Explaining the Hepatitis B Drug Pipeline

The Race is on to Find a Cure

Excitement and anticipation of a cure for hepatitis B is growing!

This is due, in large part, to the success of hepatitis C being curable. Today the race is now on for the growing number of hepatitis B drugs in the pipeline to become the next cure.

We all want a cure, but the hepatitis B virus (HBV) is complicated and even the definition of ‘cure’ is being debated. A ‘clinical cure’ can be defined as returning an individual with chronic HBV to the risk of serious liver disease to that of someone who has never been infected, or, at least, has had a ‘resolved’ infection. But achieving that goal would take many years of therapy, so it is not practical to use it for evaluating a drug’s effectiveness.

More realistic is a ‘functional cure,’ which declares success as causing a sustained reduction in virus and other disease markers in the blood even after a drug is stopped. In addition to suppressing or eliminating viral DNA, more ambitious goals for a functional cure call for loss of HBV surface antigen (HBsAg), appearance of HBV surface antibody (HBsAb), and silencing or eliminating cccDNA (covalently closed circular DNA), which is responsible for persistence of HBV infection even during prolonged antiviral therapy.

Suppression of these blood markers will most likely relate to, if not equal, a clinical cure and since these can be measured within years, if not months, of therapy, determining a drug’s efficacy is possible. Whether or not all virological markers need to be stably suppressed to achieve meaningful clinical goals is being debated.

Although the approved oral antivirals do a good job of suppressing viral DNA levels, none of them reliably achieve the goal of a functional cure.’ They are also limited in achieving ‘clinical cure’ as defined above. Thus, there is still a need to develop new drugs that attack different pathways of the HBV life cycle to achieve a cure.

There are now more than 30 new HBV drugs in the pipeline that are different from the currently approved therapies (interferons and nucleos(t)ides). In general, the new drugs being developed to treat HBV can be divided into two general categories: direct acting that target the virus and indirect acting that target the human host. 

With more than 30 new HBV drugs in the pipeline, there is great hope that a ‘functional’ cure, if not a ‘clinical’ or complete cure, will be achieved through one of these promising strategies. This article provides a brief overview of the new direct acting target the virus life cycle) and indirect acting (target the human host functions) drugs being pursued for hepatitis B.

NEW Direct Acting Antivirals

A greater understanding of the hepatitis B virus and proteins has
enabled efforts to develop multiple direct-acting antivirals (DAAs),
which are drugs targeted at specific steps within the HBV life cycle.

siRNA is short for “silencing” RNA, which are nucleotide drugs that interfere and cause the destruction of the viral RNA. Without viral RNA (which comes from cccDNA) there is no production of viral proteins. Thus, no RNA and no protein means no virus.

Tenofovir (TDF) Prodrugs are modified polymerase inhibitors (called ‘NUCS’) designed to get into the liver cells more easily and inhibit HBV. It is expected that TDF prodrugs will be used at lower doses with more suppression compared to current NUC drugs.

Entry Inhibitors interfere with HBV getting into liver cells via attachment to a specific viral protein called ‘preS1’ and a specific liver cell protein. Myrcludex B is the first drug that looks like preS1 and interferes with HBV attachment to the liver cell.

Capsid Inhibitors interfere with viral capsid formation, which is the protein shield that covers and protects the viral DNA. The capsid is made of pairs of HBV ‘core’ proteins or antigens, also called ‘HBcAg,’
which is needed to produce infectious virus.

sAg Inhibitors interfere with the production of HBV surface antigen (HBsAg), which is needed for the virus to enter and exit the liver cell. HBsAg is found in the blood of most infected people and is, therefore, thought to play a role in maintaining the state of chronic infection by suppressing the immune system.

cccDNA inhibitors are considered the ‘holy grail’ for a cure, but remain very challenging. The chromosome of HBV persists in the nucleus of the infected liver cell as a small cccDNA molecule, which is the natural source of all HBV gene products. It lasts for a very long time, even after NUC drugs appear to be effective in suppressing the virus.

CRISPR/cas and “TALEN” are genome editing systems, which due to their low cost and simplicity have become powerful new tools for discovery. For HBV, these systems can be used to attack and destroy the cccDNA. A problem with these systems is getting them into the infected viral cell nucleus because they are not ‘small molecule’ drugs.

 

New Indirect Acting Antivirals

The hepatitis B virus uses the human body as its host to grow, so indirect acting antiviral drugs are being developed that target host functions.

Therapeutic Vaccines use vaccine technology for treatment rather than prevention. These ‘vaccines’ are being used to stimulate immunity as a potential therapy since people living with HBV do not appear to have an effective immune response to the virus.

TLR Agonists are targeting the ‘toll-like receptors,’ which are the ‘sensors’ that detect infectious agents and tell the cell to defend itself. A TLR ‘agonist’ is a drug that activates our innate immune system, which is our body’s first line of defense against an infection.

STING is an innovative approach that shows a small molecule ‘Stimulator of Interferon Genes’ can eliminate all detectable viral gene products. This has been done in tissue culture, which was confirmed by a small animal study.

SMAC Mimetics are a new class of drugs designed to induce programmed cell death (or ‘apoptosis’). Use of this mechanism means HBV infected liver cells might be able to be pushed into apoptosis more easily than uninfected cells.

Ciclofillin Inhibitors are based on cyclophillins, a family of host cell proteins that help other proteins carry out their functions. They are also involved in the development of liver diseases such as HBV by helping the virus enter the liver cell. Inhibition of cyclophillins have been used to modify the immune system for therapeutic benefit and could be useful for HBV.

Combination is the Key

Most experts believe that a cure for HBV, functional or otherwise, will require at least two drugs. Perhaps a directing acting (DAA) will be taken with an indirect acting drug - the DAA will keep the virus suppressed while the immunomodulator ‘educates’ the immune system to recognize and take over suppression of the virus when the drugs are stopped.

Most logically, elimination of all markers, silencing cccDNA and loss of HBsAg with appearance of HBsAb, will come the closest to being a ‘cure.’ However, stable suppression of viral DNA after stopping a drug would be a big step forward, and if this is also accompanied by stable off-drug loss of HBsAg (and normalization of liver enzymes), the community would have lots to celebrate.

Although the future cannot be known, short duration of use, effective drugs that achieve at least a functional cure, and taken alone or in combination, are the goal and we are within reach of making hepatitis B history!

This article was written by Timothy M. Block, PhD, Co-Founder and President of the Hepatitis B Foundation and its Baruch S. Blumberg Institute