accessed on Neurocrine Biosciences' website under Investors at . A replay of the webcast will be available on the website approximately one hour after the conclusion of the event and will be archived for approximately one month. Neurocrine Biosciences' Analyst Day and Webcast on Tuesday, December 5, 2023 Neurocrine Biosciences will hold an Analyst Day in New York City on Tuesday, December 5, 2023. A live video webcast will begin at 1:00 p.m. Eastern Time and can be accessed on Neurocrine Biosciences' website under Investors at . A replay of the webcast will be available on the website approximately one hour after the conclusion of the event and will be archived for approximately one month. About Neurocrine Biosciences Neurocrine Biosciences is a 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, chorea associated with Huntington's disease, 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) Non-GAAP Financial Measures In addition to the financial results and financial guidance that are provided in accordance with accounting principles generally accepted in the United States (GAAP), this press release also contains the following non-GAAP financial measures: non-GAAP R&D expense, non-GAAP SG&A expense, and non-GAAP net income and net income per share. When preparing the non-GAAP financial results and guidance, the Company excludes certain GAAP items that management does not consider to be normal, including recurring cash operating expenses that might not meet the definition of unusual or non-recurring items. In particular, these non-GAAP financial measures exclude: non-cash stock-based compensation expense, loss on extinguishment of convertible senior notes, non-cash interest expense related to convertible debt, non-cash amortization expense related to acquired intangible assets, acquisition and integration costs, changes in fair value of equity security investments, changes in foreign currency exchange rates and certain adjustments to income tax expense. These non-GAAP financial measures are provided as a complement to results provided in accordance with GAAP as management believes these non-GAAP financial measures help indicate underlying trends in the Company's business, are important in comparing current results with prior period results and provide additional information regarding the Company's financial position. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally and to manage the Company's business and evaluate its performance. The Company provides guidance regarding combined R&D and SG&A expenses on both a GAAP and a non-GAAP basis. A reconciliation of these GAAP financial results to non-GAAP financial results is included in the attached financial information. Forward-Looking Statements 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 related to: the benefits to be derived from our products and product candidates; the value our products and/or our product candidates may bring to patients; the continued success of INGREZZA; our financial and operating performance, including our future revenues, expenses, or profits; our collaborative partnerships; expected future clinical and regulatory milestones; and the timing of the initiation and/or completion of our clinical, regulatory, and other development activities and those of our collaboration partners. Among the factors that could cause actual results to differ materially from those indicated in the forward-looking statements are: our future financial and operating performance; risks and uncertainties associated with the commercialization of INGREZZA; risks related to the development of our product candidates; risks associated with our dependence on third parties for development, manufacturing, and commercialization activities for our products and product candidates, and our ability to manage these third parties; risks that the FDA or other regulatory authorities may make adverse decisions regarding our products or product candidates; risks that clinical development activities may not be initiated or completed on time or at all, or may be delayed for regulatory, manufacturing, or other reasons, may not be successful or replicate previous clinical trial results, may fail to demonstrate that our product candidates are safe and effective, or may not be predictive of real-world results or of results in subsequent clinical trials; risks that the potential benefits of the agreements with our collaboration partners may never be realized; risks that our products, and/or our product candidates may be precluded from commercialization by the proprietary or regulatory rights of third parties, or have unintended side effects, adverse reactions or incidents of misuse; risks associated with U.S. federal or state legislative or regulatory and/or policy efforts which may result in, among other things, an adverse impact on our revenues or potential revenue; risks associated with potential generic entrants for our products; and other risks described in our periodic reports filed with the SEC, including our Quarterly Report on Form 10-Q for the quarter ended September 30, 2023. Neurocrine Biosciences disclaims any obligation to update the statements contained in this press release after the date hereof. SOURCE Neurocrine Biosciences, Inc.

Neurocrine Biosciences’ latest pediatric data will form part of the package of findings submitted to the FDA next year for crinecerfont’s approval application. A month after Neurocrine Biosciences’ drug crinecerfont renewed analysts’ hopes of its blockbuster potential by acing a phase 3 study in adults with hyperplasia, the therapy has now scored another win in the pediatric version of the trial. In the latest readout from the CAHtalyst studies, crinecerfont was shown to induce a statistically significant reduction in daily glucocorticoid dose compared to placebo after 28 weeks, while maintaining androgen control, hitting the primary endpoint. The trial enrolled 103 patients aged 2 to 17 years old with classic congenital adrenal hyperplasia as a result of 21-hydroxylase deficiency. The results mirrored similar findings from the adult version of the CAHtalyst trial in September. Specifically, the study in children demonstrated a p-value of less than 0.0001 when the reduction in daily glucocorticoid dose was measured at Week 28, which matched the p-value when measured at Week 24 in the adult trial. The most common adverse events were headache, fever, vomiting, upper respiratory tract infection and nasopharyngitis, Neurocrine noted in the Oct. 5 release. Of the “few” serious adverse events, none were considered to be related to crinecerfont, the biotech added. “The results from these studies suggest that crinecerfont could represent a new standard of care for CAH patients with the ability to reduce androgen levels through a non-glucocorticoid mechanism,” Neurocrine Chief Medical Officer Eiry Roberts, M.D., said in the release. “I am particularly excited about our positive results in the pediatric patient population and what improved androgen control in the setting of reduced glucocorticoid doses could mean for important outcomes related to growth and development." Congenital adrenal hyperplasia spans a group of genetic conditions that result in an enzyme deficiency that alters the production of adrenal hormones. Around 95% of cases are caused by a mutation that leads to a deficiency of the enzyme 21-hydroxylase, and there are currently no FDA-approved non-glucocorticoid treatments available. The latest pediatric data will form part of the package of findings submitted to the FDA next year for crinecerfont’s approval application. In a note published Monday ahead of the leatest readout, William Blair analysts said they “continue to see crinecerfont as a more than $1 billion peak sales opportunity.” Should the drug reach the market, analyst Myles Minter, Ph.D., said in the note that crinecerfont would provide “an important option to expand the company’s commercial pipeline.” For now, that pipeline still relies on the tardive dyskinesia drug Ingrezza after Neurocrine called it quits on the approved drug Ongentys in May due to what is described as an “unsustainable” launch.