Plozasiran (Redemplo): The apoC-III Silencer That Cuts Triglycerides ~80% and Slashes Pancreatitis - PALISADE, SHASTA-3 and SHASTA-4 (August 11, 2026)
Table of Contents
- A disease with almost no treatment
- The target: apolipoprotein C-III
- How the drug is built: RNA interference and a sugar tag
- PALISADE: the trial that earned approval
- FDA approval as Redemplo
- SHASTA-3 and SHASTA-4: pushing beyond a rare disease
- Plozasiran versus olezarsen
- What to watch, and what is still unproven
- The bigger picture
A disease with almost no treatment
For most people, high triglycerides are a background lipid number nudged by diet, alcohol and metabolism. But at the extreme end sits familial chylomicronemia syndrome (FCS), a rare genetic disorder in which the machinery that clears fat from the blood barely works. Triglycerides routinely climb above 1,000 mg/dL and can exceed 2,000, turning blood milky with chylomicrons and setting the stage for acute pancreatitis - a sudden, agonizing and sometimes fatal inflammation of the pancreas. Until recently, the only real management was a punishing near-fat-free diet, and even that often failed to prevent repeated hospitalizations. Plozasiran, approved in November 2025 under the brand name Redemplo, is one of the first therapies designed specifically to attack the root cause of that triglyceride overload.
The target: apolipoprotein C-III
Plozasiran works by silencing apolipoprotein C-III, or apoC-III - a small liver-made protein encoded by the APOC3 gene that acts as a brake on triglyceride clearance. ApoC-III inhibits lipoprotein lipase, the enzyme that breaks down triglyceride-rich lipoproteins, and it also slows the liver's uptake of the leftover remnant particles. Human genetics made apoC-III an unusually attractive target: people who carry natural loss-of-function mutations in APOC3 have low triglycerides and, strikingly, appear protected from cardiovascular disease. Lowering apoC-III therefore removes a brake, letting the body clear triglycerides the way it is supposed to.
How the drug is built: RNA interference and a sugar tag
Plozasiran is a small interfering RNA (siRNA) built on Arrowhead Pharmaceuticals' Targeted RNAi Molecule, or TRiM, platform. Rather than blocking a protein after it is made, RNA interference destroys the messenger RNA blueprint before the protein is ever built - a durable, upstream form of gene silencing. To reach the right cells, plozasiran is conjugated to GalNAc (N-acetylgalactosamine), a sugar that binds a receptor found almost exclusively on liver hepatocytes, delivering the drug precisely where apoC-III is produced. The practical payoff is convenience: plozasiran is a subcutaneous injection given just once every three months, with triglyceride lowering that lasts between doses.
PALISADE: the trial that earned approval
The pivotal Phase 3 PALISADE trial, published in the New England Journal of Medicine, enrolled 75 adults with persistent chylomicronemia (with or without a genetic FCS diagnosis) and randomized them to plozasiran 25 mg, plozasiran 50 mg, or placebo subcutaneously every three months for a year. The results were decisive: median fasting triglycerides fell about 80% with the 25 mg dose and 78% with 50 mg at 10 months, versus a 17% drop with placebo - a placebo-adjusted reduction on the order of 57 to 59%. Just as important, plozasiran significantly reduced adjudicated acute pancreatitis events, the complication that makes FCS dangerous. The trial met all of its alpha-controlled endpoints, and the 25 mg quarterly dose became the approved regimen.
FDA approval as Redemplo
On November 18, 2025, the U.S. Food and Drug Administration approved plozasiran as Redemplo, an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome. The approved course is four doses of 25 mg (or 50 mg) given subcutaneously once every three months over a 12-month period. Arrowhead has since secured additional approvals for FCS in China (NMPA) and Australia (TGA), and the drug carries FDA Breakthrough Therapy Designation for the broader severe hypertriglyceridemia indication. Redemplo is a prescription biologic administered under medical supervision - not a supplement, and not something that can be legitimately bought from a research-chemical vendor.
SHASTA-3 and SHASTA-4: pushing beyond a rare disease
FCS affects only a few thousand people, but severe hypertriglyceridemia (triglycerides at or above 500 mg/dL) affects millions and also raises pancreatitis risk. On July 22, 2026, Arrowhead reported topline results from the Phase 3 SHASTA-3 and SHASTA-4 trials, which together enrolled roughly 750 adults with severe hypertriglyceridemia treated with plozasiran 25 mg every three months versus placebo. Both trials met their primary endpoint, with median triglyceride reductions of 79% and 81%. Crucially, the program also showed a statistically significant reduction in acute pancreatitis events across the pooled population, with especially large reductions in the highest-risk patients, and no new safety signals. Arrowhead plans to file a supplemental New Drug Application for severe hypertriglyceridemia before the end of 2026, with detailed data slated for presentation at the European Society of Cardiology Congress on August 30, 2026.
Plozasiran versus olezarsen
Plozasiran is not the only apoC-III drug. Ionis Pharmaceuticals' olezarsen (Tryngolza), an antisense oligonucleotide against the same target, was also approved for FCS and is likewise chasing the severe hypertriglyceridemia market. The two represent a friendly rivalry between RNA-based approaches: an siRNA dosed quarterly (plozasiran) versus a monthly antisense injection (olezarsen). For patients and clinicians, the competition is good news - it means genuine, differentiated options for a condition that recently had almost none, and it will likely be decided on the balance of triglyceride lowering, pancreatitis prevention, dosing convenience and effects on blood sugar.
What to watch, and what is still unproven
The evidence that plozasiran lowers triglycerides and reduces acute pancreatitis is strong. What has not yet been established is whether it reduces hard cardiovascular outcomes such as heart attack and stroke - that would require dedicated outcomes trials in higher-risk populations. Clinicians will also watch glycemic effects: apoC-III-targeting therapies have been associated with modest increases in blood glucose or HbA1c, which matters because many people with high triglycerides also have diabetes. Injection-site reactions are the most common tolerability issue. None of these caveats diminish what plozasiran already delivers for FCS; they simply mark the questions that its expanding program will need to answer.
The bigger picture
Plozasiran sits within a rapidly maturing wave of gene-silencing lipid drugs that PepTracker Pro tracks closely - siRNAs like olpasiran, lepodisiran and zerlasiran and the antisense agent pelacarsen aimed at lipoprotein(a), and oral entrants like the CETP inhibitor obicetrapib and the Lp(a) small molecule muvalaplin. What unites them is a shift from treating lipids with daily pills that manage a number to switching off the responsible gene for months at a time. Plozasiran is one of the first of that generation to earn approval and to show that the approach does not just move a lab value - it prevents the event, acute pancreatitis, that patients actually fear.
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Citations
- [1] Watts GF, et al. - Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk (PALISADE, Phase 3), New England Journal of Medicine (2024/2025) Source
- [2] Arrowhead Pharmaceuticals - FDA Approval of REDEMPLO (plozasiran) for FCS (November 18, 2025) Source
- [3] Arrowhead Pharmaceuticals - Topline Phase 3 SHASTA-3 and SHASTA-4 Results in Severe Hypertriglyceridemia (July 22, 2026) Source
- [4] FDA - Approves drug to reduce triglycerides in adults with familial chylomicronemia syndrome Source
- [5] HCPLive - Plozasiran Meets Primary Endpoint in SHASTA-3, SHASTA-4 sHTG Trials Source
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