ACC1

Various conditions such as postpartum depression or postpartum psychosis can lead to an alteration in maternal behavior and disrupt the mother-child bonding process. A research team has conducted a study in which they were able to identify the neuronal circuits in the brain that are activated during the learning of maternal behavior. The findings can serve as a basis for developing therapeutic interventions. Various conditions such as postpartum depression or postpartum psychosis can lead to an alteration in maternal behaviour and disrupt the mother-child bonding process. A research team led by Daniela Pollak from MedUni Vienna's Center for Physiology and Pharmacology has conducted a study in which they were able to identify the neuronal circuits in the brain that are activated during the learning of maternal behaviour. The findings, published in The EMBO Journal, can serve as a basis for developing therapeutic interventions. In the course of their preclinical investigation, the scientists led by Daniela Pollak from the Division of Neurophysiology and Neuropharmacology at MedUni Vienna's Center for Physiology and Pharmacology analysed maternal behaviour of female mice towards newborn pups. While the neural processes involved in the development of maternal care behaviour in female mice after birth have already been described, the current study addressed the question which circuits in the brain are activated during the learning of care behaviour in nulliparous virgin females, female mice that have not been pregnant. The researchers found the answer in the anterior cingulate cortex (ACC), a region in the prefrontal lobe of the brain that is associated, among other things, with the recognition and evaluation of social processes and the development of emotional awareness. The mouse model showed that in females who have not been pregnant or given birth, the ACC gets activated when they acquire maternal behaviour upon first contact with pups. "Our observations have demonstrated that, through repeated experience with pups, the virgin females are capable of learning maternal behaviour that fully resembles those of mothers after delivery," explains project leader Daniela Pollak, reporting from her research. The study revealed that during this learning process ACC activity is controlled by an excitatory feedback circuit involving a specific group of neurons in a central brain region (the thalamus). Learning through repeated experience Maternal behaviour is defined, among other things, by sensitivity and responsiveness to signals of infant needs. It is instinctively displayed in virtually all mammals and upon first contact with newborns immediately after delivery. In some species, such as rodents, even animals that have never given birth may exhibit maternal care behaviour toward newborns. In this case, the care behaviour, such as returning displaced pups from outside the nest back into the nest area, where they are warm and protected from predators, are acquired through repeated experience with the pups. We know, for example from observations in adoptive parents, that humans can also learn parental behaviours. Various pathological conditions, such as postpartum depression or postpartum psychosis can lead to alterations in maternal behaviour and disrupt the mother-child bonding process. "By showing that maternal behaviours can be acquired and identifying the underlying neuronal circuits in the brain that control this acquisition, we are creating a potential basis for developing therapeutic options for these clinical situations," says Daniela Pollak, outlining the translational relevance of the study results, which were obtained in collaboration with Tibor Harkany from the Division of Molecular Neurosciences at MedUni Vienna's Center for Brain Research.

Courtesy of JHVEPhoto/GettyImages On Thursday, Pfizer announced the U.S. Food and Drug Administration granted its combinatorial therapeutic ervogastat/clesacostat Fast Track Designation. The therapeutics are intended for the treatment of Non-Alcoholic Steatohepatitis (NASH) with liver fibrosis. NASH is a type of non-alcoholic fatty liver disease marked by inflammation and damage of the liver in addition to a buildup of fat. The inflammation and damage to the liver can cause fibrosis and cirrhosis, leaving the organ scarred and permanently damaged while also increasing the risk for liver cancer. The cause of NASH is still up for debate, although researchers believe obesity, Type II Diabetes and genetics may play a role. Treatment for NASH is desperately needed, as the FDA has approved no treatments for the condition, which affects an estimated 17 million people in the U.S. Pfizer is now entering the race, armed with ervogastat and clesacostat. In nonclinical studies and a Phase IIa clinical study of the combination therapy, the treatment was effective in reducing liver fat while demonstrating a favorable safety and tolerability profile. Now, the treatment is being studied in an ongoing Phase II clinical trial evaluating the impact of the treatment on the resolution of NASH or improvement in liver fibrosis. The study is anticipated to be completed in 2024 and will inform a future Phase III clinical trial, including an arm that will investigate ervogastat as a monotherapy. "Receiving Fast Track designation from the FDA reinforces Pfizer's belief in ervogastat/clesacostat as a potential treatment for NASH, a serious, progressive liver disease with no currently approved therapies," said Pfizer senior vice president and chief development officer of interal medicine James Rusnak, M.D., Ph.D., in a press release. "We are proud to be advancing this investigational combination as part of our goal to develop innovative medicines to address some of the world's most widespread health challenges that affect millions of people—including diseases like NASH." The treatment targets two key enzymes that regulate lipid or fat metabolism called diacylglycerol O-acyltransferase 2 (DGAT2) and acetyl-CoA carboxylase (ACC). Prior research has shown that inhibiting DGAT2 and ACC can lower liver fat in patients with non-alcoholic fatty liver disease, and Pfizer believes the combination therapy will improve inflammation and fibrosis. A recent report by Vision Research Reports states that the NASH clinical trials market size is predicted to hit $4.1 billion by 2030, likely due to rising healthcare expenditure, cases of obesity and the prevalence of NASH in the population. Clinical trials for NASH have also likely grown due to newer and better imaging modalities, which can be used in early-phase NASH trials to assess liver fat content and fibrosis stage. There are currently 22 listed studies recruiting for patients with NASH. Earlier this month, Lipocine announced positive results from its Open-Label Extension study of LPCN 1144, which is an orally delivered prodrug of testosterone. Results showed that the treatment was well-tolerated, and liver injury markers reduced significantly and were maintained with extended treatment.

NEW YORK--(BUSINESS WIRE)-- Pfizer Inc. (NYSE: PFE) today announced the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to Pfizer’s investigational combination therapy for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis: ervogastat (PF-06865571, a diacylglycerol O-acyltransferase 2 inhibitor, or DGAT2i) and clesacostat (PF-05221304, an acetyl-CoA carboxylase inhibitor, or ACCi). Fast Track is a process designed to facilitate the development and expedite the review of new drugs and vaccines intended to treat or prevent serious conditions and address unmet medical need. The FDA’s decision is informed by the results of Pfizer’s nonclinical studies and a Phase 2a clinical study of ervogastat/clesacostat, which showed that treatment with ervogastat/clesacostat reduced liver fat with a favorable safety and tolerability profile. These data were recently published in Nature Medicine. “Receiving Fast Track designation from the FDA reinforces Pfizer’s belief in ervogastat/clesacostat as a potential treatment for NASH, a serious, progressive liver disease with no currently approved therapies,” said James Rusnak, M.D., Ph.D., Senior Vice President and Chief Development Officer, Internal Medicine and Hospital, Pfizer. “We are proud to be advancing this investigational combination as part of our goal to develop innovative medicines to address some of the world’s most widespread health challenges that affect millions of people—including diseases like NASH.” Pfizer is currently studying ervogastat/clesacostat in an ongoing Phase 2 clinical trial evaluating the impact of treatment on resolution of NASH or improvement in liver fibrosis (NCT04321031), expected to complete in 2024. The results of this study, which also includes arms investigating ervogastat as monotherapy, will inform a potential Phase 3 development program. About NASH Non-alcoholic steatohepatitis (NASH) is a serious, progressive form of non-alcoholic fatty liver disease (NAFLD) caused by a buildup of fat in the liver and accompanied by inflammation, liver cell damage, and in some cases scarring of the liver.1,2 Approximately 17 million patients in the U.S. are impacted by NASH (and 3-5% of the global adult population), a number that is predicted to grow significantly over the next 10-15 years due to increases in obesity and Type 2 diabetes prevalence and an aging population.3,4 NASH is largely unrecognized and underdiagnosed, increasing patients’ risk of morbidity, liver events and mortality.5,6,7 There are currently no FDA- or EMA-approved medications to treat NASH, and Pfizer researchers are working to develop treatments for the disease to fill this significant unmet medical need. About Ervogastat/Clesacostat Diacylglycerol O-acyltransferase 2 (DGAT2) and acetyl-CoA carboxylase (ACC) are two key enzymes that regulate lipid metabolism. Inhibitors of ACC and DGAT2 have demonstrated the ability to lower liver fat in patients with non-alcoholic fatty liver disease (NAFLD).8 Pfizer believes that ervogastat/clesacostat, its investigational DGAT2i/ACCi combination therapy, has the potential to deliver direct improvements in inflammation and fibrosis. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world's premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 170 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at . In addition, to learn more, please visit us on and follow us on Twitter at @Pfizer and @Pfizer News, LinkedIn, YouTube and like us on Facebook at Facebook.com/Pfizer. References 1National Institute of Diabetes and Digestive and Kidney Diseases. Definition and Facts of NAFLD and NASH. Accessed May 14, 2021. . 2Perumpail, Brandon J et al. “Clinical epidemiology and disease burden of nonalcoholic fatty liver disease.” World journal of gastroenterology vol. 23,47 (2017): 8263-8276. doi:10.3748/wjg.v23.i47.8263. 3Estes C, Razavi H, Loomba, R, Tounossi Z, Sanyal Aj. Modeling the Epidemic of Nonalcoholic Fatty Liver Disease Demonstrates an Exponential Increase in Burden of Disease. Hepatology. 2018;67(1):123-133. 4Povsic M, Wong OY, Perry R, Bottomley J. A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH). Adv Ther. 2019;36(7):1574-1594. doi:10.1007/s12325-019-00960-3 5Machado MV, Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know. World J Gastroenterol. 2014;20(36):12956-12980. doi:10.3748/wjg.v20.i36.12956 6Rinella ME, Lominadze Z, Loomba R, et al. Practice patterns in NAFLD and NASH: real life differs from published guidelines. Therap Adv Gastroenterol. 2016;9(1):4-12. doi:10.1177/1756283X15611581 7Kumar R, Priyadarshi RN, Anand U. Non-alcoholic Fatty Liver Disease: Growing Burden, Adverse Outcomes and Associations. J Clin Transl Hepatol. 2020;8(1):76-86. doi: 10.14218/JCTH.2019.00051. 8Esler WP, Bence KK. Metabolic Targets in Nonalcoholic Fatty Liver Disease. Cellular and molecular gastroenterology and hepatology. 2019;8(2):247-267. doi:10.1016/j.jcmgh.2019.04.007 Disclosure Notice The information contained in this release is as of May 26, 2022. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about Pfizer’s investigational combination therapy for the treatment of non-alcoholic steatohepatitis with liver fibrosis: ervogastat/clesacostat, including its potential benefits and a potential Phase 3 development program, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for ervogastat/clesacostat; whether and when any such applications may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether ervogastat/clesacostat will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of ervogastat/clesacostat; the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2021 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at and . View source version on businesswire.com: Contacts Media Relations: 212-733-1226 PfizerMediaRelations@pfizer.com Investor Relations: 212-733-4848 IR@pfizer.com Source: Pfizer Inc. View this news release online at: