A second apoC-III drug clears FDA for an ultra-rare fat disorder, 11 months on

The Food and Drug Administration approved Redemplo (plozasiran) injection on 18 November as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome [s1][s3]. Arrowhead Pharmaceuticals had submitted the application exactly one year earlier, on 18 November 2024 [s1].

Persistent chylomicronaemia is a genetic recessive disorder classically caused by familial chylomicronemia syndrome, and it carries a risk of recurrent acute pancreatitis [s2]. It is now the target of two approved drugs, both aimed at the same protein.

Two drugs, one target, eleven months apart

Olezarsen, marketed as Tryngolza, was approved on 19 December 2024 under priority review [s3]. Plozasiran was approved on 18 November 2025 under a standard review [s3]. Both reduce apolipoprotein C-III, a protein that impedes the clearance of triglycerides from the blood [s2].

They differ in how they do it and in how often they are given. Plozasiran is a small interfering RNA [s2]; the approved product is a 25 mg subcutaneous injection [s3]. Olezarsen is an antisense oligonucleotide, supplied in 50 mg and 80 mg autoinjector strengths [s3].

Two mechanistically related options approved eleven months apart is a lot of regulatory activity for a disorder this rare, and both were developed against the same protein target [s2][s3].

The evidence behind the approval

PALISADE was a phase 3 trial that randomly assigned 75 patients with persistent chylomicronaemia — with or without a genetic diagnosis — to subcutaneous plozasiran at 25 mg or 50 mg, or placebo, every three months for 12 months [s2].

At baseline the median triglyceride level was 2,044 mg per decilitre [s2]. The primary endpoint was the median percent change from baseline in fasting triglycerides at 10 months. It was −80% in the 25 mg group, −78% in the 50 mg group and −17% in the placebo group (P<0.001) [s2].

The incidence of acute pancreatitis was lower with plozasiran (odds ratio 0.17; 95% CI, 0.03 to 0.94; P=0.03) [s2]. That interval nearly touches 1, and the trial had 75 participants in total, so the pancreatitis finding is directional rather than precise.

The risk of adverse events was similar across groups; the most common were abdominal pain, nasopharyngitis, headache and nausea, and severe and serious adverse events were less common with plozasiran than with placebo [s2]. Hyperglycaemia occurred in some patients who had prediabetes or diabetes at baseline [s2].

One detail of the approval tracks the trial closely. The higher 50 mg dose tested in PALISADE did not produce a larger triglyceride reduction than the 25 mg dose [s2], and it is the 25 mg strength that FDA approved [s3].

What FDA required afterwards

The approval letter is where the agency records what it still does not know, and this one records three things.

FDA determined that spontaneous adverse-event reporting would not be sufficient to assess a signal of a serious risk of carcinogenicity, and required Arrowhead to complete an ongoing two-year rat carcinogenicity study of plozasiran, with study completion scheduled for December 2025 and the final report due in January 2026 [s1].

Separately, FDA determined that only a clinical trial — not a nonclinical or observational study — would be sufficient to assess signals of a serious risk of chronic drug-induced liver injury and of dysglycaemia [s1]. The required trials are the ongoing randomised, double-blind, placebo-controlled studies of plozasiran in severe hypertriglyceridaemia, AROAPOC3-3003 (SHASTA-3), including a magnetic resonance imaging proton density fat fraction substudy, and AROAPOC3-3004 (SHASTA-4) [s1].

Dysglycaemia is the postmarketing requirement most directly traceable to the trial data: PALISADE reported hyperglycaemia in some patients with prediabetes or diabetes at baseline [s2], and the agency has now made resolving that a condition of the approval [s1].

Process notes

The application was not referred to an advisory committee. FDA's stated reason was that evaluation of the safety data in FCS did not raise significant safety or efficacy issues unexpected for a drug of this class, and that there were no controversial issues that would benefit from advisory committee discussion [s1].

Because the product carries an orphan drug designation for this indication, the sponsor is exempt from the pediatric assessment requirement under the Pediatric Research Equity Act [s1]. That exemption is a statutory consequence of orphan status rather than a finding about the drug.

The expiry dating period is 24 months from manufacture when stored at 5°C [s1].

What to watch

The SHASTA-3 and SHASTA-4 trials are the substantive open question, and they extend beyond FCS into severe hypertriglyceridaemia generally — a far larger population [s1]. Whether apoC-III lowering translates from triglyceride numbers into fewer pancreatitis episodes and fewer cardiovascular events, at acceptable metabolic and hepatic cost, is not settled by a 75-person trial.

This article describes a regulatory action and the trial behind it. It is not treatment advice.

Sources

• [s1] NDA 219947 Approval Letter — Redemplo (plozasiran) injection, U.S. Food and Drug Administration, 18 November 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/219947Orig1s000ltr.pdf
• [s2] Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk, The New England Journal of Medicine, 2 September 2024. https://doi.org/10.1056/NEJMoa2409368
• [s3] Drugs@FDA: NDA 219947 (Redemplo) and NDA 218614 (Tryngolza) — approval records, U.S. Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=219947