FDA Grants Breakthrough Therapy Designation to Plozasiran for FCS

Credit: US Food and Drug Administration

The US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to investigational plozasiran as an adjunct to diet to lower triglycerides in adults with familial chylomicronemia syndrome (FCS), a severe and rare genetic disease marked by extremely high triglyceride levels.¹

As announced by Arrowhead Pharmaceuticals on September 10, 2024, the company plans to submit a New Drug Application (NDA) to the FDA by the end of 2024, with further plans to seek regulatory approval with additional global regulatory agencies.

“Receiving FDA Breakthrough Therapy designation for plozasiran provides important benefits and the potential to expedite the process of getting plozasiran to the patients who need it,” said Chris Anzalone, PhD, president and CEO of Arrowhead.¹

FCS is typically caused by various monogenic mutations, leading to extremely high triglyceride levels, often ≥880 mg/dL.² These elevations can lead to serious signs and symptoms, including pancreatitis, chronic abdominal pain, diabetes, hepatic steatosis, and cognitive issues.

Therapeutic options for adequate FCS treatment are limited – plozasiran is a first-in-class RNA interference (RNAi) therapeutic developed to reduce apolipoprotein C-III (APOC3) production.¹ APOC3 can elevate triglyceride levels by inhibiting the breakdown of triglyceride-rich lipoproteins (TRLs) and the uptake of TRL remnants in the liver.

PALISADE was a Phase 3 placebo-controlled study designed to assess the efficacy and safety of plozasiran in adults with genetically confirmed or clinically diagnosed FCS.³ A total of 75 participants, distributed across 39 sites in 18 countries, were randomized to receive 25 mg plozasiran, 50 mg plozasiran, or matching placebo once every 3 months.

Its primary endpoint was the percent change from baseline in fasting triglyceride levels versus placebo at Month 10.

Upon analysis, plozasiran was linked to a statistically significant reduction in triglyceride levels, and a lower incidence of pancreatitis, compared with placebo therapy. At 10 months, the median change from baseline in triglyceride levels was –80% with 25 mg plozasiran, –78% for 50 mg plozasiran, and –17% for placebo (P <.001).

FDA Breakthrough Therapy designation intends to accelerate the development and review of drugs intended for a serious condition, where preliminary clinical evidence points to potential substantial improvement over available therapies.⁴

Plozasiran has previously received Orphan Drug Designation and Fast Track Designation from the FDA and Orphan Drug Designation from the European Medicines Agency (EMA).¹ It is being further studied in trials for additional patient populations, including those with severe hypertriglyceridemia (SHASTA) and mixed hyperlipidemia (MUIR and CAPITAN).

“Results from clinical studies of investigational plozasiran have been highly encouraging and strongly supportive of further development and commercialization in multiple patient populations,” Anzalone added.¹

References

1. _{Arrowhead Pharmaceuticals receives FDA Breakthrough therapy designation for plozasiran. Arrowhead Pharmaceuticals, Inc. September 10, 2024. Accessed September 12, 2024. https://arrowheadpharma.com/news-press/arrowhead-pharmaceuticals-receives-fda-breakthrough-therapy-designation-for-plozasiran/.}
2. _{Regmi M, Rehman A. Familial Hyperchylomicronemia Syndrome. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK551655/}
3. _{Campbell P. Palisade: Plozasiran offers hope for treating familial chylomicronemia syndrome. HCP Live. September 2, 2024. Accessed September 12, 2024. https://www.hcplive.com/view/palisade-plozasiran-offers-hope-for-treating-familial-chylomicronemia-syndrome.}
4. _{Commissioner O of the. Breakthrough therapy. U.S. Food and Drug Administration. January 4, 2018. Accessed September 12, 2024.}