α1A-AR

Expands Adrenergic Pipeline to Address Neurogenic Orthostatic Hypotension and Major Depressive Disorder in Older Adults SAN CARLOS, Calif.--(BUSINESS WIRE)--CuraSen Therapeutics, Inc., a clinical-stage biopharmaceutical company developing oral, rapid onset, small molecule drugs to treat psychiatric and neurodegenerative diseases, announced today that it has appointed Kathleen Sereda Glaub, MBA, formerly executive chair, as chief executive officer. Dr. Anthony Ford will move to the role of president and chief scientific officer, and continue to lead research and development. Patrick Enright, managing director of Longitude Capital, will become chair of the board. Along with these executive changes, the company announced clinical program updates for its drug candidates that are each designed to restore adrenergic stimulus that declines with age or disease. CuraSen’s most recent development candidate is CuraAX (CST-3056), an alpha-1A adrenoceptor (α 1A -AR) agonist being developed as a treatment for neurogenic orthostatic hypotension (nOH). The company is planning to submit an investigational new drug (IND) application this quarter. A significant orphan indication affecting approximately 120,000-150,000 patients in the U.S., nOH is a dysfunction in the autonomic nervous system common in Parkinson’s disease (PD) and related diseases that causes sudden drops in blood pressure upon standing. This can lead to debilitating dizziness, weakness, cognitive decline and dangerous falls. CuraAX is a selective, CNS-penetrant, α 1A -AR agonist designed to provide cognitive benefit as well as control harmful blood pressure deviations. CuraCN (formerly known as CST-103/CST-107), a beta2 adrenoceptor (β 2 -AR) agonist combination, is targeted for a Phase 2b study in major depressive disorder in adults 65 and older, many of whom also suffer from cognitive decline. These plans are based on the company’s previous Phase 2 clinical study in patients that revealed compelling evidence of anti-depressant efficacy and improvements in cognition tests. CuraXN (formerly known as CST-2032/CST-107), a second β 2 -AR agonist combination, is in development for Alzheimer’s disease (AD) to address both cognitive symptoms and disease progression. All three drug candidates work by restoring adrenergic function that declines with age and, in particular, is lost early in neurodegenerative diseases such as AD & PD. CuraSen’s development candidates have strong potential to improve cognitive function and mood, in addition to addressing specific aspects of disease pathobiology. “We are thrilled to have Ms. Glaub assume the role of chief executive officer as CuraSen seeks to capitalize on the company’s adrenergic platform and clinical data to develop a broad pipeline of drugs for psychiatric and neurodegenerative diseases. These include opportunities for a significant, fast-to-market, orphan opportunity in neurogenic orthostatic hypotension,” said Mr. Enright, board chair. “CuraSen will benefit from the collective and complementary executive experience of both Ms. Glaub and Dr. Ford, both co-founders of the company.” Ms. Glaub brings more than 30 years of experience in biopharmaceutical corporate development, strategy, financing and company-building. She serves on the board of directors of IO Biotech, and previously served on the boards of Codexis, Aligos Pharmaceuticals and Escient Pharmaceuticals. Ms. Glaub was previously chief executive officer of Afferent Pharmaceuticals, which was acquired by Merck in 2016 for $1.25 billion. Under her leadership, the company advanced gefapixant to Phase 3 readiness for the treatment of chronic cough and raised $80 million in additional private funding for Afferent. Previously, she served as president of Plexxikon, and helped develop two FDA-approved drugs, Zelboraf® for metastatic melanoma and Turalio® for tenosynovial giant cell tumor (TGCT). She led Plexxikon’s business and financing strategy, negotiated multimillion-dollar partnerships, and led the sale of the company to Daiichi Sankyo for nearly $1 billion. She previously held positions as senior vice president and chief financial officer of Cell Genesys, treasurer of Genentech, and various finance and treasury roles with Intel Corporation. Ms. Glaub received her BA from the University of California, Berkeley, and her MBA from Northwestern University. “CuraSen’s expertise in adrenergic pharmacology, chemistry and clinical development has led to the discovery of three promising drug candidates focused on some of the most debilitating and common neurodegenerative and psychiatric diseases affecting patients and their families. Our adrenergic target mechanisms are already validated by approved drugs in a range of indications, and we have confirmed the ability to develop CNS-penetrant compounds with a unique approach to safety,” said Glaub. “Given the strong and rapid-onset efficacy signals pointing to an anti-depressant effect in our past studies and our understanding of adrenergic deficits in older adults, we believe there is a unique opportunity to address depression in these patients with CuraCN. With CuraXN, we hope to deliver a transformational treatment for Alzheimer’s disease with our holistic approach to restoring brain functionality and health. Lastly, with CuraAX, we believe we can offer major advantages over current treatments for nOH, including durability of efficacy and cognitive benefit, dosing convenience and improved safety.” About CuraSen Therapeutics CuraSen is focused on the development of new treatments for psychiatric and neurodegenerative diseases, including neurogenic orthostatic hypotension, major depressive disorder and Alzheimer’s disease. CuraSen’s drugs are small molecule, oral tablets designed to activate certain receptor populations in the brain to compensate for decline of the adrenergic system driven by aging and disease. The company has evaluated two β 2 -AR agonist candidates, CuraCN and CuraXN, in multiple Phase 2 clinical studies for effects on memory, attention, executive function and mood, as well as safety and tolerability. CuraSen is planning to submit an IND application by the end of 2024 for its third drug candidate CuraAX, an α 1A -AR agonist, for the treatment of nOH. For more information, please visit . Contacts Susan Kinkead Kinkead Communications susan@kinkeadcomm.com 415-509-3610

This latest deal will aid BMS in bolstering its neuroscience portfolio. Credit: Katherine Welles / Shutterstock.com. Bristol Myers Squibb (BMS) has concluded the acquisition of biopharmaceutical company Karuna Therapeutics for $14bn in cash. The transaction was finalised following a definitive agreement signed by the companies in December 2023 . Karuna now becomes a wholly owned BMS subsidiary. The deal will boost BMS’s neuroscience portfolio. BMS has acquired Karuna’s lead asset, KarXT (xanomeline-trospium), along with its early-stage and pre-clinical pipeline. KarXT is an antipsychotic with a unique mechanism of action and a promising efficacy and safety profile. See Also: CST-2140 by CuraSen Therapeutics for Orthostatic Hypotension: Likelihood of Approval Q&A: Increasing awareness around digital therapeutics key to realising full potential The US Food and Drug Administration (FDA) recently accepted a new drug application for KarXT for the treatment of adults with schizophrenia, with an approval decision anticipated on 26 September 2025 under the Prescription Drug User Fee Act. KarXT is also undergoing registrational trials as an adjunctive therapy for schizophrenia and for treating psychosis in Alzheimer’s disease patients. Its potential for further indications such as bipolar 1 disorder and agitation in Alzheimer’s disease is being explored. Financial advisory services for the deal were provided to BMS by Gordon Dyal and Citi, with Covington & Burling offering legal counsel. Goldman Sachs acted as exclusive financial adviser to Karuna, with Simpson Thacher & Bartlett providing legal counsel. Bristol Myers Squibb CEO Chris Boerner stated: “We are excited to expand our neuroscience portfolio as we welcome Karuna to Bristol Myers Squibb. “Importantly, this transaction aligns with our commitment to strengthening BMS’s growth profile in the latter half of the decade and beyond. We look forward to working with Karuna’s talented team to bring KarXT to patients with schizophrenia later this year.” The new development comes after the FDA’s committee voted eight to three to approve BMS and 2seventy bio’s Abecma to treat relapsed or refractory multiple myeloma .

Drug Combination’s Unique Mechanism of Action Enables Reactivation of Brain Adrenergic Function, Showing Improvements in Multiple Areas of Cognition SAN CARLOS, Calif. & LISBON, Portugal--(BUSINESS WIRE)-- CuraSen Therapeutics, Inc., a clinical-stage company developing small molecule therapies to treat neurodegenerative disease, announced that it will present additional positive Phase 2a data with its combination adrenergic activator, CST-2032/CST-107, in patients with mild cognitive impairment (MCI) or mild dementia from either Alzheimer’s or Parkinson’s disease. The oral presentation will take place at AD/PD™ 2024: The International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders, being held March 5-9, 2024, in Lisbon, Portugal. CST-2032 is one of CuraSen’s two lead product candidates being tested in patients with Alzheimer’s and Parkinson’s disease. Both CST-2032 and CST-103, the company’s other lead clinical candidate, are oral, brain-permeant, beta2 adrenoceptor (β2-AR) agonists delivered in combination with CST-107 (nadolol, a brain-sparing beta blocker) to inhibit peripheral effects of β2-AR agonism. Both CST-2032 and CST-103 work by enabling reactivation of brain adrenergic function lost early in the neurodegenerative disease process. The updated Phase 2a data with CST-2032/CST-107 showed statistically and clinically important effects across several cognitive domains in patients with Alzheimer’s and Parkinson’s disease, such as memory, attention, executive function, facial recognition and impulse control — areas known to be impacted by adrenergic function. Target effect sizes of 0.2-0.3 or higher, as seen in this study, predict success in larger, longer studies. “These encouraging data build on earlier results presented at October 2023’s CTAD conference, reinforcing that treatment with CST 2032/CST-107 can produce meaningful quality-of-life cognitive improvements for Alzheimer’s and Parkinson’s patients, particularly those with mild cognitive impairment, rapidly and safely,” said Anthony Ford, PhD, chief executive officer of CuraSen. “The robust, collective data set from both CST-2032 and CST-103 demonstrate that this novel mechanism of action for restoring adrenergic function to the brain is a highly compelling strategy to address unmet symptoms of neurodegeneration. We plan to evaluate additional doses and refine optimal patient profiles in our upcoming Phase 2 studies, with the goal to significantly increase cognitive performance and ultimately, halt disease progression.” The randomized, placebo-controlled, double-blinded crossover study evaluated 64 patients with MCI or mild dementia from either Alzheimer’s disease or Parkinson’s diseases: AD with MCI = 30 patients randomized; 25 completed AD with dementia = 6 patients randomized; 5 completed PD with MCI = 22 patients randomized; 21 completed PD with dementia = 6 patients randomized; 4 completed Data highlights included: Digit Symbol Substitution test, which measures complex attention, memory and executive function: AD patients with MCI = 0.36 effect size; p=0.02 on Day 14 Facial Expression Recognition response time to accurately recognize facial expressions, which measures social cognition: AD patients with MCI = 0.66 effect size; p=0.04 on Day 14 for happy expression and 0.91 effect size; p = 0.01 on Day 14 for surprise expression Stop Signal test, which measures impulse control PD patients with MCI = 0.52 effect size; p=0.04 on Day 14 Excellent safety and tolerability pro /> No serious adverse events: no increases in heart rate observed one to four hours after dose The company plans to initiate longer studies with both CST-2032/CST-107 and CST-103/CST-107 in AD and PD patients with MCI later this year, as well as develop fixed-dose combination tablets for each of these drug candidates. Study Objectives and Design The study objectives were to establish safety and tolerability of CST-2032/CST-107, identify optimal dosing, and identify cognitive tests responsive to agonist stimulus within the two-week dosing period. Measures of cognition included the digit symbol substitution test, Cambridge neuropsychological test battery, and the facial expression recognition task. The study took place at multiple sites in the United States and New Zealand. Patients received either daily 3 mg of CST-2032 with 3 mg of nadolol for 14 days, or matching placebo, followed by a wash-out period (≥7-d) before crossing over to the other treatment arm. Blood samples are being analyzed for AD biomarkers, and DNA samples for AD and PD genotyping. Abstract Details Title: “CST-2032, a Novel Beta-2 Adrenoceptor Agonist, Improves Cognition in Patients with Impairment Due to Alzheimer’s or Parkinson’s Disease” Abstract #: PO34 Presenter: Gabriel Vargas, MD, PhD, chief medical officer, CuraSen Therapeutics Session: Translational Drug Discovery and Experimental Models 05 Date: Saturday, March 9, 2024 Time: 17:25-17:40 UTC, session time,16:40 - 18:40 UTC Location: Auditorium VII About CuraSen Therapeutics CuraSen is focused on the development of new treatments for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and other related orphan conditions. CuraSen’s drugs are designed to activate certain receptor populations in the brain to compensate for critical neuronal and glial functions that have otherwise been lost due to degeneration and represent a unique approach in the field. The company is evaluating CST-103 and CST-2032, both selective β2-AR agonists, in combination with CST-107, a β-AR blocker, in multiple Phase 2 clinical studies. CST-3056, an α1A-AR agonist, is in preclinical development for the treatment of Alzheimer’s disease. For more information, please visit .