title: Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.
abstract: BACKGROUND
  Therapies for chronic hepatitis delta virus (HDV) infection are unsatisfactory. Prenylation is essential for HDV and inhibition abrogates HDV production in experimental models. In a proof-of-concept study, we aimed to assess the effect on HDV RNA levels, safety, and tolerability of the prenylation inhibitor lonafarnib in patients with chronic delta hepatitis.
  
  
  METHODS
  In this phase 2A double-blind, randomised, placebo-controlled study, patients aged 18 years or older with chronic HDV infection were randomly assigned (3:1 in group 1 and 2:1 in group 2) to receive lonafarnib 100 mg (group 1) or lonafarnib 200 mg (group 2) twice daily for 28 days with 6 months' follow-up. Participants were randomised by random-number tables blocked in groups of four without stratification. Both groups enrolled six treatment participants and two placebo participants. Group 1 placebo patients received open-label lonafarnib as group 2 participants. The primary therapeutic endpoint was a decrease in HDV RNA viral titre in serum and the primary safety endpoint was the ability to tolerate the drug at the prescribed dose for the full 4-week duration, defined as drug discontinuation due to intolerance or grade 3/4 adverse events. This trial is registered with ClinicalTrials.gov, number NCT01495585.
  
  
  RESULTS
  Between Jan 19, 2012, and April 28, 2014, 14 patients were enrolled, of whom eight were assigned to group 1 and six were assigned to group 2. At day 28, compared with placebo, mean log HDV RNA declines from baseline were -0·73 log IU/mL in group 1 (95% CI 0·17-1·31; p=0·03) and -1·54 log IU/mL in group 2 (1·21-1·93; p<0·0001). Lonafarnib serum concentrations correlated with HDV RNA change (r(2)=0·78, p<0·0001). Model fits show that hepatitis B surface antigen (HBsAg) remained stable after a short pharmacological delay (0·75 days [SE 0·24]), lonafarnib effectiveness in blocking HDV production was greater in group 2 than in group 1 (0·952 [SE 0·06] vs 0·739 [0·05], p<0·001), and the HDV half-life was 1·62 days (0·07). There was no evidence of virological resistance. Adverse events were mainly mild to moderate with group 1 patients experiencing diarrhoea in three patients (50%) and nausea in two patients (33%) and in group 2 with all patients (100%) experiencing nausea, diarrhoea, abdominal bloating, and weight loss greater than 2 kg (mean of 4 kg). No treatment discontinuations occurred in any treatment groups.
  
  
  CONCLUSIONS
  Treatment of chronic HDV with lonafarnib significantly reduces virus levels. The decline in virus levels significantly correlated with serum drug levels, providing further evidence for the efficacy of prenylation inhibition in chronic HDV.
  
  
  BACKGROUND
  National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute, National Institutes of Health, and Eiger Biopharmaceuticals Inc.
authors.affiliation: Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: Christopher.Koh@nih.gov.
authors.forename: Christopher
authors.initials: C
authors.lastname: Koh
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Canini
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA; Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM, USA.
authors.forename: Harel
authors.initials: H
authors.lastname: Dahari
authors.affiliation: Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Xiongce
authors.initials: X
authors.lastname: Zhao
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Uprichard
authors.affiliation: Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Haynes-Williams
authors.affiliation: Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & Immunology, Stanford School of Medicine, Stanford, CA, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Winters
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Gitanjali
authors.initials: G
authors.lastname: Subramanya
authors.affiliation: Division of Hepatology, California Pacific Medical Center, San Francisco, CA, USA.
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Cooper
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Pinto
authors.affiliation: Unit on Reproductive and Regenerative Medicine, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Erin F
authors.initials: EF
authors.lastname: Wolff
authors.affiliation: Consult Services Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Bishop
authors.affiliation: Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ma
authors.initials: M
authors.lastname: Ai Thanda Han
authors.affiliation: The Program for Experimental & Theoretical Modeling, Division of Hepatology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cotler
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Onur
authors.initials: O
authors.lastname: Keskin
authors.affiliation: Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Ramazan
authors.initials: R
authors.lastname: Idilman
authors.affiliation: Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Cihan
authors.initials: C
authors.lastname: Yurdaydin
authors.affiliation: Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & Immunology, Stanford School of Medicine, Stanford, CA, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Glenn
authors.affiliation: Translational Hepatology Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: TheoH@intra.niddk.nih.gov.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D004311:Double-Blind Method; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D019701:Hepatitis D, Chronic / Q000188:drug therapy*; D003698:Hepatitis Delta Virus / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D010919:Placebos / Q000008:administration & dosage; D010949:Plasma / Q000737:chemistry; D054876:Prenylation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D012367:RNA, Viral / Q000097:blood; D016896:Treatment Outcome; D019562:Viral Load; D003986:Dibenzocycloheptenes
chemical_list: D000998:Antiviral Agents; D010880:Piperidines; D010919:Placebos; D011725:Pyridines; D012367:RNA, Viral; C115354:lonafarnib; D003986:Dibenzocycloheptenes