APOC2

Arrowhead plans to file for FDA approval of plozasiran by the end of 2024. Arrowhead Pharmaceuticals has shown its hand ahead of a potential showdown with Ionis, publishing phase 3 data on a rare metabolic disease treatment that is racing toward regulators.The biotech shared topline data from the familial chylomicronemia syndrome (FCS) study in June. That release covered the highlights, showing people who took 25 mg and 50 mg of plozasiran for 10 months had 80% and 78% reductions in triglycerides, respectively, compared to 7% for placebo. But the release left out some of the details that could influence how the fight for market share with Ionis shakes out.Arrowhead shared more data at the European Society of Cardiology Congress and in The New England Journal of Medicine. The expanded dataset includes the numbers behind the previously reported hit on a secondary endpoint that looked at the incidence of acute pancreatitis, a potentially fatal complication of FCS.Four percent of patients on plozasiran had acute pancreatitis, compared to 20% of their counterparts on placebo. The difference was statistically significant. Ionis saw 11 episodes of acute pancreatitis in the 23 patients on placebo, compared to one each in two similarly sized treatment cohorts. One key difference between the trials is Ionis limited enrollment to people with genetically confirmed FCS. Arrowhead originally planned to place that restriction in its eligibility criteria but, the NEJM paper says, changed the protocol to include patients with symptomatic, persistent chylomicronemia suggestive of FCS at the request of a regulatory authority.A subgroup analysis found the 30 participants with genetically confirmed FCS and the 20 patients with symptoms suggestive of FCS had similar responses to plozasiran. A figure in the NEJM paper shows the reductions in triglycerides and apolipoprotein C-II were in the same ballpark in each subset of patients.If both biotechs receive labels that reflect their study populations, Arrowhead could potentially target a broader population than Ionis and enable physicians to prescribe its drug without genetic confirmation of the disease. Bruce Given, chief medical scientist at Arrowhead, said on an earnings call in August that he thinks “payers will go along with the package insert” when deciding who can access the treatment.  Arrowhead plans to file for FDA approval by the end of 2024. Ionis is scheduled to learn whether the FDA will approve its rival FCS drug candidate olezarsen by Dec. 19. 

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

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