Zokinvy (lonafarnib) / Eiger, AnGes MG - LARVOL DELTA

Molecular mechanism of resistance to lonafarnib conferred by mutations in the cysteine-rich region of respiratory syncytial virus fusion glycoprotein and discovery of a lonafarnib-derived antiviral PROTAC. (PubMed, J Virol) - "This novel antiviral agent effectively inhibits RSV infection by inducing degradation of the F protein. This work elucidates the molecular basis of RSV resistance to lonafarnib and establishes a strategy for developing next-generation antivirals aimed at preempting resistance."

Journal • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections • Targeted Protein Degradation • CRBN

Lonafarnib Clinical Trials Demonstrate Uncoupling of the Muscle-Bone Unit in Hutchinson-Gilford Progeria Syndrome. (PubMed, J Bone Miner Res) - "Normal muscle mass for body size at younger ages implies that there is an opportunity for early treatment to avoid impending pathology. New strategies are needed to ameliorate this phenotype in HGPS, and this study provides a benchmark for gauging future therapies."

Journal • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Heart Failure • Orthopedics • Pediatrics

Inhibition of farnesyltransferase activity diminishes hematopoietic stem cell ex vivo expansion ability. (PubMed, bioRxiv) - "The rationale underlying this work is that elucidating the contribution of farnesyltransferase activity to hematopoietic stem cell expansion ex vivo will provide knowledge needed to better support hematopoietic stem cell expansion techniques for clinical applications that rely on this approach, like hematopoietic cell transplants and gene therapy. We discovered that pharmacological inhibition of farnesyltransferase activity with lonafarnib substantially diminished the ex vivo expansion potential of human and mouse hematopoietic stem cells, highlighting that hematopoietic stem cells rely on isoprenoids for their ex vivo maintenance."

Journal • Preclinical • Gene Therapies • Transplantation

Farnesyltransferase inhibitors decrease matrix-vesicle-mediated mineralization in SaOS-2 cells. (PubMed, Mol Biol Rep) - "Our findings demonstrate that FTIs Lonafarnib and Tipifarnib impair MVM, highlighting the essential role of farnesylation in biomineralization."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • COL1A1 • RUNX2

Baricitinib Augments Lonafarnib Therapy to Preserve Colonic Homeostasis and Microbial Balance in a Mouse Model of Progeria. (PubMed, Aging Cell) - "While both monotherapies induced distinct shifts in gut microbiota, combination therapy preserved a profile more closely resembling healthy controls. These findings expand the current understanding of GI involvement in HGPS and identify the colon as a site where JAK-STAT inhibition enhances the therapeutic profile of FTI."

Journal • Preclinical • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Inflammation • STAT1

Selection of specific and efficient siRNAs in new cellular model for Hutchinson-Gilford progeria syndrome therapy. (PubMed, Mol Ther Nucleic Acids) - "Additionally, we observed an additive effect of the combination of our siRNAs with lonafarnib-the sole drug approved by the Food and Drug Administration for progeria syndrome therapy. The selected siRNAs also worked efficiently in all three tested patient fibroblast lines, even after extended post-transfection incubation with low siRNA doses. Therefore, we believe that the development of genetic drugs may be a promising therapeutic tool for Hutchinson-Gilford progeria syndrome."

Journal • Gene Therapies • Genetic Disorders • LMNA

LONAFARNIB AS FINITE TREATMENT FOR CHRONIC HEPATITIS D: LONG-TERM FOLLOW-UP DATA (AASLD 2025) - "Patients achieving a 2 log drop in HDV RNA from baseline and normal ALT at 6 months after stopping any finite lonafarnib-based treatment regimen have no major clinical events (liver decompensation, liver cancer, or death) in up to 10 years of follow-up."

Hepatology • Infectious Disease • Inflammation • Liver Cancer • Liver Failure • Solid Tumor

LONAFARNIB AS FINITE TREATMENT FOR CHRONIC HEPATITIS D: LONG-TERM FOLLOW-UP DATA (AASLD 2025) - "Patients achieving a 2 log drop in HDV RNA from baseline and normal ALT at 6 months after stopping any finite lonafarnib-based treatment regimen have no major clinical events (liver decompensation, liver cancer, or death) in up to 10 years of follow up."

Hepatology • Infectious Disease • Inflammation • Liver Cancer • Liver Failure • Solid Tumor

COMPARING THE EFFICACY OF BULEVERTIDE, INTERFERONS, AND NUCLEOSIDE ANALOGS IN THE MANAGEMENT OF CHRONIC HEPATITIS DELTA: A SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS (AASLD 2025) - "Several therapies such as Lamivudine, Tenofovir, Interferons, and newer drugs like Lonafarnib, Bulevirtide have been tried with variable success. Bulevirtide in combination with Pegylated interferon alpha may be the most promising therapy for chronic Hepatitis D, while monotherapy with HBV-directed NAs are not as effective. The side effects of interferon therapy also cannot be overstated. Larger RCTs with Bulevirtide + Peginterferon alpha should be conducted."

Retrospective data • Review • Fibrosis • Hepatology • Immunology • Inflammation

The Fall of the Armor: Lamin Dysregulation and a Wide Network of Laminopathies. (PubMed, Subcell Biochem) - "Lamins have also been shown to be dysregulated in a multitude of cancers, and research has uncovered a diabolical role of lamins in oncogenesis. The understanding of laminopathies and dysregulation of lamins resulting in disorders is critical in developing novel therapeutic strategies through drug repurposing and epigenetic modulation to curb the burden of the diseases."

Journal • Review • Cardiomyopathy • Cardiovascular • Genetic Disorders • Lipodystrophy • Metabolic Disorders • Muscular Dystrophy • Oncology • LMNA • LMNB1 • LMNB2

Hepatitis Delta Virus Infection: An Overview. (PubMed, Pathogens) - "Bulevirtide is the recently available treatment against hepatitis delta. The results of efficacy studies and new drugs (lonafarnib) are under discussion. New therapeutic strategies are in development, revealing a critical need for valid next-generation treatments to cure HDV."

Journal • Review • Fibrosis • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Oncology • Solid Tumor

In Vitro synergy of Farnesyltransferase inhibitors in combination with colistin against ESKAPE bacteria. (PubMed, PLoS One) - "Tipifarnib exhibited more potent antimicrobial activity against gram-negative strains than lonafarnib...In contrast, alpha-hydroxy farnesyl phosphonic acid, an FPP analog, and bempedoic acid, targeting the mevalonate pathway, showed no antibacterial activity...This might be due to a mechanism distinct from their eukaryotic targets, potentially involving the disruption of multiple biosynthetic pathways. Future studies will focus on elucidating these mechanisms of FTIs and exploring the therapeutic potential of FTI/colistin combinations against ESKAPE and other multidrug-resistant pathogens."

Journal • Preclinical • Infectious Disease • Oncology • Pneumonia

Discovery of Tricyclic Derivative as Novel and Potent Respiratory Syncytial Virus Fusion Glycoprotein Inhibitor with an Improved Pharmacokinetic Profile. (PubMed, J Med Chem) - "Additionally, CGR-51 exhibits an improved pharmacokinetic profile and effectively suppresses RSV replication in a BALB/c mouse model of RSV infection, while showing lower toxicity compared to lonafarnib. Collectively, CGR-51 represents a promising RSV F protein inhibitor candidate for the treatment of RSV infection."

Journal • PK/PD data • Infectious Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Surgical Aortic Valve Replacement Combined With Coronary Artery Bypass Grafting in a Patient With Progeria. (PubMed, JACC Case Rep) - "Surgical aortic valve replacement may be considered among the potential treatment options for selected patients with HGPS."

Journal • Cardiovascular • Coronary Artery Disease

Updates on Recent Advancements in Hepatitis D Virus Treatment. (PubMed, Viruses) - "Meanwhile, bulevirtide, an entry inhibitor, became the first agent to be approved for use in chronic HDV infections by the European Medicines Agency (EMA), and several other therapies are currently being investigated as well. In this review, we provide updates on recent advancements in HDV treatment and novel therapies."

Journal • Review • Fibrosis • Hepatitis B • Hepatitis C • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Oncology • Solid Tumor

The Hypomethylating Agent 5-Azacitidine Potentiates the Effect of RAS and Sp1 Inhibitors in Neuroblastoma Cells. (PubMed, Acta Naturae) - "Mithramycin A and lonafarnib were the two drugs that, in combination with 5-azacitidine, appeared to exert a synergistic effect on SH-SY5Y cell death. An analysis of the signaling pathways also revealed an activation of the signaling pathways associated with neuroblastoma cell differentiation, as well as apoptosis induction, as confirmed by multiplex and confocal microscopy. Hence, by analyzing the changes in the signaling pathways, the mechanisms of cell death and cell adaptation to hypomethylating agents can be understood, and this can be further used to develop novel therapeutic approaches to neuroblastoma therapy."

Journal • Gene Therapies • Neuroblastoma • Oncology • Pediatrics • Solid Tumor

Comparative Efficacy of Treatment Regimens for Chronic Hepatitis D Virus Infection: A Systematic Review and Network Meta-Analysis. (PubMed, Liver Int) - "Bulevirtide plus PEG-IFN-alpha combination therapy was superior in achieving virological response, both in magnitude and duration, compared to bulevirtide or PEG-IFN-alpha monotherapies in patients with chronic HDV infection."

Clinical • Journal • Retrospective data • Review • Infectious Disease • Inflammation • IFNA1

National survey of Hutchinson-Gilford progeria syndrome and progeroid laminopathy in Japan. (PubMed, Aging (Albany NY)) - "This study provides updated epidemiological and clinical insights into HGPS and related laminopathies in Japan. The introduction of lonafarnib has the potential to extend survival, emphasizing the need to monitor for late-stage complications."

Journal • Cardiovascular • Genetic Disorders • Immunology • Metabolic Disorders • Muscular Dystrophy • Scleroderma • Systemic Sclerosis • LMNA

Hope on the horizon: Emerging therapies for hepatitis D. (PubMed, World J Hepatol) - "Pegylated interferon lambda acts on interferon-lambda (Type III) receptors predominantly expressed in hepatocytes. In 2023, bulevirtide was approved in the European Union and Russia for treating chronic hepatitis D. This drug works by binding to and inhibiting the sodium taurocholate co-transporting polypeptide receptor on liver cells, which is the primary entry point for the virus...Two more viral entry inhibitors are HH003 and tobevibart. Other agents include nucleic acid polymers (REP 2139-Mg), prenylation inhibitors (lonafarnib), and RNA interference-based therapies (elebsiran)...The efficacy and safety of these drugs will further be evaluated in ECLIPSE 1, 2, and 3 trials. With these new treatments on the horizon, the prospects for improved HDV patient outcomes are promising."

Journal • Review • Hepatitis B • Infectious Disease • Inflammation • IFNA1

Advances in treatment of hepatitis delta virus infection: Update on novel investigational drugs. (PubMed, World J Virol) - "Significant unmet medical needs remain in the treatment of HDV, and recent advances in drug development offer hope for meaningful advances in drug therapy which may improve virologic response rates and clinical outcomes. This review summarizes trial design and available efficacy data from key phase 2 and 3 trials for investigational therapies including entry inhibitors (bulevirtide), prenylation inhibitors (lonafarnib), novel IFNs (peginterferon lambda), RNA interference molecules (JNJ-3989, elebsiran), monoclonal antibodies (tobevibart), and nucleic acid polymers (REP2139), and addresses future directions in HDV pharmacotherapy."

Journal • Review • Fibrosis • Gastroenterology • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure • Oncology • Solid Tumor

Assessing the Efficacy of Small Molecule Drugs in Hutchinson-Gilford Progeria Syndrome: A Review of Clinical Trials. (PubMed, Rev Recent Clin Trials) - "Farnesyltransferase inhibitors (FTIs) have shown potential in mitigating disease phenotypes in preclinical models, with lonafarnib achieving FDA approval in 2020 as the first-and currently only-drug for progeria treatment. This review focuses on the clinical trial outcomes of small-molecule therapeutics for progeria, with particular emphasis on emerging small molecules from recent research. These novel compounds, with their unique mechanisms of action, hold promise not only for improving disease management but potentially offering a cure for this devastating condition."

Journal • Atherosclerosis • Cardiovascular • Congestive Heart Failure • Heart Failure • Metabolic Disorders • Myocardial Infarction • Rare Diseases • LMNA

Hepatitis D Virus Infection: Pathophysiology, Epidemiology and Treatment. Report From the Third Delta Cure Meeting 2024. (PubMed, Liver Int) - "The improved knowledge of the HDV life cycle has led to the development and approval of the first HDV-direct antiviral, Bulevirtide (BLV)...Despite recent advances in antiviral treatment, strategies to achieve HBsAg loss, which most closely resembles HDV cure, are not available and antiviral treatment for patients with advanced liver disease is limited. The third international Delta Cure meeting, held in Milan in October 2024, aimed to share the latest findings, and this review highlights key takeaways from the lectures and research on HDV."

Journal • Review • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Oncology • Solid Tumor • IFNA1 • KEAP1

Baricitinib and Lonafarnib Synergistically Target Progerin and Inflammation, Improving Lifespan and Health in Progeria Mice. (PubMed, Int J Mol Sci) - "Mechanistically, BAR decreased the SASP and inflammatory markers (e.g., IL-6 and PAI-1), complementing the progerin-targeting effects of FTI. This preclinical study demonstrates the synergistic potential of BAR + FTI therapy in addressing HGPS systemic and tissue-specific pathologies, offering a promising strategy for enhancing both lifespan and health."

Journal • Preclinical • Cataract • Fibrosis • Immunology • Inflammation • Ophthalmology • IL6

Fibronectin Extra Domain A Degradation as an Antifibrotic Approach in Lung Fibrosis (ATS 2025) - "FN-EDA half-life is ∼12 h and its turnover occurs in lysosomes. The farnesyl-transferase inhibitor lonafarnib increased lysosomal activity in primary human lung fibroblasts and reduced FN-EDA levels in vitro. Lonafarnib reversed the effects of TGFβ-induced FN-EDA up-regulation."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis • TGFB1

Clinical Trials for Hepatitis Delta Virus in the WHO African region: A neglected virus among neglected viruses. (PubMed, J Infect) - "HDV-focused CT are needed in the WHO African region, as the region with the highest disease burden, and unique genotypes (5-8); to evaluate efficacy of novel anti-HDV compounds and to ensure that new treatments can be distributed and deployed as they become available."

Journal • Review • Inflammation