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Potential new therapy for HDV shows efficacy in proof-of-concept study
Lonafarnib, a prenylation inhibitor, made its debut in The Lancet Infectious Diseases as it showed a dose-dependent reduction in chronic hepatitis delta virus RNA over 4 weeks of treatment.
“In this first-in-man, proof-of-concept study, we show that lonafarnib can decrease serum HDV levels in a dose-dependent manner during 28 days of therapy. This study has value in that it shows that an oral small molecule prenylation inhibitor can affect HDV and thereby warrants further study in a field with unmet medical needs,” the researchers wrote. “Although small in patient numbers and short in duration, this study provides evidence in human beings of a novel mechanism for potential therapeutic eradication of HDV.”
In this phase 2A, double-blind, randomized, placebo-controlled study, Christopher Koh, MD, staff clinician, Liver Diseases Virology Section, Liver Diseases Branch of the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases, and colleagues looked at the prenylation inhibitor lonafarnib (Eiger Biopharmaceuticals, Inc.).
They explained that there is currently no FDA approved therapy for HDV and experimental models have shown prenylation is necessary to the spread of HDV. The aim of the study was to assess lonafarnib’s effect on HDV RNA levels, safety and tolerability.
At the NIH Clinical Center, patients who were 18 years of age and older (median age, 38 years; 71% male) who had chronic HDV infection were randomly assigned to received either placebo, lonafarnib 100 mg (n = 6) or lonafarnib 200 mg (n = 6) twice daily for 28 days. Patients were followed for 6 months. Exclusion criteria included: other forms of liver disease, hepatocellular carcinoma, HIV co-infection, active substance abuse, contraindication to lonafarnib, other experimental therapies within 6 months and pregnancy.
Between January 19, 2012, and April 28, 2014, the 28-day results showed that HDV RNA did decline in correlation with lonafarnib serum concentrations (r2 = 0.78; P < .0001) with declines from baseline seen at all weeks of therapy. Decline in the placebo group was – 0.13 log IU/mL. In comparison, the 100-mg group decline was – 0.73 log IU/mL (95% CI, 0.17-1.31; P = .03) while the decline in the 200-mg group was – 1.54 log IU/mL (95% CI, 1.21-1.93; P < .0001).
“There was no evidence of virological resistance,” the researchers wrote.
Adverse events were described by researchers as “mild to moderate,” though 50% of patients in the 100-mg group experienced diarrhea and 33% experienced nausea while 100% of patients in the 200-mg group experienced nausea, diarrhea, abdominal bloating and weight loss greater than 2 kg. None of the patients discontinued treatments. The researchers noted that the symptoms in the 100-mg group were “indistinguishable” from those of patients in the placebo group, but those symptoms in the 200-mg group were noticeably different.
By week 4 of the post-therapy follow-up period, all patients’ HDV RNA levels returned to baseline.
“As further evidence supporting the antiviral efficacy of prenylation inhibition against HDV, two-thirds of patients in the higher dosing group had HDV virological rebound with accompanied [alanine aminotransferase] flare after stopping therapy. Although this is the first demonstration of virological rebound after stopping prenylation inhibitor therapy, the concept of HDV rebound after treatment cessation has been shown in interferon-based studies for HDV,” the researchers wrote.
In an accompanying commentary, Mario Rizzetto, MD, PhD, and Alessia Ciancio, MD, PhD, of the department of medicine at the University of Turin, Italy, gave insight into the potential of this treatment and the possible hurdles.
“Of note, no HDV mutations associated with lonafarnib non-response were detected in the study,” they wrote. “Depriving the HDV access to a crucial host function challenges the highly mutagenic HDV to develop resistance, as the relevant genetics are not under its control.”
Still, they said there is need for further research.
“In the context of the HBsAg carrier, HDV remains infectious and ready to reactivate even at very low titers. Thus … higher dosages of lonafarnib, longer therapy, or both, seem necessary to significantly diminish HDV. This however raises a problem of tolerance: with the most effective 400 mg dosage of the drug all patients had gastrointestinal symptoms … and weight loss,” they wrote. “Further studies are needed to establish the role of lonafarnib in human HDV disease; rather than using lonafarnib as a single therapy for treating hepatitis delta, this drug might prove an important partner in combined therapies with novel agents such as myrcludex B or nuclei acid polymers.” – by Katrina Altersitz
Disclosure: Koh reports no relevant financial disclosures. Please see the full study for a list of all other authors’ relevant financial disclosures. Rizzetto and Ciancio report no relevant financial disclosures.