A Study to Evaluate Pegylated Interferon Lambda Monotherapy in Patients With Chronic Hepatitis Delta Virus Infection

A Phase 2 Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Pegylated Interferon Lambda Monotherapy in Patients With Chronic Hepatitis Delta Virus Infection (LIMT)

To evaluate safety and tolerability of lambda over a 48-week treatment period in HDV patients.

Lambda is the pegylated form of interferon lambda-1a (IFN-λ), a conjugate of recombinant human interleukin 29 (rIL-29) and a linear polyethylene glycol (PEG) chain. IFN-λ and interferon alpha (IFN-α) share the common interferon (IFN)-stimulated gene induction pathway that leads to broad-spectrum antiviral activities. Since IFN-α has demonstrated anti-hepatitis delta virus (HDV) activity in patients with chronic hepatitis delta (CHD), it is postulated that pegylated IFN-λ could also induce HDV ribonucleic acid (RNA) decline in patients with CHD. Based on IFN-λ's more limited receptor distribution and previous data from studies involving treatment with IFN-λ in patients with hepatitis B virus (HBV) or hepatitis C virus (HCV), it is postulated that Lambda treatment could be associated with fewer adverse effects than IFN-α treatment. This Phase II study is designed as randomized, open-label study of Lambda 120 or 180 μg subcutaneous (SC) injection weekly for 48 weeks in patients with chronic HDV infection, and the primary objectives of the study are as follows:

• To evaluate the safety and tolerability of treatment with 2 dose levels of Lambda over a 48-week treatment period.
• To evaluate the effect of treatment with 2 different doses of Lambda on HDV RNA levels.

Inclusion Criteria:

• Chronic HDV infection of at least 6 months' duration documented by a positive HDV antibody (Ab) test, detectable and quantifiable HDV RNA by qPCR at study entry
• Serum alanine aminotransferase (ALT) > upper limit of the normal range (ULN) and <10 × ULN at screening
• Electrocardiogram (ECG) demonstrating no acute ischemia or clinically significant abnormality and a QT interval corrected for heart rate (QTcF) <450 ms for male patients and <460 ms for female patients
• Thyroid-stimulating hormone (TSH) and/or free T4 within 0.8 to 1.2 × ULN, or adequately controlled thyroid function as assessed by the investigator.
• Dilated retinal examination ≤1 year before screening
• Female patients of childbearing potential and male patients with partners of childbearing potential must agree to use adequate methods of contraception during the study and through 90 days after the last dose of study medication

Exclusion Criteria:

General Exclusions:

• Participation in a clinical trial with or use of any investigational agent within 30 days before screening, or treatment with interferons (IFNs) or immunomodulators within 12 months before screening
• Previous use of Lambda. Patients who previously participated in a clinical trial of Lambda but are confirmed to have received placebo or other non-Lambda IFNs are allowed.
• History or evidence of any intolerance or hypersensitivity to IFNs or other substances contained in the study medication.
• Female patients who are pregnant or breastfeeding. Male patients must confirm that their female sexual partners are not pregnant.

Exclusions Based on Disease

• Current or previous history of decompensated liver disease (Child-Pugh Class B or C)

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

• Past history or current evidence of decompensated liver disease, defined as any of the following at screening:

  1. Bilirubin level ≥ 2.5 mg/dL unless due to Gilbert's disease
  2. Serum albumin level <3.5 g/dL
  3. International normalized ratio (INR) ≥1.5
  4. Alpha fetoprotein ≥100 ng/mL

• Evidence of significant portal hypertension; current presence or history of variceal bleeding, ascites requiring diuretics or paracentesis, or hepatic encephalopathy

• Any of the following abnormal laboratory test results at screening:

  1. Platelet count <90,000 cells/mm^3
  2. White blood cell count <3,000 cells/mm^3
  3. Absolute neutrophil count <1,500 cells/mm^3
  4. Hemoglobin <11 g/dL for women and <12 g/dL for men
  5. Serum creatinine concentration ≥1.5× ULN
  6. Confirmed creatinine clearance (CrCl) < 50 mL/min by Cockcroft-Gault

• Evidence of another form of viral hepatitis or another form of liver disease

• History of hepatocellular carcinoma

• Patients with any of the following:

  1. Current eating disorder or alcohol abuse
  2. Excessive alcohol intake
  3. In the opinion of the investigator, an alcohol use pattern that will interfere with study conduct
  4. Drug abuse within the previous 6 months before screening, with the exception of cannabinoids and their derivatives

• Prior history or current evidence of any of the following:

  1. Immunologically mediated disease
  2. Retinal disorder or clinically relevant ophthalmic disorder
  3. Any malignancy within 5 years before screening
  4. Cardiomyopathy or significant ischemic cardiac or cerebrovascular disease.
  5. Chronic pulmonary disease
  6. Pancreatitis
  7. Severe or uncontrolled psychiatric disorder
  8. Active seizure disorder
  9. Bone marrow or solid organ transplantation

• Other significant medical condition that may require intervention during the study

Exclusions Based on Concurrent Medication Use

• Therapy with an immunomodulatory agent
• Use of telbivudine
• Current use of heparin or Coumadin
• Received blood products within 30 days before study randomization
• Use of hematologic growth factors within 30 days before study randomization
• Systemic antibiotics, antifungals, or antivirals for treatment of active infection other than HBV within 14 days before study randomization
• Any prescription or herbal product that is not approved by the investigator
• Long-term treatment (> 2 weeks) with agents that have a high risk for nephrotoxicity or hepatotoxicity unless it is approved by the medical monitor
• Receipt of systemic immunosuppressive therapy within 3 months before screening