APOA5

Pictured: CSL's building in Prague, Czech Republic/iStock, josefkubes CSL on Sunday announced that its investigational cholesterol efflux enhancer CSL112 failed the Phase III AEGIS-II trial, unable to significantly improve outcomes in patients who had suffered a heart attack. The company did not provide specific data in its announcement but said that CSL112 did not significantly reduce major adverse cardiovascular events versus placebo at 90 days after an acute myocardial infarction episode. AEGIS-II did detect any major safety or tolerability issues with CSL112. However, CSL no longer has near-term plans to seek regulatory approval for the candidate, according to its announcement. CSL’s stock dipped around 5% on Monday in response to the late-stage failure. Bill Mezzanotte, executive vice president and head of R&D at CSL, in a statement called AEGIS-II the “most ambitious study” in the company’s history, adding that it will continue to analyze the findings to better understand the data and “determine any development path ahead for this asset.” “We are proud of the quality of the study we delivered and the enhanced capabilities we developed to do so,” Mezzanotte said. “We plan to apply these capabilities as well as our plasma protein platform to future unmet medical need in cardiovascular and metabolic conditions as well as those in our other strategic therapeutic areas." CSL intends to present results from AEGIS-II at the upcoming American College of Cardiology Scientific Sessions in April 2024. AEGIS-II is a randomized, double-blinded, parallel-group and placebo-controlled study that enrolled 18,200 patients across nearly 50 countries, making it CSL’s largest-ever trial. The study was first announced in December 2017 and dosed its first patient a few months later in March 2018. At the time, CSL CSO Andrew Cuthbertson said that CSL112 had “the potential to change the current treatment paradigm for heart attack survivors and improve global health outcomes for the millions of people at risk for early recurrent cardiovascular events.” CSL112 is CSL’s novel and proprietary formulation of the plasma-derived protein apolipoprotein A-I, which is the main component of high-density lipoprotein and is an important player in regulating cholesterol levels. The candidate works by boosting the body’s natural capability to remove cholesterol from plaques and carrying them to the liver for detoxification. In November 2016, CSL announced positive data from the Phase IIb AEGIS-I study showing that CSL112 was safe overall and did not trigger “significant changes in liver or kidney function.” The mid-stage trial also underscored its tolerability in acute myocardial infarction patients and validated its mechanism of action, demonstrating an up to four-fold jump in cholesterol efflux capacity versus baseline. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

TOULOUSE, France & LAKELAND, MI, USA I January 16, 2023 I ABIONYX Pharma (FR0012616852 – ABNX – PEA PME eligible), a new generation biotech company dedicated to the discovery and development of innovative therapies for patients, today reported that the pilot Phase 2a clinical trial evaluating CER-001, the only natural recombinant apoA-I, as a treatment for septic patients at high risk of developing Acute Kidney Injury (AKI) met its primary objective. There are no approved treatments for septic patients in the world. Loreto Gesualdo, full Professor, Head of the Nephrology, Dialysis and Transplantation Unit, University of Bari Aldo Moro, Italy, and lead investigator of the RACERS study stated: “ We are incredibly excited to share results from this pilot Phase 2a trial evaluating CER-001 in septic patients at high risk of developing acute kidney injury. There is a complete lack of treatment options for septic patients at high risk of developing acute kidney injury, a disease that in 2019 had an estimated 13.7 million related deaths globally (Lancet 2022; 400: 2221–48). The trial shows promising positive results across a variety of primary and secondary endpoints. CER-001 was significantly able to scavenge endotoxins, modulate the cytokine storm, and provide endothelial protection. The trend observed in reducing renal damage, the need for organ support and ICU-day stay underscores the potential clinical significance of these results.” The RACERS study included 20 patients with gram-negative sepsis who were at high risk for acute kidney injury due to high levels of endotoxin activity and decline in function of one or more organ systems. Patients received either standard of care treatment alone, or in combination with one of three dosage regimens of CER-001 (five patients per group). The main objective of this pilot study was to investigate whether the use of CER-001 at different doses, in combination with standard of care (SOC) treatment, is safe and effective, providing a potential new strategy to treat septic patients, reducing the inflammatory response to endotoxin and preventing the progression to AKI according to KDIGO (Kidney Disease: Improving Global Outcomes) criteria, as well as safety and tolerability of the dosage regimens in order to select the optimal dose of CER-001. One of the metabolic characteristics of bacterial (like sepsis) or virus infections (like sars-Cov-2) is the strong decrease of circulating lipoprotein and particularly the High-Density Lipoprotein (HDL) with its main containing protein apolipoprotein A-I (apoA-I). As an example, apoA-I level was recently described as the biomarker predictive of long-term mortality after surgical sepsis 1 . The rational of Abionyx was to restore, using CER-001, the apoA-I levels to reestablish all the functionality of this individualized biomarker leading to potential benefit in sepsis pathology. RACERS pilot study has shown for the first time in a human pilot trial that the recovery of a normal apoA-I level in patient stop the cytokine storm and improve the clinical outcomes. CER-001 demonstrated rapid and sustained reduction in endotoxin levels and consequent reduction in the inflammatory cascade or “cytokine storm” relative to SOC alone. Endothelial biomarkers demonstrated a significant protective effect of CER-001. Trends towards fewer ICU days, lower requirement for organ support and improved 30-day survival. Evaluation of safety data, taken together with the pharmacokinetic and pharmacodynamic data, has identified the dose that will be used in subsequent studies. Connie Peyrottes, Senior VP clinical development at ABIONYX Pharma, added: “In this pilot study, CER-001 was shown to directly decrease endotoxin and inhibit inflammation, limiting the associated downward spiral that septic patients often experience. The broad pleiotropic effect of our apoA-I bioproduct can target multiple facets of septic disease, rather than focusing on a single step in the inflammatory process. Primary and secondary endpoints showed benefits of CER-001 therapy when added to standard treatments. The positive results from this Phase 2a trial show CER-001 has the potential to be a gamechanger for critical illnesses marked by inflammation and organ failure across different high mortality clinical indications which continue to have high unmet medical needs.” Michael Davidson, M.D., Chairman of the Scientific Advisory Board of ABIONYX concluded: “The impressive results of this Phase 2a study confirm that CER-001 may potentially treat sepsis and other severe, acute inflammatory diseases. These results are consistent with the previously published results in COVID-19 and opens a new chapter in the development of CER-001 in the field of short-term therapy for acute conditions.” The observed safety and efficacy in RACERS were generally consistent with historical data including clinical results for CER-001 in COVID-19 that were published recently in the scientific journal "Frontiers in Medicine", a specialty medicine journal, in September 2022. The potential use of CER-001 in septic patients is currently under clinical development. These data will be discussed with regulatory authorities, starting with Europe but also the U.S. later this year in order to design an appropriate clinical and regulatory development strategy for this disease state that currently has no available treatment options. About RACERS RACERS is a clinical trial named RACERS (a RAndomized study comparing short-term CER-001 infusions at different doses to prevent Sepsis-induced acute kidney injury) with CER-001 in septic patients at high risk of developing acute kidney injury. Following the positive signals observed in the Temporary Authorization for Named Use (ATUn) in an ultra-rare kidney disease, the study assessed the role of CER-001, a novel, in preventing Acute Kidney Injury (AKI) in septic patients. The core component of the program is the launch of a 30-day Phase 2a clinical dose-finding trial with the Company's lead product candidate, CER-001, in the prevention of AKI in septic patients. Researchers have demonstrated that in humans, reconstituted HDLs have a scavenger role in reducing circulating endotoxin, as well as major anti-inflammatory and endothelial activity. These important effects were also demonstrated with CER-001 in a rigorous preclinical model of sepsis-induced AKI developed in collaboration with an Italian Veterinarian Hospital (Surgical Section, Chief: Prof. Antonio Crovace). Several other AKI/sepsis models showed that HDL is a critical factor in modifying the disease. This clinical study, designed in concert with expert Italian nephrologists (Nephrology, Dialysis and Transplantation Unit, Chief: Prof. Loreto Gesualdo) and intensivists (Anesthesiology and Resuscitation Unit, Chief: Prof. Salvatore Grasso), was a randomized, open labelled, placebo-controlled, parallel-group study evaluating the safety and efficacy of intravenously administered CER-001 in patients with sepsis at high risk for AKI based on their endotoxin levels and Sequential Organ Failure Assessment (SOFA score). A total of 20 patients were randomized to receive 8 doses of CER-001 over 6 days on top of standard of care, or standard of care alone. The primary endpoint of the study was the onset and severity of AKI according to KDIGO criteria as well as safety and tolerability of the dosage regimens in order to select the optimal dose of CER-001. The clinical study was partnered with the University of Bari. About CER-001 in COVID The complete data are available in the article: “Apolipoprotein-A-I for severe COVID-19-induced hyperinflammatory states: A prospective case study” https://www.frontiersin.org/articles/10.3389/fphar.2022.936659/full About ABIONYX Pharma ABIONYX Pharma is a new generation biotech company that aims to contribute to health through innovative therapies in indications where there is no effective or existing treatment, even the rarest ones. Thanks to its partners in research, medicine, biopharmaceuticals and shareholding, the company innovates on a daily basis to propose drugs for the treatment of renal and ophthalmological diseases, or new HDL vectors used for targeted drug delivery. 1 Guirgis, Faheem W.,et al. Annals of Intensive Care 11, n 1 (décembre 2021): 82. https://doi.org/10.1186/s13613-021-00865-x . SOURCE: Abionyx

Pictured: Regeneron logo on a light brown building Shutterstock/Lev Radin A recent Phase II trial show Regeneron’s monoclonal antibody evinacumab significantly reduced fasting triglycerides in patients with severe hypertriglyceridemia. lev radin/Shutterstock Findings from a recent Phase II trial show Regeneron ’s monoclonal antibody evinacumab significantly reduced fasting triglycerides in patients with severe hypertriglyceridemia. Still, these findings were not replicated in a subgroup of patients with rare familial chylomicronemia syndrome (FCS). The data from the study were presented during a late-breaking clinical trial session held Sunday at the American College of Cardiology 2021 Scientific Session. Study investigator Robert Rosenson, MD, of the Icahn School of Medicine at Mount Sinai in New York, presented the data during the meeting. Dr. Rosenson noted the findings hold important clinical implications, given patients with severe hypertriglyceridemia experience chronic abdominal pain, have to adhere to a strict low-fat diet, and experience acute pancreatitis that increases their risk for other health conditions. Evinacumab, a fully human monoclonal antibody and angiopoietin-like protein 3 inhibitor, was approved by the U.S. Food and Drug Administration (FDA) in February as an adjunct LDL cholesterol-lowering treatment for homozygous familial hypercholesterolemia (HoFH). This approval was made based on data published in 2020 that showed the agent significantly reduced cholesterol without increasing the risk of severe side effects. But in the new study, researchers examined the effects of the therapy in 51 patients with severe triglyceridemia who were using diet and maximally tolerated lipid-lowering treatments. All patients in this study were stratified by genotype. After stratification, study participants were randomly assigned to either intravenous evinacumab at 15 mg/kg every four weeks or a placebo for the initial double-blind treatment phase. After the double-blind period, all patients then received evinacumab for 12 weeks. Participants were followed for another 20 weeks to examine safety outcomes. At baseline, the median fasting triglycerides across the overall sample ranged between 1,000 and 3,000 mg/dL. After the double-blind and single-blind treatment periods, the mean reduction in triglycerides from baseline was 27.1% in the cohort of patients with multifactorial chylomicronemia syndrome (MCS) without LPL pathway mutations. The investigators observed significant reductions in the median triglyceride levels during the initial double-blind period with evinacumab compared with placebo in patients with MCS with known heterozygous loss-of-function mutations in APOA5 , APOC2 , GPIHBP1 , LMF1 , or LPL (-64.8% vs. 9.4%, respectively; p=0.0076). A similar clinically meaningful finding was reported in patients with MCS without LPL pathway mutations (-81.7% vs. 80.9%; p=0.0418). Over the 12 weeks, the same groups of patients experienced marked reductions in non-HDL-cholesterol, Apo-CIII, and ApoB48. Despite the promising efficacy, the researchers did not observe clinically meaningful reductions in mean triglycerides for patients with FCS who had bi-allelic loss-of-function mutations in APOA5 , APOC2 , GPIHBP1 , LMF1 , or LPL . A similar proportion of patients in the evinacumab and placebo arms experienced treatment-emergent adverse events throughout the study (71.4% vs. 68.8%, respectively). A proportionally lower number of serious adverse events were reported in the active treatment arm (11.4%) vs the placebo group (18.8%). A total of two cases of acute pancreatitis were reported in the placebo group, while three cases were reported in the evinacumab-treated patients. Regeneron currently has planned a Phase IIb study that will examine intravenous evinacumab at 20 mg/kg every four weeks for the treatment of acute pancreatitis. Featured Jobs on BioSpace