Christie Ballantyne, MD: 'Exciting' Time for FCS Pipeline

A rare genetic disease characterized by elevated triglyceride levels and episodes of pancreatitis, a lack of approved therapies has left cardiologists and families searching for answers in the management of familial chylomicronemia syndrome (FCS). However, movement in the pharmacological pipeline has offered the medical community hope, with phase 3 trial data suggesting not just 1, but 2 therapies may soon earn approval from the US Food and Drug Administration (FDA) for the management of FCS: olezarsen and plozasiran.^1,2

“None of our medications work well for [FCS],” said Christie Ballantyne, MD, professor of Medicine and chief of Cardiology and Cardiovascular Research at Baylor College of Medicine, in an interview with HCPLive Cardiology. “We have 2 really exciting therapies for this. One is an antisense oligonucleotide, olezarsen. The other is a small interfering RNA, plozasiran. These had both shown excellent efficacy in patients with FCS.”

Supported by data from the BALANCE trial, Ionis Pharmaceuticals announced the FDA’s acceptance of their New Drug Application for olezarsen in June 2024. According to the announcement, the FDA was not planning an advisory committee meeting and had set an action date of December 19, 2024 for the application.¹

Although no formal announcements have been made regarding a filing, plozasiran received a Breakthrough Therapy designation from the FDA in September 2024 following the publication of data from their phase 3 PALISADE trial. The agent had previously been awarded Orphan Drug and Fast Track designations. In their announcement of the Breakthrough Therapy designation, Arrowhead expressed its intent to submit an NDA to the FDA by the end of 2024.²

BALANCE

Presented at the American College of Cardiology 2024 Scientific Sessions and simultaneously published in the New England Journal of Medicine, BALANCE was a multicenter, double-blind, placebo-controlled designed to assess the effects of olezarsen at a dose of 80 mg or 50 mg relative to placebo therapy delivered subcutaneously every 4 weeks for 49 weeks. Conducted at 29 centers in 11 countries, the trial randomized 66 patients aged 18 years and older a fasting triglyceride levels of 880 mg/dL or greater and suspected FCS in a 1:1 ratio to olezarsen 50 mg or 80 mg and, within each dose cohort, underwent randomization again in a 2:1 ratio to olezarsen or placebo.^1,3

The primary outcomes of interest for the trial were the difference in the percent change in the fasting triglyceride level from baseline to 6 months in the 80 mg olezarsen group as compared with the placebo group and in the 50 mg olezarsen group as compared with the placebo group.^1,3

Results indicated use of olezarsen was associated with a significant reduction in triglyceride levels at 6 months (−43.5 percentage points; 95% confidence interval [CI], −69.1 to −17.9; P <.001) relative to placebo therapy. However, the observed difference for triglyceride levels at 6 months failed to reach statistical significance when comparing the olezarsen 50 mg group against placebo therapy (−22.4 percentage points; 95% CI, −47.2 to 2.5; P = .08).^1,3

Additional analysis pointed to a trend towards benefit for difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months with 80 mg olezarsen (−73.7 percentage points; 95% CI, −94.6 to −52.8) and 50 mg olezarsen (−65.5 percentage points; 95% CI, −82.6 to −48.3) relative to placebo therapy. Study investigators also highlighted safety analyses conducted at week 53 revealing 11 episodes of acute pancreatitis among the placebo group relative to a single episode among the pooled olezarsen group (rate ratio, 0.12; 95% CI, 0.02 to 0.66).^1,3

PALISADE

Presented at the European Society of Cardiology Congress 2024 and simultaneously published in the New England Journal of Medicine, PALISADE was a multicenter, double-blind, placebo-controlled designed to assess the effects of plozasiran at a dose of 25 mg or 50 mg relative to placebo therapy delivered subcutaneously every 3 months for 12 months. Conducted at 58 sites in 21 countries, the trial randomized 75 patients aged 18 years or older with a diagnosis of severe hypertriglyceridemia and fasting triglyceride level of 1000 mg/dL in a 2:1:2:1 ratio to receive 25 mg of plozasiran or volume-matched placebo or to receive 50 mg of plozasiran or volume-matched placebo.^2,4

The primary outcomes of interest for the trial were the median percent change from baseline in the fasting triglyceride level at 10 months. Results indicated the median change from baseline in the fasting triglyceride level at 10 monthswas −80% in the 25 mg plozasiran group, −78% in the 50 mg plozasiran group, and −17% in the placebo group (P < .001).^2,4

Further analysis examining apolipoprotein C-III levels suggested the 25 mg dose of plozasiran reduced values by −93% at 10 months and −89% at 12 months, which corresponds to absolute reductions of −91 and −87 percentage points compared with placebo (P <.001 for both). Investigators highlighted similar reductions were observed with the 50 mg plozasiran, with apolipoprotein C-III levels decreasing by −96% at 10 months and −88% at 12 months, which corresponds to absolute reductions of —93 and —88 percentages points compared with (P <.001 for both).^2,4

Safety analyses found 2 incident cases of pancreatitis occurred among 2 of 50 patients (4%) receiving plozasiran, and 7 incident cases occurred among 5 of 25 patients (20%) receiving placebo (odds ratio, 0.17; 95% CI, 0.03 to 0.94; P = .03).^2,4

Check out the rest of our interview clip with Ballantyne from the floor of the Family Heart Foundation’s 2024 Family Heart Global Summit.

Relevant disclosures for Ballantyne include Arrowhead, AstraZeneca, Eli Lilly and Company, Abbott Diagnostics, NewAmsterdam, and others.

References:

1. Ionis Pharmaceuticals, Inc. Ionis announces Olezarsen FCS New Drug Application accepted for Priority Review and enrollment in phase 3 shtg program completed. Ionis Pharmaceuticals, Inc. June 25, 2024. Accessed September 29, 2024. https://ir.ionis.com/news-releases/news-release-details/ionis-announces-olezarsen-fcs-new-drug-application-accepted.
2. Arrowhead Pharmaceuticals Inc. Arrowhead Pharmaceuticals receives FDA Breakthrough therapy designation for plozasiran. Arrowhead Pharmaceuticals Inc. September 10, 2024. Accessed September 29, 2024. https://ir.arrowheadpharma.com/news-releases/news-release-details/arrowhead-pharmaceuticals-receives-fda-breakthrough-therapy.
3. Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, et al. Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome. N Engl J Med. 2024;390(19):1781-1792. doi:10.1056/NEJMoa2400201
4. Watts GF, Rosenson RS, Hegele RA, et al. Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. N Engl J Med. Published online September 2, 2024. doi:10.1056/NEJMoa2409368