A Randomised, Controlled Trial to Investigate the Effect of a Six Week Intensified Pharmacological Treatment for Bipolar Depression Compared to Treatment as Usual in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

Bipolar disorders affect approximately 4.5 million people across the European Union (EU) and are associated with high annual healthcare and societal costs. Bipolar disorder I and II represent disorders that cause extreme fluctuation in a person's mood, energy, and ability to function, in which symptoms of (hypo)mania and depression alternate. The depressive episodes of bipolar disorders are often referred to as bipolar depression (BD). In other words: it is a phase/state of the disorder. For many patients with BD, the depressive polarity is often more pervasive and more debilitating than manic states, with estimates that depressed mood accounts for up to two-thirds of the time spent unwell, even with treatment. The burden of not received an effective treatment for BD is high: more severe psychopathology, higher rates of unemployment, more hospitalisations, lower quality of life, lower cognitive functioning, risk of suicide, comorbidities and poorer social and occupational functioning and thus more carer burden. For BD, the treatment guidelines are very heterogeneous, amongst other reasons because the disease is heterogeneous and treatments should be tailored to the patients. There is no clear treatment algorithm and it cannot yet be predicted which treatment will be effective. Especially the place of adjunctive antidepressants is under debate. Usually, for psychiatric disorders (including bipolar disorder), a patient is considered to be treatment-resistant is two medicinal treatments have been tried (in sufficient duration and dosage) without sufficient success. For BD, there is no consensus on when to consider a patient as treatment-resistant, but the most common definition is after one prior treatment failure. This raises the research question whether adjunctive antidepressants to treat BD should be introduced earlier in the treatment. Additionally, The INTENSIFY trial is part of the larger Horizon 2021 project, with the central goal of paving the way for a shift towards a treatment decision-making process tailored for the individual at risk for treatment resistance. To that end, we aim to establish evidence-based criteria to make decisions of early intense treatment in individuals at risk for treatment resistance across the major psychiatric disorders of schizophrenia, bipolar disorder and major depression.

Start Date31 Jan 2025

Sponsor / Collaborator

University Medical Center of Utrecht

[+1]

NCT05603104

/ RecruitingPhase 3IIT

A Randomised, Controlled Trial to Investigate the Effect of an Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

Schizophrenia, bipolar and major depressive disorders collectively affect over 10 million people across the EU and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers or antipsychotics. It is unknown whether this first-line treatment will be successful. After this first-line treatment fails, usually a second-line treatment is initiated, and when this is not successful either a third-line treatment is initiated. Third-line treatments are quite successful, especially when compared to second-line treatments. The research question is whether the third-line treatments (early-intensified treatments) would be more efficacious than the current second-line treatments (treatment as usual) for schizophrenia, bipolar and major depressive disorders. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs.

Start Date30 Jan 2025

Sponsor / Collaborator

University Medical Center of Utrecht

[+1]

NCT06729970

/ Not yet recruitingPhase 1

A Phase 1, 4-part, Open-label, Fixed-sequence Study to Evaluate the Effects of Lithium and Valproic Acid on the Single-dose Pharmacokinetics of KarXT and Effects of KarXT on the Single-dose Pharmacokinetics of Lithium and Valproic Acid in Healthy Participants

The purpose of this study is to evaluate the effects of lithium and valproic acid on the single-dose pharmacokinetics (PK) of KarXT and the effect of KarXT on the single-dose PK of lithium and valproic acid in healthy participants.

Start Date23 Dec 2024

Sponsor / Collaborator

Karuna Therapeutics, Inc.

100 Clinical Results associated with Valproic Acid

100 Translational Medicine associated with Valproic Acid

100 Patents (Medical) associated with Valproic Acid

20,700

Literatures (Medical) associated with Valproic Acid

01 Sep 2025·Neural Regeneration Research

Enhanced autophagic clearance of amyloid-β via histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer’s disease in vitro and in vivo

Article

Author: Liu, Yuanjie ; Tang, Qing ; Ge, Chuanhua ; Long, Zhimin ; He, Guiqiong ; Zeng, Qinghua ; Zhao, Yueyang ; Dong, Zhifang

JOURNAL/nrgr/04.03/01300535-202509000-00025/figure1/v/2024-12-31T000210Z/r/image-tiff Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-β in neurons, which is a key step in senile plaque formation. Therefore, restoring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer’s disease. Microtubule acetylation/deacetylation plays a central role in lysosomal acidification. Here, we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer’s disease. Furthermore, we found that treatment with valproic acid markedly enhanced autophagy, promoted clearance of amyloid-β aggregates, and ameliorated cognitive deficits in a mouse model of Alzheimer’s disease. Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer’s disease, in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

01 May 2025·Journal of Environmental Sciences

Consumer products are important reservoirs and sources of organophosphate tri-esters and di-esters: Characteristics, mass inventory, and implication for waste management

Article

Author: Gu, Jiayi ; Zhou, Jie ; Salamova, Amina ; Liang, Chan ; Li, Jinyun ; Liu, Liangying

Numerous studies documented the occurrence of organophosphate tri-esters (tri-OPEs) and di-esters (di-OPEs) in the environment. Little information is available on their occurrence in waste consumer products, reservoirs and sources of these chemicals. This study collected and analyzed 92 waste consumer products manufactured from diverse polymers, including polyurethane foam (PUF), polystyrene (PS), acrylonitrile butadiene styrene (ABS), polypropylene (PP), and polyethylene (PE) to obtain information on the occurrence and profiles of 16 tri-OPEs and 10 di-OPEs. Total concentrations of di-OPEs (18-370,000 ng/ g, median 1,700 ng/g) were one order of magnitude lower than those of tri-OPEs (94-4,500,000 ng/g, median 5,400 ng/g). The concentrations of both tri- and di-OPEs in products made of PUF, PS, and ABS were orders of magnitude higher than those made of PP and PE. The compositional patterns of OPEs varied among different polymer types but were generally dominated by bisphenol A bis(diphenyl phosphate), triphenyl phosphate, tris(1-chloro-2-propyl) phosphate, di-phenyl phosphate (DPHP), and bis (2-ethylhexyl) phosphate. Two industrially applied di-OPEs (di-n-butyl phosphate and DPHP) exhibited higher levels than their respective tri-OPEs, contrary to their production volumes. Some non-industrially applied chlorinated di-OPEs were also detected, with concentrations up to 97,000 ng/g. These findings suggest that degradation of tri-OPEs during the manufacturing and use of products is an important source of di-OPEs. The mass inventories of tri-OPEs and di-OPEs in consumer products were estimated at 3,100 and 750 tons/year, respectively. This study highlights the importance of consumer products as emission sources of a broad suite of OPEs.

01 Mar 2025·Neuropharmacology

Mechanistic insights into retinoic-acid treatment for autism in the improvement of social behavior: Evidence from a multi omics study in rats

Article

Author: Dai, Chunfang ; Liu, Juan ; Zhu, Jiang ; Hu, Yan ; Cheng, Boli ; Lai, Xi ; Zhang, Yaoyin ; Cao, Qingjiu ; Tan, Mei ; Liu, Huan ; Liang, Jingjing

BACKGROUNDAutism spectrum disorder (ASD) is a lifelong condition. It is characterized by complex etiologies, including disruptions in exogenous retinoic acid (RA) signaling, which may serve as an environmental risk factor. Targeting the RA pathway presents a promising therapeutic avenue, though the precise mechanisms remain to be elucidated.METHODSFemale Sprague-Dawley rats were treated with valproic acid (VPA) during pregnancy to induce an ASD model in their offspring. Some offspring received RA treatment postnatally. Social behavior and brain-functional connectivity were assessed using behavioral tests and functional magnetic resonance imaging (fMRI), respectively. Transcriptomics analysis and proteomics analysis of the hypothalamus identified differentially expressed genes (DEGs) and differentially expressed proteins (DEPs). These were intersected with ASD pathogenic genes (APGs) and ASD pathogenic proteins (APPs) to identify differentially expressed APGs (DE-APGs) and differentially expressed APPs (DE-APPs), which were validated by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. Analyses of enrichment of signaling pathways were done using the Kyoto Encyclopedia of Genes and Genomes database.RESULTSRA treatment significantly improved social behaviors and revealed distinct patterns of hypo- and hyper-connectivity across various brain regions, with notable changes involving the hypothalamus and facial nerve. Differential analysis revealed 4165 DEGs (DEG 1) and 329 DEPs (DEP 1) between control and VPA groups, and 1610 DEGs (DEG 2) and 197 DEPs (DEP 2) between VPA and RA supplementation (RAS) groups. Twenty-two DE-APGs and five DE-APPs were identified, with key associations found between proteins such as Tbl1xr1 and Myo5a and >13 genes including Nrxn1, Cacna1e, and Gabrb2. Significant alterations in DE-APGs, including Grin2b, Nrxn1, Cacna1e, and Gabrb2, were confirmed via real-time RT-PCR and western blotting. In addition, 22 key signaling pathways were enriched in DEPs and DEGs.CONCLUSIONRA supplementation in ASD rats induced by VPA may ameliorate social deficits and modulated functional connectivity, especially in the hypothalamus and facial nerve regions. This suggests potential therapeutic benefits for neural circuitry dysregulation in ASD. Additionally, RA altered critical gene and protein expressions in hypothalamus, implicating its role in modulating key signaling pathways to mitigate social deficits in ASD. This study provides new insights into the molecular mechanisms of ASD and supports the development of novel therapeutic strategies.

News (Medical) associated with Valproic Acid

14 Jan 2025

·pmlive.com

J&J expands neuroscience capabilities with $14.6bn Intra-Cellular acquisition

Johnson & Johnson (J&J) has announced that it will be expanding its neuroscience capabilities by acquiring Intra-Cellular Therapies for approximately $14.6bn. The deal gives J&J access to Intra-Cellular’s central nervous system disorder drugs, including antipsychotic medication Caplyta (lumateperone). The once-daily oral therapy is already approved by the US Food and Drug Administration (FDA) to treat adults with schizophrenia, and depressive episodes associated with bipolar I or II disorder as a monotherapy and adjunctive therapy with lithium or valproate. Schizophrenia and bipolar disorder affect approximately 2.4 million and 6.1 million adults in the US, respectively. A supplemental new drug application has also been submitted to the US regulator for the use Caplyta as an adjunctive treatment for major depressive disorder, which affects as estimated 21 million adults in the US, while additional late-stage trials of the drug in other mental health disorders are underway. Beyond Caplyta, the acquisition includes a phase 2 candidate being evaluated in generalised anxiety disorder and Alzheimer’s disease-related psychosis and agitation, as well as a clinical-stage pipeline that “further complements and strengthens” J&J’s current areas of focus. Jennifer Taubert, executive vice president, worldwide chairman, Innovative Medicine, J&J, said: “We are excited to welcome Intra-Cellular Therapies’ talented people and world-class expertise to J&J. Together, we have an opportunity to impact even more patients living with neuropsychiatric and neurodegenerative disorders, significantly advancing care and helping improve the lives of millions worldwide.” Under the terms of the agreement, which is expected to close later this year subject to applicable regulatory approvals, J&J will acquire all outstanding shares of Intra-Cellular Therapies for $132 per share in cash. Also commenting on the acquisition, Sharon Mates, chairman and chief executive officer of Intra-Cellular Therapies, said: “Caplyta’s success and the robust pipeline we have built demonstrates the passion and dedication of our… team, and we are proud of the hundreds of thousands of patients we have helped. “J&J has a longstanding commitment to neuroscience, and we believe together, we can reach even more patients around the world.”

Cell TherapyDrug ApprovalAcquisitionPhase 2

13 Jan 2025

·pipelinereview.com

Johnson & Johnson Strengthens Neuroscience Leadership with Acquisition of Intra-Cellular Therapies, Inc.

Acquisition includes CAPLYTA ® (lumateperone), the first and only U.S. FDA-approved treatment for bipolar I and II depression as an adjunctive and monotherapy; also approved for the treatment of schizophrenia in adults sNDA submitted to U.S. FDA for CAPLYTA ® as adjunctive treatment for major depressive disorder; if approved, CAPLYTA ® has potential to become a standard of care for most common depressive disorders CAPLYTA ® adds to Johnson & Johnson’s robust lineup of therapies with $5 billion+ potential in peak year sales i and further solidifies sales growth above analyst expectations now through the remainder of the decade Promising clinical-stage pipeline with best-in-disease potential in generalized anxiety disorder and Alzheimer’s disease-related psychosis and agitation NEW BRUNSWICK, NJ & BEDMINSTER, NJ, USA I January 13, 2025 I Johnson & Johnson (NYSE: JNJ) and Intra-Cellular Therapies, Inc. (Nasdaq: ITCI) announced today that they have entered into a definitive agreement under which Johnson & Johnson will acquire all outstanding shares of Intra-Cellular Therapies, a biopharmaceutical company focused on the development and commercialization of therapeutics for central nervous system (CNS) disorders, for $132.00 per share in cash for a total equity value of approximately $14.6 billion. “Building on our nearly 70-year legacy in neuroscience, this unique opportunity to add Intra-Cellular Therapies to our Innovative Medicine business demonstrates our commitment to transforming care and advancing research in some of today’s most devastating neuropsychiatric and neurodegenerative disorders,” said Joaquin Duato, Chairman and Chief Executive Officer, Johnson & Johnson. “This acquisition further differentiates our portfolio, serves as a strategic near- and long-term growth catalyst for Johnson & Johnson and offers compelling value to patients, health systems and shareholders.” With this agreement, Johnson & Johnson adds Intra-Cellular Therapies’ CAPLYTA ® (lumateperone), a once-daily oral therapy approved to treat adults with schizophrenia, as well as depressive episodes associated with bipolar I or II disorder (bipolar depression), as a monotherapy and adjunctive therapy with lithium or valproate. The acquisition also includes ITI-1284, a promising Phase 2 compound being studied in generalized anxiety disorder (GAD) and Alzheimer’s disease-related psychosis and agitation, as well as a clinical-stage pipeline that further complements and strengthens Johnson & Johnson’s current areas of focus. “We are excited to welcome Intra-Cellular Therapies’ talented people and world-class expertise to Johnson & Johnson,” said Jennifer Taubert, Executive Vice President, Worldwide Chairman, Innovative Medicine, Johnson & Johnson. “Together, we have an opportunity to impact even more patients living with neuropsychiatric and neurodegenerative disorders, significantly advancing care and helping improve the lives of millions worldwide.” “CAPLYTA ® ’s success and the robust pipeline we have built demonstrates the passion and dedication of our talented team, and we are proud of the hundreds of thousands of patients we have helped,” said Dr. Sharon Mates, Chairman and CEO of Intra-Cellular Therapies. “Johnson & Johnson has a longstanding commitment to neuroscience, and we believe together, we can reach even more patients around the world.” In December 2024, Intra-Cellular Therapies announced the submission of a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration (FDA) for CAPLYTA ® as an adjunctive treatment for adults with major depressive disorder (MDD). In two global, double-blind, placebo-controlled Phase 3 studies, CAPLYTA ® , as an adjunctive treatment to antidepressants, demonstrated a statistically significant and clinically meaningful improvement in depressive symptoms, as measured by both clinician-rated and patient-reported outcomes. The safety profile of CAPLYTA ® in both studies was consistent with the existing body of clinical data for CAPLYTA ® , and no new safety concerns were identified. If approved, CAPLYTA ® has the potential to be the first treatment approved for MDD and depressive symptoms associated with bipolar I and II in more than 15 years. Additional Phase 3 trials are underway with CAPLYTA ® in bipolar I disorder with manic episodes or manic episodes with mixed features (bipolar mania). Positive topline results evaluating the efficacy and safety of CAPLYTA ® for the prevention of relapse in adult patients with schizophrenia were shared in November 2024. While its exact mechanism of action is unknown, CAPLYTA ® is uniquely characterized by high serotonin 5-HT 2A receptor occupancy and lower amounts of dopamine D 2 receptor occupancy at therapeutic doses. In short-term clinical studies across all three approved indications, CAPLYTA ® was similar to placebo in weight change, metabolic effects, and extrapyramidal symptoms, which are often cited as reasons for treatment discontinuation. The most common reported adverse events were somnolence/sedation, dizziness, nausea, and dry mouth. Across all three approved indications, CAPLYTA ® can be taken at any time of day with or without food and does not require titration, allowing adult patients to start treatment at the effective dose. “CAPLYTA ® has robust efficacy, proven safety and favorable tolerability across all three approved indications, without the need for dose titration frequently associated with this class of therapies,” said John Reed, M.D., Ph.D., Executive Vice President, R&D, Innovative Medicine, Johnson & Johnson. “With positive Phase 3 data in MDD as an adjunctive therapy and additional Phase 3 trials in other mental health disorders underway, we believe CAPLYTA ® has the potential to become a new standard of care for the treatment of some of today’s most prevalent and debilitating mental health disorders.” As the mental health crisis surges and the global population ages, more than one billion people worldwide – or 1 in every 8 people – are living with a neuropsychiatric or neurodegenerative disorder. In the United States: Transaction Details and Path to Completion Under the terms of the agreement, Johnson & Johnson will acquire all outstanding shares of Intra-Cellular Therapies for a payment of $132.00 per share in cash. Johnson & Johnson expects to fund the transaction through a combination of cash on hand and debt. Johnson & Johnson expects to maintain a strong balance sheet and to continue to support its stated capital allocation priorities of R&D investment, competitive dividends, value-creating acquisitions, and strategic share repurchases. The closing of the transaction is expected to occur later this year subject to applicable regulatory approvals, approval by Intra-Cellular Therapies’ stockholders and other customary closing conditions for a transaction of this type. Following completion of the transaction, Intra-Cellular Therapies’ common stock will no longer be listed for trading on the Nasdaq Global Select Market. Johnson & Johnson will provide commentary on any potential impact to Adjusted Earnings Per Share (EPS) from the transaction when it provides its initial full year 2025 guidance during the fourth quarter earnings call on Wednesday, January 22, 2025. Advisors Citi is serving as financial advisor to Johnson & Johnson, and Cravath, Swaine & Moore is serving as legal advisor. Centerview Partners LLC and Jefferies are serving as financial advisors to Intra-Cellular Therapies, and Davis Polk & Wardwell LLP is serving as legal advisor. Indication CAPLYTA ® (lumateperone) is indicated in adults for the treatment of schizophrenia and for the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. Important Safety Information Boxed Warnings: Contraindications: CAPLYTA ® is contraindicated in patients with known hypersensitivity to lumateperone or any components of CAPLYTA ® . Reactions have included pruritus, rash (e.g., allergic dermatitis, papular rash, and generalized rash), and urticaria. Warnings & Precautions: Antipsychotic drugs have been reported to cause: Drug Interactions: CAPLYTA ® should not be used with CYP3A4 inducers. Dose reduction is recommended for concomitant use with strong CYP3A4 inhibitors or moderate CYP3A4 inhibitors. Special Populations: Newborn infants exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Dose reduction is recommended for patients with moderate or severe hepatic impairment. Adverse Reactions : The most common adverse reactions in clinical trials with CAPLYTA ® vs. placebo were somnolence/sedation, dizziness, nausea, and dry mouth. CAPLYTA ® is available in 10.5 mg, 21 mg, and 42 mg capsules. Please click here to see full Prescribing Information including Boxed Warning . About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity. Learn more at www.jnj.com/ . About Intra-Cellular Therapies, Inc. Intra-Cellular Therapies is a biopharmaceutical company founded on Nobel Prize-winning research that allows us to understand how therapies affect the inner workings of cells in the body. The company leverages this intracellular approach to develop innovative treatments for people living with complex psychiatric and neurologic diseases. For more information, please visit www.intracellulartherapies.com . ADDITIONAL INFORMATION AND WHERE TO FIND IT This press release may be deemed to be solicitation material in respect of the proposed acquisition of Intra-Cellular Therapies by Johnson & Johnson. In connection with the proposed transaction, Intra-Cellular Therapies intends to file relevant materials with the U.S. Securities and Exchange Commission (“SEC”), including Intra-Cellular Therapies’ proxy statement in preliminary and definitive form. INVESTORS AND STOCKHOLDERS OF INTRA-CELLULAR THERAPIES ARE URGED TO READ ALL RELEVANT DOCUMENTS FILED WITH THE SEC, INCLUDING INTRA-CELLULAR THERAPIES’ PROXY STATEMENT (WHEN THEY ARE AVAILABLE), BECAUSE THEY CONTAIN OR WILL CONTAIN IMPORTANT INFORMATION ABOUT THE PROPOSED TRANSACTION AND THE PARTIES TO THE PROPOSED TRANSACTION. Investors and stockholders of Intra-Cellular Therapies are or will be able to obtain these materials (when they are available) free of charge at the SEC’s website at www.sec.gov , or free of charge from Intra-Cellular Therapies’ website at www.intracellulartherapies.com . PARTICIPANTS IN THE SOLICITATION Johnson & Johnson and Intra-Cellular Therapies and certain of their respective directors and executive officers, under SEC rules, may be deemed to be “participants” in the solicitation of proxies from stockholders of Intra-Cellular Therapies in connection with the proposed transaction. Information about Johnson & Johnson’s directors and executive officers is available in Johnson & Johnson’s Annual Report on Form 10-K for the year ended December 31, 2023, which was filed with the SEC on February 16, 2024, and Johnson & Johnson’s definitive proxy statement for its 2024 annual meeting of stockholders, which was filed with the SEC on March 13, 2024. Information about Intra-Cellular Therapies’ directors and executive officers is available in Intra-Cellular Therapies’ Annual Report on Form 10-K for the year ended December 31, 2023, which was filed with the SEC on February 22, 2024, and Intra-Cellular Therapies’ definitive proxy statement for its 2024 annual meeting of stockholders, which was filed with the SEC on April 29, 2024. To the extent holdings of Johnson & Johnson’s or Intra-Cellular Therapies’ securities by their respective directors or executive officers have changed since the amounts set forth in such 2024 proxy statements, such changes have been or will be reflected on Initial Statements of Beneficial Ownership on Form 3 or Statements of Change in Ownership on Form 4 filed with the SEC, including the Form 3 filed by Sanjeev Narula on August 14, 2024 and the Form 4s filed by: Sharon Mates on August 23, 2024 , August 28, 2024 , August 30, 2024 and December 6, 2024 ; Joel S. Marcus on June 18, 2024 and June 25, 2024 ; Rory B. Riggs on June 18, 2024 , June 25, 2024 , July 2, 2024 , October 2, 2024 , October 15, 2024 and January 3, 2025 ; Eduardo Rene Salas on June 18, 2024 and June 25, 2024 ; Robert L. Van Nostrand on June 18, 2024 , June 21, 2024 , June 25, 2024 and July 2, 2024 ; Michael Halstead on November 14, 2024 ; Mark Neumann on August 20, 2024 ; and Sanjeev Narula on August 14, 2024 . Investors and stockholders of Intra-Cellular Therapies are or will be able to obtain these documents free of charge from the SEC’s website at www.sec.gov, from Johnson & Johnson on Johnson & Johnson’s website at www.jnj.com , from Intra-Cellular Therapies on Intra-Cellular Therapies’ website at www.intracellulartherapies.com or on request from Johnson & Johnson or Intra-Cellular Therapies. Additional information concerning the interests of Intra-Cellular Therapies’ participants in the solicitation, which may, in some cases, be different than those of Intra-Cellular Therapies’ stockholders generally, will be set forth in Intra-Cellular Therapies’ proxy statement relating to the proposed transaction when it becomes available. Footnotes i Non risk adjusted peak year sales including partner sales ii World Health Organization. Schizophrenia. Accessed December 2024. https://www-who-int.libproxy1.nus.edu.sg/news-room/fact-sheets/detail/schizophrenia iii Regier DA, Farmer ME, Rae DS, et al. One–month prevalence of mental disorders in the United States and sociodemographic characteristics: the epidemiologic catchment area study. Acta Psychiatr Scand. (1993);88(1):35-47. doi:10.1111/j.1600-0447.1993.tb03411. iv US Census Bureau. 2010 US Census. Accessed December 23, 2024. https://www.census.gov/topics/population/data.html v Harvard Medical School, 2007. National Comorbidity Survey (NSC). (2017, August 21). Retrieved from https://www.hcp.med.harvard.edu/ncs/index.php . Data Table 2: 12-month prevalence DSM-IV/WMH-CIDI disorders by sex and cohort. vi Mayo Clinic. Bipolar disorder. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/bipolar-disorder/symptoms-causes/syc-20355955 . Published August 14, 2024. Accessed December 23, 2024. vii Substance Abuse and Mental Health Services Administration. Key Substance Use and Mental Health Indicators in the United States: Results from the 2021 National Survey on Drug Use and Health. Published December 2022. Accessed December 23, 2024. https://www.samhsa.gov/data/sites/default/files/reports/rpt39443/2021NSDUHFFRRev010323.pdf viii 2024 Alzheimer’s disease facts and figures. Alzheimer’s Dement. 2024;20(5):3708-3821. doi:10.1002/alz.13809. SOURCE: Johnson & Johnson

Phase 3Cell TherapyDrug ApprovalPhase 2Clinical Result

11 Dec 2024

·www.globenewswire.com

Intra-Cellular Therapies Presents Data from the CAPLYTA Adjunctive MDD Phase 3 Program at the American College of Neuropsychopharmacology Annual Meeting

Presentations complement topline data with new data from two pivotal studies (Studies 501 and 502) evaluating lumateperone as an adjunctive therapy for the treatment of major depressive disorder Data shows robust remission and response efficacy rates in patients taking CAPLYTA Robust improvements in anxiety symptoms were also observed in patients taking CAPLYTA as measured by the Generalized Anxiety Disorder Questionnaire (GAD-7) Pooled safety and tolerability data from Studies 501 and 502 show favorable safety and tolerability profile for CAPLYTA consistent with prior studies A post-hoc analysis from Study 403 in mixed features shows CAPLYTA significantly improved anhedonia symptoms as measured by the MADRS anhedonia factor score BEDMINSTER, N.J., Dec. 11, 2024 (GLOBE NEWSWIRE) -- Intra-Cellular Therapies, Inc. (Nasdaq: ITCI), a biopharmaceutical company focused on the development and commercialization of therapeutics for central nervous system (CNS) disorders, today announced presentations at the 63rd Annual Meeting of the American College of Neuropsychopharmacology (ACNP) which included new efficacy, safety, and tolerability analyses from its CAPLYTA adjunctive major depressive disorder (MDD) pivotal program. “We have previously shared positive results from Studies 501 and 502 demonstrating a robust clinical profile of CAPLYTA as an adjunctive treatment in MDD with strong efficacy results in the Montgomery Asberg Depression Rating Scale (MADRS) total score, the Clinical Global Impression Scale for Severity of Illness (CGI-S) and the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR-16) scale. We are excited to share new data that further characterize CAPLYTA’s robust efficacy and favorable safety and tolerability profile,” said Dr. Suresh Durgam, Executive Vice President and Chief Medical Officer of Intra-Cellular Therapies. “In addition, the improvements in anhedonia symptoms observed in Study 403 further contribute to enriching CAPLYTA’s profile in the treatment of MDD and bipolar depression.” Details of the presentations are as follows: Poster T126 “Lumateperone as Adjunctive Therapy in Patients with Major Depressive Disorder: Results from a Randomized, Double-blind, Phase 3 Trial,” Tuesday, December 10 Poster W85 “Adjunctive Lumateperone in Patients With Major Depressive Disorder: Results From an Additional Randomized, Double-Blind, Phase 3 Trial,” Wednesday, December 11 These poster presentations highlight the efficacy of lumateperone 42mg adjunctive to anti-depressant therapy (ADT) shown in two similarly designed trials (Studies 501 and 502). In these studies, lumateperone 42 mg demonstrated significant and clinically meaningful efficacy over placebo, improving depressive symptoms and disease severity. Lumateperone plus ADT improved depression as measured by both clinician-rated and patient-reported outcomes (MADRS total score, CGI-S score, and QIDS-SR-16 total score). Subject to FDA approval, we believe these results demonstrate lumateperone represents a promising new treatment option for adults with MDD with inadequate response to prior ADT. In both studies, MADRS response and remission rates were significantly greater with lumateperone compared to placebo. Specifically, in Study 501 the response rates for CAPLYTA were 45.6% vs. 24.0% for placebo (p<0.0001) and remission rates were 25.9% vs. 13.6% for placebo (p<0.001). In Study 502 the response rates for CAPLYTA were 40.1% vs. 25.3% for placebo (p<0.01) and remission rates were 25.0% vs. 13.5% for placebo (p<0.01). In Study 501 anxiety symptoms were measured using the GAD-7 scale. Lumateperone plus ADT significantly improved self-reported anxiety symptoms, as measured by the GAD-7 total score, compared with placebo from baseline to Day 43 (Cohen’s d effect size (ES): 0.43; p<0.0001). Poster W84 “Safety and Tolerability of Lumateperone 42 mg for the Treatment of Major Depressive Disorder: A Pooled Analysis of 2 Randomized Placebo-Controlled Trials,” Wednesday, December 11 A pooled analysis of Studies 501 and 502 demonstrates the safety and tolerability of lumateperone 42 mg plus ADT in patients with MDD who had inadequate response to ADT. The most common adverse reactions in the lumateperone group (defined as ≥5% of patients and at more than twice the rate of placebo) were dizziness, dry mouth, somnolence, nausea, and fatigue. In Studies 501 and 502 changes in cardiometabolic parameters, prolactin levels and body morphology with lumateperone were similar to placebo. The risk of extrapyramidal symptoms and motor symptoms with lumateperone was low. Poster W88 “Lumateperone Treatment for Major Depressive Episodes With Mixed Features in Major Depressive Disorder and Bipolar I or Bipolar II Disorder: A Post Hoc Analysis of Anhedonia,” Wednesday, December 11 The poster reports on a post-hoc analysis from Study 403 evaluating the efficacy of lumateperone 42mg monotherapy in improving the anhedonia factor score in patients with MDD or bipolar depression with mixed features. The results from this analysis support lumateperone to treat the broad range of anhedonia symptoms of a major depressive episode in these patient populations. Anhedonia, which is diminished interest or pleasure, occurs in approximately 70% of patients with MDD and approximately 50% of patients with bipolar depression. Heightened levels of anhedonia in mood disorders are associated with more severe and recurrent depressive illness, a greater risk of suicidal ideation, and poorer treatment response compared with lower levels of anhedonia. Lumateperone significantly improved the MADRS anhedonia factor score from baseline to Day 43 compared with placebo in the combined MDD/bipolar depression population with mixed features (least squares mean difference (LSMD)= -3.4; ES= 0.63; p<0.0001) as well as both individual populations of patients with MDD with mixed features (LSMD= -3.4; ES= 0.63; p<0.0001) and bipolar depression with mixed features (LSMD= -3.3; ES= 0.61; p<0.0001). CAPLYTA® (lumateperone) is indicated in adults for the treatment of schizophrenia and for the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. Important Safety Information Boxed Warnings: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. CAPLYTA is not approved for the treatment of patients with dementia-related psychosis.Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adults in short-term studies. All antidepressant-treated patients should be closely monitored for clinical worsening, and for emergence of suicidal thoughts and behaviors. The safety and effectiveness of CAPLYTA have not been established in pediatric patients. Contraindications: CAPLYTA is contraindicated in patients with known hypersensitivity to lumateperone or any components of CAPLYTA. Reactions have included pruritus, rash (e.g., allergic dermatitis, papular rash, and generalized rash), and urticaria. Warnings & Precautions: Antipsychotic drugs have been reported to cause: Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis, including stroke and transient ischemic attack. See Boxed Warning above.Neuroleptic Malignant Syndrome (NMS), which is a potentially fatal reaction. Signs and symptoms include: high fever, stiff muscles, confusion, changes in breathing, heart rate, and blood pressure, elevated creatinine phosphokinase, myoglobinuria (and/or rhabdomyolysis), and acute renal failure. Patients who experience signs and symptoms of NMS should immediately contact their doctor or go to the emergency room.Tardive Dyskinesia, a syndrome of uncontrolled body movements in the face, tongue, or other body parts, which may increase with duration of treatment and total cumulative dose. TD may not go away, even if CAPLYTA is discontinued. It can also occur after CAPLYTA is discontinued.Metabolic Changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain. Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma or death, has been reported in patients treated with antipsychotics. Measure weight and assess fasting plasma glucose and lipids when initiating CAPLYTA and monitor periodically during long-term treatment.Leukopenia, Neutropenia, and Agranulocytosis (including fatal cases). Complete blood counts should be performed in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. CAPLYTA should be discontinued if clinically significant decline in WBC occurs in absence of other causative factors.Decreased Blood Pressure & Dizziness. Patients may feel lightheaded, dizzy or faint when they rise too quickly from a sitting or lying position (orthostatic hypotension). Heart rate and blood pressure should be monitored and patients should be warned with known cardiovascular or cerebrovascular disease. Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension.Falls. CAPLYTA may cause sleepiness or dizziness and can slow thinking and motor skills, which may lead to falls and, consequently, fractures and other injuries. Patients should be assessed for risk when using CAPLYTA.Seizures. CAPLYTA should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold.Potential for Cognitive and Motor Impairment. Patients should use caution when operating machinery or motor vehicles until they know how CAPLYTA affects them.Body Temperature Dysregulation. CAPLYTA should be used with caution in patients who may experience conditions that may increase core body temperature such as strenuous exercise, extreme heat, dehydration, or concomitant anticholinergics.Dysphagia. CAPLYTA should be used with caution in patients at risk for aspiration. Drug Interactions: CAPLYTA should not be used with CYP3A4 inducers. Dose reduction is recommended for concomitant use with strong CYP3A4 inhibitors or moderate CYP3A4 inhibitors. Special Populations: Newborn infants exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Dose reduction is recommended for patients with moderate or severe hepatic impairment. Adverse Reactions: The most common adverse reactions in clinical trials with CAPLYTA vs. placebo were somnolence/sedation, dizziness, nausea, and dry mouth. CAPLYTA is available in 10.5 mg, 21 mg, and 42 mg capsules. Please click here to see full Prescribing Information including Boxed Warning. About CAPLYTA (lumateperone) CAPLYTA 42 mg is an oral, once daily atypical antipsychotic approved in adults for the treatment of schizophrenia and the treatment of depressive episodes associated with bipolar I or II disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. While the mechanism of action of CAPLYTA is unknown, the efficacy of CAPLYTA could be mediated through a combination of antagonist activity at central serotonin 5-HT2A receptors and postsynaptic antagonist activity at central dopamine D2 receptors. Lumateperone is being studied for the treatment of major depressive disorder, and other psychiatric and neurological disorders. Lumateperone is not FDA-approved for these disorders. About Intra-Cellular Therapies Intra-Cellular Therapies is a biopharmaceutical company founded on Nobel prize-winning research that allows us to understand how therapies affect the inner-workings of cells in the body. The company leverages this intracellular approach to develop innovative treatments for people living with complex psychiatric and neurologic diseases. For more information, please visit www.intracellulartherapies.com. Forward-Looking Statements This news release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the potential approval of CAPLYTA (lumateperone) for the treatment of major depressive disorder as adjunctive therapy; our expectations regarding the commercialization of CAPLYTA; our plans to conduct clinical or non-clinical trials and the timing of developments with respect to those trials, including enrollment, initiation or completion of clinical conduct, or the availability or reporting of results; plans to make regulatory submissions to the FDA and the timing of such submissions and any product approvals; whether clinical trial results will be predictive of future real-world results; whether CAPLYTA will serve an unmet need; the goals of our development programs; our beliefs about the potential utility of our product candidates; and development efforts and plans under the caption “About Intra-Cellular Therapies.” All such forward-looking statements are based on management's present expectations and are subject to certain factors, risks and uncertainties that may cause actual results, outcome of events, timing and performance to differ materially from those expressed or implied by such statements. These risks and uncertainties include, but are not limited to, the following: there are no guarantees that CAPLYTA will be commercially successful; we may encounter issues, delays or other challenges in commercializing CAPLYTA; whether CAPLYTA receives adequate reimbursement from third-party payors; the degree to which CAPLYTA receives acceptance from patients and physicians for its approved indications; challenges associated with execution of our sales activities, which in each case could limit the potential of our product; results achieved in CAPLYTA in the treatment of schizophrenia and bipolar depression following commercial launch of the product may be different than observed in clinical trials, and may vary among patients; challenges associated with supply and manufacturing activities, which in each case could limit our sales and the availability of our product; risks associated with our current and planned clinical trials; we may encounter unexpected safety or tolerability issues with CAPLYTA following commercial launch for the treatment of schizophrenia or bipolar depression or in ongoing or future trials and other development activities; there is no guarantee that a generic equivalent of CAPLYTA will not be approved and enter the market before the expiration of our patents; there is no guarantee that our supplemental New Drug Application (sNDA) for the treatment of MDD will be approved, if at all, on the timeline that we expect; our other product candidates may not be successful or may take longer and be more costly than anticipated; product candidates that appeared promising in earlier research and clinical trials may not demonstrate safety and/or efficacy in larger-scale or later clinical trials or in clinical trials for other indications; our proposals with respect to the regulatory path for our product candidates may not be acceptable to the FDA; our reliance on collaborative partners and other third parties for development of our product candidates; impacts on our business, including on the commercialization of CAPLYTA and our clinical trials, as a result of the COVID-19 pandemic, the conflicts in Ukraine, Russia and the Middle East, global economic uncertainty, inflation, higher interest rates or market disruptions; and the other risk factors detailed in our public filings with the Securities and Exchange Commission. All statements contained in this press release are made only as of the date of this press release, and we do not intend to update this information unless required by law. Contact: Intra-Cellular Therapies, Inc.Juan Sanchez, M.D. Vice President, Corporate Communications and Investor Relations646-440-9333 Burns McClellan, Inc.Cameron Radinoviccradinovic@burnsmc.com646-930-4406

Clinical ResultPhase 3Cell TherapyDrug ApprovalASCO

100 Deals associated with Valproic Acid

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KEGG	Wiki	ATC	Drug Bank
D00399	Valproic Acid	N03AG01	DB00313

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy, Temporal Lobe	Phase 1	AU	Cerebral Therapeutics, Inc.	01 Aug 2016
Seizures	Phase 1	AU	Cerebral Therapeutics, Inc.	01 Aug 2016
Spinal Muscular Atrophy	Phase 1	US	Abbott Laboratories	01 Jul 2007
Alcoholism	Phase 1	US	AstraZeneca PLC	01 Jan 2006
Dementia	Phase 1	US	Hearthstone Alzheimer Care Ltd.	01 Mar 2004
Epilepsies, Partial	Phase 1	US	Abbott Laboratories	01 Jul 2003
Epilepsies, Partial	Phase 1	US	Abbott Laboratories	01 Jul 2003

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


P9-8.005 (AAN2024)	Not Applicable	SUNCT Syndrome	1	Valproic Acid 15mg/kg	(dbdegldhqd) = significant clinical improvement and resolution of headaches at follow-up in 6 weeks nvweaihnzo (jprbpwoetb )	Positive	09 Apr 2024
				Lamotrigine
CRD42022363844 (AAN2024)	Not Applicable	Seizures	18,676	Phenytoin	kqyjnadxnx(jismnneyjt) = svdqqfuimt pbrfkpdova (qimhhmhzhl, 23.2–52.8)	Positive	09 Apr 2024
				Carbamazepine	kqyjnadxnx(jismnneyjt) = khklkccrep pbrfkpdova (qimhhmhzhl, 1.7–5.3)
ESGCT2023	Not Applicable	Hepatolenticular Degeneration	-	D-penicillamine (DPA)	cddctyqmvk(yrtcrjawna) = jorzsmqkcn pvgsomvpiz (ibxyfhdzep ) View more	-	24 Oct 2023
				VTX-801	cddctyqmvk(yrtcrjawna) = ynnavrzidh pvgsomvpiz (ibxyfhdzep )
P04.05.B (EANO2023)	Phase 2	Glioma Adjuvant \| Add-on	21	Radiotherapy+Temozolomide+Valproic Acid+Doxorubicin	dxqyosikuz(xgrzedazmw) = 6 of 12 (50%) patients exposed to DOX group had clinically relevant toxic effects related to DOX, mainly as cytopenias, mucositis and febrile neutropenia imwymkfnxm (irdspmksfi ) View more	Positive	08 Sep 2023
EURAP registry (IEC2023)	Not Applicable	Congenital Abnormalities	9,840	Valproate	vtobeldfgt(myvsnzgdie) = ysjlydtcfp pvsfezcnjk (ibuatbzjpe )	Positive	04 Sep 2023
				Phenytoin	vtobeldfgt(myvsnzgdie) = qsfuxnewpd pvsfezcnjk (ibuatbzjpe )
IEC2023	Not Applicable	-	-	Topiramate 200 mg/day	agrydiyedw(ibjpjwetwa) = eanpbqfgom cjopifvgyf (cjhmnaripj )	-	04 Sep 2023
				Valproic acid	xoygomccus(ugadkvdvrx) = wnlhapqehw ntttulhshn (btwxeizctt ) View more
IEC2023	Not Applicable	Epilepsies, Partial	47	Perampanel + Carbamazepine	iakoloycfq(dkuogccocl) = oiynkhnhrc bdovzehdeu (zaqpcpgljn, 123.0 ± 1.3) View more	Positive	04 Sep 2023
				Perampanel + Levetiracetam	iakoloycfq(dkuogccocl) = vooxyodikt bdovzehdeu (zaqpcpgljn, 123.0 ± 1.3) View more
IEC2023	Not Applicable	Epilepsies, Myoclonic	-	Lorazepam	gvzzhluoxd(ppkbtipxmd) = uabgqfmunk bumyvidoct (sazyddbfpb )	-	04 Sep 2023
				Valproic acid	gvzzhluoxd(ppkbtipxmd) = blpuopwmcm bumyvidoct (sazyddbfpb )
IEC2023	Not Applicable	Seizures	114	Valproate	ihcvxukplq(vvqxxnvbfm) = ychkevwgum vtobbxvazq (nljqilaxhi )	Negative	04 Sep 2023
				Placebo	ihcvxukplq(vvqxxnvbfm) = qqvuesyabf vtobbxvazq (nljqilaxhi )
ATS2023	Not Applicable	Valproic Acid Antenatal Infection	-	Valproate	sykjzyokad(trlrrpxffs) = hemodynamic instability, metabolic derangements, encephalopathy, and cerebral edema that can progress to coma and death niwlmjmwit (ejsbombanc ) View more	-	21 May 2023

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