TAC1

The urge to vomit after eating contaminated food is the body's natural defensive response to get rid of bacterial toxins. However, the process of how our brain initiates this biological reaction upon detecting the germs remains elusive. For the first time, researchers mapped out the detailed neural pathway of the defensive responses from the gut to the brain in mice. The urge to vomit after eating contaminated food is the body's natural defensive response to get rid of bacterial toxins. However, the process of how our brain initiates this biological reaction upon detecting the germs remains elusive. For the first time, researchers mapped out the detailed neural pathway of the defensive responses from the gut to the brain in mice. The study, presented November 1 in the journal Cell, could help scientists develop better anti-nausea medications for cancer patients who undergo chemotherapy. Many foodborne bacteria produce toxins in the host after being ingested. The brain, after sensing their presence, will initiate a series of biological responses, including vomit and nausea, to get rid of the substances and develop an aversion toward foods that taste or look the same. "But details on how the signals are transmitted from the gut to the brain were unclear, because scientists couldn't study the process on mice," says Peng Cao, the paper's corresponding author at the National Institute of Biological Sciences in Beijing. Rodents cannot vomit, likely because of their long esophagus and weaker muscle strength compared to their body size. As a result, scientists have been studying vomit in other animals like dogs and cats, but these animals are not comprehensively studied and thus failed to reveal the mechanism of nausea and vomiting. Cao and his team noticed that while mice don't vomit, they retch -- meaning they also experience the urge to vomit without throwing up. The team found that after receiving Staphylococcal enterotoxin A (SEA), which is a common bacterial toxin produced by Staphylococcus aureus that also leads to foodborne illnesses in humans, mice developed episodes of unusual mouth opening. Mice that received SEA opened their mouths at angles wider than those observed in the control group, where mice received saline water. Moreover, during these episodes, the diaphragm and abdominal muscles of the SEA-treated mice contract simultaneously, a pattern seen in dogs when they are vomiting. During normal breathing, animals' diaphragm and abdominal muscles contract alternatively. "The neural mechanism of retching is similar to that of vomiting. In this experiment, we successfully build a paradigm for studying toxin-induced retching in mice, with which we can look into the defensive responses from the brain to toxins at the molecular and cellular levels," Cao says. In mice treated with SEA, the team found the toxin in the intestine activates the release of serotonin, a type of neurotransmitter, by the enterochromaffin cells on the lining of the intestinal lumen. The released serotonin binds to the receptors on the vagal sensory neurons located in the intestine, which transmits the signals along the vagus nerves from the gut to a specific type of neurons in the dorsal vagal complex -- Tac1+DVC neurons -- in the brainstem. When Cao and his team inactivated the Tac1+DVC neurons, SEA-treated mice retched less compared with mice with normal Tac1+DVC neuron activities. In addition, the team investigated whether chemotherapy drugs, which also induce defensive responses like nausea and vomiting in recipients, activate the same neural pathway. They injected mice with doxorubicin, a common chemotherapy drug. The drug made mice retch, but when the team inactivated their Tac1+ DVC neurons or serotonin synthesis of their enterochromaffin cells, the animals' retching behaviors were significantly reduced. Cao says some of the current anti-nausea medications for chemotherapy recipients, such as Granisetron, work by blocking the serotonin receptors. The study helps explain why the drug works. "With this study, we can now better understand the molecular and cellular mechanisms of nausea and vomiting, which will help us develop better medications," Cao says. Next, Cao and his colleagues want to explore how toxins act on enterochromaffin cells. Preliminary research shows that enterochromaffin cells don't sense the presence of toxins directly. The process likely involves complex immune responses of damaged cells in the intestine. "In addition to foodborne germs, humans encounter a lot of pathogens, and our body is equipped with similar mechanisms to expel these toxic substances. For example, coughing is our body's attempt to remove the coronavirus. It's a new and exciting field of research about how the brain senses the existence of pathogens and initiates responses to get rid of them." Cao says, adding that future research may reveal new and better targets for drugs, including anti-nausea medicines. This work was supported by the National Key R&D Program of China and the National Natural Science Foundation of China.

$3 million awarded to University of North Carolina (UNC) to support a proposed 180-patient, randomized, placebo-controlled trial in trauma patients Proposed investigator sponsored trial to evaluate the potential for ACER-801 to reduce the frequency and severity of acute stress disorder and post-traumatic stress disorder (PTSD) Up to 20% of people who have experienced a traumatic event will develop PTSD1 leading to over 12 million adults in the US suffering from PTSD during a given year2 NEWTON, Mass., Oct. 06, 2022 (GLOBE NEWSWIRE) -- Acer Therapeutics Inc. (Nasdaq: ACER), a clinical stage pharmaceutical company focused on the acquisition, development and commercialization of therapies for serious rare and life-threatening diseases with significant unmet medical needs, today announced that the University of North Carolina (UNC) Institute for Trauma Recovery has been awarded a $3 million grant from the Department of Defense (DoD) to investigate the potential of ACER-801 (osanetant) to reduce the frequency and severity of acute stress disorder and post-traumatic stress disorder (PTSD). Acute stress disorder refers to the body’s immediate response to trauma, whereas PTSD is the long-term effects of trauma. “Historically, we have been able to provide emergency care to address immediate and long-term problems after visible wounds using tools such as sutures and antibiotics. However, we still have nothing to offer trauma survivors, whether in the emergency department or on the battlefield immediately after trauma, to prevent the development of ‘invisible wounds’,” said Samuel McLean, MD, Professor at UNC, School of Medicine, and lead principal investigator of the proposed study. Dr. McLean continued, “We need to investigate potential treatments like ACER-801 in an effort to better address these challenges.” The proposed Osanetant After Stress to Increase recovery Success (OASIS) trial will examine the safety and efficacy of ACER-801 to reduce acute stress response symptoms, post-traumatic stress disorder symptoms and behavioral changes among patients presenting to the emergency department after a motor vehicle collision. It is intended to enroll a total of 180 subjects who will be randomized in the emergency department, to receive a low or high dose of ACER-801 or placebo in the emergency department and be discharged with a two-week supply of study drug. Participating sites would include Washington University in St. Louis, University of Massachusetts Chan Medical School, Rhode Island Hospital, University of Florida College of Medicine – Jacksonville, and Indiana University School of Medicine. Initiation of patient enrollment in the proposed investigator sponsored OASIS trial is anticipated in the first half of 2023, subject to Investigational New Drug (IND) application filing and U.S. Food and Drug Administration (FDA) clearance. The OASIS trial will build upon a foundation of knowledge and infrastructure developed through the UNC-led, $40 million AURORA initiative. The AURORA study is a major national research initiative to improve the understanding, prevention, and recovery of individuals who have experienced a traumatic event. AURORA is supported by funding from NIH, One Mind, private foundations, and partnerships with leading tech companies such as Mindstrong Health and Verily Life Sciences, the health care arm of Google’s parent company Alphabet. “We are proud to be partnering with a leading academic institution in the field of trauma recovery as we seek to explore ACER-801 as a treatment option to reduce the frequency and severity of PTSD. Leveraging the support from the AURORA initiative allows Acer and UNC to streamline trial efficiency, reduce costs and increase trial power through enriching the target patient population, while utilizing the Department of Defense’s non-dilutive capital to primarily fund OASIS,” said Adrian Quartel, MD, FFPM, Chief Medical Officer of Acer. “The data from thousands of motor vehicle collisions collected through the AURORA initiative should allow us to better predict the correlation of the emergence of acute stress disorder or PTSD symptoms following a motor vehicle collision. We look forward to the planned OASIS trial following IND filing and FDA clearance.” Added Brandon Staglin, President of One Mind “We are thrilled to see how our funding to the AURORA initiative over the last five years is accelerating further advancements such as the OASIS Trial. The targeted outcomes of the OASIS Trial are the types of results that One Mind supports and of incredible value to anyone who experiences trauma and traumatic stress.” Acute and chronic stress disorders can affect both civilian and military populations. According to the National Center for PTSD, in the US about 60% of men and 50% of women experience at least one trauma in their lives.2 In the US alone, one-third of emergency department visits (40-50 million patients per year) are for evaluation after trauma exposures, and in a 2014 study involving 3,157 US veterans, 87% reported exposure to at least one potentially traumatic event during their service.3 Moreover, as many as 500,000 US troops who served in wars between 2001 and 2015 were diagnosed with PTSD.4 Rationale for ACER-801 (osanetant) Evaluation in Post-Traumatic Stress Disorder. The Tacr3 gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, Neurokinin B (NKB), which is encoded by the Tac3 (human) gene. The role of NKB-NK3R in growth and reproduction has been extensively studied, but NKB-NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system.5 In animal models, Tac2 (mice) mRNA levels are rapidly up-regulated during fear consolidation 30 minutes after fear conditioning, and subsequent NKB-NK3R activation can lead to over stress sensitization and the consolidation of fear,6 and treatment with osanetant has been shown to block a critical fear/stress sensitization step in the brain.7,8,9 An effective therapeutic to reduce acute and persistent/long-term psychological and somatic symptoms would fulfill a large unmet need. About Acer TherapeuticsAcer is a pharmaceutical company focused on the acquisition, development and commercialization of therapies for serious rare and life-threatening diseases with significant unmet medical needs. Acer’s pipeline includes four investigational programs: ACER-001 (sodium phenylbutyrate) for treatment of various inborn errors of metabolism, including urea cycle disorders (UCDs) and Maple Syrup Urine Disease (MSUD); ACER-801 (osanetant) for treatment of induced Vasomotor Symptoms (iVMS) and post-traumatic stress disorder (PTSD); EDSIVO™ (celiprolol) for treatment of vascular Ehlers-Danlos syndrome (vEDS) in patients with a confirmed type III collagen (COL3A1) mutation; and ACER-2820 (emetine), a host-directed therapy against a variety of viruses, including cytomegalovirus, Zika, dengue, Ebola and COVID-19. For more information, visit www.acertx.com. References Sidran Institute. Traumatic Stress Education & Advocacy Fact Sheet.National Center for PTSD. How Common is PTSD in Adults?Wisco et al. 2014 J Clin Psychiatry. Posttraumatic stress disorder in the US veteran population: results from the National Health and Resilience in Veterans Study. J Clin Psychiatry . 2014 Dec;75(12):1338-46Thompson 2015. Unlocking the secrets of PTSD. Time 2015;185:40–43Zhang et al. ACS Chemical Neuroscience 2020 11 (19), 2935-2943Al Abed et. Al, Biological Psychiatry 2021Andero R, Dias BG, Ressler KJ. A role for Tac2, NkB, and Nk3 receptor in normal and dysregulated fear memory consolidation. Neuron. 2014;83(2):444-454Andero R, Daniel S, Guo JD, et al. Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning. Neuropsychopharmacology. 2016;41(11):2714-2722Zelikowsky M, Ding K, Anderson DJ. Neuropeptidergic Control of an Internal Brain State Produced by Prolonged Social Isolation Stress. Cold Spring Harb Symp Quant Biol. 2018;83:97-103 Acer Forward-Looking StatementsThis press release contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in this press release are forward-looking statements. Examples of such statements include, but are not limited to, statements about the role we believe ACER-801 could play in reducing the frequency and severity of PTSD, the planned clinical evaluation of ACER-801 for such indication, plans with respect to the OASIS trial, including enrollment, timing and participants, and the continued development of ACER-801 for treatment of iVMS. Our pipeline products (including ACER-801) are under investigation and their safety and efficacy have not been established and there is no guarantee that any of our investigational products in development will receive health authority approval or become commercially available for the uses being investigated. We may not actually achieve the plans, carry out the intentions or meet the expectations or projections disclosed in the forward-looking statements and you should not place undue reliance on these forward-looking statements. Such statements are based on management’s current expectations and involve risks and uncertainties. Actual results and performance could differ materially from those projected in the forward-looking statements as a result of many factors, including, without limitation, the availability of financing to fund our pipeline product development programs and general corporate operations as well as risks related to drug development and the regulatory approval process, including the timing and requirements of regulatory actions. We disclaim any intent or obligation to update these forward-looking statements to reflect events or circumstances that exist after the date on which they were made. You should review additional disclosures we make in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K and Quarterly Reports on Form 10-Q. You may access these documents for no charge at http://www.sec.gov. Acer ContactsCorporate contact:Jim DeNikeAcer Therapeutics Inc.jdenike@acertx.com+1-844-902-6100 Investor contact:Nick ColangeloGilmartin Groupnick@gilmartinIR.com+1-332-895-3226

Acer Therapeutics Announces Expansion of ACER-801 (osanetant) Development Indications to Include Post-Traumatic Stress Disorder Licensed exclusive worldwide rights from Emory University to patents and patent applications for certain methods of treating or preventing post-traumatic stress disorder (PTSD) with osanetant Osanetant targets a distinct group of brain cells in a region of the brain that controls the formation and consolidation of fear memories, which may aid in preventing PTSD1 Up to 20% of people who have experienced a traumatic event will develop PTSD2 leading to over 12 million adults in the US suffering from PTSD during a given year3 NEWTON, Mass., Oct. 05, 2022 (GLOBE NEWSWIRE) -- Acer Therapeutics Inc. (Nasdaq: ACER), a pharmaceutical company focused on the acquisition, development and commercialization of therapies for serious, rare and life-threatening diseases with significant unmet medical needs, today announced the expansion of ACER-801 (osanetant) into a new indication, for the reduction of the frequency and severity of acute stress disorder and post-traumatic stress disorder (PTSD). Acute stress disorder refers to the body’s immediate response to trauma, whereas PTSD is defined as the long-term effects of trauma. Studies conducted at Emory University screened thousands of genes that were activated in the brains of mice following fear conditioning events. The top gene identified was Tac2, which is responsible for the production of the peptide, Neurokinin B (NKB), in mice. The researchers showed that the Tac2 gene, expressed by neurons specifically within the amygdala, is required for modulating fear memories, and that NKB, and its specific receptor, NK3R, are also involved in the consolidation of fear memories. By administering the potent and specific NK3R antagonist, osanetant, they were able to block fear memory consolidation shortly after exposure to a trauma, potentially providing a novel therapeutic approach for disorders with altered fear learning such as PTSD.1 “Immediately – hours to several days – after trauma exposure, memory remains in a labile state, called the memory consolidation period, and blocking fear memory consolidation after trauma exposure could lower the frequency and severity of PTSD in trauma patients,” said Kerry Ressler, MD, PhD, Chief Scientific Officer and James and Patricia Poitras Chair in Psychiatry at McLean Hospital. “Activation of the NK3 receptor pathway in the central amygdala is necessary and sufficient for the modulation of fear memories, and we have learned that by blocking this pathway with osanetant, we can block the consolidation of fear memories in animal models,”1 added Dr. Ressler. “Osanetant is a promising agent that could reduce the frequency and of severity of PTSD for millions of people who experience a traumatic event.” Acer previously entered into an agreement with Emory for an exclusive world-wide license to US Patent No. 10,314,835, US Application 15/320,952, and European Patent No. EP3160469 covering certain methods of treating or preventing PTSD with osanetant. “We are pleased to further expand our ACER-801 development program into PTSD, an increasingly prevalent psychiatric disorder that affects millions every year. Today’s announcement further validates Acer’s strategy of identifying and developing treatments based on promising technology that can be applied in new ways for use in diseases with high unmet need,” commented Chris Schelling, CEO and Founder of Acer Therapeutics. “While the role of the NK3R pathway in the hypothalamus to manage thermoregulation is well-established in clinical trials, this opportunity explores an entirely different mechanism of action for the drug. We look forward to presenting our clinical development plan for ACER-801 for the reduction of frequency and severity of PTSD in the near future.” According to the National Center for PTSD, in the US about 6 of every 10 men (or 60%) and 5 of every 10 women (or 50%) experience at least one trauma in their lives leading to about 12 million adults in the U.S. have PTSD during a given year.3 In the US alone, one-third of emergency department visits are for evaluation after trauma exposures and up to 20% of people who have experienced a traumatic event will develop PTSD.4 Rationale for ACER-801 (osanetant) Evaluation in Post-Traumatic Stress Disorder. The Tacr3 gene encodes tachykinin receptor 3 (NK3R), which belongs to the tachykinin receptor family. This family of proteins includes typical G protein-coupled receptors and belongs to the rhodopsin subfamily. NK3R functions by binding to its high-affinity ligand, Neurokinin B (NKB), which is encoded by the Tac3 (human) gene. The role of NKB-NK3R in growth and reproduction has been extensively studied, but NKB-NK3R is also widely expressed in the nervous system from the spinal cord to the brain and is involved in both physiological and pathological processes in the nervous system.5 In animal models, Tac2 (mice) mRNA levels are rapidly up-regulated during fear consolidation 30 minutes after fear conditioning, and subsequent NKB-NK3R activation can lead to over stress sensitization and the consolidation of fear,6 and treatment with osanetant has been shown to block a critical fear/stress sensitization step in the brain.1,7,8 An effective therapeutic to reduce acute and persistent/long-term psychological and somatic symptoms would fulfill a large unmet need. About Acer Therapeutics Acer is a pharmaceutical company focused on the acquisition, development and commercialization of therapies for serious rare and life-threatening diseases with significant unmet medical needs. Acer’s pipeline includes four investigational programs: ACER-001 (sodium phenylbutyrate) for treatment of various inborn errors of metabolism, including urea cycle disorders (UCDs) and Maple Syrup Urine Disease (MSUD); ACER-801 (osanetant) for treatment of induced Vasomotor Symptoms (iVMS) and post-traumatic stress disorder (PTSD); EDSIVO™ (celiprolol) for treatment of vascular Ehlers-Danlos syndrome (vEDS) in patients with a confirmed type III collagen (COL3A1) mutation; and ACER-2820 (emetine), a host-directed therapy against a variety of viruses, including cytomegalovirus, Zika, dengue, Ebola and COVID-19. For more information, visit www.acertx.com. References Andero R, Dias BG, Ressler KJ. A role for Tac2, NkB, and Nk3 receptor in normal and dysregulated fear memory consolidation. Neuron. 2014;83(2):444-454 Sidran Institute. Traumatic Stress Education & Advocacy Fact Sheet. National Center for PTSD. How Common is PTSD in Adults? Sidran Institute. Traumatic Stress Education & Advocacy Fact Sheet. Zhang et al. Tacr3/NK3R: Beyond Their Roles in Reproduction. ACS Chemical Neuroscience 2020 11 (19), 2935-2943 Al Abed et. Al, Biological Psychiatry 2021 Andero R, Daniel S, Guo JD, et al. Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning. Neuropsychopharmacology. 2016;41(11):2714-2722 Zelikowsky M, Ding K, Anderson DJ. Neuropeptidergic Control of an Internal Brain State Produced by Prolonged Social Isolation Stress. Cold Spring Harb Symp Quant Biol. 2018;83:97-103