LIMITED HEPATIC LAMBDA RECEPTOR DISTRIBUTION RESULTS IN FEWER IFN-ASSOCIATED ABNORMALITIES

IFN-α AND IFN-λ SIGNALS THROUGH SAME DOWNSTREAM SIGNALING PATHWAY

Hepatitis Delta is a disease with a significant impact on global health, which may affect up to 20 million people worldwide

The prevalence of HDV varies among different parts of the world. Globally, HDV infection is reported to be present in approximately 4% to 6% of chronic Hepatitis B carriers. The prevalence of HDV in patients infected with chronic HBV is even higher in certain regions, including certain parts of Mongolia, China, Russia, Central Asia, Pakistan, Turkey, Africa, Middle East, and South America, with an HDV prevalence as high as 60% being reported in HBV-infected patients in Mongolia and Pakistan.

Hdv worldwide prevalence: 15-20 million

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References: 1. Fattovich G, Boscaro S, Noventa F, et al. Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B. J Infect Dis. 1987;155(5):931-5. 2. Calle Serrano B, Grosshennig A, Heidrich B, et al. Comparing the long-term outcome of hepatitis delta and HBV monoinfection: Is HDV-infection really worse? Poster presented at: The International Liver Congress™ 2011; March 31, 2011; Berlin, Germany. 3. Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7(1):31-40.

HDV causes the most rapid liver disease progression

The Hepatitis Delta Virus expresses only one protein, the Hepatitis Delta antigen (HDAg), which comprises a nucleocapsid-like structure with the genome. There are two forms of HDAg, small and large. Together, these and the single-stranded RNA genome are surrounded by a lipid envelope, which is embedded with HBV-derived surface antigen (HBsAg) proteins. Indeed, HDV does not encode its own envelope proteins and must “steal” them from HBV. Hence natural HDV infections always occur in the presence of a co‑existing HBV infection. HBsAg is the only element of HBV relied upon by HDV; HDV replication can occur independent of HBV replication.

HDV: MOST RAPID PROGRESSION OF DISEASE

50% of HDV-Infected Patients are Cirrhotic at Diagnosis

Peginterferon lambda in HDV clinical studies

PHASE 2 LIMT-1 HDV (LAMBDA MONOTHERAPY) STUDY

LIMT-1 HDV was a 1:1 randomized, open-label study of Lambda 120 or 180 μg subcutaneous injections administered weekly for 48 weeks in 33 patients with chronic HDV. End of treatment was followed by a treatment-free 24-week observation period. The primary objective of the Phase 2 study was to evaluate the safety, tolerability, and efficacy of treatment with 2 dose levels of Lambda monotherapy in patients with chronic HDV infection. All patients were administered an anti-hepatitis B virus nucleos(t)ide analog throughout the study. LIMT-1 HDV was an international study with 4 sites in New Zealand, Israel, and Pakistan. The Phase 2 LIMT-1 HDV study has completed. For more information, go to clinicaltrials.gov. Primary Endpoint:

• Evaluate safety, tolerability, efficacy

Secondary Endpoint:

• Proportion of patients with HDV RNA BLQ 24 weeks after EOT

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In Phase 2, Peginterferon Lambda was dosed once weekly in HDV infected patients for 48 weeks with 24-week follow-up. 36% of patients who received Peginterferon Lambda achieved a Durable Virologic Response (DVR), defined as HDV RNA below limit of quantitation or undetectable at 24 weeks post-treatment. This post-treatment DVR endpoint is most meaningful for both regulatory agencies and physicians as it demonstrates durability of response to treatment and potential for an HDV cure.

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Phase 2 LIFT (Lambda Combo with Lonafarnib and Ritonavir) Study

LIFT is an open-label, Phase 2 study evaluating Lambda + Lonafarnib + Ritonavir in 26 HDV-infected patients. Patients will be dosed for 24 weeks + undergo follow up for 24 weeks. Primary endpoint will be > 2 log10 decline in HDV RNA at end of treatment. Secondary endpoints will include histology (> 2 point improvement in histological activity index and no progression in fibrosis) at end of follow up. LIFT is being conducted within the National Institutes of Health (NIH) at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). For more information, see clinicaltrials.gov

LIMT-2 Lambda Phase 3 Study

SINGLE PIVOTAL STUDY

Primary Endpoint* DVR (Arm 1) versus HDV RNA BLQ After 12 Weeks No TRx (Arm 2) DVR (Durable Virologic Response) = Below the Limit of Quantification (BLQ) at 24 Weeks Post-Treatment