Olezarsen

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. 

Arrowhead Pharmaceuticals has unveiled highly anticipated pancreatitis results from a late-phase trial of plozasiran for a rare lipid disorder, several months after reporting topline data. Arrowhead has been putting a lot of effort into its siRNA candidate to the point that it shelved another asset , zodasiran, so it could focus on getting plozasiran to market. The company is in a development race with Ionis Pharmaceuticals which has its own RNA-based therapeutic for lipid diseases. In a key secondary endpoint of the 75-participant Phase 3 PALISADE trial in familial chylomicronemia syndrome (FCS), less than 5% of patients taking plozasiran had an acute pancreatitis event at 12 months compared with 20% of the placebo cohort, according to results presented Monday at the European Society of Cardiology annual meeting in London. The numbers work out to an 83% relative risk reduction in the instance of positively adjudicated pancreatitis, PALISADE principal investigator Gerald Watts told Endpoints News in an interview ahead of the meeting. In contrast, Ionis’ antisense oligonucleotide olezarsen cut acute pancreatitis events by 100% in the Phase 3 BALANCE trial in FCS, according to data unveiled a year ago. Updated results from April showed there was one episode of acute pancreatitis in the 80 mg olezarsen group and another in the 50 mg cohort. The pancreatitis data are important because these events can be life-threatening for patients with FCS and lead to hospitalization. But Ionis and Arrowhead’s respective trials tested patients with different histories of pancreatitis at baseline, Watts said. In Arrowhead’s trial, 89% of patients taking 25 mg plozasiran and 92% of patients taking 50 mg plozasiran had a previous episode of pancreatitis. Meanwhile, Ionis’ trial was designed to enroll at least 65% of patients with a history of pancreatitis. Robert Rosenson, PALISADE investigator and the cardiometabolics unit director of Mount Sinai Hospital, said it is difficult to differentiate between Arrowhead and Ionis’ results because the reduction in acute pancreatitis was “dramatic” in both trials. Rather, the main difference between the drugs that could influence physician and patient preference is frequency of dosing, Rosenson told Endpoints in an interview. Plozasiran is administered every three months while olezarsen is given every four weeks. “In patients with chronic illness, we know that less frequent dosing results in greater long-term adherence to therapy,” Rosenson said. Elsewhere, while it is difficult to compare data across trials, plozasiran seems to be associated with a greater reduction in triglycerides than olezarsen, Watts said. Plozasiran met the PALISADE primary endpoint as announced in June, with 25 mg and 50 mg doses attaining 80% and 78% median reductions in triglycerides at 10 months, respectively, compared with 17% for placebo. The drug also met all key secondary endpoints, including a change from baseline in levels of APOC3, which plays a key role in slowing the clearance of triglycerides. At the time, Arrowhead CEO Christopher Anzalone described the plozasiran data as “best in class.” Meanwhile, In BALANCE, 80 mg olezarsen achieved a 59% placebo-adjusted reduction in triglyceride levels at 12 months (p<0.001). People with FCS lack or have very little of an enzyme called lipoprotein lipase which is responsible for clearing triglycerides from the blood. These triglycerides can then build up to more than ten times the normal amount. The only option available for patients is to follow an extremely low-fat diet. Arrowhead is working on regulatory filings for plozasiran in FCS. In April, GlobalData analysts said plozasiran could hit $707 million in sales in 2032. However, current peak sales expectations may need to be adjusted to take into account the candidate’s potential in severe hypertriglyceridemia (SHTG), which affects around 3.4 million people in the US, TD Cowen analyst Brendan Smith told Endpoints in an interview ahead of the meeting. The drug has the potential to move from an ultra-orphan indication to a much broader dyslipidemia market, he added. Plozasiran hit the primary endpoint in a Phase 2b trial of patients with SHTG back in April and is currently being tested in a pair of Phase 3 studies in the disease called SHASTA-3 and SHASTA-4. Editor’s note: This article was updated to add a doctor’s comments, more context on the registrational olezarsen data and to correct plozasiran’s mechanism of action.