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

EFFICACY AND SAFETY OF TREATMENTS FOR CHRONIC HEPATITIS D: A SYSTEMATIC REVIEW AND META-ANALYSIS OF 19 RANDOMIZED CONTROLLED TRIALS (DDW 2025) - "Objective: This meta-analysis evaluates the efficacy and safety of pharmacological treatments for chronic HDV, including Lamivudine, Peg-IFN, Ribavirin, IFN alfa-2a, Adefovir, Bulevirtide, Lonafarnib, TDF, and Entecavir... Bulevirtide with Peg-IFN is the most effective and safest treatment for chronic HDV, particularly in cirrhotic patients. TDF shows potential but requires further study in larger, long-term trials. Adverse effects from therapies like Peg-IFN and Lonafarnib emphasize the need for careful monitoring."

Retrospective data • Review • Anemia • Fatigue • Gastrointestinal Disorder • Hematological Disorders • Hepatitis B • Hepatology • Infectious Disease • Inflammation • Liver Cirrhosis • Pain

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

Mesenchymal Stem Cell Therapy for Hutchinson-Gilford Progeria: Improvements in Arterial Stiffness and Bone Mineral Density in a Single Case. (PubMed, Children (Basel)) - "MSC therapy may offer short-term benefits in arterial stiffness, bone health and inflammation in HGPS without notable safety concerns. Further studies are warranted to validate these findings, explore earlier intervention, and determine long-term efficacy and optimal dosing strategies."

Journal • Atherosclerosis • Cardiovascular • CNS Disorders • Genetic Disorders • Inflammation • Musculoskeletal Diseases • Vascular Neurology • LMNA

Combining prelamin A accumulation and oxidative stress: A strategy to target glioblastoma. (PubMed, Eur J Cell Biol) - "By inhibiting the farnesyltransferase enzyme using SCH66336 (Lonafarnib), we promote the accumulation of lamin A precursor (prelamin A) in glioblastoma cells, thereby increasing their susceptibility to oxidative stress induced by Menadione administration, while sparing normal human astrocytes...These findings indicate that inhibiting prelamin A processing could be a potential strategy to reduce glioblastoma aggressiveness and enhance therapeutic outcomes, particularly for treatment-resistant glioblastoma stem cell populations. This approach shows potential for integrating prelamin A processing disruption as a complementary strategy in glioblastoma therapy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Current and future therapeutic options for chronic hepatitis D virus infection. (PubMed, Front Cell Infect Microbiol) - "The old weapons are PegIFNα and recently PegIFN-lambda (PegIFNλ). PegIFNα, for which there are more data, appears to be an excellent combination regimen, if not contraindicated, both for Bulevirtide (BLV), data supported by important clinical trials and real-world studies, and probably for lonarfanib, although in the latter case the results are not yet definitive as the studies are fewer. However, data on long-term follow-up are needed."

Journal • Review • Hepatology • Infectious Disease • Inflammation • IFNA1

Study to Determine Optimal Dose and Evaluate Safety, Tolerability, and Pharmacokinetics of Progerinin in Patients with Hutchinson-Gilford Progeria Syndrome (HGPS) (clinicaltrials.gov) - P2 | N=16 | Recruiting | Sponsor: PRG Science & Technology Co., Ltd.

New P2 trial

Longitudinal Changes in Myocardial Deformation in Hutchinson-Gilford Progeria Syndrome. (PubMed, Circ Cardiovasc Imaging) - No abstract available

Journal • Cardiovascular

Antiviral therapy for chronic hepatitis delta: new insights from clinical trials and real-life studies. (PubMed, Gut) - "In 2020, the European Medicines Agency approved bulevirtide (BLV) at 2 mg/day, an entry inhibitor of hepatitis B virus (HBV)/hepatitis delta virus (HDV), which proved to be safe and effective as a monotherapy for up to 144 weeks in clinical trials and real-life studies, including patients with cirrhosis...The PegIFN lambda study has been discontinued due to liver toxicity issues, while lonafarnib boosted with ritonavir showed limited off-therapy efficacy in a phase 3 study. Nucleic acid polymer-based therapy is promising but large studies are still lacking. New controlled trial data come from molecules, such as monoclonal antibodies and/or small interfering RNA, that target HBsAg or HBV RNAs, which demonstrated not only profound HDV suppression, but also HBsAg decline.While waiting for new compounds to be approved as monotherapy or in combination, BLV monotherapy 2 mg/day remains the only approved therapy for CHD, at least in the European Union region."

Journal • Review • Fibrosis • Hepatitis B • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • IFNA1

Lonafarnib Protects Against Muscle Atrophy Induced by Dexamethasone. (PubMed, J Cachexia Sarcopenia Muscle) - "Lonafarnib mitigates dexamethasone-induced muscle atrophy by enhancing mitochondrial function and activating anabolic pathways. These findings support further investigation of lonafarnib as a therapeutic agent for muscle atrophy in clinical settings."

Journal • Muscular Atrophy • ANGPTL4

Repurposing of lonafarnib as a treatment for SARS-CoV-2 infection. (PubMed, JCI Insight) - "LNF at clinically relevant dose suppressed viral titer in the respiratory tract and improved pulmonary pathology and clinical parameters. Our study demonstrated that LNF, an approved oral drug with excellent human safety data, is a promising antiviral against SARS-CoV-2 that warrants further clinical assessment for treatment of COVID-19 and potentially other viral infections."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Chronic Hepatitis D Virus Infection and Its Treatment: A Narrative Review. (PubMed, Microorganisms) - "These newer antiviral therapies include buleviritide (which blocks HDV entry), lonafarnib (which prevents HDV assembly), and REP-2139 (which prevents HDV export). In this manuscript, we discuss the characteristics of HDV infection and review the new antiviral therapies approved for treatment and those under investigation."

Journal • Review • Fibrosis • Hematological Disorders • Hepatitis B • Hepatocellular Cancer • Hepatology • Immunology • Infectious Disease • Inflammation • Neutropenia • Oncology • Psychiatry • Solid Tumor • Thrombocytopenia

Circular-RNA telomerase reverses endothelial senescence (AHA 2024) - "These hallmarks of aging are substantially reversed by treatment with telomerase (hTERT) linear RNA,with greater benefit in HGPS cells than the current therapy, lonafarnib... hTERT circRNA is more effective than hTERT linear RNA in rejuvenating senescent ECs, possibly because of its longer half-life. The novel hTERT circRNA is a promising therapy for HGPS and other disorders associated with accelerated vascular aging."

Circular RNA • Cardiovascular • CDKN1A • CXCL8 • IL1B • IL6

Lonafarnib and Temozolomide in Treating Patients with Glioblastoma Multiforme That is Recurrent or Did Not Respond to Previous Treatment with Temozolomide (clinicaltrials.gov) - P1 | N=34 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial primary completion date: Dec 2025 ➔ Mar 2025

Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor

CHARACTERIZATION OF HDV RNA AND HBSAG DURING PEGYLATED INTERFERON-ALPHA AND RITONAVIR-BOOSTED LONAFARNIB COMBINATION THERAPY: THE D-LIVR STUDY (AASLD 2024) - P3 | "The MP, BP, and TP kinetic profiles were associated with reaching on treatment HDV TND. Not reaching HDV TND at EOT had a 97% NPV for sustained HDV TND. Lastly, a >1.5 log decline in HBsAg was associated with sustained HDV TND."

Combination therapy • Hepatitis B • Hepatology • Infectious Disease • Inflammation

Lonafarnib and Temozolomide in Treating Patients With Glioblastoma Multiforme That Is Recurrent or Did Not Respond to Previous Treatment With Temozolomide (clinicaltrials.gov) - P1 | N=35 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2022 ➔ Dec 2025 | Trial primary completion date: Dec 2022 ➔ Dec 2025

Trial completion date • Trial primary completion date • Brain Cancer • CNS Tumor • Glioblastoma • Gliosarcoma • Oncology • Sarcoma • Solid Tumor

EXPLORING BLOOD-BRAIN BARRIER-PENETRATING DRUGS FOR THE IDENTIFICATION OF NOVEL THERAPIES IN GLIOBLASTOMA (SIOP 2024) - " Seven drugs: Obatoclax (Mesylate), COG1410, Fingolimod, Ozanimod, Lonafarnib, BMS-202 and Bazedoxifene (acetate) were screened out as potential candidates, with consistent efficacy against glioblastoma cells, providing promising avenues for standalone therapies in GBM or as enhancers of existing conventional chemotherapy regimens. This multi-faceted approach aims to develop personalized and effective treatment strategies for the challenging landscape of glioblastoma tumors. This work was supported by FAPESP grant numbers 2022/09037-3, National Council for Scientific and Technological Development (CNPq, MCTI, Brazil) grant number 406484/2022-8 (INCT BioOncoPed)"

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Farnesyltransferase inhibitor Lonafarnib regulates cytokine production in influenza A virus infected human alveolar epithelial cells and macrophages (ISIRV-OPTIONS XII 2024) - No abstract available

Infectious Disease • Influenza • Respiratory Diseases

The NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice. (PubMed, Aging Cell) - "The combination of both drugs reduced the inflammation and senescence, extended survival and ameliorated various progeroid defects both in vitro and in vivo, compared with treatment using lonafarnib alone. These findings and the safety of dapansutrile demonstrated in several clinical trials proposes it as a possible co-adjuvant treatment with lonafarnid in HGPS."

Journal • Preclinical • Hepatology • Inflammation • NLRP3

Anesthetic Management of Cardiopulmonary Bypass in Hutchinson-Gilford Progeria Syndrome: A Case Report. (PubMed, A A Pract) - "Treatment with lonafarnib has improved survival in patients with HGPS; however, in extended longitudinal follow-up, there has been an increase in the prevalence of rapidly progressive calcific aortic stenosis. The evolving course of HGPS has prompted reconsideration of conservative management and led to the development of strategies for anatomic treatment. In this case report, we describe the anesthetic management of patients with HGPS undergoing surgical management of aortic stenosis with cardiopulmonary bypass."

Journal • Anesthesia • Atherosclerosis • Cardiovascular • CNS Disorders • Dyslipidemia • Vascular Neurology

Farnesyltransferase-inhibitors exert in vitro immunosuppressive capacity by inhibiting human B-cells. (PubMed, Front Transplant) - "The two FTI Lonafarnib and tipifarnib both suppressed TLR-9-induced B-cell proliferation. FTI suppress in vitro B-cell proliferation and plasma cell formation while partially preserving IL-10 as well as GrB production of B-cells. Thus, FTI may have immunosuppressive capacity encouraging further studies to investigate the potential immunomodulatory value of this agent."

Journal • Preclinical • Antibody-mediated Rejection • Nephrology • Oncology • Transplantation • GZMB • IL10 • TLR9

Targeting the RAS upstream and downstream signaling pathway for Cancer treatment. (PubMed, Eur J Pharmacol) - "For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation...Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins...Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins..."

Journal • Review • Breast Cancer • Colorectal Cancer • Endocrine Cancer • Hematological Disorders • Hematological Malignancies • Lung Cancer • Lymphoma • Multiple Myeloma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF • PIK3CA • PTEN

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein. (PubMed, Signal Transduct Target Ther) - "Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection."

Journal • Infectious Disease • Pneumonia • Pulmonary Disease • Respiratory Diseases • Respiratory Syncytial Virus Infections

Modeling dual antiviral activity of lonafarnib to explain hepatitis D virus RNA negativity 24 weeks after end of therapy despite RNA positivity at end of therapy: The D-LIVR study (EASL-ILC 2024) - P3 | "We identified 2 patients in the Phase 3 D-LIVR study who had detectable HDV RNA at the end of therapy (EOT) with lonafarnib (LNF)+ritonavir for 48 weeks and became HDV RNA negative at the end of 24-week follow up (EOFU). This new HDV model can explain why patients, despite having detectable HDV RNA by EOT, subsequently achieved negative HDV RNA status during follow-up. Further research is needed to validate the existence of V i and V ni dynamics in LNF-treated patients to be able to test and refine our theoretical efforts in understanding LNF antiviral mode of action."

Hepatology • Inflammation

Precision-cut liver slices as a pre-clinical model for the evaluation of host-targeting agents against hepatitis B virus and hepatitis delta virus infection (EASL-ILC 2024) - "The impact of HTAs targeting hepatocytes (i.e. Bulevirtide – 1 µM), non-parenchymal immune cells (i.e. Selgantolimod – 1 µM) or multiple populations (i.e. Lonafarnib – 2 µM) was evaluated by the quantification of viral parameters and the production of inflammatory cytokines. Our results represent the first characterization of PCLS as a relevant ex vivo study model of HBV/HDV co-infection. Moreover, the evaluation of HTAs directed against parenchymal and non- parenchymal hepatic cell populations highlights the potential relevance of this system for the pre-clinical study of novel molecules aimed to achieve HBV/HDV cure."

Preclinical • Hepatitis B • Hepatology • Infectious Disease • Inflammation • IL6

Peginterferon Lambda and Lonafarnib Boosted With Ritonavir 48-Week Combination Therapy for Delta Hepatitis (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | N=30 ➔ 0 | Trial completion date: Oct 2028 ➔ May 2024 | Not yet recruiting ➔ Withdrawn | Trial primary completion date: Oct 2027 ➔ May 2024

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal • Hepatology • Inflammation