A Phase 2 Study of Peginterferon Lambda, Lonafarnib and Ritonavir for 24 Weeks: End-of-Treatment Results from the LIFT HDV Study

Koh, Christopher; Hercun, Julian; Rahman, Farial Naima; Huang, Amy; Da, Ben L.; Surana, Pallavi; Kapuria, Devika; Rotman, Yaron; Vittal, Anusha; Gilman, Christy; Yakov, Gil Ben; Lai, Walter; Dahari, Harel; Glenn, Jeffrey S.; Heller, Theo

doi:10.1016/s0168-8278(20)30774-1

Cited by 45 publications

(45 citation statements)

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“…Triple combination therapy with lonafarnib 50 and ritonavir 100 mg twice daily plus peginterferon lambda-1a 180 μg weekly for 24 weeks demonstrated antiviral efficacy in patients with chronic HDV infection participating in a phase 2a, open-label, first-in-humans LIFT HDV study (NCT03600714; n = 26) [ 20 , 21 ]. Twenty-two of 26 patients completed 24 weeks of treatment [ 21 ].…”

Section: Scientific Summarymentioning

confidence: 99%

Lonafarnib: First Approval

Dhillon

2021

Drugs

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Lonafarnib (Zokinvy™) is an orally active farnesyltransferase inhibitor developed by Eiger BioPharmaceuticals under license from Merck & Co. for the treatment of hepatitis D virus (HDV) infections, and progeria and progeroid laminopathies. The drug was originally discovered by Merck & Co as an investigational drug in oncology. In progeria, lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the nucleus and cellular cytoskeleton. In November 2020, lonafarnib received its first approval in the USA to reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS) and for the treatment of processing-deficient progeroid laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation, or homozygous or compound heterozygous ZMPSTE24 mutations) in patients ≥ 12 months of age with a body surface area (BSA) of ≥ 0.39 m 2 . Lonafarnib is under regulatory review in the European Union. Clinical development for the treatment of HDV infections is underway in multiple countries. This article summarizes the milestones in the development of lonafarnib leading to this first approval.

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Section: Scientific Summarymentioning

confidence: 99%

Lonafarnib: First Approval

Dhillon

2021

Drugs

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“…A combination of IFN and these inhibitors is predicted to provide better antiviral activity by targeting both HDV-spreading pathways. This hypothesis is supported by recent clinical studies demonstrating strong synergistic antiviral effects with a combination of pegylated IFN-α and Hepcludex/Lonafarnib [ 158 , 159 , 160 , 161 ]. To verify the effect of this combination treatment in vitro, we recently generated a model supporting both spreading pathways using HuH7-NTCP cells stably expressing HBV envelope proteins.…”

Section: Ifn Response During Hdv Infectionmentioning

confidence: 65%

Interplay between Hepatitis D Virus and the Interferon Response

Zhang

Urban

2020

Viruses

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Chronic hepatitis D (CHD) is the most severe form of viral hepatitis, with rapid progression of liver-related diseases and high rates of development of hepatocellular carcinoma. The causative agent, hepatitis D virus (HDV), contains a small (approximately 1.7 kb) highly self-pairing single-strand circular RNA genome that assembles with the HDV antigen to form a ribonucleoprotein (RNP) complex. HDV depends on hepatitis B virus (HBV) envelope proteins for envelopment and de novo hepatocyte entry; however, its intracellular RNA replication is autonomous. In addition, HDV can amplify HBV independently through cell division. Cellular innate immune responses, mainly interferon (IFN) response, are crucial for controlling invading viruses, while viruses counteract these responses to favor their propagation. In contrast to HBV, HDV activates profound IFN response through the melanoma differentiation antigen 5 (MDA5) pathway. This cellular response efficiently suppresses cell-division-mediated HDV spread and, to some extent, early stages of HDV de novo infection, but only marginally impairs RNA replication in resting hepatocytes. In this review, we summarize the current knowledge on HDV structure, replication, and persistence and subsequently focus on the interplay between HDV and IFN response, including IFN activation, sensing, antiviral effects, and viral countermeasures. Finally, we discuss crosstalk with HBV.

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“…The LOWR-HDV-4 [ 127 ] study is a dose-escalation study performed to investigate whether a rapid stepwise increase in the lonafarnib dosage from 50 mg to 100 mg BID (associated with ritonavir 100 mg BID fixed dosage and HBV nucleo(s)tide analogue) might increase the number of patients achieving higher lonafarnib doses [ 129 ]. If well tolerated, lonafarnib was increased to 75 mg BID after at least 4 weeks, and then to 100 mg BID after at least 2 weeks from the previous escalation [ 125 ].…”

Section: Therapeutic Attempts For Hdv-chmentioning

confidence: 99%

“…An open-label Phase 2a study was performed to evaluate the safety and the antiviral effect of lonafarnib/RTV + peg-IFN lambda-1a given for 24 weeks to 26 HDV-CH patients [ 129 ]. At the end of treatment, the median HDV RNA decline from baseline was −3.4 log10 ( p < 0.0001), with 7 patients become HDV RNA negative and 3 with serum HDV RNA not quantifiable.…”

Section: Therapeutic Attempts For Hdv-chmentioning

confidence: 99%

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HBV/HDV Co-Infection: Epidemiological and Clinical Changes, Recent Knowledge and Future Challenges

Sagnelli

Russo

et al. 2021

Life

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Several investigations have been published on Hepatitis Delta Virus (HDV) infection in recent years, from which we have drawn the salient data to provide readers with useful information to improve their knowledge on the subject. HDV genotypes 5–8 have been recently imported to Western countries from central Africa, whose clinical relevance deserves further investigation. Ongoing HDV replication has been identified as an independent predictor of progression to cirrhosis and HCC for patients with HDV chronic hepatitis (HDV-CH). Long-term treatments of HDV-CH with standard or pegylated interferon alfa (peg-IFN-α) have all been unsatisfactory, leading to a sustained virological response (SVR) only in 20–30% of patients treated, faced with a poor tolerability and frequent serious adverse reactions; the addition of HBV nucleo(s)tide analogues to peg-IFN- α did not improve the rate of SVR. The improved knowledge of the HDV life cycle has allowed the development of direct acting agents towards key-points of the HDV life cycle, namely bulevirtide, lonafarnib and nucleic acid polymers. Preliminary data have shown that these drugs are more effective than interferon-based therapies, but adverse reactions are also common, which however seem toned down in combination therapy with other antivirals.

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A Phase 2 Study of Peginterferon Lambda, Lonafarnib and Ritonavir for 24 Weeks: End-of-Treatment Results from the LIFT HDV Study

Cited by 45 publications

References 0 publications

Lonafarnib: First Approval

Lonafarnib: First Approval

Interplay between Hepatitis D Virus and the Interferon Response

HBV/HDV Co-Infection: Epidemiological and Clinical Changes, Recent Knowledge and Future Challenges

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