By Christine Kukka
For more than 25 years, Timothy Block, Ph.D,, has worked tirelessly to find a cure for hepatitis B, promoting research, writing papers, mentoring students and collaborating with experts around the world to find a cure for the 240 million people living with this deadly liver disease.
Today, the cofounder and president of the Hepatitis B Foundation, the Baruch S. Blumberg Institute and the Pennsylvania Biotechnology Center, is optimistic and believes there are new therapies in sight for those living with chronic hepatitis B.
An unprecedented number of researchers are scrutinizing every stage of the hepatitis B virus (HBV) replication cycle to find its vulnerabilities and develop drugs to permanently disable it. The cure Block wants would completely eradicate the infection so no one would ever wake up worrying about the risk of liver damage or cancer to themselves or a loved one.
This global, active march towards a cure is in stark contrast to 1991 when Block began his solitary quest, after a friend’s devastating hepatitis B infection made him rethink his career and start focusing on the liver disease that infects more than one in three people worldwide.
Twenty-five years ago, the only available treatment was conventional interferon, which was largely ineffective. The first antiviral, lamivudine, appeared shortly thereafter. It would be one of several to emerge from HIV’s drug arsenal. Since then, more antivirals designed to disrupt HBV’s replication process have been developed that target the polymerase—the essential enzyme needed for HBV replication.
“But they are not cures,” Block explained during a recent webinar. “They’re good at reducing viral load (HBV DNA), but they don’t get rid of the virus, and considerable viral DNA and hepatitis B surface antigen (HBsAg) remain in liver cells.” Nor do current antivirals get rid of the HBV chromosome called cccDNA that embed in liver cells and stubbornly remain, ready to churn out more virus if a person stops taking antiviral drugs, or if their immune system weakens due to advancing age or another illness.
There are other roadblocks that make hepatitis B far harder to cure than hepatitis C. HBV generates massive amounts of HBsAg that appear to overwhelm the immune system’s B cells, whose job is to produce antibodies to eradicate HBV’s antigens. When newborns or young children are infected, these B-cells become paralyzed or “exhausted” by the flood of HBsAg engulfing them and they don’t generate the antibodies needed to fight infection. In contrast, when healthy adults are infected, these B-cells act quickly and aggressively to eradicate HBsAg within six months.
“Now for the first time, we’re looking beyond the polymerase to find more targets that are essential for HBV replication,” Block explained. HIV researchers have already done this and have identified more than 30 different “targets” in the HIV replication process. Hepatitis B researchers are also expanding their target range.
There are now new drugs in development, some have even reached Phase II clinical trials, that target new HBV reproductive terrain. They employ a variety of strategies ranging from immune system enhancers to molecular weapons designed to halt cccDNA integration into liver cells.
“If you can suppress cccDNA, the game would be over,” Block said, “but cccDNA is small, tough target. It’s so small compared to other material, that it’s almost impossible to distinguish from other molecules.” However, biologicals that are able to “inhibit” or block cccDNA from entering a liver cell could stop the virus from hijacking and reproducing in liver cells. Here are some types of drug strategies currently in development that could lead to a cure:
Restructured versions of tenofovir: There are two new tenofovir “prodrug” compounds, called TAF and CMX 157, that are more effective at reaching liver cells and impeding HBV replication. TAF is now in Phase III clinical trials and is expected to reach the U.S. Food and Drug Administration (FDA) this month (November 2016).
Molecular agents that target and disable HBV replication:
- A new agent, called the CRISPR/Cas9 system, may be able to operate on a molecular level to search out and destroy HBV cccDNA molecules.
- One of the more advanced molecular strategies, already in Phase II trials, is a “silencing” RNA process. This approach uses RNAi gene silencers to target and destroy HBV RNA to prevent viral reproduction. “CccDNA remains,” Block explained, “but all of its gene products it needs are choked.”
Entry inhibitors: Some of these drugs resemble HBsAg, but they work as decoys to prevent the virus from entering or binding to the liver cell. One is in Phase II clinical trial.
Capsid inhibitors: This approach interferes with the viral DNA’s ability to connect or glue together during the replication process. Several of these drugs are in Phase II clinical trials.
HBsAg inhibition and eradication: “There are 1 million more HBsAg as the actual virus,” Block observed. “Why are there so many? What is it doing in the blood? Why is it able to exhaust our B-cells?” Because HBsAg appears to hold a key in stopping infection, researchers are working to develop a way to eradicate HBsAg. Two of these HBsAg eradicator products are in Phase II trials.
Adaptive and innate host defense: This approach involves a two-step strategy, first reducing viral load to undetectable levels by helping liver cells become “in-hospitable” hosts to HBV’s reproductive efforts, and then introducing a vaccine or some other immune enhancer that can break the B-cell exhaustion cycle while firing up immune cells to aggressively fight and eradicate the infection. There are several of these drugs in Phase I and II clinical trials.
Block told his webinar audience that ideally one of these drugs would emerge as a single, simple cure. “But every infectious disease today, such as hepatitis C and HIV, is almost always treated with a combination of drugs. We might see two direct-acting antivirals and maybe a third drug that work as an immune system activator.”
When asked which patients would get first access to a new cure, Block predicted that people with high viral loads and liver damage would be treated first based on medical need. “As drugs get safer, I hope we will treat people in the immune tolerant phase (with high viral load but no signs of liver damage yet), before they begin to have signs of liver damage.”
- To view this webinar, click Current and Future HBV Treatment and Research Towards Finding a Cure at the sponsor Hep B United’s website.
- The next webinar in this series, Why Clinical Trials for Hepatitis B Therapies Are So Important, is scheduled for 3 p.m. EST (12 p.m. PST) Wednesday, Nov. 30, 2016. To register, click here.
- To see a complete list of hepatitis B drugs in development, along with their developer’s information and clinical trial status, please visit the Hepatitis B Foundation’s Drug Watch page.