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Abstract:
This TWiV Special episode features Rich Condit interviewing Professor Stephan Urban at the 2024 International Hepatitis B Virus (HBV) Meeting. Professor Urban recounts his career journey, starting from an early interest in chemistry and biochemistry, leading to his involvement in HBV research during his PhD. He details the challenges of studying HBV entry due to the lack of a known receptor and suitable cell culture systems, which led him to initially use the duck HBV model. Although the duck receptor homolog wasn't the human receptor, the peptide inhibition strategy developed was successfully applied to human HBV. This resulted in the identification of highly potent peptide inhibitors targeting the HBV/HDV entry mechanism. Urban describes the lengthy process of optimizing these peptides, preclinical testing, and navigating clinical trials (Phase 1 and 2) for the drug initially called Mercludex B (now Bulevirtide), including the crucial later identification of the NTCP transporter as the receptor. Due to the high unmet medical need for Hepatitis Delta Virus (HDV), which requires HBV for propagation and lacked effective treatments, the clinical development pivoted to focus on HDV patients. Bulevirtide received conditional approval for HDV treatment. Urban discusses its mechanism, efficacy (particularly in combination with interferon for potential HDV cure), and the establishment of the Stephan Urban Foundation using proceeds from the drug's success to support science, public health, and education in underserved regions.
TWiV Special: Stephan Urban on HBV/HDV Research and Drug Development
0:00 Introduction: Rich Condit interviews Professor Stephan Urban at the 2024 International HBV Meeting in Chicago about his career in HBV and HDV research.
1:04 Early Career Path: Urban initially studied chemistry and biochemistry, driven by a deep interest since school, eventually focusing on biochemistry at the University of Tübingen.
3:04 First Contact with HBV: While a student at the Max Planck Institute for Biochemistry, Urban encountered HBV research and became fascinated with using viruses to understand host cell biology.
4:25 Postdoc & Receptor Challenge: Urban moved to Heidelberg to work with Heinz Schaller, focusing on the HBV receptor, which was unknown at the time, making cell culture studies difficult.
6:38 Duck HBV Model: To overcome challenges with human HBV, Urban's lab developed a system using primary hepatocytes from HBV-negative Pekin ducks to study the duck hepatitis B virus entry and identify its receptor.
8:54 Duck Receptor Identified, Human Homolog Fails: They successfully identified the duck HBV receptor, but cloning the human homolog proved it was not the human HBV receptor.
10:43 Human HBV Peptide Inhibitors: Urban's team adapted their peptide inhibition approach to human HBV, using primary human hepatocytes and later a susceptible cell line, identifying highly potent peptides (nanomolar range) that block HBV entry.
13:20 Therapeutic Development (Mercludex B): The potent peptides were developed as potential entry inhibitors (Mercludex B). Preclinical studies in humanized mice showed high efficacy at low doses (0.2 mg/kg).
15:11 Phase 1 Clinical Trials: Around 2011, Phase 1 trials began, involving challenges like GMP peptide production and toxicity studies with an unknown cellular target. The peptide showed liver-specific targeting (hepatotropism).
20:20 HBV/HDV Receptor Identified (NTCP): The receptor was identified by another group (later confirmed by Urban's) as NTCP, a liver-specific bile acid transporter. This helped focus safety monitoring. The existence of humans with natural NTCP knockouts without symptoms provided safety reassurance.
24:04 Pivot to Hepatitis Delta Virus (HDV): While initially targeting HBV, skepticism about entry inhibitors for chronic HBV and lack of pharma interest led to a focus on HDV. HDV requires the HBV envelope for infection, causes severe, accelerated liver disease, and had no approved treatments.
27:00 HDV Biology: Urban explains that HDV is a "parasite on a parasite," using the HBV envelope proteins to enter liver cells, making it dependent on HBV co-infection. The entry inhibitor peptide works equally well against HDV.
31:13 HDV Clinical Success & Approval: Phase 2 trials in HDV patients showed significant benefits (ALT normalization, viral load reduction). The drug (now Bulevirtide) received Orphan Drug Designation and conditional approval in Europe (2020) based on Phase 2 data and ongoing Phase 3 trials.
35:02 Bulevirtide Details: The drug is an optimized, modified peptide administered via daily subcutaneous injection. Patients generally comply due to its efficacy.
36:30 Efficacy in HBV vs. HDV: Bulevirtide prevents de novo HBV infection efficiently but is less effective as monotherapy for chronic HBV due to persistent CCC DNA.
37:07 Combination Therapy for HDV: HDV can persist via cell division. Combining Bulevirtide (blocks entry) with interferon (blocks cell-division spread) shows high rates (~46%) of sustained virological response (potential cure) for HDV, even without curing the underlying HBV.
40:34 Stephan Urban Foundation: Following the acquisition of the drug rights by Gilead, Urban used personal proceeds to establish a foundation dedicated to supporting science, public health initiatives, diagnostics, education, and access to treatment in low-resource settings, fulfilling a commitment to give back to science.