mAChRs x H1 receptor

- Approval marks fourth indication for VRAYLAR, backed by proven efficacy and well-established tolerability as an adjunctive treatment for major depressive disorder (MDD) with an antidepressant therapy (ADT), showing improvement in symptoms when compared to placebo + ADT Designed for specific mood disorders, VRAYLAR is now the first and only dopamine and serotonin partial agonist FDA-approved for the most common forms of depression – as an adjunctive treatment for MDD and the treatment of depressive episodes associated with bipolar I disorder About one in five U.S. adults will experience MDD during their lifetime, and many of them may have partial response to the treatment with an ADT NORTH CHICAGO, Ill. Dec. 16, 2022 /PRNewswire/ -- AbbVie (NYSE: ABBV) today announced that the U.S. Food and Drug Administration (FDA) has approved VRAYLAR (cariprazine) as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults. Supported by clinical data demonstrating efficacy and well-established tolerability, this additional indication provides a new option for adults who have a partial response to the treatment of an antidepressant. Experience the interactive Multimedia News Release here: https://www.multivu.com/players/English/9107351-vraylar-cariprazine-fda-approval-major-depressive-disorder/ "Many living with major depressive disorder find that their ongoing antidepressant therapy doesn't offer meaningful relief from the symptoms they experience every day," said Thomas Hudson , M.D., senior vice president, research and development, chief scientific officer, AbbVie. "Today's approval of VRAYLAR provides an important new treatment option to meet a critical unmet medical need. AbbVie is committed to driving progress and advancing solutions for patients living with complex neuropsychiatric conditions." MDD is one of the most common mental disorders in the U.S.; approximately one in five adults will experience this disorder during their lifetime. In a large U.S. study of adults with MDD, approximately 50 percent still had depressive symptoms with their first antidepressant. If some symptoms of depression persist while on an antidepressant, adding a different type of medication, often referred to as an adjunctive treatment, to the existing regimen may help. "Patients with inadequate response to standard antidepressant medication are often frustrated by the experience of trying multiple medicines and still suffering from unresolved symptoms. Instead of starting over with another standard antidepressant, VRAYLAR works with an existing treatment and can help build on the progress already made," said Gary Sachs , MD, clinical vice president at Signant Health, associate clinical professor of psychiatry at Massachusetts General Hospital, and lead Phase 3 clinical trial investigator. "For adults living with major depressive disorder, because of inadequate improvement in response to standard antidepressants, VRAYLAR is an efficacious adjunctive treatment option with a well-characterized safety profile." Cariprazine is marketed as VRAYLAR in the U.S., and in addition to being approved as an adjunctive therapy to antidepressants for the treatment of MDD in adults, it is FDA-approved to treat adults with depressive, acute manic and mixed episodes associated with bipolar I disorder, as well as schizophrenia. Cariprazine is co-developed by AbbVie and Gedeon Richter Plc. More than 8,000 patients worldwide have been treated with cariprazine across more than 20 clinical trials evaluating the efficacy and safety of cariprazine for a broad range of psychiatric disorders. "When we were in the early stages of development for cariprazine, we focused on designing a compound that covers a range of symptoms for mental health conditions and affects the dopamine D3 receptor," said István Greiner, Ph.D., research and development, director, Gedeon Richter . "While schizophrenia and bipolar manic and mixed episodes were the first indications in the U.S. market, we are thrilled to see the full potential of cariprazine unlocked with approvals in bipolar I depression, and now, as an antidepressant adjunct in major depressive disorder." Highlights from the clinical program supporting the approval include: A Phase 3 Study 3111-301-001 showed a clinically and statistically significant change from baseline to week six in the Montgomery -Åsberg Depression Rating Scale (MADRS) total score for patients treated with cariprazine at 1.5 mg/day + ADT compared with placebo + ADT. A second registration-enabling study, RGH-MD-75, showed a clinically and statistically significant change from baseline to week eight in the MADRS total score for patients treated with cariprazine at 2-4.5 mg/day (mean dose 2.6 mg) + ADT compared with placebo + ADT. Cariprazine was generally well tolerated in 6- and 8-week studies. Mean weight change was < 2lbs and ≤ 3% of patients had a weight increase of ≥ 7%. The starting dosage of VRAYLAR is 1.5 mg once daily. Depending upon clinical response and tolerability, the dosage can be increased to 3 mg once daily on Day 15. In clinical trials, dosage titration at intervals of less than 14 days resulted in a higher incidence of adverse reactions. The maximum recommended dosage is 3 mg once daily. Most common adverse reactions observed in the adjunctive MDD studies (≥ 5% and at least twice the rate of placebo) were: Akathisia, nausea, and insomnia at the recommended doses in 6-week, fixed-dose trials Akathisia, restlessness, fatigue, constipation, nausea, increased appetite, dizziness, insomnia, and extrapyramidal symptoms in one 8-week flexible-dose trial at a titration of less than 14 days About Major Depressive Disorder (MDD) MDD is one of the most common mental disorders in the U.S., characterized by symptoms such as overwhelming feelings of sadness and/or loss of interest that don't go away after two weeks. MDD can cause severe functional impairment, adversely affect interpersonal relationships, and may impact the quality of life. It is a leading cause of disability in the world, and has a lifetime prevalence of 20% for adults in the U.S. Symptoms can include depressed mood, loss of pleasure or interest in activities, feelings of worthlessness, lack of energy, poor concentration, appetite changes, sleep disturbances, suicidal thoughts, and feeling restless or moving or talking more slowly. In the U.S., the estimated economic burden of MDD has been estimated to be around $326 billion in 2020. About Study 3111-301-001 Study 3111-301-001 is a randomized, double-blind, placebo-controlled, multicenter trial with 751 participants conducted in the United States Bulgaria Estonia Germany Hungary Ukraine and the United Kingdom . Following a screening period of up to 14 days, patients with an inadequate clinical response to their antidepressant monotherapy (ADT) were randomized into three treatment groups (1:1:1). The first group received cariprazine 1.5 mg/day + ADT, the second group received cariprazine 3.0 mg/day + ADT, and the third group received placebo + ADT. For six weeks, the medication was given once daily in addition to the ongoing ADT treatment. Patients treated with cariprazine 3.0 mg/day + ADT demonstrated improvement in MADRS total score at week six over placebo + ADT but did not meet statistical significance. About Study RGH-MD-75 Study RGH-MD-75 is a randomized, double-blind, placebo-controlled, flexible-dose, outpatient, multicenter trial with 808 participants, conducted in the United States Estonia Finland Slovakia Ukraine Sweden . After 7-14 days of screening and washout of prohibited medications, eligible patients entered an 8-week, double-blind treatment period in which they continued antidepressant treatment and were randomized (1:1:1) to adjunctive cariprazine 1-2 mg/day, cariprazine 2-4.5 mg/day, or placebo. Data from Study RGH-MD-75 were published in the Journal of Clinical Psychiatry Patients treated with cariprazine 1-2 mg/day + ADT demonstrated improvement in MADRS total score at week eight over placebo + ADT but did not meet statistical significance. About VRAYLAR (cariprazine) VRAYLAR is an oral, once-daily atypical antipsychotic approved as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults (1.5 or 3 mg/day), for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults (1.5 or 3 mg/day), and for the acute treatment of adults with manic or mixed episodes associated with bipolar I disorder (3 to 6 mg/day). VRAYLAR is also approved for the treatment of schizophrenia in adults (1.5 to 6 mg/day). While the mechanism of action of VRAYLAR is unknown, the efficacy of VRAYLAR is thought to be mediated through a combination of partial agonist activity at central dopamine D₂ and serotonin 5-HT receptors and antagonist activity at serotonin 5-HT receptors. Pharmacodynamic studies with VRAYLAR have shown that it may act as a partial agonist with high binding affinity at dopamine D , dopamine D , and serotonin 5-HT receptors. VRAYLAR demonstrated up to ~8-fold greater in vitro affinity for dopamine D receptors. VRAYLAR also acts as an antagonist at serotonin 5-HT and 5-HT receptors with high and moderate binding affinity, respectively as well as it binds to the histamine H receptors. VRAYLAR shows lower  binding affinity to the serotonin 5-HT and α - adrenergic receptors and has no appreciable affinity for cholinergic muscarinic receptors. The clinical significance of these in vitro data is unknown. VRAYLAR is developed jointly by AbbVie and Gedeon Richter Plc, with AbbVie responsible for commercialization in the U.S., Canada, Japan, Taiwan and certain Latin American countries (including Argentina Bolivia Brazil Chile Colombia Ecuador Mexico Venezuela Visit www.vraylar.com for more information. VRAYLAR (cariprazine) Uses and Important Safety Information VRAYLAR is a prescription medicine used in adults: to treat schizophrenia for short-term (acute) treatment of manic or mixed episodes that happen with bipolar I disorder to treat depressive episodes that happen with bipolar I disorder (bipolar depression) along with antidepressant medicines to treat major depressive disorder What is the most important information I should know about VRAYLAR? Elderly people with dementia-related psychosis (having lost touch with reality due to confusion and memory loss) taking medicines like VRAYLAR are at an increased risk of death. VRAYLAR is not approved for treating patients with dementia-related psychosis. VRAYLAR and antidepressants may increase suicidal thoughts or actions in some children and young adults especially within the first few months of treatment or when the dose is changed. Depression and other mental illnesses are the most important causes of suicidal thoughts and actions. Patients on antidepressants and their families or caregivers should watch for new or worsening depression symptoms, especially sudden changes in mood, behaviors, thoughts, or feelings. This is very important when VRAYLAR or the antidepressant is started or when the dose is changed. Report any change in these symptoms immediately to the doctor. VRAYLAR may cause serious side effects, including: Stroke (cerebrovascular problems) in elderly people with dementia-related psychosis that can lead to death Neuroleptic malignant syndrome (NMS): Call your healthcare provider or go to the nearest hospital emergency room right away if you have high fever, stiff muscles, confusion, increased sweating, or changes in breathing, heart rate, and blood pressure. These can be symptoms of a rare but potentially fatal side effect called NMS. VRAYLAR should be stopped if you have NMS. Uncontrolled body movements (tardive dyskinesia or TD): VRAYLAR may cause movements that you cannot control in your face, tongue, or other body parts. Tardive dyskinesia may not go away, even if you stop taking VRAYLAR. Tardive dyskinesia may also start after you stop taking VRAYLAR. Late-occurring side effects: VRAYLAR stays in your body for a long time. Some side effects may not happen right away and can start a few weeks after starting VRAYLAR, or if your dose increases. Your healthcare provider should monitor you for side effects for several weeks after starting or increasing dose of VRAYLAR. Problems with your metabolism, such as: High blood sugar and diabetes: Increases in blood sugar can happen in some people who take VRAYLAR. Extremely high blood sugar can lead to coma or death. Your healthcare provider should check your blood sugar before or soon after starting VRAYLAR and regularly during treatment. Tell your healthcare provider if you have symptoms such as feeling very thirsty, very hungry, or sick to your stomach, urinating more than usual, feeling weak, tired, confused, or your breath smells fruity. Increased fat levels (cholesterol and triglycerides) in your blood: Your healthcare provider should check fat levels in your blood before or soon after starting VRAYLAR and during treatment. Weight gain: Weight gain has been reported with VRAYLAR. You and your healthcare provider should check your weight before and regularly during treatment. Low white blood cell count: Low white blood cell counts have been reported with antipsychotic drugs, including VRAYLAR. This may increase your risk of infection. Very low white blood cell counts, which can be fatal, have been reported with other antipsychotics. Your healthcare provider may do blood tests during the first few months of treatment with VRAYLAR. Decreased blood pressure (orthostatic hypotension): You may feel lightheaded or faint when you rise too quickly from a sitting or lying position. Falls: VRAYLAR may make you sleepy or dizzy, may cause a decrease in blood pressure when changing position (orthostatic hypotension), and can slow thinking and motor skills, which may lead to falls that can cause fractures or other injuries. Seizures (convulsions) Sleepiness, drowsiness, feeling tired, difficulty thinking and doing normal activities: Do NOT drive, operate machinery, or do other dangerous activities until you know how VRAYLAR affects you. VRAYLAR may make you drowsy. Increased body temperature: Do not become too hot or dehydrated during VRAYLAR treatment. Do not exercise too much. In hot weather, stay inside in a cool place if possible. Stay out of the sun. Do not wear too much clothing or heavy clothing. Drink plenty of water. Difficulty swallowing that can cause food or liquid to get into your lungs Who should not take VRAYLAR? Do not take VRAYLAR if you are allergic to any of its ingredients. Get emergency medical help if you are having an allergic reaction (eg, rash, itching, hives, swelling of the tongue, lip, face or throat). What should I tell my healthcare provider before taking VRAYLAR? Tell your healthcare provider about any medical conditions and if you: have or have had heart problems or a stroke have or have had low or high blood pressure have or have had diabetes or high blood sugar in you or your family have or have had high levels of total cholesterol, LDL-cholesterol, or triglycerides; or low levels of HDL-cholesterol have or have had seizures (convulsions) have or have had kidney or liver problems have or have had low white blood cell count are pregnant or plan to become pregnant. VRAYLAR may harm your unborn baby. Taking VRAYLAR during your third trimester of pregnancy may cause your baby to have abnormal muscle movements or withdrawal symptoms after birth. Talk to your healthcare provider about the risk to your unborn baby if you take VRAYLAR during pregnancy. If you become pregnant or think you are pregnant during treatment, talk to your healthcare provider about registering with the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or http://www.womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/ are breastfeeding or plan to breastfeed. It is not known if VRAYLAR passes into breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with VRAYLAR. Tell your healthcare provider about all medicines that you take, including prescriptions, over-the-counter medicines, vitamins, and supplements. VRAYLAR may affect the way other medicines work, and other medicines may affect how VRAYLAR works. Do not start or stop any medicines while taking VRAYLAR without talking to your healthcare provider. What are the most common side effects of VRAYLAR? The most common side effects include difficulty moving or slow movements, tremors, uncontrolled body movements, restlessness and feeling like you need to move around, sleepiness, nausea, vomiting, indigestion, constipation, feeling tired, trouble sleeping, increased appetite, and dizziness. These are not all the possible side effects of VRAYLAR. Please see the full Prescribing Information , including Boxed Warnings, and Medication Guide You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. If you are having difficulty paying for your medicine, AbbVie may be able to help. Visit AbbVie.com/myAbbVieAssist to learn more. About AbbVie in Mental Health AbbVie is driving the pursuit of better mental health. Over the last 30 years, the company's scientists and clinicians have worked to tackle the complexity of mental illness and today offer a portfolio of medicines and a pipeline of innovation that spans depression, anxiety, bipolar I disorder, and schizophrenia. To learn more about AbbVie's work to support individuals throughout their mental health journey, please visit www.abbvie. or follow @abbvie on Twitter Facebook Instagram YouTube LinkedIn About AbbVie AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com Follow @abbvie on Twitter Facebook Instagram YouTube LinkedIn Forward-Looking Statements Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, failure to realize the expected benefits from AbbVie's acquisition of Allergan plc ("Allergan"), failure to promptly and effectively integrate Allergan's businesses, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, changes to laws and regulations applicable to our industry and the impact of public health outbreaks, epidemics or pandemics, such as COVID-19. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2021 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission, as updated by its subsequent Quarterly Reports on Form 10-Q. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law. US-VRAA-220055 References: Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States JAMA Psychiatry . 2018;75(4):336-346. Trivedi MH, Rush AJ, Wisniewski SR, et al. Am J Psychiatry. 2006;163(1):28-40. National Institute of Mental Health (2022). Depression. Available at: https://www.nimh.nih.gov/health/topics/depression . Accessed December 2022 Bains N, Abdijadid S. Major Depressive Disorder. [Updated 2022 Jun 1 ]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK559078/ . Accessed December 2022 Friedrich MJ. Depression Is the Leading Cause of Disability Around the World . JAMA. 2017;317(15):1517. Greenberg P, Fournier AA, Sistsky T, et al. Pharmacoeconomics. 2021;39(6):653-65. Durgam S, Earley W, Guo H, et al. J Clin Psychiatry. 2016;77(3):371-8. VRAYLAR. Package insert. Allergan , Inc; 2022. Contacts US Media Mary Byun +1 (646) 709-4409 [email protected] Global Media Mabel Martinez +1 (224) 306-4412 [email protected] Investors Liz Shea +1 (847) 935-2211 [email protected] SOURCE AbbVie

CHATHAM, N.J., Aug. 22, 2022 (GLOBE NEWSWIRE) -- Tonix Pharmaceuticals Holding Corp. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced that the first participant was enrolled in the Phase 2 PREVAIL study of TNX-102 SL1 as a potential treatment for a subset of patients with Long COVID syndrome (Long COVID) whose symptoms overlap with fibromyalgia. Long COVID is known officially as Post-Acute Sequelae of COVID-19 (PASC)2. “We are pleased to be starting a Phase 2 clinical study in this indication which is a growing problem and for which no drug is currently approved. We believe Long COVID, characterized by multi-site pain, fatigue and sleep disturbance, has features of central sensitization syndromes similar to fibromyalgia. Fibromyalgia is considered one of the clusters of chronic overlapping pain conditions that have much in common with Long COVID,” said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. “Findings from our retrospective observational database study in over 50,000 Long COVID patients showed that more than 40% of Long COVID patients in the sample have fibromyalgia-like multi-site pain symptoms, suggesting that we should be able to recruit a robust cohort of participants to test the effects of TNX-102 SL in treating this condition. Our experience with TNX-102 SL in fibromyalgia is the motivation for undertaking the development of TNX-102 SL in patients with Long COVID whose symptoms overlap with fibromyalgia. We recognize the need to better understand and develop treatment for Long COVID.” “This retrospective observational database study also revealed the rate of opioid use in Long COVID patients,” said Greg Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals. “Opioid use was noted in 36% of Long COVID patients with multi-site pain symptoms relative to 19% of Long COVID patients without multi-site pain. In those with multi-site pain, opioid use increased to 39% of patients when fatigue was present, and 50% when insomnia was present. We look forward to continuing to progress this study with the goal of developing a non-addictive, centrally acting analgesic which potentially treats not only pain but also the sleep disturbance and fatigue that are common in Long COVID.” About the Phase 2 PREVAIL Study The Phase 2 PREVAIL study is 14-week double-blind, randomized, multicenter, placebo-controlled study to evaluate the efficacy and safety of TNX-102 SL taken daily at bedtime in patients with multi-site pain associated with post-acute sequelae of SARS-COV-2 infection (PASC). The trial is being conducted at approximately 30 sites in the U.S. and is expected to enroll approximately 470 patients (235 per arm) who will be randomized in a 1:1 ratio to treatment with TNX-102 SL or placebo tablets. The primary efficacy endpoint will be changed from baseline in the weekly average of daily self-reported worst pain intensity scores at the Week 14 endpoint. Key secondary efficacy endpoints include change from baseline in self-reported scores for sleep disturbance, fatigue and cognitive function. An interim analysis is expected to be completed after the first 50% of enrolled patients have completed the study for the purpose of possible sample size re-estimation or to stop the study early for efficacy, currently anticipated in the first half of 2023. For more information, see ClinicalTrials.gov Identifier: NCT05472090. About Long COVID or Post-Acute Sequelae of COVID-19 (PASC) Although most people recover from COVID-19 within weeks of the acute illness, a substantial portion develop a chronic syndrome called Long COVID. These individuals experience a constellation of disabling symptoms long past the time of recovery from acute COVID-19. Most Long COVID patients who have been studied appear to have cleared the SARS-CoV-2 infection from their systems. The symptoms of Long COVID can include fatigue, sleep disorders, multi-site pain, fevers, shortness of breath, cognitive impairment described as “brain fog” or memory disturbance, gastrointestinal symptoms, anxiety, and depression. Long COVID can persist for many months and can range in severity from mild to incapacitating. Several cohort studies have reported that persistence of symptoms following SARS-CoV-2 infection occurs in more than 30% of patients.3-5 While typically associated with moderate or severe COVID-19, Long COVID can occur after mild COVID-19 or even after asymptomatic SARS-CoV-2 infection. Patients with Long COVID are sometimes referred to as “long-haulers”. Long COVID is a chronic disabling condition that is expected to result in a significant global health and economic burden.4-7 In response to the urgent need for therapies that address Long COVID, Congress awarded $1.15 billion to the National Institutes of Health to study Long COVID in December 2020.8 While the vaccines available in the U.S. through either FDA approval or under Emergency Use Authorization have been shown to prevent acute COVID, their ability to prevent Long COVID is unknown. There is currently no approved drug for the treatment of Long COVID. About TNX-102 SL TNX-102 SL is a patented sublingual tablet formulation of cyclobenzaprine hydrochloride which provides rapid transmucosal absorption and reduced production of a long half-life active metabolite, norcyclobenzaprine, due to bypass of first-pass hepatic metabolism. As a multifunctional agent with potent binding and antagonist activities at the serotonin-5-HT2A, α1-adrenergic, histaminergic-H1, and muscarinic-M1 receptors, TNX-102 SL is in clinical development as a daily bedtime treatment for Long COVID, fibromyalgia, PTSD, alcohol use disorder, and agitation in Alzheimer’s disease. The U.S. Patent and Trademark Office (USPTO) has issued United States Patent No. 9636408 in May 2017, Patent No. 9956188 in May 2018, Patent No. 10117936 in November 2018, Patent No. 10,357,465 in July 2019, and Patent No. 10736859 in August 2020. The Protectic™ protective eutectic and Angstro-Technology™ formulation claimed in these patents are important elements of Tonix’s proprietary TNX-102 SL composition. These patents are expected to provide TNX-102 SL, upon NDA approval, with U.S. market exclusivity until 2034/2035. Tonix Pharmaceuticals Holding Corp.* Tonix is a clinical-stage biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics to treat and prevent human disease and alleviate suffering. Tonix’s portfolio is composed of central nervous system (CNS), rare disease, immunology and infectious disease product candidates. Tonix’s CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s lead CNS candidate, TNX-102 SL (cyclobenzaprine HCl sublingual tablet), is in mid-Phase 3 development for the management of fibromyalgia with a new Phase 3 study launched in the second quarter of 2022 and interim data expected in the first quarter of 2023. TNX-102 SL is also being developed to treat Long COVID, a chronic post-acute COVID-19 condition. Tonix initiated a Phase 2 study in Long COVID in the third quarter of 2022 and expects interim data in the first half of 2023. TNX-1300 (cocaine esterase) is a biologic designed to treat cocaine intoxication and has been granted Breakthrough Therapy designation by the FDA. A Phase 2 study of TNX-1300 is expected to be initiated in the fourth quarter of 2022. TNX-1900 (intranasal potentiated oxytocin), a small molecule in development for chronic migraine, is expected to enter the clinic with a Phase 2 study in the first half of 2023. Tonix’s rare disease portfolio includes TNX-2900 (intranasal potentiated oxytocin) for the treatment of Prader-Willi syndrome. TNX-2900 has been granted Orphan Drug designation by the FDA. Tonix’s immunology portfolio includes biologics to address organ transplant rejection, autoimmunity and cancer, including TNX-1500, which is a humanized monoclonal antibody targeting CD40-ligand (CD40L or CD154) being developed for the prevention of allograft and xenograft rejection and for the treatment of autoimmune diseases. A Phase 1 study of TNX-1500 is expected to be initiated in the first half of 2023. Tonix’s infectious disease pipeline consists of a vaccine in development to prevent smallpox and monkeypox, next-generation vaccines to prevent COVID-19, and a platform to make fully human monoclonal antibodies to treat COVID-19. TNX-801, Tonix’s vaccine in development to prevent smallpox and monkeypox, also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious diseases. A Phase 1 study of TNX-801 is expected to be initiated in Kenya in the first half of 2023. Tonix’s lead vaccine candidate for COVID-19 is TNX-1850, a live virus vaccines based on Tonix’s recombinant pox live virus vector vaccine platform. A Phase 1 study of the COVID-19 vaccine is expected to be initiated in the second half of 2023.

Results from Planned Interim Analysis Expected First Half 2023 Long COVID Afflicts More Than 30% of Patients Following Infection with SARS-CoV-2, the Virus that Causes COVID-19, and is Expected to be a Global Health Burden Concerning Rate of Opioid Use Observed in Long COVID Patients with Multi-Site Pain CHATHAM, N.J., Aug. 22, 2022 (GLOBE NEWSWIRE) -- Tonix Pharmaceuticals, Inc. (Nasdaq: TNXP) (Tonix or the Company), a clinical-stage biopharmaceutical company, today announced that the first participant was enrolled in the Phase 2 PREVAIL study of TNX-102 SL1 as a potential treatment for a subset of patients with Long COVID syndrome (Long COVID) whose symptoms overlap with fibromyalgia. Long COVID is known officially as Post-Acute Sequelae of COVID-19 (PASC)2. “We are pleased to be starting a Phase 2 clinical study in this indication which is a growing problem and for which no drug is currently approved. We believe Long COVID, characterized by multi-site pain, fatigue and sleep disturbance, has features of central sensitization syndromes similar to fibromyalgia. Fibromyalgia is considered one of the clusters of chronic overlapping pain conditions that have much in common with Long COVID,” said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. “Findings from our retrospective observational database study in over 50,000 Long COVID patients showed that more than 40% of Long COVID patients in the sample have fibromyalgia-like multi-site pain symptoms, suggesting that we should be able to recruit a robust cohort of participants to test the effects of TNX-102 SL in treating this condition. Our experience with TNX-102 SL in fibromyalgia is the motivation for undertaking the development of TNX-102 SL in patients with Long COVID whose symptoms overlap with fibromyalgia. We recognize the need to better understand and develop treatment for Long COVID.” “This retrospective observational database study also revealed the rate of opioid use in Long COVID patients,” said Greg Sullivan, M.D., Chief Medical Officer of Tonix Pharmaceuticals. “Opioid use was noted in 36% of Long COVID patients with multi-site pain symptoms relative to 19% of Long COVID patients without multi-site pain. In those with multi-site pain, opioid use increased to 39% of patients when fatigue was present, and 50% when insomnia was present. We look forward to continuing to progress this study with the goal of developing a non-addictive, centrally acting analgesic which potentially treats not only pain but also the sleep disturbance and fatigue that are common in Long COVID.” About the Phase 2 PREVAIL Study The Phase 2 PREVAIL study is 14-week double-blind, randomized, multicenter, placebo-controlled study to evaluate the efficacy and safety of TNX-102 SL taken daily at bedtime in patients with multi-site pain associated with post-acute sequelae of SARS-COV-2 infection (PASC). The trial is being conducted at approximately 30 sites in the U.S. and is expected to enroll approximately 470 patients (235 per arm) who will be randomized in a 1:1 ratio to treatment with TNX-102 SL or placebo tablets. The primary efficacy endpoint will be changed from baseline in the weekly average of daily self-reported worst pain intensity scores at the Week 14 endpoint. Key secondary efficacy endpoints include change from baseline in self-reported scores for sleep disturbance, fatigue and cognitive function. An interim analysis is expected to be completed after the first 50% of enrolled patients have completed the study for the purpose of possible sample size re-estimation or to stop the study early for efficacy, currently anticipated in the first half of 2023. For more information, see ClinicalTrials.gov Identifier: NCT05472090. About Long COVID or Post-Acute Sequelae of COVID-19 (PASC) Although most people recover from COVID-19 within weeks of the acute illness, a substantial portion develop a chronic syndrome called Long COVID. These individuals experience a constellation of disabling symptoms long past the time of recovery from acute COVID-19. Most Long COVID patients who have been studied appear to have cleared the SARS-CoV-2 infection from their systems. The symptoms of Long COVID can include fatigue, sleep disorders, multi-site pain, fevers, shortness of breath, cognitive impairment described as “brain fog” or memory disturbance, gastrointestinal symptoms, anxiety, and depression. Long COVID can persist for many months and can range in severity from mild to incapacitating. Several cohort studies have reported that persistence of symptoms following SARS-CoV-2 infection occurs in more than 30% of patients.3-5 While typically associated with moderate or severe COVID-19, Long COVID can occur after mild COVID-19 or even after asymptomatic SARS-CoV-2 infection. Patients with Long COVID are sometimes referred to as “long-haulers”. Long COVID is a chronic disabling condition that is expected to result in a significant global health and economic burden.4-7 In response to the urgent need for therapies that address Long COVID, Congress awarded $1.15 billion to the National Institutes of Health to study Long COVID in December 2020.8 While the vaccines available in the U.S. through either FDA approval or under Emergency Use Authorization have been shown to prevent acute COVID, their ability to prevent Long COVID is unknown. There is currently no approved drug for the treatment of Long COVID. 1TNX-102 SL is an investigational new drug and has not been approved for any indication. 2Feb. 24, 2021 - White House COVID-19 Response Team press briefing; Feb 25, 2021 - policy brief from the World Health Organization on long COVID. 3Harris, H, et al. Tonix data on file. 2022 4Briggs, A, and Vassall, A. (2021) "Count the cost of disability caused by COVID-19." Nature 593(7860): 502-505. 5Nittas V, et al. (2022) “Long COVID Through a Public Health Lens: An Umbrella Review.” Public Health Rev. 43:1604501. Published 2022 Mar 15. doi:10.3389/phrs.2022.1604501 6Davis, HE., et al. (2021) "Characterizing long COVID in an international cohort: 7 months of symptoms and their impact." EClinicalMedicine 38: 101019. 7Martin C, et al. (2021) “A model framework for projecting the prevalence and impact of Long-COVID in the UK.” PLoS One. 16(12):e0260843. Published 2021 Dec 2. doi:10.1371/journal.pone.0260843 8The NIH provision of Title III Health and Human Services, Division M--Coronavirus Response and Relief Supplemental Appropriations Act, 2021, of H.R. 133, The Consolidated Appropriations Act of 2021. The bill was enacted into law on 27 December 2020, becoming Public Law 116-260. About TNX-102 SL TNX-102 SL is a patented sublingual tablet formulation of cyclobenzaprine hydrochloride which provides rapid transmucosal absorption and reduced production of a long half-life active metabolite, norcyclobenzaprine, due to bypass of first-pass hepatic metabolism. As a multifunctional agent with potent binding and antagonist activities at the serotonin-5-HT2A, α1-adrenergic, histaminergic-H1, and muscarinic-M1 receptors, TNX-102 SL is in clinical development as a daily bedtime treatment for Long COVID, fibromyalgia, PTSD, alcohol use disorder, and agitation in Alzheimer’s disease. The U.S. Patent and Trademark Office (USPTO) has issued United States Patent No. 9636408 in May 2017, Patent No. 9956188 in May 2018, Patent No. 10117936 in November 2018, Patent No. 10,357,465 in July 2019, and Patent No. 10736859 in August 2020. The Protectic™ protective eutectic and Angstro-Technology™ formulation claimed in these patents are important elements of Tonix’s proprietary TNX-102 SL composition. These patents are expected to provide TNX-102 SL, upon NDA approval, with U.S. market exclusivity until 2034/2035. Tonix Pharmaceuticals Holding Corp.* Tonix is a clinical-stage biopharmaceutical company focused on discovering, licensing, acquiring and developing therapeutics to treat and prevent human disease and alleviate suffering. Tonix’s portfolio is composed of central nervous system (CNS), rare disease, immunology and infectious disease product candidates. Tonix’s CNS portfolio includes both small molecules and biologics to treat pain, neurologic, psychiatric and addiction conditions. Tonix’s lead CNS candidate, TNX-102 SL (cyclobenzaprine HCl sublingual tablet), is in mid-Phase 3 development for the management of fibromyalgia with a new Phase 3 study launched in the second quarter of 2022 and interim data expected in the first quarter of 2023. TNX-102 SL is also being developed to treat Long COVID, a chronic post-acute COVID-19 condition. Tonix initiated a Phase 2 study in Long COVID in the third quarter of 2022 and expects interim data in the first half of 2023. TNX-1300 (cocaine esterase) is a biologic designed to treat cocaine intoxication and has been granted Breakthrough Therapy designation by the FDA. A Phase 2 study of TNX-1300 is expected to be initiated in the fourth quarter of 2022. TNX-1900 (intranasal potentiated oxytocin), a small molecule in development for chronic migraine, is expected to enter the clinic with a Phase 2 study in the first half of 2023. Tonix’s rare disease portfolio includes TNX-2900 (intranasal potentiated oxytocin) for the treatment of Prader-Willi syndrome. TNX-2900 has been granted Orphan Drug designation by the FDA. Tonix’s immunology portfolio includes biologics to address organ transplant rejection, autoimmunity and cancer, including TNX-1500, which is a humanized monoclonal antibody targeting CD40-ligand (CD40L or CD154) being developed for the prevention of allograft and xenograft rejection and for the treatment of autoimmune diseases. A Phase 1 study of TNX-1500 is expected to be initiated in the first half of 2023. Tonix’s infectious disease pipeline consists of a vaccine in development to prevent smallpox and monkeypox, next-generation vaccines to prevent COVID-19, and a platform to make fully human monoclonal antibodies to treat COVID-19. TNX-801, Tonix’s vaccine in development to prevent smallpox and monkeypox, also serves as the live virus vaccine platform or recombinant pox vaccine (RPV) platform for other infectious diseases. A Phase 1 study of TNX-801 is expected to be initiated in Kenya in the first half of 2023. Tonix’s lead vaccine candidate for COVID-19 is TNX-1850, a live virus vaccines based on Tonix’s recombinant pox live virus vector vaccine platform. A Phase 1 study of the COVID-19 vaccine is expected to be initiated in the second half of 2023. *All of Tonix’s product candidates are investigational new drugs or biologics and have not been approved for any indication. This press release and further information about Tonix can be found at . Forward Looking Statements Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimate,” “expect,” and “intend,” among others. These forward-looking statements are based on Tonix's current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, risks related to the failure to obtain FDA clearances or approvals and noncompliance with FDA regulations; delays and uncertainties caused by the global COVID-19 pandemic; risks related to the timing and progress of clinical development of our product candidates; our need for additional financing; uncertainties of patent protection and litigation; uncertainties of government or third party payor reimbursement; limited research and development efforts and dependence upon third parties; and substantial competition. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. Tonix does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in the Annual Report on Form 10-K for the year ended December 31, 2021, as filed with the Securities and Exchange Commission (the “SEC”) on March 14, 2022, and periodic reports filed with the SEC on or after the date thereof. All of Tonix's forward-looking statements are expressly qualified by all such risk factors and other cautionary statements. The information set forth herein speaks only as of the date thereof. Contacts Jessica Morris (corporate) Tonix Pharmaceuticals [email protected] (862) 904-8182 Olipriya Das, Ph.D. (media) Russo Partners [email protected]