For this month’s Innovation That Matters feature, we interviewed Dr. Osvaldo (Lalo) Flores, CSO of Novira Therapeutics, a leading biotech based in Philadelphia, PA, which is testing novel approaches to anti-hepatitis B (anti-HBV) drug discovery. Hepatitis B infection presents a significant unmet medical need. An estimated 350 million people worldwide are living with chronic HBV infection, and many face a higher risk of developing cirrhosis and liver cancer. Current drugs approved for the treatment of HBV can effectively suppress virus replication, but rarely lead to a cure. As an antiviral drug discovery company, Novira Therapeutics is focused on the discovery of first-in-class antiviral therapeutics for the treatment of chronic HBV and human immunodeficiency virus (HIV) infections. The company recently began a Phase 1a clinical study of NVR-1221, a small-molecule, direct-acting antiviral for treatment of HBV infection.
Novira’s NVR-1221 is one of a new class of agents that targets the viral core. Can you explain why NVR-1221 is a promising approach for treatment of HBV? How would it work as a monotherapy versus in combination with existing therapies?
Flores: The problem with current HBV therapy is that it rarely leads to cures or durable response. NVR-1221 belongs to a new class of antiviral drugs that target the viral capsid or core protein. The HBV core protein forms the protein shell called capsid that protects the viral genome. Until recently it was believed that capsid assembly was the only role of HBV core in the virus life cycle. However, it turns out that HBV core is also involved in several processes that allow the virus to persist during antiviral therapy, which include: 1) formation and maintenance of the viral mini-chromosome or cccDNA copy number in the nuclei of infected hepatocytes; 2) maintenance of the cccDNA in a transcriptionally active state; and 3) suppression of the host antiviral innate immune response.
NVR-1221 was discovered and optimized based on the ability of the drug to bind to core and disrupt capsid assembly in vitro and HBV DNA synthesis in hepatoma cell lines. However, binding of NVR-1221 to HBV core has the potential to inhibit all the other HBV core functions I mentioned, which is likely to translate in potent durable antiviral response in patients.
While we believe that NVR-1221 will be highly efficacious as monotherapy, the experience with other viral diseases such as HIV and hepatitis C virus (HCV) has taught us that cross-class combination regimes have usually proven to be more effective than monotherapy. For that reason, we plan to study NVR-1221 both alone and in combination with Interferon and a first line nucleoside in the Phase 1b trial that we are about to start.
Since this is a new class of therapeutic, what were some of the challenges in finding the lead candidate and how did you overcome those challenges?
Flores: An easy path would have been to identify and optimize proprietary leads using as starting point capsid inhibitor compounds already described in the literature. This is a common approach used by pharma scientists but one that we decided not to pursue for many reasons. Instead, our goal was to identify completely novel chemical classes of HBV core inhibitors and to do that we performed high-throughput drug screens that allowed us to identify multiple novel, attractive chemical classes of HBV core inhibitors. The challenge was then to find the right CRO partner to help us prosecute an efficient and rigorous lead optimization program that could transform screening hits into viable drug candidates. We were fortunate to partner with WuXi AppTec, who has been an outstanding partner. WuXi’s ability to provide integrated medicinal chemistry, pharmacology, DMPK, ADME and toxicology support was essential for the rapid progression of the lead program and to the selection of NVR-1221 as the clinical candidate.
Why did you pursue the clinical trial application filing in New Zealand over other locations?
Flores: Pharma and biotech companies are increasingly going to New Zealand for their first-in-man studies. New Zealand has established an efficient, independent regulatory body along with sophisticated, top-tier clinical development capabilities.
Were there any unique regulatory challenges you faced in bringing this new class of agent into clinic?
Flores: We do not expect regulatory challenges. The regulatory path for HBV drugs has been established by HBV drugs approved over the last decade, including 5 nucleos(t)ides (Nucs) and 2 interferons. Development of combination regimens with NVR-1221 and other HBV agents is expected to follow the path established for HIV and HCV, which is also helpful.
Looking at the broader antiviral R&D landscape, do you see resurgence coming? What would be the most promising areas for innovations?
Flores: Yes, I think that the HCV field has created a lot of excitement that has had a positive impact on antiviral drug development in general and on HBV in particular. It is also apparent that many players in industry and academia are beginning to shift their focus from HCV into HBV.
I think HBV drug development will become a very exciting and active area of R&D, and that core inhibitors such as NVR-1221 will become the cornerstone of future curative regimens for HBV.