Targeting Antivirals With Program for Hepatitis B

Company to Watch – Venatorx Pharmaceuticals

For more than ten years, Venatorx Pharmaceuticals has used its medicinal chemistry chops to develop a robust pipeline of novel anti-infectives that address multi-drug resistant bacterial infections — superbugs that could become the next pandemic — and hard-to-treat viral infections. On day three of this series, we focus on the company’s antiviral program targeting chronic Hepatitis B virus.

by Marie Daghlian

Hepatitis B is the most prevalent blood borne disease that infects the liver, with over 250 million people chronically infected around the world, primarily in Asia. The majority of adults infected with HBV are able to clear the virus resulting in an acute infection. Unfortunately, however, approximately 10 to 15 percent of adults become chronically infected. In the United States, the majority of infections are passed from mother to child. Children, however, are not as able to clear the virus and about 90 percent of those infected at birth will become chronically infected. Chronic infection with Hepatitis B leads to progressive liver disease including liver fibrosis, cirrhosis or liver cancer and results in approximately one million deaths globally every year.

Even though there is a safe and effective vaccine, it is unable to eradicate the virus once the infection has been established in the liver. Chronic Hepatitis B is currently managed with either direct acting antivirals that block the viral polymerase or with interferon therapy that stimulates the host’s immune response to fight off the virus. These agents slow the progression of liver disease but are not curative and generally require life-long therapy once initiated.

“After Hepatitis C was effectively cured, a mini-arms race began with several companies turning their attention towards a functional cure for Hepatitis B,” says Tony Meehan, Ph.D., chief business officer at Venatorx. “It’s a little more challenging because so far, nothing completely eliminates the viral reservoir in the liver — a problem similar to that observed for HIV infection. What’s encouraging is that 90 percent of adults can clear an acute infection. Once chronically infected, however, spontaneous resolution is very rare occurring in about one percent of patients per year.”

The need for new agents targeting Hepatitis B presented Venatorx with an opportunity to enter the antiviral field and its scientists immediately went to work. The result was the discovery of VNRX-9945, a core protein allosteric modulator (CpAM) that has been selected as a clinical candidate for the treatment of chronic HBV infection.  In the absence of a CpAM, the core protein packages the virus’ genetic information into a structure known as the nucleocapsid.  VNRX-9945 interacts with the core protein and induces the formation of empty nucleocapsids that lack the HBV genome rendering the virus non-infectious.

VNRX-9945 is a third generation, dual-mechanism inhibitor with activity that affects both nucleocapsid assembly and formation of the virus’ genomic reservoir (known as cccDNA). While proof of the first mechanism has been established in patients, the second mechanism has yet to be demonstrated clinically. VNRX-9945 demonstrates broad antiviral activity against different HBV genotypes and suppresses HBV DNA to below the lower limit of qualification in a mouse model of HBV infection.

Venatorx is one of a half dozen to a dozen companies developing novel CpAMs. The most advanced are in Phase 2 development as combination therapies. “Our current belief is that we will also combine VNRX-9945 with other agents,” says Meehan. “We think Hepatitis B will follow a path similar to Hepatitis C and HIV where the new treatment paradigm will be a combination therapy that attacks the virus at different points in the virus lifecycle.”

Venatorx’s goal is to obtain a functional cure for chronic HBV infection. It sees the discovery and advancement of highly potent CpAMs, including VNRX-9945, as representing an exciting opportunity to achieve deeper and more complete levels of antiviral suppression in chronic HBV patients that has the potential to form the basis for future combination therapies that lead to a functional cure.

Venatorx plans to initiate clinical development in the second quarter 2021, starting with a Phase 1 trial in New Zealand, and is pursuing mutually beneficial partnership and/or collaboration opportunities for VNRX-9945.


NEXT: A Conversation with Dr. Christopher Burns, founder, president, and CEO of Venatorx

This is part of the Big4Bio Company to Watch program for May 2021: Venatorx Pharmaceuticals.
For more information on the series, click here.