Curing Hep B

The success in curing hep C fuels race to cure B
by Larry Buhl

[dropcap]I[/dropcap]n 2013, a revolution happened: A drug regimen was developed that could cure, not just treat, patients with the hepatitis C virus (HCV). Since then hundreds of thousands of people have been cured of HCV.

Now the race is on to cure hep C’s more complicated and more common cousin, hepatitis B.

One of the players in the holy grail of a functional cure for hep B is a familiar name: Michael Sofia, who was behind the creation of sofosbuvir, or Sovaldi.

“We’re gunning for a cure,” Sofia told Bloomberg News last year. “With Sovaldi, we clearly brought innovation with the drug’s discovery and getting it to market. We feel we can translate that experience to hep B.”

Sofia’s new company, Arbutus, sits in a nondescript office building thirty miles north of Philadelphia. It’s called the Pennsylvania Biotechnology Center.

Adam Cutler, the Senior VP of Corporate Affairs at Arbutus, told A&U that Sofia’s success with hepatitis C is informing his approach to a hep B cure. And he said that combination therapy is the key.

“We have assembled a pipeline of several programs with different mechanisms of action. Pursuing these programs under one roof allows for preclinical and clinical evaluation of different combinations with the goal of developing combination treatment regimens that generate improved cure rates for HBV patients.”

The challenge of B
A vaccine to prevent hepatitis B infection has been around since the 1980s, but people still fall through the cracks.

Approximately 200 million worldwide are infected with the hepatitis B virus, mainly in Asia and Africa. In the U.S., an estimated 1.5 million are infected. Hepatitis B is mainly transmitted at birth, from mother to child, though it can be transmitted through sexual activity and blood.

Hepatitis B is responsible for up to eighty percent of liver cancer cases worldwide. And up to forty percent of hepatitis B patients who acquire HBV early in life are likely to develop serious complications.

Hepatitis B is more common than hep C but more difficult to treat, and a cure has remained elusive. Unlike the antiviral medications that cure hep C, antiviral regimens now available for hep B suppress the infection but don’t cure it.

Like HCV, HBV attacks the liver, but its biology is much more complex than HCV. And like HCV, HBV can leave people asymptomatic and unaware of infection for decades, all while doing great damage to the liver.

Hep C drugs like Gilead’s antiviral Sovaldi work by inhibiting an RNA polymerase that promotes viral replication. But there’s another hurdle to curing HBV. In addition to viral replication, chronic HBV infections are enabled by the production of antigens that attenuate the host immune response.

Cutler adds that HBV also has reservoirs of viral genetic material called cccDNA. The formation and recycling of cccDNA limits the efficacy of current antiviral therapies.

In effect, HBV “hides” in liver cells, and has a viral engine that keeps producing more virus all the time.

The general consensus in the research community is that a cure for HBV, while difficult to find, is possible. And Arbutus isn’t the only company aggressively pursuing a cure.

In February, a San Diego startup, Chromis Therapeutics, raised $3 million in seed financing from Torrey Pines Investment for its work in treating hepatitis B. Chromis’ antiviral mechanisms include cccDNA inhibitors, entry inhibitors and capsid assembly inhibitors. The company says it is developing small molecules that can reduce or eliminate the cccDNA from the nuclei of infected liver cells, and block reinfection mechanisms.

Earlier this year Arrowhead Pharmaceuticals offered mid-stage findings into potential efficacy for its clinical-stage hepatitis B drug ARC-520. The company showed that ARC-520 delivers RNA that blocks messenger RNA to reduce the production of hepatitis B viral proteins. Arrowhead says that using ARC-520 alongside commonly used hepatitis B drug Baraclude delivered a 99.99 percent knockdown in serum hepatitis B DNA, a measure of disease activity.

For now Arbutus appears to have a solid lead in the race to find a cure for HBV. According to the company, its lead program, ARB-1467, an RNAi therapeutic, is currently in a Phase II clinical trial in chronically infected HBV patients and initial results are expected later this year.
Cutler tells A&U that before the end of 2016, Arbutus plans to file INDs or equivalents for its core protein/capsid assembly inhibitor AB-423 and RNAi agent ARB-1740. And later this year Arbutus will begin a study of ARB-1598, the company’s TLR-9 agonist, to evaluate changes in immune biomarkers in HBV patients.

Watch this space for future developments.

Larry Buhl is a radio news reporter, screenwriter, and novelist living in Los Angeles.