miravirsen (SPC3649) / BMS - LARVOL DELTA

From Laboratory to Clinic: Translational Challenges, Lessons, and Future Strategies for microRNA Delivery Systems. (PubMed, Curr Drug Deliv) - "This review critically evaluates representative clinical and advanced translational programs, including Miravirsen, MRX34, Cobomarsen, Remlarsen, RGLS4326, and farabursen (RGLS8429), to compare molecular designs, delivery approaches, development outcomes, and translational bottlenecks. Drawing on these lessons, we propose a Four-Pillar Framework integrating Delivery Systems, Immune Safety, CMC and Manufacturing Readiness, and biomarker-guided Clinical Design. Together, these principles support coordinated optimization across biological, pharmaceutical, and clinical dimensions rather than isolated improvement of individual delivery parameters."

Journal

MicroRNA-122 as a regulator and biomarker of liver disease. (PubMed, J Mol Med (Berl)) - "Finally, we critically appraise the failed clinical translation of anti-miR-122 therapeutics (miravirsen, RG-101), highlighting viral resistance, safety liabilities, and the tumor-suppressor paradox that constrains inhibition-based strategies. Collectively, miR-122 emerges as a minimally invasive biomarker and a biologically informative, though therapeutically challenging, target in liver disease."

Biomarker • Journal • Review • Colorectal Cancer • Fibrosis • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Liver Cancer • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • AMPK • CCNG1 • MIR122 • STK11 • TLR4

Small Non-Coding RNA in Breast Cancer Therapy: Yin-Yang. (PubMed, Mini Rev Med Chem) - "Furthermore, the potential use of small noncoding RNAs such as Patisiran and Miravirsen in cancer treatment has been promising. However, our understanding of miRNA and siRNA is limited, and their therapeutic uses are currently restricted by challenges related to delivery, stability, and offtarget activity. Ongoing research aimed at overcoming these limitations may enable RNA-based therapeutics to become effective tools for the diagnosis and treatment of breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor

RNA Therapeutics in Viral Infections and Cancer: Mechanisms, Challenges, and Prospects: A Review. (PubMed, Pharmaceutics) - "Approaches include targeting viral transcripts directly (e.g., siRNAs against HBV surface antigen) or host factors critical for viral replication (e.g., anti-miR-122 miravirsen for HCV)...These include TargomiR (a miR-16 mimic for mesothelioma), cobomarsen (an anti-miR-155 for lymphomas), and MRX34 (a miR-34a mimic for various solid tumours)...Despite promising preclinical results, clinical translation has been hampered by issues like insufficient delivery efficiency to human tumours, toxicity, and the complex, interconnected regulatory networks of miRNAs, which can lead to unpredictable off-target effects. While RNA therapeutics hold immense promise, overcoming delivery barriers and enhancing understanding of RNA regulatory networks are essential for future success."

Journal • Review • Breast Cancer • Hematological Malignancies • Hepatitis B • Human Immunodeficiency Virus • Infectious Disease • Lymphoma • Mesothelioma • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • BCL2 • KRAS • MIR122 • MIR155 • MIR16 • MIR221 • MIR34A

Non-coding RNAs in the viral host-pathogen interaction: molecular regulation and therapeutic potential. (PubMed, Front Cell Infect Microbiol) - "We discuss translational applications such as Miravirsen, a miRNA inhibitor that reached clinical trials for Hepatitis C Virus (HCV) and diagnostic relevance of lncRNA NEAT1 in SARS-CoV-2 infection. In the end, we have also addressed the current challenges and limitations involved in translating research observations of ncRNAs to clinical outcomes."

Journal • Review • Hepatitis C • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • NEAT1

RNA Therapeutics: Delivery Problems and Solutions-A Review. (PubMed, Pharmaceutics) - "This review critically assesses the landscape of RNA-derived medicines, examining world-renowned mRNA vaccines (Spikevax, BNT162b2/Comirnaty) and RNA-based therapeutics like Miravirsen (anti-miR-122). RNA-mediated macrophage reprogramming emerges as a promising strategy, potentially enhancing both delivery and clinical efficacy. This review highlights that while approved RNA therapies primarily target rare diseases due to delivery limitations, novel approaches in RNA modification, targeted delivery systems, and enhanced understanding of molecular mechanisms are crucial for expanding their application to prevalent diseases and unlocking their full therapeutic potential."

Journal • Review • Immunology • Infectious Disease • Oncology • Rare Diseases • MIR122

MicroRNA-based therapeutics for inflammatory disorders of the microbiota-gut-brain axis. (PubMed, Pharmacol Res) - "With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research."

Journal • Review • CNS Disorders • Gastrointestinal Disorder • Inflammation • Mental Retardation • Psychiatry

Functional and Clinical Significance of Dysregulated microRNAs in Liver Cancer. (PubMed, Cancers (Basel)) - "Clinical treatment drugs have been developed based on miR-34 and miR-122 (MRX34 and Miravirsen, respectively), but their side effects have not yet been overcome. Future research is needed to address these weaknesses and establish a feasible microRNA-based treatment strategy for liver cancer."

Clinical • Journal • Review • Gastrointestinal Cancer • Hepatitis C • Hepatology • Infectious Disease • Inflammation • Liver Cancer • Oncology • Solid Tumor • MIR122 • MIR21 • MIR214 • MIR34A

Role of non-coding RNAs in Dengue virus-host interaction. (PubMed, Front Biosci (Schol Ed)) - "The idea of RNA based therapies has been greatly backed by a Hepatitis C virus drug, Miravirsen which has successfully completed phase II clinical trial. In the present review, we will discuss the implications of different non-coding RNAs in dengue infection. Differential expression of small ncRNA may serve as a reliable biomarker of disease severity during different stages of infection and can also play regulatory roles in disease progression."

Journal • Review • Dengue Fever • Hepatitis C • Hepatology • Infectious Disease • Inflammation

miRCOVID-19: Potential Targets of Human miRNAs in SARS-CoV-2 for RNA-Based Drug Discovery. (PubMed, Noncoding RNA) - "As a proof of principle, we have shown that human miR-122, a previously known co-factor of another RNA virus, the hepatitis C virus (HCV) whose genome it binds as a prerequisite for pathogenesis, was predicted to also bind the SARS-CoV-2 RNA genome with high affinity, suggesting the perspective of repurposing anti-HCV RNA-based drugs, such as Miravirsen, to treat COVID-19. Our study is the first to identify all high-confidence binding sites of human miRNAs in the SARS-CoV-2 genome using multiple tools. Our work directly facilitates experimental validation of the reported targets, which would accelerate RNA-based drug discovery for COVID-19 and has the potential to provide new avenues for treating symptomatic COVID-19, and block SARS-CoV-2 replication, in humans."

Journal • Hepatitis C • Hepatology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Role of microRNAs in antiviral responses to dengue infection. (PubMed, J Biomed Sci) - "The only licensed vaccine, Dengvaxia, has low efficacy against serotypes 1 and 2. Major hurdles lie in the development of chemical modifications and delivery systems for in vivo delivery. Nevertheless, advancement in miRNA formulations and delivery systems hold great promise for the therapeutic potential of miRNA-based therapy, as supported by Miravirsen for treatment of Hepatitis C infection which has successfully completed phase II clinical trial."

Journal • Review • Dengue Fever • Hepatitis C Virus • Infectious Disease

Replicons of a rodent hepatitis C model virus permit selection of highly permissive cells. (PubMed, J Virol) - "RHV-rn1 replication was inhibited by the HCV polymerase inhibitor sofosbuvir and high concentrations of HCV NS5A antivirals but not by NS3 protease inhibitors. The microRNA-122 antagonist miravirsen inhibited RHV-rn1 replication, demonstrating the importance of this HCV host factor for RHV...HCV antivirals targeting NS5A, NS5B and microRNA-122 efficiently inhibited RHV replication. Hence, several important aspects of HCV replication are shared by the rodent virus system, reinforcing its utility as an HCV model."

Journal • Preclinical • Hepatitis C Virus • Hepatology • Immunology • Infectious Disease

The Race of 10 Synthetic RNAi-Based Drugs to the Pharmaceutical Market. (PubMed) - Pharm Res - "...The siRNAs in focus are PF-04523655, TKM-080301, Atu027, SYL040012, SYL1001, siG12D-LODER (phase 2), QPI-1002, QPI-1007, and patisiran (phase 3)...Miravirsen is an AntimiR-122 for hepatitis C virus infection. The flexibility of RNAi technology is easily understood taking into account: (i) the different drug targets (i.e. p53, caspase 2, PKN3, β2-adrenergic receptor, mutated KRAS, microRNAs); (ii) therapeutic conditions, including ophthalmic diseases, kidney injury, amyloidosis, pancreatic cancer, viral hepatitis; and (iii) routes of administration (ocular, intravenous, subcutaneous, intratumoral). Although some issues are still matters of concern (delivery, toxicity, cost, and biological barriers), RNAi definitively opens a wide avenue for drug development."

Journal • Review • Biosimilar • Gastrointestinal Cancer • Hepatitis C Virus • Immunology • Oncology • Ophthalmology • Pancreatic Cancer • Renal Disease

Sequence analysis of HCV variants from a phase IIA trial of miravirsen (MIR), an oligonucleotide targeting miR-122, in treatment naïve patients with chronic HCV infection (EASL 2012) - Presentation time: 21.04.2012, 09:00-18:00; P2a, N=NA; MIR was associated with dose-dependent, sustained reductions in HCV RNA that continued after the completion of MIR therapy; No resistance-associated nucleotide changes were observed in S1, S2 and S3 at the end of treatment (wk 5) in any MIR treated pts

P2 data • Hepatitis C Virus

Miravirsen (MIR), an oligonucleotide targeting miR-122, produced long-lasting suppression of HCV RNA in treatment naïve patients with genotype 1 (GT1) chronic HCV infection (HEP DART 2011) - P=NA, N=36; In Cohort 3 (dose 7 mg/Kg bodyweight) the mean of the maximum change from baseline in HCV RNA (log10 IU/mL) through week 10 was -2.777 vs -0.347 (p =0.012) in Miravirsen (MIR) & PBO groups respectively; Four of nine MIR pts became HCV RNA undetectable without the addition of SOC; In Cohorts 1 & 2 (dose 3 & 5 mg/Kg bodyweight, respectively) MIR subjects, no significant nucleotide changes were observed in the HCV miR-122 binding sites

Clinical data • Hepatitis C Virus

Miravirsen study in null responder to pegylated interferon alpha plus ribavirin subjects with chronic hepatitis C (clinicaltrials.gov) - P2, N=10; Recruiting; Sponsor: Santaris Pharma A/S; New P2 trial

New P2 trial • Hepatitis C Virus

Multiple ascending dose study of miravirsen in treatment-naïve chronic hepatitis C subjects (clinicaltrials.gov) - P2, N=40; Recruiting → Active, not recruiting

Enrollment closed • Hepatitis C Virus

Santaris Pharma A/S phase 2a data of miravirsen shows dose-dependent, prolonged viral reduction of 2-3 logs HCV RNA after four-week treatment in hepatitis C patients (Market Watch) - P2, N=NA; Miravirsen given as a four-week monotherapy treatment provided robust, dose-dependent antiviral activity with a mean reduction of 2 to 3 logs from baseline in HCV RNA (log10 IU/mL) that was maintained for more than four weeks beyond the end of therapy; Four of nine pts treated at the highest dose with miravirsen became HCV RNA undetectable during the study; Data to be presented in a late-breaking oral presentation on Nov 07, 2011 at The Liver Meeting 2011 AASLD in California

P2 data • P2 data presentation • Hepatitis C Virus

Genotype analysis of HCV variants from the proof of concept study of miravirsen (MIR), an oligonucleotide targeting miR-122, in treatment naïve patients with genotype 1 (GT1) chronic HCV infection (HEP DART 2011) - P2a, N=36; In Cohorts 1 & 2 (dose 3 & 5 mg/Kg bodyweight, respectively) MIR subjects, no nucleotide changes were observed in S1, S2 & S3 at the end of treatment (wk 5); In Cohorts 1 & 2, three & five MIR subjects experienced HCV RNA rebound (>1 log HCV RNA decline with subsequent greater than 1 log HCV RNA increase); In these eight subjects no nucleotide changes were observed in S1, S2 & S3 following HCV RNA rebound

P2 data • Hepatitis C Virus

Long-Term Extension Study of Miravirsen Among Participants With Genotype 1 Chronic Hepatitis C (CHC) Who Have Not Responded to Pegylated-Interferon Alpha Plus Ribavirin (clinicaltrials.gov) - P=N/A; N=10; Active, not recruiting; Sponsor: Hoffmann-La Roche

New trial • Biosimilar • Hepatitis C Virus • Immunology • Inflammation

Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients (Antiviral Res) - P=NA, N=36; "No long-term safety issues were observed among 27 miravirsen-treated patients. Targeting miR-122 may be an effective and safe treatment strategy for HCV infection and should be investigated in larger clinical trials."

Retrospective data • Hepatitis C Virus

The role of microRNAs in hepatitis C virus replication and related liver diseases (J Microbiol) - "Recently, a phase IIa clinical trial with miravirsen, an LNA form of antimiR-122 oligonucleotides, showed significant reduction in serum HCV levels in patients chronically infected with HCV with no detectible evidence of resistance....In this review, we summarize the features of miRNAs critical for HCV replication and HCV-mediated liver abnormalities..."

Review • Hepatitis C Virus

How close are miRNAs from clinical practice? A perspective on the diagnostic and therapeutic market. (PubMed, EJIFCC) - "...Miravirsen (produced by Roche/Santaris) and RG-101 (produced by Regulus Therapeutics), designed to treat hepatitis C, are considered the flagship products of this class of future drugs...However, acquisition of miRNA-based companies by major pharmas is sending a positive feedback on their potentials. With multiple initiatives on their way, the next years will definitely be determinant for the miRNA market that is still in his infancy."

Clinical • Journal