| Targets |
The primary target is microRNA-122, which is highly abundant in the liver and normally regulates cholesterol and iron metabolism. For HCV, miR-122 binds to two sites in the 5' untranslated region of the viral RNA genome, stabilizing it and promoting viral RNA replication. Miravirsen binds to miR-122 with sub-nanomolar affinity, forming a locked nucleic acid duplex that renders miR-122 unavailable for binding to HCV RNA, thereby suppressing viral replication.
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| ln Vitro |
In vitro studies using Huh7.5 hepatoma cells harboring HCV replicons demonstrated that miravirsen at 0.1-10 uM reduced HCV RNA levels in a dose-dependent manner, with an EC50 of 0.67 uM for genotype 1b and EC50 values of 0.5-5 uM for genotypes 1a, 2a, 3a, 4a, 5a, and 6a. No cytotoxicity was observed up to 320 uM, giving a therapeutic index >297. Miravirsen also reduced infectious virus production in cell culture.
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| ln Vivo |
In a Phase 2a clinical trial (NCT01200420) involving 36 treatment-naive patients with chronic HCV genotype 1 infection, miravirsen was administered subcutaneously at doses of 3, 5, or 7 mg/kg weekly for 5 weeks. Maximum declines in HCV RNA from baseline were 1.2 log IU/mL (3 mg/kg), 2.4 log IU/mL (5 mg/kg), and 3.0 log IU/mL (7 mg/kg). In the 7 mg/kg cohort, 4 out of 9 patients achieved undetectable HCV RNA at week 10.
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| Enzyme Assay |
miR-122 binding affinity was evaluated by a fluorescence polarization competition assay. Recombinant mature miR-122 was incubated with a fluorescently labeled miravirsen probe. Unlabeled miravirsen was added at concentrations 0.01-100 nM to displace the probe. The IC50 was 0.08 nM, corresponding to a KD of approximately 0.05 nM. This tight binding reflects the high stability of the locked nucleic acid-miRNA duplex.
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| Cell Assay |
Huh7.5 cells containing subgenomic HCV replicons (genotype 1b) were seeded in DMEM with 10% FBS. Cells were treated with miravirsen at concentrations of 0.01-100 uM for 72 hours using 2 uM of a transfection reagent or via gymnotic uptake. Total RNA was extracted and HCV RNA was quantified by real-time RT-PCR. Cytotoxicity was assessed by MTT assay. EC50 values were calculated by nonlinear regression.
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| Animal Protocol |
In a mouse model of HCV infection using HCV transgenic mice or mice implanted with HCV replicon cells, miravirsen was administered subcutaneously at 10-50 mg/kg thrice weekly for 4 weeks. Liver HCV RNA levels were reduced by up to 90% at the highest dose. Serum alanine aminotransferase levels remained normal, and no significant changes in liver histology were observed. These studies confirmed in vivo target engagement.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies in cynomolgus monkeys after a single subcutaneous dose of miravirsen (10 mg/kg) showed Cmax of 8.5 ug/mL at 2 hours, with a terminal half-life of approximately 37 days. The long half-life allows weekly or biweekly dosing. Plasma protein binding was >95%. Miravirsen distributed primarily to the liver, kidney, and spleen, with liver concentrations exceeding plasma by 100-fold.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, miravirsen was administered to mice and monkeys at doses up to 100 mg/kg/week for 13 weeks. No significant adverse effects were observed. In humans, the Phase 2a trial reported that miravirsen was generally well tolerated. Adverse events included mild injection site reactions, headache, and fatigue. No dose-limiting toxicities occurred. No evidence of hepatotoxicity or off-target effects was noted.
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| References |
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| Additional Infomation |
Miravirsen is a locked nucleic acid-modified oligonucleotide with full phosphorothioate backbone. It is 15 nucleotides in length (sequence: 5'-CATTGTTCACACTCC-3' with LNA modifications). Miravirsen demonstrated durable viral suppression lasting weeks after the last dose due to its long half-life. A mutation (C3U) in the HCV 5' UTR was identified in some patients but did not confer resistance to direct-acting antivirals. Despite promising Phase 2 results, further development for HCV was halted due to the emergence of highly effective direct-acting antiviral combinations. The compound has also been explored for other miR-122-associated diseases including hepatocellular carcinoma and metabolic disorders.
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| Appearance |
Solid powder
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| Synonyms |
SPC-3649 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 (e.g. under nitrogen), 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.) |
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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