Ionis Pharmaceuticals announced positive topline results for the Phase 3 Balance study of olezarsen in people with familial chylomicronemia syndrome (FCS). The study demonstrated a statistically significant reduction in triglyceride (TG) levels and a 100 percent reduction in acute pancreatitis events compared to placebo. Olezarsen, an investigational LICA medicine, inhibits the production of apoC-III, a protein that regulates TG metabolism. If approved, olezarsen will be the first available treatment for FCS in the United States. This article explores the study’s findings, the impact of FCS, and the potential of olezarsen as a breakthrough treatment.
Familial chylomicronemia syndrome (FCS) is a rare genetic disease characterized by extremely elevated triglyceride levels. People with FCS have impaired lipoprotein lipase (LPL) function, leading to an inability to break down chylomicrons, which are triglyceride-rich particles. This condition puts individuals at high risk for acute pancreatitis and other chronic health issues. Currently, there are no FDA-approved therapies for FCS, and patients must rely on restrictive diets to manage their condition.
Ionis Pharmaceuticals has developed olezarsen, an investigational LIgand Conjugated Antisense (LICA) medicine, to address the unmet medical need in FCS treatment. Olezarsen inhibits the production of apoC-III, a protein that regulates triglyceride metabolism. The Phase 3 Balance study evaluated the efficacy and safety of olezarsen in FCS patients and yielded promising results.
The Phase 3 Balance Study Results
The Phase 3 Balance study (NCT04568434) enrolled 66 patients with confirmed FCS and evaluated the effects of olezarsen on triglyceride levels and the incidence of acute pancreatitis events. The study participants received background therapies, including statins, fibrates, and omega-3 fatty acids, in addition to the study drug. The primary endpoint of the study was the percent change from baseline in fasting triglyceride levels at six months compared to placebo.
The topline results of the Phase 3 Balance study demonstrated a statistically significant reduction in triglyceride levels with the olezarsen 80 mg monthly dose compared to placebo (p=0.0009). The reduction in triglyceride levels continued to improve at 12 months, indicating the sustained efficacy of olezarsen. Additionally, olezarsen 80 mg showed a remarkable 100 percent reduction in acute pancreatitis events compared to placebo, meeting a key secondary endpoint.
Importance of Triglyceride Reduction in FCS Treatment
Triglyceride reduction is a crucial aspect of FCS treatment as elevated triglyceride levels contribute to the development of acute pancreatitis. Acute pancreatitis is a severe and potentially fatal condition characterized by inflammation of the pancreas. By reducing triglyceride levels, olezarsen addresses one of the primary drivers of acute pancreatitis in FCS patients, offering a potential breakthrough in the management of this debilitating condition.
Dose-Dependent Effect and Safety Profile
The Phase 3 Balance study evaluated two doses of olezarsen: 80 mg and 50 mg, administered once every four weeks via subcutaneous injection. The study results demonstrated a dose-dependent effect, with both doses showing a substantial reduction in pancreatitis. However, the lower 50 mg dose did not reach statistical significance at six months on the primary endpoint of triglyceride lowering (p=0.0775).
In terms of safety and tolerability, olezarsen demonstrated a favorable profile. Adverse events were more frequent in the placebo group, primarily due to pancreatitis events. The majority of adverse events in the olezarsen groups were mild in severity, with a low incidence of injection site reactions. No hepatic or renal toxicity events were reported, and there were no clinically meaningful reductions in platelet counts. Only one death was reported in the study, which was deemed unrelated to the study drug.
Regulatory Filings and Potential Approval
Ionis Pharmaceuticals plans to file a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) in early 2024, seeking approval for olezarsen as a treatment for FCS. The FDA has granted olezarsen Fast Track designation, which expedites the review process for drugs that address unmet medical needs. If approved, olezarsen would be the first available treatment for FCS in the United States, providing hope and relief for individuals living with this rare genetic disease.
In addition to the FDA filing, Ionis intends to pursue regulatory filings in the European Union. The company aims to present the Phase 3 olezarsen FCS data at future medical congresses, further supporting the potential of olezarsen as a breakthrough treatment.
Future Implications in Severe Hypertriglyceridemia (SHTG)
The success of the Phase 3 Balance study paves the way for further evaluation of olezarsen in patients with severe hypertriglyceridemia (SHTG). Ionis Pharmaceuticals is conducting ongoing Phase 3 studies to assess the efficacy and safety of olezarsen in a broader patient population. If the results are favorable, olezarsen has the potential to become a significant therapeutic option for individuals with SHTG, expanding its impact beyond FCS.
Conclusion
The positive topline results from the Phase 3 Balance study demonstrate the potential of olezarsen as a breakthrough treatment for familial chylomicronemia syndrome (FCS). With its ability to reduce triglyceride levels and prevent acute pancreatitis events, olezarsen addresses the key challenges faced by individuals living with FCS. Ionis Pharmaceuticals’ commitment to developing innovative therapies for rare diseases has resulted in the promising development of olezarsen, offering hope to those who currently have no FDA-approved treatment options. As the regulatory process progresses, the potential approval of olezarsen could be a significant milestone in the management of FCS and pave the way for further advancements in the treatment of severe hypertriglyceridemia.
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