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

Hierarchical Homeostatic Failure in Hutchinson-Gilford Progeria Syndrome: From Nuclear Lesion to Systemic Decline. (PubMed, Mech Ageing Dev) - "Lonafarnib, proteostasis-directed interventions, JAK-STAT inhibition and genome-, RNA-, and progerin-directed strategies are therefore considered complementary approaches acting at distinct levels of the hierarchy. HGPS is not a replica of physiological aging, but a genetically defined system that reveals how persistent nuclear stress can progressively erode conserved adaptive networks."

Journal • Inflammation • LMNA

Protein farnesylation: from molecular mechanisms to therapeutic targeting in cancer, aging, and beyond. (PubMed, Front Pharmacol) - "The critical importance of farnesylation is highlighted in Hutchinson-Gilford progeria syndrome, where permanently farnesylated progerin disrupts nuclear architecture, and the FTI lonafarnib extends patient survival. Emerging roles-including driving K-Ras liquid-liquid phase separation and contributing to neurodegeneration and pulmonary hypertension-further broaden the pathophysiological relevance of this modification. Targeting farnesylation through dual prenylation inhibitors, PROTACs, and mevalonate pathway modulation offers promising therapeutic strategies across cancer, progeroid syndromes, and age-related diseases."

Journal • Review • Cardiovascular • CNS Disorders • Hematological Disorders • Hematological Malignancies • Hypertension • Oncology • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • Solid Tumor • KRAS

Comparative Efficacy and Safety of Emerging Therapies for Chronic Hepatitis Delta Virus Infection: A Systematic Review and Network Meta-Analysis (ACG 2026) - "A total of 18 randomized controlled trials involving 4,862 patients with chronic HDV infection were included. Overall, 3,041 patients (62.5%) were male, mean age was 46.8±9.7 years, 38.4% had compensated cirrhosis, and baseline HDV RNA averaged 6.1 log10 copies/mL. Treatment groups included Hepcludex monotherapy (n=1,248), bulevirtide plus pegylated interferon-α (n=962), lonafarnib-based regimens (n=1,031), pegylated interferon monotherapy (n=884), and placebo/standard care (n=737)."

Retrospective data • Review • Fibrosis • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis • Liver Failure

Computational Characterization of Pathogenic LMNA Missense Variants: Structural Instability, Altered Binding, and Conformational Dynamics. (PubMed, Hum Mutat) - "Variants localized within globular domains-N456D, N456T, and G465D-together with the known pathogenic variant M540T as a positive control, were selected for three-dimensional structural modeling using PyMOL and AlphaFold2, molecular docking with lonafarnib as a reference ligand via AutoDock Vina, and 100 ns molecular dynamics simulations using GROMACS with the Amber ff14SB force field...This integrated computational framework provides a systematic strategy for prioritizing pathogenic LMNA variants and characterizing their structural consequences at the atomic level. The identified variants-N456D, N456T, and G465D-represent structurally disruptive substitutions consistent with the established role of globular domain destabilization in other laminopathy-associated variants, offering testable hypotheses for experimental validation in cellular and animal models."

Journal • Cardiomyopathy • Muscular Dystrophy • LMNA

Clinical efficacy and safety of lonafarnib in children with Hutchinson-Gilford progeria syndrome (PubMed, Zhonghua Er Ke Za Zhi) - "Early gastrointestinal adverse events were mostly reversible and manageable, with no significant drug-related hepatic or renal impairment observed. Short-term follow-up showed that only low-density lipoprotein improved significantly, with no clear evidence of growth benefit, and no progressive aggravation of vascular or skeletal lesions was detected."

Journal • Allergy • Dyslipidemia • Immunology • Renal Disease

EIT Pharma Announces FDA Acceptance of New Drug Application for Lonafarnib for Treatment of Chronic Hepatitis D (PRNewswire) - "The NDA is supported by data from the Phase 3 D-LIVR study..."

FDA filing • Infectious Disease

Mathematical Modeling of HDV RNA, HBV DNA, and HBsAg Dynamics During Lonafarnib-Based Therapy: Insights from the LOWR HDV-1 Study. (PubMed, Bull Math Biol) - "LNF monotherapy led to a flat-partial-response (often followed by VB), while LNF combination therapy with ritonavir or pegylated interferon-α (PEG-IFN ) was associated with a biphasic HDV decline (without VB). The model explained the increase in serum HBV DNA by a median four-fold [interquartile range, IQR: 1-28] increase in HBV DNA production rate when HDV declined below an inhibitory threshold. The stability of serum HBsAg was explained by a constant number of HBsAg-producing cells."

Journal • Hepatitis B • Infectious Disease • Inflammation

17β-Estradiol Maintains Mitochondrial Homeostasis in Osteoblasts by Inhibiting MMP-8 and Activating the Ras Signaling Pathway in Postmenopausal Osteoporosis. (PubMed, FASEB J) - "Conversely, the adverse impacts of MMP-8 overexpression on osteoblast differentiation, mitochondrial homeostasis, and Ras activation were further aggravated by Lonafarnib treatment. 17β-estradiol maintains mitochondrial homeostasis in osteoblasts via inhibiting MMP-8 and activating the Ras pathway, which provides novel potential targets for postmenopausal osteoporosis management."

Journal • Osteoporosis • Rheumatology • BGLAP • TNFRSF11B

Biomarkers and therapies Associated with Hutchinson-Gilford Syndrome. (PubMed, Ageing Res Rev) - "Lonafarnib improves vascular outcomes and survival; however, persistent cardiovascular decline indicates residual unmet need. Emerging interventions-including mTOR modulation, senolytics, anti-inflammatory agents, metabolic support, antisense oligonucleotides, and gene-editing strategies targeting progerin production-may benefit from biomarker-guided implementation. The integration of multi-parameter biomarker panels with mechanism-based combination therapies represents a promising direction toward precision management in HGPS."

Biomarker • Journal • Review • Cardiovascular • Lipodystrophy • Metabolic Disorders • Muscular Dystrophy • Musculoskeletal Diseases • LMNA

Hepatitis D in the Middle East: A Review of Disease Burden, Health-System Barriers, and Strategic Directions for Management and Elimination. (PubMed, Cureus) - "While new therapies like bulevirtide and lonafarnib show promising virologic and biochemical results, access remains limited due to regulatory delays, costs, and fragmented care. Hence, improving routine screening for HBsAg-positive individuals, expanding access to affordable RNA testing, increasing access to approved and emerging therapies, and establishing integrated HBV-HDV management protocols are vital for reducing the disease burden. Including HDV in national elimination efforts, boosting surveillance, and enhancing workforce capacity are crucial steps to meet the WHO 2030 hepatitis goals and curb HDV's growing public health impact in the Middle East."

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

Inhibitory effect of lonafarnib on anaplastic thyroid carcinoma cell lines and a nude mouse xenograft model (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "Lonafarnib effectively suppresses the malignant progression of anaplastic thyroid carcinoma both in ATC cell lines and in a BALB/c nude mouse xenograft model. The mechanism involves inhibition of Ras farnesylation and the downstream ERK signaling pathway, leading to activation of Caspase-3/PARP-mediated apoptosis and GSDME-mediated pyroptosis."

Journal • Preclinical • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • ANXA5 • CASP3 • GSDME

Lonafarnib for Chronic Hepatitis Delta: Clinical Mechanism of Action, Development, and Evolving Role in Combination Therapy. (PubMed, Antiviral Res) - No abstract available

Journal • Review • Inflammation

Lonafarnib as finite treatment for chronic hepatitis D: Long-term effect on hard endpoints (EASL 2026) - No abstract available

Hepatology • Inflammation

Lonafarnib/ritonavir and peg-Interferon alfa drive histological improvement and inflammation resolution in chronic hepatitis D: results of the multicenter phase 3 D-LIVR study (EASL 2026) - "In patients with chronic hepatitis D, reduction of hepatic inflammation is a critical step toward histological improvement and long-term clinical benefit. LNF/RTV, a first-in-class oral CHD therapy, alone and in combination with peg-interferon alfa, significantly reduces HDV viral load and normalizes ALT, and combination treatment translates into meaningful improvements in liver histology after only 48 weeks of treatment. These findings support LNF/RTV-based regimens as disease-modifying therapies for CHD and highlight the added histological benefit of combination therapy."

Clinical • P3 data • Fibrosis • Hepatology • Inflammation

Lonafarnib/ritonavir with or without peginterferon achieves rapid, durable responses in a chronic hepatitis D: extended analyses from the phase 3 D-LIVR trial (EASL 2026) - "LNF/RTV is a first-in-class CHD therapy with efficacy and safety in patients with CHD and substantial benefit after treatment cessation. The addition of Peg further increases response rates with a favorable safety profile and rapid treatment response kinetics. LNF/RTV represents a valuable addition to the CHD therapeutic armamentarium and because it is the only drug targeting virion assembly and the only oral CHD therapeutic under development, it may represent a backbone for combination treatments."

P3 data • Hepatology • Inflammation

Lonafarnib as finite treatment for chronic hepatitis D: Long-term effect on hard endpoints (EASL 2026) - "Achieving a 2 log drop in HDV RNA from baseline and normal ALT at 6 months after stopping any finite lonafarnib-based treatment regimen is associated with long-term event-free survival (i.e. no liver decompensation, liver cancer, liver transplant, or death in up to 10 over years of follow up). Event-free survival is also improved for all LNF-treated patients."

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

Renaissance of farnesyltransferase inhibitors in cancer. (PubMed, J Transl Med) - "The "second chance" for FTIs is here but the successful clinical implementation of FTIs can only be achieved if the design of the new clinical trials do not repeat mistakes of the past: application of these drugs without predictive markers."

Journal • Review • Head and Neck Cancer • Infectious Disease • Oncology • Respiratory Syncytial Virus Infections • Solid Tumor • EGFR • HRAS • KRAS

Hutchinson-Gilford Progeria Syndrome: Genetic Insights, Clinical Challenges, and Innovative Therapeutic Approaches. (PubMed, Curr Gene Ther) - "While lonafarnib provides modest clinical benefit, long-term management of HGPS will likely depend on advances in gene editing, RNA-based therapies, and targeted pharmacological strategies to reduce progerin toxicity. Further research is needed to enhance precision and safety in gene therapies and to explore new molecular targets for broader therapeutic impact."

Journal • Cardiovascular • Gene Therapies • Genetic Disorders • LMNA

Increased Telomere Mobility in Progeria is Restored by Isoprenylcysteine Carboxyl Methyltransferase Inhibition. (PubMed, bioRxiv) - "Our results reveal that Lonafarnib partially rescues telomere dynamics, shifting chromatin motion back towards healthy control levels, and that C75 provides a complete rescue of the dynamics for all parameters quantified. These findings provide a quantitative framework for understanding how nuclear lamina mutations induce aberrant genome dynamics and the efficacy of HGPS therapies on restoring those dynamics."

Journal • Genetic Disorders

LOWR6: Once Daily Dosing of Lonafarnib Co-administered With Ritonavir for Treatment of Chronic Hepatitis D Virus Infection (clinicaltrials.gov) - P3 | N=10 | Completed | Sponsor: Soroka University Medical Center | N=30 ➔ 10 | Active, not recruiting ➔ Completed

Enrollment change • Trial completion • Infectious Disease • Inflammation

Comparative Efficacy of Bulevirtide, Interferons, and Nucleos(t)ide Analogs for Chronic Hepatitis Delta: A Systematic Review and Network Meta-Analysis. (PubMed, Int J Hepatol) - "Several new therapies are emerging, including bulevirtide and lonafarnib. Histological response (five studies, n = 183) was not statistically significant with any intervention compared with control. Bulevirtide and peginterferon alpha combination therapy may offer the most promising treatment for chronic hepatitis D. More studies are needed to assess the efficacy of this regimen and establish the optimum dose and duration of treatment."

Journal • Retrospective data • Hepatitis B • Infectious Disease • Inflammation

Pegylated Interferon Lambda and Lonafarnib Treatment (APASL 2026) - No abstract available

Hepatology

Lonafarnib as finite treatment for chronic hepatitis D: Long-term follow-up data (APASL 2026) - No abstract available

Hepatology • Inflammation

Mapping the Landscape of Hutchinson-Gilford Progeria Syndrome Research: A Bibliometric Analysis (1995-2025). (PubMed, Ageing Res Rev) - "This bibliometric survey defines the age and focus of the research into HGPS, with published research being highly concentrated and collaborative and showing possible future research directions in regenerative therapy and epigenetic control. Although the modern knowledge about the progeria condition has grown significantly, there is still a significant drawback of the psychosocial research, prolonged therapy trials, and equity in research participation globally. The results thus highlight the need for multidisciplinary and cross-country collaboration in case science on progeria and wider related research on aging keeps evolving."

Journal • Review • Cardiovascular • Gene Therapies • Rare Diseases • LMNA

Phase I/II Trial of Everolimus in Combination With Lonafarnib in Progeria (clinicaltrials.gov) - P1/2 | N=80 | Enrolling by invitation | Sponsor: Boston Children's Hospital | Trial completion date: Dec 2023 ➔ Mar 2027 | Trial primary completion date: Dec 2023 ➔ Mar 2027

Trial completion date • Trial primary completion date