A phase 2, open-label study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic activity of titrating-dose lonafarnib/ritonavir in patients chronically infected with hepatitis delta virus (HDV)

This is a Phase 2 study of 24 weeks of treatment with a dose-titration regimen of lonafarnib/ritonavir in up to 15 patients chronically infected with HDV: lonafarnib starting at 50 mg twice daily (BID) in combination with ritonavir 100 mg BID and escalating lonafarnib as tolerated.

The duration of the study for each patient is approximately 13 months (up to 4 weeks for screening, 24 weeks of treatment, 4 weeks for the primary follow-up visit, and monthly safety follow-up visits for 5 months thereafter). The 6-month follow-up after the last dose of study drug is designed to allow evaluation of the clinical and virologic course after completion of the 24-week Treatment Period.

Key Inclusion Criteria:

1. Male or female, 18 to 65 years of age, inclusive
2. Chronic HDV infection documented by a positive HDV antibody (Ab) test of at least 6 months duration and detectable HDV ribonucleic acid (RNA) by quantitative polymerase chain reaction (qPCR) at study entry
3. Liver biopsy demonstrating evidence of chronic hepatitis
4. Willingness to practice appropriate contraception

Key Exclusion Criteria:

1. Previous use of lonafarnib

2. Co-infected with human immunodeficiency virus (HIV) or hepatitis C virus (HCV)

3. Active jaundice defined by total bilirubin level >2.0 mg/dL and known not to have Gilbert's disease

4. Decompensated liver disease or cirrhosis, history of bleeding esophageal varices, ascites, or hepatic encephalopathy

5. Serum creatinine concentration ≥1.5 times upper limit of normal (ULN)

6. Evidence of another form of viral hepatitis (not including hepatitis B virus or HCV) or another form of liver disease

7. Evidence of hepatocellular carcinoma

8. Use of alfa interferon, either interferon alfa-2a or interferon alfa-2b, or peginterferon alfa-2a within 2 months before the start of screening

9. Concomitant use of any of the following:

   1. Medications or foods that are known moderate or strong inducers or inhibitors of CYP3A4 or CYP2C19
   2. Drugs known to prolong the PR interval or QT interval of the electrocardiogram
   3. Receipt of systemic immunosuppressive therapy within the 3 months before start of screening
   4. Statins, due to inhibition of mevalonate synthesis, which reduces protein prenylation
   5. Medications contraindicated in the prescribing information for ritonavir

6 months on treatment, 6 months off-treatment follow-up.