Plozasiran (Redemplo)

Number: 1096

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses plozasiran (Redemplo) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Redemplo has been identified as an Aetna Gene-based, Cellular & Other Innovative Therapies (GCIT®) product that receives dedicated review by the Aetna GCIT team for Commercial lines of business. 

Note: Requires Precertification: 

Precertification of plozasiran (Redemplo) is required of all Aetna participating providers and members in applicable plan designs. For precertification of plozasiran (Redemplo), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.  

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a cardiologist, endocrinologist, lipid specialist, geneticist, or a prescriber specialized in the treatment of familial chylomicronemia syndrome (FCS). 

2. Criteria for Initial Approval

   Aetna considers plozasiran (Redemplo) medically necessary for the treatment of familial chylomicronemia syndrome (FCS) (type 1 hyperlipoproteinemia) in adult members when all of the following criteria are met:

   1. Member meets either of the following:

      1. Member has a confirmed FCS diagnosis by genetic testing (i.e., biallelic pathogenic variants in FCS-causing genes [e.g., LPL, GPIHBP1, APOA5, APO2, LMF1, GPD1, CREB3L3]); or
      2. Genetic testing was inconclusive, and the member has confirmed FCS diagnosis by either of the following:
         
         
         1. North American familial chylomicronemia syndrome (NAFCS) score greater than or equal to 45; or
         2. Moulin score greater than or equal to 10; and
   2. Member has a fasting triglycerides (TG) level of more than or equal to 880 mg/dL; and
   3. Member is currently receiving a very-low fat diet (e.g., less than or equal to 20 to 30 grams of total fat per day, 10% to 15% of calories of fat); and
   4. Member will not use the requested  medication concomitantly with olezarsen (Tryngolza).

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of plozasiran (Redemplo) therapy medically necessary for adult members requesting reauthorization for FCS when all of the following criteria are met:

   1. Member has demonstrated a positive clinical response with the requested medication (e.g., reduction in TG level from baseline, reduction in episodes of acute pancreatitis); and
   2. Member is currently receiving a very-low fat diet (e.g., less than or equal to 20 to 30 grams of total fat per day, 10% to 15% of calories of fat); and
   3. Member will not use the requested medication concomitantly with Tryngolza.

4. Related Policies

   1. CPB 0140 - Genetic Testing
   2. CPB 0525 - Screening for Lipid Disorders

Dosage and Administration

Redemplo is supplied for injection in a single-dose prefilled syringe containing 25 mg/0.5 mL of plozasiran for subcutaneous use.  

The recommended dosage is 25 mg injected subcutaneously once every 3 months. 

Individuals and/or caregivers may be trained to administer the medication into the front of the thigh or abdomen. The outer area of the upper arm can be used as an injection site if a healthcare provider or caregiver administers the injection.

Source: Arrowhead Pharmaceuticals, 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
FCS diagnosis by genetic testing (i.e., biallelic pathogenic variants in FCS-causing genes [e.g., LPL, GPIHBP1, APOA5, APO2, LMF1, GPD1, CREB3L3]) -no specific code
84478	Triglycerides
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met:
Plozasiran (Redemplo) - no specific code
HCPCS codes not covered for indications listed in the CPB:
Olezarsen (Tryngolza) -no specific code
ICD-10 codes covered if selection criteria are met:
E78.3	Hyperchylomicronemia
K85.00 – K85.92	Acute pancreatitis

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Redemplo is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS).

Plozasiran, branded as Redemplo (Arrowhead Pharmaceuticals, Inc.), is a small interfering ribonucleic acid (siRNA) therapeutic that targets and degrades the messenger RNA responsible for producing apolipoprotein C-III (apoC-III). By utilizing the RNA interference mechanism, it suppresses apoC-III production, resulting in enhanced clearance of triglycerides from the bloodstream. 

There are no reported contraindications for the use of Redemplo. The most common adverse reactions in patients treated with Redemplo (occurring in 10% or more of patients and at least 5% more frequently than with placebo) include hyperglycemia, headache, nausea, and injection site reactions.

Familial Chylomicronemia Syndrome

Familial chylomicronemia syndrome (FCS) is a rare inherited disorder marked by extremely high levels of triglycerides in the blood, resulting from genetic variants that disrupt the normal breakdown of triglycerides carried by chylomicrons, the particles that transport dietary fats through the bloodstream. The condition is most commonly linked to mutations in the Lipoprotein Lipase (LPL) gene, which encodes an enzyme crucial for triglyceride metabolism, although variants in other genes can also contribute to FCS, which follows an autosomal recessive inheritance pattern. A hallmark of FCS is persistent and severe hypertriglyceridemia, often exceeding 1,000 mg/dL, significantly increasing the risk of acute pancreatitis, a serious condition characterized by inflammation of the pancreas that can lead to systemic complications and organ failure. Symptoms may include recurrent abdominal pain, nausea, vomiting, eruptive xanthomas (visible fat deposits in the skin), fatigue, and difficulty concentrating due to metabolic disturbances. Diagnosis can be challenging due to the rarity of FCS and symptom overlap with more common conditions, often requiring genetic testing for confirmation. The primary treatment involves a strict low-fat diet to limit triglyceride intake and reduce chylomicron production. Therapies such as olezarsen (Tryngolza; Ionis Pharmaceuticals, Inc.) have been approved by the U.S. Food and Drug Administration (FDA) to help lower triglyceride levels in adults with FCS (NORD, 2025).

Approximately 80% of familial hyperchylomicronemia syndrome is caused by inherited defects in both alleles of the lipoprotein lipase gene, while the remaining 20% results from mutations in other genes associated with lipoprotein lipase function, including apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), high-density lipoprotein binding protein 1 (GP1HBP1), and lipase maturation factor 1 (LMF1), along with other unidentified mutations. These genetic alterations lead to the dysfunction of the lipoprotein lipase enzyme. FCS is often under-reported due to its nonspecific symptoms, making it difficult to determine its true prevalence with certainty; estimates suggest it affects between 3,000 and 5,000 patients worldwide, occurring in 1 to 10 individuals per million people. There is no observed correlation with gender or race, although higher incidences have been noted in specific regions, such as Quebec among French Canadians and within South Afrikaner populations (Regmi and Rehman, 2023).

Dietary modification is the cornerstone of managing familial chylomicronemia syndrome. Lipid-lowering therapies, such as fibrates, niacin, and omega-3 fatty acids, have minimal effectiveness in this condition, as they primarily work by reducing VLDL levels or enhancing lipoprotein lipase activity, neither of which impacts chylomicrons in FCS. Consequently, patients are advised to adhere to a very-low-fat diet, limiting fat intake to less than 10% to 15% of daily calories (approximately 20 to 30 grams of fat per day). They are encouraged to use medium-chain triglycerides, which are water-soluble, not incorporated into chylomicrons, and easily absorbed through the portal vein. Additionally, patients should include essential fatty acids, such as alpha-linolenic acid and linoleic acid, along with fat-soluble vitamins in their diet. It is also important for them to avoid alcohol and be cautious with certain medications that may elevate triglyceride levels, including beta-blockers, thiazide diuretics, and exogenous estrogen. The primary goal of these dietary modifications is to maintain triglyceride levels below the threshold for acute pancreatitis, ideally in the range of 750 mg/dL to 880 mg/dL. However, the strict nature of the diet can make it challenging for patients to adhere consistently, highlighting the need for counseling and regular follow-up with a dietitian, as well as collaboration with an endocrinologist or lipidologist (Regmi and Rehman, 2023).

Spagnuolo and Hegele (2024) highlight that FCS is a rare autosomal recessive disorder, making effective treatment crucial due to the associated risk of severe and potentially fatal acute pancreatitis. They review recent advancements in pharmacologic treatments for FCS, particularly focusing on biological inhibitors of apolipoprotein C-III and angiopoietin-like protein 3 (ANGPTL3). FCS is characterized by a biallelic inheritance pattern, where individuals inherit two pathogenic loss-of-function alleles from one of five causal genes—LPL (in 60-80% of patients), GPIHBP1, APOA5, APOC2, and LMF1—resulting in a lack of lipolytic activity. Patients typically present in childhood with severely elevated triglyceride (TG) levels exceeding 10 mmol/L, although most individuals with severe hypertriglyceridemia do not have FCS. The current first-line treatment is a strict low-fat diet, as existing lipid-lowering therapies have limited effectiveness in this condition. Emerging therapies, such as apo C-III inhibitors, have shown efficacy and safety in clinical trials for lowering TG levels. Conversely, ANGPTL3 inhibitors require at least partial lipoprotein lipase activity to effectively reduce plasma TG, proving beneficial for patients with multifactorial chylomicronemia but not for those with FCS who completely lack this enzyme. The authors conclude that apo C-III inhibitors currently under development hold promise as effective treatments for FCS.

In November 2025, the U.S. FDA approved Redemplo as an adjunct to diet to reduce triglycerides in adults with FCS. Approval was based on the results of a randomized, placebo-controlled, double-blind trial (PALISADE trial, NCT05089084) that demonstrated the efficacy of Redemplo in adults with genetically confirmed or clinically diagnosed FCS who were adhering to a low-fat diet (≤20 grams of fat per day). In this study, patients were randomly assigned to receive either four doses of Redemplo at 25 mg or a matching placebo, administered subcutaneously once every three months over a 12-month period. The primary endpoint was the percentage change in fasting triglycerides (TGs) from baseline to month 10, with the Redemplo group showing a median percent change of -59% compared to the placebo group.

Redemplo is given as a 25 mg injection every three months into the front of the thigh or abdomen, with the outer area of the upper arm also available as an injection site if administered by a healthcare provider or caregiver. Common side effects include hyperglycemia, headache, nausea, and injection site reactions. Redemplo has received Fast Track, Breakthrough Therapy, and Orphan Drug designations for this indication.

Watts et al. (2025) state that persistent chylomicronemia is a genetic recessive disorder primarily caused by FCS, but can also have multifactorial causes, and is associated with an elevated risk of recurrent acute pancreatitis. In the phase 3 PALISADE trial, Watts et al. investigated the efficacy of plozasiran in 75 patients with persistent chylomicronemia, regardless of genetic diagnosis. Patients were randomly assigned to receive subcutaneous plozasiran (25 mg or 50 mg) or a placebo every three months for 12 months. The primary endpoint was the median percent change in fasting triglyceride levels from baseline at 10 months, while key secondary endpoints included changes in fasting triglyceride levels at 10 and 12 months, changes in fasting apolipoprotein C-III levels, and the incidence of acute pancreatitis. At baseline, the median triglyceride level was 2044 mg per deciliter. By 10 months, the median change in fasting triglyceride levels was -80% for the 25 mg plozasiran group, -78% for the 50 mg group, and -17% for the placebo group (P<0.001). The plozasiran groups also showed a significantly lower incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03) compared to the placebo group. Adverse events were similar across all groups, with the most common being abdominal pain, nasopharyngitis, headache, and nausea; however, severe and serious adverse events were less frequent in the plozasiran groups. Some patients with prediabetes or diabetes experienced hyperglycemia while on plozasiran. The authors concluded that patients with persistent chylomicronemia treated with plozasiran experienced significantly lower triglyceride levels and a reduced incidence of pancreatitis compared to those receiving placebo.

The inclusion criteria for the PALISADE trial (ClinicalTrials.gov ID NCT05089084) require participants to have fasting triglyceride (TG) levels of at least 10 mmol/L (≥ 880 mg/dL) at screening that are resistant to standard lipid-lowering therapies, a confirmed diagnosis of FCS, and a willingness to adhere to dietary counseling as determined by the investigator based on local standards of care. Participants of childbearing potential, both males and females, must use highly effective contraception during the study and for at least 24 weeks after the last dose of the study medication, with males prohibited from donating sperm during this period. Women of childbearing potential must have a negative pregnancy test at screening and cannot be breastfeeding, and those on hormonal contraceptives must have been stable on their medication for at least two menstrual cycles prior to Day 1. Exclusion criteria include current or recent use (within the last 365 days) of any hepatocyte-targeted siRNA or antisense oligonucleotide, newly diagnosed diabetes mellitus within 12 weeks of screening or an HbA1c of 9.0% or higher at screening, active pancreatitis within 12 weeks before Day 1, a history of acute coronary syndrome within 24 weeks of Day 1, major surgery within 12 weeks of Day 1, uncontrolled hypertension, treatment with HIV antiretroviral therapy, seropositivity for hepatitis B virus (HBV) or hepatitis C virus (HCV), and New York Heart Association (NYHA) Class II, III, or IV heart failure.

Brown et al. (2025) suggest that patients with FCS may benefit from emerging therapies, although definitive genetic testing is available, there is a need for more accessible clinical tools. The North American FCS (NAFCS) Score was calculated for patients in the Balance trial who had genetically confirmed FCS. Many patients with FCS are often misdiagnosed, and while a positive genetic diagnosis is definitive, clinical scoring systems can also help identify affected individuals. The NAFCS Score aims to pinpoint patients likely to test positive for the genetic mutation, although its sensitivity has yet to be quantified. In this study, NAFCS Scores were calculated for 66 patients from the Balance study of olezarsen, revealing that 95.5% (63/66) had scores of 45 or higher, indicating "likely FCS," and 74.2% (49/66) had scores of 60 or higher, indicating "definite FCS." Notably, no patients scored below 30, which indicates "unlikely FCS," while 4.5% (3/66) had scores between 30 and 44, categorized as "uncertain FCS." The strong correlation between a NAFCS Score of 45 or higher and a positive genetic diagnosis suggests that either method can be used for diagnosis, except in cases of "uncertain FCS," which necessitate genetic testing. Additionally, the NAFCS Score may provide clinical support for an FCS diagnosis when genetic testing yields indeterminate results due to variants of unknown significance. Overall, 95.5% of patients in the Balance study had a NAFCS score of 45 or higher, indicating a strong concordance between this score and genetically confirmed FCS.

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References