Randomized Phase 2 Study of Valproic Acid Combined with Rechallenge Anti-EGFR Based Regimen Regimens in Pretreated Patients with RAS/BRAF Wild-type Metastatic Colorectal Cancer - VICTORIA Trial

The investigators hypothesize that the epigenetic agent valproic acid improve the activity of anti-EGFR agents, prevent and revert the emergence of EGFR resistance, in a rechallenge setting.
Correlative mechanistic studies on tissue and blood samples, liquid biopsies, could identify potential biomarkers of efficacy and help understanding the evolutionary dynamics of tumors in response to therapy thus optimizing the treatment approach with a personalized anti- EGFR treatment strategy.

Start Date20 Dec 2024

Sponsor / Collaborator

National Cancer Institute

IRCT20200623047902N42 / Suspended

Bioequivalence study of valproic acid 500mg sustained release tablet (Valpact) manufactured by Alborzzagros versus originator brand in healthy volunteers in the fasted condition

Start Date21 Oct 2024

Sponsor / Collaborator-

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 Sep 2024

Sponsor / Collaborator

University Medical Center of Utrecht

[+1]

100 Clinical Results associated with Valproic Acid

100 Translational Medicine associated with Valproic Acid

100 Patents (Medical) associated with Valproic Acid

19,958

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

JOURNAL/nrgr/04.03/01300535-202509000-00025/figure1/v/2024-11-05T132919Z/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: Li, Jinyun ; Liang, Chan ; Liu, Liangying ; Zhou, Jie ; Gu, Jiayi ; Salamova, Amina

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·Journal of Environmental Sciences

Carbonyl-amine condensation coupled ozonolysis of dipropylamine and styrene: Decay kinetics, reaction mechanism, secondary organic aerosol formation and cytotoxicity

Article

Author: Ji, Yuemeng ; An, Taicheng ; Chen, Jiangyao ; Lin, Qinhao ; Li, Wanying

Oxidation of organic amines (OAs) or aromatic hydrocarbons (AHs) produces carbonyls, which further react with OAs to form carbonyl-amine condensation products, threatening environmental quality and human health. However, there is still a lack of systematic understanding of the carbonyl-amine condensation reaction processes of OAs or between OAs and AHs, and subsequent environmental health impact. This work systematically investigated the carbonyl-amine condensation coupled ozonolysis kinetics, reaction mechanism, secondary organic aerosol (SOA) formation and cytotoxicity from the mixture of dipropylamine (DPA) and styrene (STY) by a combined method of product mass spectrometry identification, particle property analysis and cell exposure evaluation. The results from ozonolysis of DPA and STY mixture revealed that STY inhibited the ozonolysis of DPA to different degrees to accelerate its own decay rate. The barycenter of carbonyl-amine condensation reactions was shifted from inside of DPA to between DPA and STY, which accelerated STY ozonolysis, but slowed down DPA ozonolysis. For the first time, ozonolysis of DPA and STY mixture to complex carbonyl-amine condensation products through the reactions of DPA with its carbonyl products, DPA with STY's carbonyl products and DPA's bond breakage product with STY's carbonyl products was confirmed. These condensation products significantly contributed to the formation and growth of SOA. The SOA containing particulate carbonyl-amine condensation products showed definite cytotoxicity. These findings are helpful to deeply and comprehensively understand the transformation, fate and environmental health effects of mixed organics in atmospheric environment.

News (Medical) associated with Valproic Acid

06 Dec 2024

·www.prnewswire.com

Jazz Pharmaceuticals to Showcase New Real-World Evidence Reinforcing Epidiolex® (cannabidiol) Benefits and Broad-Spectrum Efficacy in Treatment-Resistant Epilepsies at the American Epilepsy Society 2024 Annual Meeting

Data from nine abstracts to be presented, including first data from the EpiCom Trial, a prospective evaluation of behavioral outcomes in patients with tuberous sclerosis complex, which suggests improvements in severity of behavioral symptoms Real-world data from the BECOME (BEhavior, COgnition and More with Epidiolex®) surveys, which show outcomes reported by long-term care facility nurses and tuberous sclerosis complex caregivers For U.S. media and investors only DUBLIN, Dec. 6, 2024 /PRNewswire/ -- Jazz Pharmaceuticals plc (Nasdaq: JAZZ) today announced nine company-sponsored Epidiolex® (cannabidiol) posters are being presented at the American Epilepsy Society (AES) 2024 Annual Meeting, being held December 6-10 in Los Angeles, California. Data presented at the meeting includes updated analyses of real-world data from the BECOME-TSC (BEhavior, COgnition, and More with Epidiolex) caregiver survey, which characterizes and quantifies seizure and non-seizure outcomes in patients with epilepsy and tuberous sclerosis complex (TSC) treated with Epidiolex. An additional presentation showcases data from the BECOME-LTC survey, which evaluated the perspectives of nurses who care for patients with epilepsy in long-term care (LTC) facilities and group homes, reporting improvements in seizure frequency and in certain non-seizure outcomes associated with Epidiolex treatment. Further, the first presentation of data from the EpiCom trial, a prospective, interventional trial evaluating the impact of adjunctive Epidiolex on TSC-associated neuropsychiatric disorders (TAND), revealed improvements in behavioral symptom severity following treatment initiation. "Our real-world data presentations at AES 2024, including novel findings from the BECOME-LTC, BECOME-TSC and EpiCom studies, demonstrate the meaningful impact of Epidiolex in the treatment of patients with rare epilepsies," said Sarah Akerman, MD, head of neuroscience global medical and scientific affairs of Jazz Pharmaceuticals. "These findings increase our understanding of Epidiolex's benefits beyond seizure control, addressing unmet needs across a range of epilepsy syndromes for people living with rare epilepsies and demonstrating reproducibility and consistency of effect across different populations." Data highlights include: A prespecified three-month analysis of the EpiCom trial reporting TSC-associated neuropsychiatric disorders (TAND)-associated outcomes demonstrated improvements after initiating adjunctive Epidiolex treatment in the severity of behavioral problems in patients with TSC as reported by the TAND Self-Report Quantified Checklist and Aberrant Behavior Checklist. Two updated analyses of real-world outcomes from the BECOME-TSC study showed that, of 55 caregivers who completed the survey, 89% planned to continue Epidiolex treatment for their loved one. The most important stated reasons for continuing Epidiolex included seizure and non-seizure benefits such as reduced seizure frequency and severity/duration, as well as TAND-related improvements in cognition and language/communication. Results from the BECOME-LTC (BEhavior, COgnition, and More with Epidiolex in the Long-Term Care Setting) survey found that, among 102 nurses surveyed, 85% reported a reduction in overall frequency of any seizure type after Epidiolex initiation, with 49% reporting a greater than 50% reduction. Improvements were also observed across different seizure subtypes as well as in non-seizure outcomes, with nurses reporting improvements in emotional functioning, sleep, cognitive abilities, ability to communicate, and physical functioning. Results from CARE-EpiC (Caregiver Analysis of Real-world Epidiolex in Epilepsy Context), a cross-sectional caregiver survey, demonstrated reduced caregivers' need for additional support of their dependents' physical, emotional, and behavioral care after Epidiolex initiation and characterized improvements in their dependents' well-being as well as caregivers' experiences. A subgroup analysis evaluating treatment outcomes in patients with TSC (TSC group) versus other types of focal epilepsy (non-TSC group) treated with Epidiolex in the U.S. Expanded Access Program, found Epidiolex has similar effectiveness in TSC and other focal epilepsies, regardless of focal epilepsy type, further reinforcing the clinical profile of Epidiolex as a broad-spectrum agent. In the TSC group, Epidiolex was associated with a median reduction from baseline of 51%–87% in focal seizures and 44%–87% in total seizures. In the non-TSC group, Epidiolex was also associated with a median reduction from baseline of 46%–75% in focal and 46%–74% in total seizures. Epidiolex is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome or TSC in patients one year of age and older. All AES 2024 abstracts are available online at the following link: . A full list of Jazz Pharmaceuticals' presentations follows below: About Tuberous Sclerosis Complex Tuberous sclerosis complex (TSC) is a rare genetic condition.1 The condition causes mostly benign tumors to grow in vital organs of the body including the brain, skin, heart, eyes, kidneys and lungs2 and is a leading cause of genetic epilepsy.3 People with TSC may experience a variety of seizure types. One of the most common is infantile spasms that typically present in the first year of life; focal (or partial) seizures are also very common.4 TSC is associated with an increased risk of autism and intellectual disability5 and the severity of the condition can vary widely. In some children the disease is very mild, while others may experience life-threatening complications.4 Epilepsy is present in about 85 percent of patients with TSC and may progress to become intractable to medication.4,6,7 More than 60 percent of individuals with TSC do not achieve seizure control8 with standard treatments such as antiepileptic drugs, epilepsy surgery, ketogenic diet, or vagus nerve stimulation8 compared to 30-40 percent of individuals with epilepsy who do not have TSC who are drug resistant.9,10 About Dravet Syndrome Dravet syndrome (DS) is a rare genetic condition that appears during the first year of life with frequent fever-related seizures (febrile seizures). Later, other types of seizures typically arise, including myoclonic seizures (involuntary muscle spasms).11 Additionally, status epilepticus, a potentially life-threatening state of continuous seizure activity requiring emergency medical care, may occur. Children with DS typically experience poor development of language and motor skills, hyperactivity and difficulty relating to others. About Lennox-Gastaut Syndrome Lennox-Gastaut syndrome (LGS) begins in childhood. It is characterized by multiple types of seizures. People with LGS begin having frequent seizures in early childhood, usually between ages 3 and 5.12 More than three-quarters of affected individuals have tonic seizures, which cause the muscles to contract uncontrollably. Almost all children with LGS develop learning problems and intellectual disability. Many also have delayed development of motor skills such as sitting and crawling. Most people with LGS require help with usual activities of daily living. About Epidiolex®/Epidyolex® (cannabidiol) Epidiolex/Epidyolex is a prescription, plant-derived cannabis-based medicine administered as an oral solution which contains highly purified cannabidiol (CBD). Cannabidiol, the active ingredient in Epidiolex, is a cannabinoid that naturally occurs in the Cannabis sativa L. plant. The precise mechanisms by which Epidiolex exerts its anticonvulsant effect in humans are unknown. Epidiolex was approved by the U.S. Food and Drug Administration (FDA) for use in the U.S., the European Commission (EC) for use in Europe, the Medicines and Healthcare products Regulatory Agency (MHRA) for use in Great Britain, the Therapeutic Goods Administration for use in Australia, Swissmedic for use in Switzerland, the Food & Nutrition Services of the Israel Ministry of Health for use in Israel, and the New Zealand Medicines and Medical Devices Safety Authority for use in New Zealand, is an oral solution which contains highly purified cannabidiol (CBD). In the U.S., Epidiolex is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) or tuberous sclerosis complex (TSC) in patients one year of age and older. Epidiolex has received approval in the European Union under the tradename Epidyolex for adjunctive use in conjunction with clobazam to treat seizures associated with LGS and DS in patients two years and older, and for adjunctive use to treat seizures associated with TSC, in patients two years of age and older. Epidiolex has received Orphan Drug Designation (ODD) from the U.S. FDA for the treatment of seizures associated with LGS, DS, and TSC. Similarly, Epidyolex received ODD from the European Medicines Agency (EMA) for the same indications. Important Safety Information & Indications CONTRAINDICATION: HYPERSENSITIVITY EPIDIOLEX (cannabidiol) oral solution is contraindicated in patients with a history of hypersensitivity to cannabidiol or any ingredients in the product. WARNINGS & PRECAUTIONS Hepatic Injury: EPIDIOLEX can cause dose-related transaminase elevations. Concomitant use of valproate and elevated transaminase levels at baseline increase this risk. Obtain transaminase and bilirubin levels prior to starting treatment, at 1, 3, and 6 months after initiation of treatment, and periodically thereafter, or as clinically indicated. Resolution of transaminase elevations occurred with discontinuation of EPIDIOLEX, reduction of EPIDIOLEX and/or concomitant valproate, or without dose reduction. For patients with elevated transaminase levels, consider dose reduction or discontinuation of EPIDIOLEX or concomitant medications known to affect the liver (e.g., valproate or clobazam). Dose adjustment and slower dose titration is recommended in patients with moderate or severe hepatic impairment. Consider not initiating EPIDIOLEX in patients with evidence of significant liver injury. There have been postmarketing reports of cholestatic or mixed patterns of liver injury. Elevated ammonia levels were reported in some patients with transaminase elevations; most taking concomitant valproate, clobazam, or both. Consider discontinuation or dose adjustment of valproate or clobazam if ammonia is elevated. Somnolence and Sedation: EPIDIOLEX can cause somnolence and sedation that generally occurs early in treatment and may diminish over time; these effects occur more commonly in patients using clobazam and may be potentiated by other CNS depressants. Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including EPIDIOLEX, increase the risk of suicidal thoughts or behavior. Inform patients, caregivers, and families of the risk and advise them to monitor and report any signs of depression, suicidal thoughts or behavior, or unusual changes in mood or behavior. If these symptoms occur, consider if they are related to the AED or the underlying illness. Withdrawal of Antiepileptic Drugs: As with most AEDs, EPIDIOLEX should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. ADVERSE REACTIONS: The most common adverse reactions in patients receiving EPIDIOLEX (≥10% and greater than placebo) include transaminase elevations; somnolence; decreased appetite; diarrhea; pyrexia; vomiting; fatigue, malaise, and asthenia; rash; insomnia, sleep disorder and poor-quality sleep; and infections. Hematologic abnormalities were also observed. PREGNANCY: EPIDIOLEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage women who are taking EPIDIOLEX during pregnancy to enroll in the EPIDIOLEX Pregnancy Surveillance Program and the North American Antiepileptic Drug (NAAED) Pregnancy Registry. DRUG INTERACTIONS: Strong inducers of CYP3A4 and CYP2C19 may affect EPIDIOLEX exposure. EPIDIOLEX may affect exposure to CYP2C19 substrates (e.g., clobazam, diazepam, stiripentol), orally administered P-gp substrates, or other substrates (see full Prescribing Information). Consider dose reduction of orally administered everolimus, with appropriate therapeutic drug monitoring, when everolimus is combined with EPIDIOLEX. A lower starting dose of everolimus is recommended when added to EPIDIOLEX therapy. Concomitant use of EPIDIOLEX and valproate increases the incidence of liver enzyme elevations. Pneumonia was observed more frequently with concomitant use of EPIDIOLEX and clobazam. Dosage adjustment of EPIDIOLEX or other concomitant medications may be necessary. INDICATIONS: EPIDIOLEX (cannabidiol) oral solution is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC) in patients 1 year of age and older. Please read the EPIDIOLEX full Prescribing Information for additional important information here . About Jazz Pharmaceuticals Jazz Pharmaceuticals plc (Nasdaq: JAZZ) is a global biopharma company whose purpose is to innovate to transform the lives of patients and their families. We are dedicated to developing potentially life-changing medicines for people with serious diseases — often with limited or no therapeutic options. We have a diverse portfolio of marketed medicines, including leading therapies for sleep disorders and epilepsy, and a growing portfolio of cancer treatments. Our patient-focused and science-driven approach powers pioneering research and development advancements across our robust pipeline of innovative therapeutics in oncology and neuroscience. Jazz is headquartered in Dublin, Ireland with research and development laboratories, manufacturing facilities and employees in multiple countries committed to serving patients worldwide. Please visit for more information. Contacts: Media: Kristin Bhavnani Head of Global Corporate Communications Jazz Pharmaceuticals plc [email protected] Ireland +353 1 637 2141 U.S. +1 215 867 4948 Investors: Jeff Macdonald Executive Director, Investor Relations Jazz Pharmaceuticals plc [email protected] Ireland +353 1 634 3211 U.S. +1 650 496 2717 SOURCE Jazz Pharmaceuticals plc WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Clinical ResultDrug ApprovalOrphan Drug

06 Dec 2024

·www.drugs.com

Many Women With Epilepsy Unaware of Seizure Meds' Risks to Pregnancy

FRIDAY, Dec. 6, 2024 -- Many women with epilepsy who are of childbearing age might not realize their anti-seizure drugs can raise the risk of birth defects or dampen the effectiveness of their birth control, a new study warns. Likewise, some birth control methods can cause anti-seizure meds to be less effective, researchers reported Friday in a presentation at the annual meeting of the American Epilepsy Society in Los Angeles. “Many neurologists do not learn about birth control in their training, even though they know that anti-seizure medications may have some risks in pregnancy,” said senior researcher Dr. Sarah Betstadt , an associate professor of obstetrics and gynecology at the University of Rochester Medical Center. “We hope this study raises awareness for patients and encourages health care providers from neurology and reproductive health care to work together to ensure the best care for these patients,” Betstadt added in a society news release. For the study, researchers surveyed 107 women ages 18 to 49 who were taking anti-seizure medications about their reproductive plans. Six said they were pregnant or planning to become pregnant, and another 69 said they were using some sort of birth control that could interfere with their anti-seizure meds, researchers said. The survey quizzed women on their knowledge regarding birth control and anti-seizure meds, and found that: “Survey participants may not have known that their answers were wrong and so did not feel they needed more information,” Betstadt noted. Only about a third of the women were receiving medical care that aligned with their reproductive plans, researchers found. Anti-seizure medications that increase the risk of birth defects include valproic acid , topiramate , carbamazepine , phenobarbital and phenytoin. Further, anti-seizure drugs that can make hormonal contraceptives like pills, patches and rings less effective include carbamazepine, phenytoin , phenobarbital, and higher doses of topiramate and oxcarbazepine . Despite that, no anti-seizure drug is as dangerous for an expecting mother or her fetus as uncontrolled seizures , the researchers noted. Women who want to become pregnant should talk with their doctor about drugs that are less risky but still can control their seizures, researchers said. “Neurology and reproductive health care providers should collaborate to provide the safest and most effective care for their patients of reproductive age who are taking anti-seizure medications,” Betstadt said. “This collaboration can help patients navigate their reproductive choices while minimizing drug-drug interactions that may reduce the effectiveness of seizure medications and/or birth control methods,” Betstadt added. Findings presented at medical meetings should be considered preliminary until they’re published in a peer-reviewed journal. Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

03 Dec 2024

·www.globenewswire.com

Intra-Cellular Therapies Submits Supplemental New Drug Application (sNDA) to FDA for CAPLYTA® (lumateperone) for the Treatment of Major Depressive Disorder as Adjunctive Therapy

The sNDA submission is based on positive results from Studies 501 and 502 demonstrating CAPLYTA’s robust antidepressant efficacy and favorable safety and tolerability profileCAPLYTA, if approved as an adjunctive therapy in MDD, would be indicated for the treatment of three different major psychiatry indications affecting over 30 million adult patients in the US BEDMINSTER, N.J., Dec. 03, 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, announced that it has recently submitted a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) for CAPLYTA (lumateperone) for the treatment of Major Depressive Disorder (MDD) in adults, as adjunctive therapy to antidepressants. “MDD is a highly prevalent condition with a significant need for efficacious, safe, and well-tolerated medicines, as more than half of patients do not adequately respond to an antidepressant alone,” said Dr. Suresh Durgam, Executive Vice President and Chief Medical Officer of Intra-Cellular Therapies. “Given CAPLYTA’s efficacy and safety profile, we believe CAPLYTA can become a first-choice treatment for the adjunctive treatment of MDD pending FDA approval, and we look forward to working with the FDA during this review process.” Studies 501 and 502 are two positive Phase 3 global, double-blind, placebo-controlled studies in patients with a primary diagnosis of MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria who have had an inadequate response to ongoing anti-depressant therapy. These studies form the basis of the sNDA. CAPLYTA, added to an antidepressant, demonstrated robust efficacy for the treatment of MDD in the primary endpoint, the Montgomery Asberg Depression Rating Scale (MADRS) total score, with a large separation versus placebo of 4.9 points (effect size 0.61) in Study 501 and 4.5 points (effect size 0.56) versus placebo in Study 502. CAPLYTA’s efficacy is complemented with a favorable safety and tolerability profile - including a favorable metabolic, weight and movement disorder profile. In the pooled safety data for Studies 501 and 502, the most commonly reported adverse events that were observed at a rate greater than or equal to 5% for lumateperone and greater than twice the rate of placebo were dizziness, dry mouth, somnolence/sedation, nausea, and fatigue. Importantly, metabolic and weight changes were similar to placebo and the rates of extrapyramidal symptoms were low. About Major Depressive Disorder Major Depressive Disorder (MDD) is a common mood disorder in the U.S. affecting an estimated 21 million adults each year. Depressive disorders are the second cause of years lived with disability in the world. Symptoms include sadness, hopelessness, helplessness, feelings of guilt, irritability, loss of interest in formerly pleasurable activities, cognitive impairment, disturbed sleep patterns, and suicide ideation or behavior. MDD can cause severe functional impairment, adversely affecting interpersonal relationships, and may impact quality of life. Approximately two-thirds of patients with depression fail to achieve remission with first-line treatment. 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 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 ResultCell TherapyPhase 3Drug Approval

100 Deals associated with Valproic Acid

External Link

KEGG	Wiki	ATC	Drug Bank
D00399	Valproic Acid	N03AG01	DB00313

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Mania	US	Bionpharma, Inc.Startup	29 Jul 2008
Migraine Disorders	US	Bionpharma, Inc.Startup	29 Jul 2008
Epilepsy	US	AbbVie, Inc.	28 Feb 1978

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Alcoholism	Phase 3	US	AstraZeneca PLC	01 Jan 2006
Epilepsies, Partial	Phase 3	US	Abbott Laboratories	01 Jul 2003
Epilepsy, Temporal Lobe	Phase 2	AU	Cerebral Therapeutics, Inc.	01 Aug 2016
Seizures	Phase 2	AU	Cerebral Therapeutics, Inc.	01 Aug 2016
Spinal Muscular Atrophy	Phase 2	US	Abbott Laboratories	01 Jul 2007
Contraception	Phase 1	GB	Estetra SRL	12 Apr 2018
Thrombosis	Phase 1	SE	Cereno Scientific AB	06 Oct 2017
Shock, Hemorrhagic	Phase 1	US	University of Michigan	01 Sep 2013
Wounds and Injuries	Phase 1	US	University of Michigan	01 Sep 2013
Psychotic Disorders	Phase 1	US	Johnson & Johnson Pharmaceutical Research & Development LLC	01 Feb 2009

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05821556 (VESPA, Pubmed \| BMC Cancer)	Phase 2	Pancreatic adenocarcinoma metastatic CA 19.9	240	VPA/SIM plus gemcitabine/nab-paclitaxel-based regimens	pbifgvnznj(ldmpmekcvu) = mlstkikcua cmehpyqjui (bwhlwappey )	-	19 Sep 2024
				Chemotherapy alone	pbifgvnznj(ldmpmekcvu) = vvqgcjslgj cmehpyqjui (bwhlwappey )
NCT05821556 (VESPA, ESMO2024)	Phase 2	Pancreatic adenocarcinoma metastatic First line CA19.9	240	Valproic acid/Simvastatin plus gemcitabine/nab-paclitaxel-based regimens	sxfchdjoey(hitmcehdmt) = zsqdqbvxje xvyhtvbqjf (hahjsgqari )	Positive	16 Sep 2024
				Chemotherapy alone	sxfchdjoey(hitmcehdmt) = cffthynsya xvyhtvbqjf (hahjsgqari )
P9-8.005 (AAN2024)	Not Applicable	SUNCT Syndrome	1	Valproic Acid 15mg/kg	yltlqdooee(hxlhvdwyuu) = significant clinical improvement and resolution of headaches at follow-up in 6 weeks wunfvpghob (szigvgxtiy )	Positive	09 Apr 2024
				Lamotrigine
CNS2023	Phase 1/2	Migraine Disorders	17	Normal Saline, Prochlorperazine, Ketorolac	ukrjzmmpwr(fwkakffvdq) = ayfnxdtsly sviknafgvd (twkmxfwnsk ) View more	Positive	01 Oct 2023
IEC2023	Not Applicable	Seizures	114	Valproate	kunhdsqrca(vcnrgwoikt) = prxdpjmwfv ktodesdmbi (nilijflbhz )	Negative	04 Sep 2023
				Placebo	kunhdsqrca(vcnrgwoikt) = iqinatdoun ktodesdmbi (nilijflbhz )
EURAP registry (IEC2023)	Not Applicable	Congenital Abnormalities	9,840	Valproate	bbihgwqotg(slxqrsdswr) = tgqlnasovy tgugezebnv (fkhzsslyid )	Positive	04 Sep 2023
				Phenytoin	bbihgwqotg(slxqrsdswr) = dxtgujovjt tgugezebnv (fkhzsslyid )
IEC2023	Not Applicable	Valproic Acid Antenatal Infection	-	Valproate monotherapy	bbvoeatjok(ebdiwzllcy) = mreisbdwft knpubbjxfc (jlwhwzhjum ) View more	-	04 Sep 2023
P10-9.010 (AAN2023)	Not Applicable	Alexander Disease	59	Valproic Acid	ecwdtuzcol(tdmvbdodid) = 1 in a non-ambulatory patient jkseywxcam (hwcyyzwcio ) View more	-	25 Apr 2023
				Anti-reflux medications
ASN2022	Not Applicable	Toxicity	-	Valproic acid (VPA) 1,500 mg	omswwkissq(romxbbdpny) = altered mental status, disorientation, tremors, asterixis pcsoxxxlzv (wcarixpnpw )	-	04 Nov 2022
NCT02068586 (ASCO2022) Manual	Phase 2	Uveal Melanoma Adjuvant	88	Sunitinib 25 mg daily	whrhqfcjlf(mrxzrwtqeo) = tlnaewzexg ryilhqpffj (brajxseefh, 86.5 - 98.6) Met View more	Positive	02 Jun 2022
				Valproic acid 750 mg daily	whrhqfcjlf(mrxzrwtqeo) = mirpitbdqp ryilhqpffj (brajxseefh, 80.1 - 95.8) Met View more

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