Study of the Efficacy and Safety of Lonafarnib / Ritonavir With and Without Pegylated Interferon -Alfa-2a

This partially double-blind, randomized study will employ a matrix (factorial) design to evaluate the efficacy and safety of LNF 50 mg/RTV 100 mg twice per day (BID) with and without PEG IFN-alfa-2a 180 mcg once-weekly (QW) for 48 weeks compared to no treatment (placebo LNF and placebo RTV) in patients chronically infected with hepatitis delta virus (HDV) and receiving anti-HBV (hepatitis B virus) nucleos(t)ide maintenance therapy.

Approximately 400 patients will be randomized with an allocation ratio of 7:5:2:2 All patients will receive/maintain background anti-HBV nucleos(t)ide therapy with entecavir or tenofovir for at least 12 weeks prior to initiating study therapy.

All patients who complete 48 weeks of treatment will have a liver biopsy for histology assessment at EOT and will be followed for an additional 24 weeks off study treatment.

Inclusion criteria

• Chronic HDV infection for at least 6 months in duration, documented by a positive HDV antibody test and HDV RNA ≥ 500 IU/mL.

Note: All genotypes of HDV permitted.

• Demonstrable suppression of HBV DNA following at least 12 weeks of anti-HBV nucleos(t)ide treatment with entecavir or tenofovir prior to initiating therapy.
• Serum ALT > 1.3 x upper limit of the normal range (ULN) and < 10 x ULN.
• Baseline liver biopsy demonstrating evidence of chronic hepatitis.
• ECGs demonstrating no acute ischemia or clinically significant abnormality.
• Normal dilated retinal examination.

Exclusion criteria

General Exclusions

• Previous use of LNF within 12 months.
• Current or previous history of decompensated liver disease.
• Co-infected with human immunodeficiency virus or hepatitis C virus (HCV) by detectable HIV RNA and HCV RNA, respectively.
• Evidence of significant portal hypertension.
• Current evidence or history of ascites requiring diuretics or paracentesis, or hepatic encephalopathy.
• History of hepatocellular carcinoma.
• Patients with any of the following:

• Current eating disorder
• Evidence of alcohol substance use disorder.
• Drug abuse within the previous 6 months before screening.
• Prior history or current evidence of any of the following:

• Immunologically mediated disease,
• Retinal disorder or clinically relevant ophthalmic disorder,
• Any malignancy within 5 years before screening,
• Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease,
• Chronic pulmonary disease,
• Pancreatitis or colitis,
• Severe or uncontrolled psychiatric disorder.
• Other significant medical condition that may require intervention during the study.
• Any condition that may impact proper absorption.
• Therapy with an immunomodulatory agent, IFN-α (eg, IFN alfa-2a or IFN-alfa-2b, or pegylated IFN-alfa-2a or alfa 2b), cytotoxic agent, or chronic systemic corticosteroids within 12 months of screening.
• Use of heparin or warfarin.
• Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than HBV.
• Receipt of systemic immunosuppressive therapy.
• History or evidence for any intolerance or hypersensitivity to LNF, RTV, PEG IFN-alfa-2a, tenofovir or entecavir.