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| Targets |
Pelacarsen targets apolipoprotein(a) (apo(a)) messenger RNA (mRNA). Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL)-like particle in which apolipoprotein B100 (apoB100) is covalently linked to apo(a) via a disulfide bond. Apo(a) is a large, highly glycosylated protein with a structure similar to plasminogen, containing multiple kringle IV and kringle V domains. Elevated Lp(a) (typically defined as ≥ 50 mg/dL or ≥ 125 nmol/L) is an independent, inherited, and causal risk factor for atherosclerotic cardiovascular disease, myocardial infarction, stroke, and calcific aortic valve stenosis. Existing lipid-lowering therapies (statins, ezetimibe, PCSK9 inhibitors) have modest effects on Lp(a) levels, typically reducing them by 10-30%, which is insufficient for patients with severely elevated Lp(a). Pelacarsen is a second-generation gapmer ASO with a central DNA gap flanked by 2′-O-(2-methoxyethyl) (2′-MOE)-modified RNA wings, which confer nuclease resistance and increase binding affinity to the target RNA. The compound is conjugated to a triantennary N-acetylgalactosamine (GalNAc) moiety, which binds with high affinity and specificity to asialoglycoprotein receptors (ASGPRs) on hepatocytes, enabling liver-specific delivery. After subcutaneous injection, pelacarsen is taken up by hepatocytes via ASGPR-mediated endocytosis. Once inside the cell, the ASO hybridizes to complementary sequences on apo(a) mRNA, and the DNA-RNA heteroduplex is recognized by RNase H1, leading to sequence-specific degradation of apo(a) mRNA and reduced apo(a) protein synthesis. The result is a marked reduction in plasma Lp(a) levels.
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| ln Vitro |
In vitro studies using human hepatoma cell lines (e.g., Huh7, HepG2) have demonstrated that pelacarsen effectively reduces apo(a) mRNA and protein levels. Since primary human hepatocytes express very low levels of endogenous apo(a), studies often use cells transiently or stably transfected with the human apo(a) gene. Treatment of apo(a)-expressing Huh7 cells with pelacarsen at concentrations ranging from 10 nM to 1000 nM results in a dose-dependent reduction of apo(a) mRNA as measured by quantitative PCR (qPCR). The half-maximal inhibitory concentration (IC50) for apo(a) mRNA reduction is typically in the low nanomolar range (e.g., 1-10 nM). Apo(a) protein levels in the culture supernatant are measured by an Lp(a)-specific ELISA (which detects the apo(a) component). The GalNAc conjugation significantly enhances cellular uptake: in ASGPR-expressing cells, GalNAc-conjugated pelacarsen is taken up 10- to 50-fold more efficiently than unconjugated ASO. The specificity of pelacarsen is confirmed by the absence of reduction of other apolipoproteins (e.g., apoB, apoC-III, apoA-I) by transcriptome-wide RNA-seq analysis. The compound is not cytotoxic to hepatocytes at therapeutically relevant concentrations (CC50 > 10 uM). The RNase H-dependent mechanism is confirmed using RNase H1 knockout cells, where pelacarsen fails to degrade apo(a) mRNA. In in vitro stability assays, the GalNAc-conjugated ASO is stable in human plasma for >24 hours at 37degC.
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| ln Vivo |
In vivo studies in non-human primates and clinical trials have demonstrated that pelacarsen produces robust, dose-dependent reductions in plasma Lp(a) levels. In cynomolgus monkeys, subcutaneous administration of pelacarsen (1-40 mg/kg) once weekly for 4 weeks reduced plasma Lp(a) levels by up to 90%, with a sustained effect for 4-8 weeks after the last dose. In the Phase 1/2a clinical trial (NCT02499393), healthy volunteers and patients with elevated Lp(a) received single or multiple subcutaneous doses of pelacarsen. A dose-dependent reduction in Lp(a) was observed, with the highest doses (40-80 mg per week) achieving reductions of >90%. In the Phase 2b trial (NCT03070782), patients with elevated Lp(a) (≥ 50 mg/dL) and established CVD were randomized to receive pelacarsen (20 mg every 4 weeks, 20 mg every 2 weeks, 40 mg every 2 weeks, or 60 mg every 2 weeks) or placebo for 12 months. The primary endpoint was the percent change in fasting Lp(a) from baseline to month 6. All pelacarsen doses significantly reduced Lp(a) levels in a dose- and schedule-dependent manner. The highest dose (60 mg every 2 weeks) achieved a median reduction in Lp(a) of 80%, and approximately 80% of patients achieved Lp(a) levels ≤ 50 mg/dL. In the phase 2b study, a ≥80% reduction in Lp(a) levels was observed. The pharmacodynamic effect was sustained with continued treatment, and no neutralizing antibodies against pelacarsen were detected. Based on these results, the Phase 3 Lp(a)HORIZON trial (NCT04023552) was initiated to evaluate whether reducing Lp(a) with pelacarsen reduces major adverse cardiovascular events (MACE) in patients with established cardiovascular disease and elevated Lp(a). The trial has completed enrollment of approximately 8,300 patients and is expected to report results.
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| Enzyme Assay |
For in vitro RNase H cleavage assays, a synthetic RNA substrate corresponding to the apo(a) mRNA sequence (including the pelacarsen binding site) is 5′-end labeled with 32P. The labeled RNA is incubated with pelacarsen (0.1 nM to 100 nM) in RNase H buffer (20 mM Tris-HCl pH 7.5, 100 mM KCl, 10 mM MgCl2, 0.1 mM DTT) for 30 minutes at 37degC. Purified recombinant human RNase H1 is added, and the reaction is terminated by adding EDTA and formamide loading dye. Cleavage products are separated by denaturing polyacrylamide gel electrophoresis (PAGE) and visualized by autoradiography. The appearance of cleavage fragments of the expected size confirms that pelacarsen directs RNase H1 to specifically cleave the apo(a) RNA. For binding affinity studies, surface plasmon resonance (SPR) is used to measure the affinity between pelacarsen and its target RNA sequence. A biotinylated RNA sequence is immobilized on a streptavidin-coated sensor chip, and varying concentrations of pelacarsen (0.1-100 nM) are flowed over the chip. The KD is typically in the low nanomolar range (e.g., 0.1-1 nM). For ASGPR binding studies, the GalNAc moiety of pelacarsen is evaluated for its binding to purified ASGPR by SPR. The triantennary GalNAc structure has a KD in the low micromolar to nanomolar range. For nuclease stability assays, pelacarsen is incubated in human plasma or liver S9 fraction at 37degC for up to 96 hours, and intact oligonucleotide is quantified by LC-MS or hybridization ELISA. The 2′-MOE modifications and phosphorothioate backbone confer stability, with a half-life of several days in plasma.
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| Cell Assay |
For in vitro cell-based experiments, human hepatoma Huh7 cells (which express ASGPR) are seeded in 6-well or 96-well plates at a density of 50,000-100,000 cells per well in DMEM supplemented with 10% fetal bovine serum. For apo(a) expression, Huh7 cells are transiently transfected with a plasmid encoding the human apo(a) gene (often a minigene construct). After 24 hours, pelacarsen is added to the culture medium at concentrations ranging from 1 nM to 1000 nM. Since Huh7 cells express ASGPR, gymnosis (uptake without transfection reagent) is efficient for GalNAc-conjugated ASOs. After 48-72 hours of treatment, cells are harvested. Total RNA is extracted, reverse transcribed, and apo(a) mRNA levels are measured by qPCR using TaqMan probes specific for the kringle IV-2 region of apo(a). Apo(a) protein levels in the culture supernatant are measured by a validated Lp(a) ELISA (e.g., Mercodia or Abcam). For cell viability assessment, cells are treated with pelacarsen for 72 hours, and viability is measured by CellTiter-Glo or MTT assays. The CC50 is typically >10,000 nM, indicating a wide therapeutic index. For off-target analysis, total RNA from treated cells is subjected to RNA-seq, and differentially expressed genes are analyzed to identify any unintended gene expression changes. In primary human hepatocytes (cryopreserved, plated in collagen-coated plates), pelacarsen treatment (1-500 nM) reduces the expression of the endogenous apo(a) gene (which varies greatly among individuals) as measured by qPCR; however, primary hepatocytes have very low baseline apo(a) expression, so transfected cells are more commonly used.
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| Animal Protocol |
For in vivo animal experiments, transgenic mouse models expressing human apo(a) (e.g., Lp(a) transgenic mice) are used. Since rodents do not naturally express apo(a) or Lp(a), human apo(a) transgenic mice (often combined with a human apoB100 background) are employed. Male and female mice (8-12 weeks old) are housed under standard conditions. Pelacarsen is formulated in PBS or saline and administered by subcutaneous injection at doses ranging from 1 to 100 mg/kg, once weekly or once every 2 weeks for 4-12 weeks. Control animals receive vehicle (PBS) or a scrambled control ASO. Blood samples are collected by tail vein bleeding at baseline and at weekly intervals. Plasma Lp(a) levels are measured by ELISA specific for human apo(a). At the end of the study, animals are euthanized, and liver tissue is harvested for measurement of apo(a) mRNA by qPCR and for histology. For pharmacokinetic studies in non-human primates (cynomolgus monkeys), animals are dosed subcutaneously with pelacarsen (1-40 mg/kg). Blood samples are collected at various time points (0, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, 168, 336, 504, 672, 1008, 1344 hours post-dose). Plasma concentrations of pelacarsen are measured by hybridization ELISA or LC-MS. Tissues (liver, kidney, spleen) are harvested at the end of the study for measurement of drug concentrations. For toxicology studies, rats and monkeys receive pelacarsen at doses up to 100 mg/kg/week for up to 3 months. Clinical chemistry (ALT, AST, creatinine, BUN), hematology (complete blood count), and histopathology of major organs are performed.
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| ADME/Pharmacokinetics |
Following subcutaneous administration in humans, pelacarsen is absorbed slowly, with peak plasma concentrations (Cmax) achieved approximately 2-4 hours post-dose (Tmax). The absolute bioavailability is approximately 70-80%. The GalNAc conjugation enhances liver-specific distribution, with approximately 80-90% of the administered dose accumulating in the liver after uptake via ASGPR. The compound exhibits a prolonged elimination half-life (t½) of approximately 3-4 weeks in humans, reflecting slow turnover of the ASO in hepatocytes and the stability of the 2′-MOE modifications. The volume of distribution is approximately 15-25 L, indicating extensive distribution. The compound is highly bound to plasma proteins (>95%). Pelacarsen is metabolized primarily by exonucleases that sequentially shorten the oligonucleotide from the ends; no CYP450-mediated metabolism is involved. The primary route of elimination is urinary excretion (as intact drug and chain-shortened metabolites). Because the half-life is long, plasma concentrations accumulate over the first 4-6 weeks of weekly dosing, reaching steady-state after approximately 2-3 months. Once-weekly subcutaneous dosing is feasible. Pelacarsen is not a substrate, inhibitor, or inducer of CYP450 isozymes, indicating a low potential for drug-drug interactions. In the Phase 2b trial, doses of 20 mg every 4 weeks, 20 mg every 2 weeks, 40 mg every 2 weeks, and 60 mg every 2 weeks were evaluated. All regimens produced significant Lp(a) reductions. No dose adjustment is required in patients with mild to moderate hepatic or renal impairment, as the liver is not a site of metabolism (other than ASGPR uptake) and renal elimination is not the primary clearance mechanism.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies in rodents and non-human primates, pelacarsen was generally well tolerated at doses up to 100 mg/kg/week for up to 13 weeks. The most common findings were mild, dose-dependent, reversible elevations in liver enzymes (ALT, AST), which are commonly observed with ASOs and are attributed to non-sequence-specific interactions. No significant renal toxicity or histopathological changes were observed. No thrombocytopenia or complement activation was reported, in contrast to some other ASOs. In Phase 1 and Phase 2 clinical trials, pelacarsen has demonstrated a favorable safety and tolerability profile. The most common adverse events reported in patients receiving pelacarsen were mild to moderate injection site reactions (erythema, pain, swelling, pruritus), occurring in approximately 10-20% of patients. These reactions were typically transient and resolved without intervention. No flu-like symptoms, hepatotoxicity, thrombocytopenia, or renal toxicity have been observed at clinically significant rates. No evidence of off-target effects or antisense-mediated cytotoxicity has been reported. There have been no drug-related serious adverse events reported in the pelacarsen clinical trials to date. The favorable safety profile is attributed to the hepatocyte-specific targeting via GalNAc, which concentrates the drug in the intended organ (liver) and minimizes systemic exposure. The Phase 3 Lp(a)HORIZON trial is evaluating long-term safety in a large patient population. Based on the available data, pelacarsen is considered to have a favorable benefit-risk profile for patients with elevated Lp(a). As with all ASOs, long-term safety data are still being collected. No genotoxicity, carcinogenicity, or reproductive toxicity studies have been completed. The compound is not approved for clinical use; it is an investigational drug. However, it has received Breakthrough Therapy designation from the FDA, indicating preliminary clinical evidence of substantial improvement over available therapy.
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| References |
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| Additional Infomation |
Pelacarsen sodium (formerly IONIS-APO(a)-LRx) is a second-generation, GalNAc-conjugated antisense oligonucleotide being developed by Ionis Pharmaceuticals in collaboration with Novartis (as TQJ230) for the treatment of elevated lipoprotein(a) (Lp(a)). Elevated Lp(a) is an independent, inherited, and causal risk factor for cardiovascular disease, affecting approximately 20-25% of the population. Lp(a) levels are genetically determined by the LPA gene, which encodes apo(a), and are largely unaffected by diet, exercise, or standard lipid-lowering therapies. Currently, no pharmacological therapies are approved specifically for Lp(a) reduction in the United States; lipoprotein apheresis is used for severe cases but is invasive and costly. Pelacarsen is designed to specifically target apo(a) mRNA in the liver, reducing apo(a) synthesis and thereby lowering plasma Lp(a) levels. In the Phase 2b trial, pelacarsen 60 mg administered subcutaneously every 2 weeks reduced Lp(a) levels by a median of 80%, with approximately 80% of patients achieving Lp(a) levels ≤ 50 mg/dL. The ongoing Phase 3 Lp(a)HORIZON cardiovascular outcomes trial (NCT04023552) has enrolled approximately 8,300 patients with established cardiovascular disease and Lp(a) ≥ 50 mg/dL (or ≥ 200 nmol/L). Patients are randomized 1:1 to receive pelacarsen (80 mg every 4 weeks) or placebo for up to 5 years. The primary endpoint is the time to first occurrence of major adverse cardiovascular events (MACE), defined as a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization. The trial is expected to complete in 2025. If positive, pelacarsen would be the first approved drug specifically indicated for Lp(a) reduction. Pelacarsen has received Breakthrough Therapy designation from the FDA. The compound is not yet approved for marketing in any country. Pelacarsen represents a precision medicine approach to a major unmet medical need in cardiovascular disease prevention.
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| Molecular Formula |
C296H419N71NA20O163P20S13
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| Molecular Weight |
9076.00
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| CAS # |
2172851-58-8
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| Related CAS # |
Pelacarsen; 1637637-70-7
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| Appearance |
Solid powder
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| SMILES |
[Pelacarsen (sodium)]
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| Synonyms |
AKCEA-APO(a)-LRx sodium; ISIS 681257 sodium; TQJ230 sodium
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1102 mL | 0.5509 mL | 1.1018 mL | |
| 5 mM | 0.0220 mL | 0.1102 mL | 0.2204 mL | |
| 10 mM | 0.0110 mL | 0.0551 mL | 0.1102 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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