ABCA1

This review paper summarizes numerous research studies that address the role of kidney cholesterol and lipid accumulation in the development and progression of chronic kidney disease (CKD).ZyVersa’s Cholesterol Efflux Mediator™ VAR 200 is in development to reduce renal cholesterol and lipid accumulation that damages the kidneys' filtration system in patients with glomerular diseases, including diabetic kidney disease, focal segmental glomerulosclerosis, and Alport Syndrome. WESTON, Fla., Oct. 11, 2023 (GLOBE NEWSWIRE) -- ZyVersa Therapeutics, Inc. (Nasdaq: ZVSA, or “ZyVersa”), a clinical stage specialty biopharmaceutical company developing first-in-class drugs for treatment of renal and inflammatory diseases, announces publication of a paper in the peer-reviewed journal, Nature Reviews Nephrology, that summarizes data highlighting how lipid accumulation in the kidneys contributes to CKD development and disease progression. In the review paper titled, “Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease,” the following key points were made: Lipids and lipid-related enzymes have a major role in modulating the function of the kidney’s filtration system, and lipid accumulation can drive CKD irrespective of circulating lipid levels and use of systemic lipid lowering drugs like statins.Although several lipid types, including cholesterol, triglycerides, fatty acids, and phospholipids, are dysregulated in the kidney and contribute to CKD progression, dysregulation of cholesterol metabolism is one of the hallmarks of kidney injury in CKD. Cholesterol accumulation occurs in association with impaired transport of cholesterol out of the kidney.Accumulation of fatty acids triggers kidney cell damage by promoting inflammation and fibrosis. The paper includes a brief overview of Cholesterol Efflux Mediator™ VAR 200 (hydroxy-propyl-beta-cyclodextrin), highlighting that it reduced cholesterol accumulation and cell death (apoptosis) in podocytes in vitro, and provided protection from kidney disease progression in mouse models of diabetic kidney disease, FSGS, and Alport Syndrome. The authors concluded this section by stating that VAR 200, which is in development for patients affected by several forms of kidney disease, provides therapeutic potential for diseases characterized by ABCA1 deficiency. To read the article, Click Here. “The numerous studies summarized in the paper published in Nature Reviews Nephrology reinforce the importance of addressing kidney accumulation of cholesterol and lipids to help attenuate progression of chronic kidney disease, which affects over 35 million adults in the United States,” commented Stephen C. Glover, ZyVersa’s Co-founder, Chairman, CEO, and President. “Currently, over 130,000 patients with kidney disease progress to renal failure each year, and more than 800,000 patients are living with renal failure requiring dialysis or transplant to sustain life. We are hopeful that protection against kidney injury, fibrosis, and disease progression seen with VAR 200 in animal models of diabetic kidney disease, FSGS, and Alport Syndrome will translate to humans. Our first clinical trial with VAR 200 in patients with diabetic kidney disease is planned to begin in early 2024.” To review a white paper summarizing the preclinical research with VAR 200, Click Here. About Cholesterol Efflux Mediator™ VAR 200 Cholesterol Efflux Mediator™ VAR 200 (2-hydroxypropyl-beta-cyclodextrin, 2HPβCD) is a phase 2a-ready drug in development to ameliorate renal lipid accumulation that damages the kidneys’ filtration system, leading to kidney disease progression. VAR 200 passively and actively removes excess lipids from the kidney. Preclinical studies with VAR 200 in animal models of FSGS, Alport syndrome, and diabetic kidney disease demonstrate that removal of excess cholesterol and lipids from kidney podocytes protects against structural damage and reduces excretion of protein in the urine (proteinuria). The lead indication for VAR 200 is orphan kidney disease focal segmental glomerulosclerosis (FSGS). VAR 200 has potential to treat other glomerular diseases, including orphan Alport syndrome and diabetic kidney disease. About ZyVersa Therapeutics, Inc. ZyVersa (Nasdaq: ZVSA) is a clinical stage specialty biopharmaceutical company leveraging advanced, proprietary technologies to develop first-in-class drugs for patients with renal and inflammatory diseases who have significant unmet medical needs. The Company is currently advancing a therapeutic development pipeline with multiple programs built around its two proprietary technologies – Cholesterol Efflux Mediator™ VAR 200 for treatment of kidney diseases, and Inflammasome ASC Inhibitor IC 100, targeting damaging inflammation associated with numerous CNS and other inflammatory diseases. For more information, please visit www.zyversa.com. Cautionary Statement Regarding Forward-Looking Statements Certain statements contained in this press release regarding matters that are not historical facts, are forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995. These include statements regarding management’s intentions, plans, beliefs, expectations, or forecasts for the future, and, therefore, you are cautioned not to place undue reliance on them. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. ZyVersa Therapeutics, Inc (“ZyVersa”) uses words such as “anticipates,” “believes,” “plans,” “expects,” “projects,” “future,” “intends,” “may,” “will,” “should,” “could,” “estimates,” “predicts,” “potential,” “continue,” “guidance,” and similar expressions to identify these forward-looking statements that are intended to be covered by the safe-harbor provisions. Such forward-looking statements are based on ZyVersa’s expectations and involve risks and uncertainties; consequently, actual results may differ materially from those expressed or implied in the statements due to a number of factors, including ZyVersa’s plans to develop and commercialize its product candidates, the timing of initiation of ZyVersa’s planned preclinical and clinical trials; the timing of the availability of data from ZyVersa’s preclinical and clinical trials; the timing of any planned investigational new drug application or new drug application; ZyVersa’s plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of ZyVersa’s product candidates; ZyVersa’s commercialization, marketing and manufacturing capabilities and strategy; ZyVersa’s ability to protect its intellectual property position; and ZyVersa’s estimates regarding future revenue, expenses, capital requirements and need for additional financing. New factors emerge from time-to-time, and it is not possible for ZyVersa to predict all such factors, nor can ZyVersa assess the impact of each such factor on the business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Forward-looking statements included in this press release are based on information available to ZyVersa as of the date of this press release. ZyVersa disclaims any obligation to update such forward-looking statements to reflect events or circumstances after the date of this press release, except as required by applicable law. This press release does not constitute an offer to sell, or the solicitation of an offer to buy, any securities. Corporate and IR Contact:Karen CashmereChief Commercial Officerkcashmere@zyversa.com786-251-9641 Media ContactsTiberend Strategic Advisors, Inc.Casey McDonaldcmcdonald@tiberend.com646-577-8520 Dave Schemeliadschemelia@tiberend.com609-468-9325

Published data demonstrate that a deficiency in cholesterol transporter ABCA1 increases deposition of cellular cholesterol, contributing to inflammation, cell death (apoptosis), and damage to the kidney’s filtration barrier in type 2 diabetic mice and in human renal glomerular endothelial cells cultured to simulate type 2 diabetes ZyVersa’s Cholesterol Transport Mediator™ VAR 200 is in development to reduce renal cholesterol and lipid accumulation that damages the kidneys’ filtration system in patients with glomerular diseases (diabetic kidney disease, focal segmental glomerulosclerosis, and Alport Syndrome) VAR 200 mediates transport of excess cholesterol out of kidney cells passively and by upregulating cholesterol transporter ABCA1 WESTON, Fla., May 15, 2023 (GLOBE NEWSWIRE) -- ZyVersa Therapeutics, Inc. (Nasdaq: ZVSA, or “ZyVersa”), a clinical stage specialty biopharmaceutical company developing first-in-class drugs for treatment of inflammatory and renal diseases, announces publication of an article in the peer-reviewed journal, Metabolism, which supports the mechanism of action of Cholesterol Efflux Mediator™ VAR 200 in development to treat kidney diseases. In the paper titled, “ABCA1 deficiency-mediated glomerular cholesterol accumulation exacerbates glomerular endothelial injury and dysfunction in diabetic kidney disease,” the authors reported that ABCA1 deficiency contributes to injury and dysfunction of the kidney’s filtration system (glomerular endothelium) in early diabetic kidney disease (“DKD”). They proposed that ABCA1 transporter deficiency results in glomerular cholesterol/lipid accumulation leading to inflammation and cell death. This causes structural and functional damage to the kidney’s filtration system and in turn, protein spillage into the urine (proteinuria) and DKD progression. The authors concluded that therapies which effectively reduce elevated glomerular cholesterol levels have potential to combat early DKD. To read the article, Click Here. “The research published in Metabolism demonstrating that deposition of glomerular cholesterol contributes to structural damage and dysfunction of the kidney’s filtration system in models of type 2 diabetes is consistent with data from VAR 200’s preclinical program. Our preclinical program showed similar results not only in models of DKD, but also in models of two orphan kidney diseases, focal segmental glomerular sclerosis (FSGS) and Alport Syndrome. More importantly, by mediating cholesterol transport out of the glomeruli through passive transport and upregulation of ABCA1 transporters, VAR 200 protected against glomerular injury and fibrosis, and significantly reduced protein spillage into the urine in all three kidney diseases,” commented Stephen C. Glover, ZyVersa’s Co-founder, Chairman, CEO and President. “Given the unmet needs for effective treatments for kidney disease, we are hopeful that VAR 200 will demonstrate similar results in patients with kidney disease in studies planned to initiate late this year,” continued Mr. Glover. About Cholesterol Efflux Mediator™ VAR 200 Cholesterol Efflux Mediator™ VAR 200 (2-hydroxypropyl-beta-cyclodextrin, 2HPβCD) is a phase 2a-ready drug in development to ameliorate renal lipid accumulation that damages the kidneys’ filtration system, leading to kidney disease progression. VAR 200 passively and actively removes excess lipids from the kidney. Preclinical studies with VAR 200 in animal models of FSGS, Alport syndrome, and diabetic kidney disease demonstrate that removal of excess cholesterol and lipids from kidney podocytes protects against structural damage and reduces excretion of protein in the urine (proteinuria). The lead indication for VAR 200 is orphan kidney disease focal segmental glomerulosclerosis (FSGS). VAR 200 has potential to treat other glomerular diseases, including orphan Alport syndrome and diabetic kidney disease. About ZyVersa Therapeutics, Inc. ZyVersa (Nasdaq: ZVSA) is a clinical stage specialty biopharmaceutical company leveraging advanced, proprietary technologies to develop first-in-class drugs for patients with renal and inflammatory diseases who have significant unmet medical needs. The Company is currently advancing a therapeutic development pipeline with multiple programs built around its two proprietary technologies – Cholesterol Efflux Mediator™ VAR 200 for treatment of kidney diseases, and Inflammasome ASC Inhibitor IC 100, targeting damaging inflammation associated with numerous CNS and other inflammatory diseases. For more information, please visit . Cautionary Statement Regarding Forward-Looking Statements Certain statements contained in this press release regarding matters that are not historical facts, are forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and the Private Securities Litigation Reform Act of 1995. These include statements regarding management’s intentions, plans, beliefs, expectations, or forecasts for the future, and, therefore, you are cautioned not to place undue reliance on them. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. ZyVersa Therapeutics, Inc. (“ZyVersa”) uses words such as “anticipates,” “believes,” “plans,” “expects,” “projects,” “future,” “intends,” “may,” “will,” “should,” “could,” “estimates,” “predicts,” “potential,” “continue,” “guidance,” and similar expressions to identify these forward-looking statements that are intended to be covered by the safe-harbor provisions. Such forward-looking statements are based on ZyVersa’s expectations and involve risks and uncertainties; consequently, actual results may differ materially from those expressed or implied in the statements due to a number of factors, including ZyVersa’s plans to develop and commercialize its product candidates, the timing of initiation of ZyVersa’s planned preclinical and clinical trials; the timing of the availability of data from ZyVersa’s preclinical and clinical trials; the timing of any planned investigational new drug application or new drug application; ZyVersa’s plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits and market acceptance of ZyVersa’s product candidates; ZyVersa’s commercialization, marketing and manufacturing capabilities and strategy; ZyVersa’s ability to protect its intellectual property position; and ZyVersa’s estimates regarding future revenue, expenses, capital requirements and need for additional financing. New factors emerge from time-to-time, and it is not possible for ZyVersa to predict all such factors, nor can ZyVersa assess the impact of each such factor on the business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in any forward-looking statements. Forward-looking statements included in this press release are based on information available to ZyVersa as of the date of this press release. ZyVersa disclaims any obligation to update such forward-looking statements to reflect events or circumstances after the date of this press release, except as required by applicable law. This press release does not constitute an offer to sell, or the solicitation of an offer to buy, any securities. Corporate and IR Contact: Karen Cashmere Chief Commercial Officer kcashmere@zyversa.com 786-251-9641 Media Contacts Tiberend Strategic Advisors, Inc. Casey McDonald cmcdonald@tiberend.com 646-577-8520 Dave Schemelia dschemelia@tiberend.com 609-468-9325

The words that researchers use to describe their results can be harnessed to discover potential new treatments for Parkinson's disease, according to a new study. The study employed an artificial intelligence (AI) system to identify an existing anti-cholesterol drug that has the ability to promote the disposal of mitochondria, energy-making components of the cell which are damaged in the disease. The words that researchers use to describe their results can be harnessed to discover potential new treatments for Parkinson's disease, according to a new study publishing March 2 in the open access journal PLOS Biology by Angus McQuibban of the University of Toronto, Canada, and colleagues. The study employed an artificial intelligence (AI) system to identify an existing anti-cholesterol drug that has the ability to promote disposal of mitochondria, energy-making components of the cell which are damaged in the disease. The full pathogenic pathway leading to Parkinson's disease (PD) is unknown, but one clear contributor is mitochondrial dysfunction and the inability to dispose of defective mitochondria, a process called mitophagy. At least five genes implicated in PD are linked to impaired mitophagy, either directly or indirectly, and so the authors sought compounds that could enhance the mitophagy process. Several such compounds have been identified, but most of them also cause harm to cells, ruling them out as drug candidates. That led the authors to ask whether the literature describing these compounds might lead them to other compounds, ones not previously linked to mitophagy enhancement but which are described with terms that also appear in papers that discuss the known enhancers. Identifying patterns of such "semantic similarity" is one of the core skills of IBM Watson for Drug Discovery, an AI program run on a supercomputer that analyzes the published literature for patterns of key words, phrases, and juxtapositions. The team used the program to develop a semantic "fingerprint" of bona fide mitophagy enhancers, and then looked for similar fingerprints in the literature on a set of over three thousand candidates from a drug database. The top 79 candidates were screened in cell culture against a mitochondrial poison. The three top candidates from that assay were then tested on several other mitophagy assays, which identified probucol, a cholesterol-lowering drug, as the compound with the best combination of effectiveness and likely safety. Probucol was also found to improve motor function, survival, and neuron loss in two different animal models of Parkinson's disease (PD is primarily a movement disorder). Probucol's effect on mitophagy required the formation and action of lipid droplets, transient cell structures that help maintain mitochondrial integrity during stress, and that accumulate abnormally in Parkinson's disease. Probucol is known to target ABCA1, a protein involved in lipid transport, and reduction in levels of ABCA1 reduced probucol's ability to promote mitophagy, suggesting that ABCA1 is a likely mediator of the role of lipid droplets in mitophagy. "Our study showcased a dual in silico/cell-based screening methodology that identified known and new mechanisms leading to mitophagy enhancement," McQuibban said. "Given the linkage between lipid droplet accumulation and ABCA1, it seems likely that probucol enhances mitophagy through mobilization of lipid droplets. Targeting this mechanism may be advantageous." McQuibban adds, "In our study we used the AI-platform IBM Watson to efficiently identify currently approved drugs that could potentially be re-purposed as therapies for Parkinson's disease."