Current therapies need improvement as they do not deliver a functional cure, said Dr Pietro Lampertico, head, Gastroenterology and Hepatology Division, Milan University, Italy. Asia claims the majority of the HBV market ($500m in 2017), followed by the EU ($300m) and US ($200m).

Although drugs in development called capsid inhibitors or modulators can stop HBV inhibition, there are too many in development and their clinical data is too early to definitively name a frontrunner. Capsid inhibitor/modulators under investigation include Assembly Biosciences’Phase I/II ABI-H0731, Johnson & Johnson’s Phase II JNJ-379 (formerly JNJ-56136379) and Phase I NVR3-778, Arbutus Biopharma’s Phase I AB-423 and preclinical AB-506 and Roche’s Phase I RG7907.

Meanwhile, Spring Bank Pharmaceuticals’ Phase II inarigivir (formerly SB9200) immunomodulator shows early promise as a pegylated interferon alternative without the side-effect burden. A potential HBV therapy wildcard is Replicor’s REP2139, which has a unique mechanism trapping surface antigen (HBsAg) inside the cell, with significant early data in reducing HBsAg, but there is doubt over potential side effects due to the mechanism not yet being fully understood.

Combo needed for functional cure a reality

Most patients take nucleoside/nucleotide analogues (NUCs) like Bristol-Myers Squibb’s Baraclude (entecavir) and Gilead Sciences’ Viread (tenofovir), as they reduce HBV complications and improve survival rates, Lampertico noted. Yet, they require long-term, even life-long, use, added Lampertico and Dr Man-Fung Yuen, division chief, Gastroenterology and Hepatology, University of Hong Kong.

Only a few patients – around 10% – take immunomodulator peg-interferon due to its poor side-effect profile, which includes flu-like symptoms and fatigue, both experts noted, speaking on the sidelines of April’s EASL International Liver Congress in Paris.

The current challenge is to shorten HBV treatment but this could only happen via a combination approach, noted Lampertico and Stephen Locarnini, divisional head, Molecular Research and Development, Doherty Institute, Melbourne, Australia. One such combo would be capsid inhibitor/modulators stopping HBV replication, RNA interference (RNAi)-based therapies blocking HBsAg production and finally immunomodulators boosting immune system efficacy, Lampertico said. One example of RNAi-based therapy is Arbutus’ Phase II ARB-1467.

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But Locarnini noted NUCs are likely to still be a part of combo therapy. Chronic HBV is associated with immune system flares, which causes cell damage, he said. In some trials where NUCs dose was low, unexpected flares would occur, showing NUCs’ importance, he added.

With that in mind, capsid inhibition/modulation is currently the most popular mechanism being investigated for HBV with at least five compounds investigated by different companies, said Dr Patrick Kennedy, hepatologist, Barts and the London School of Medicine and Dentistry.

This mechanism may provide a clear path to reducing HBsAg, which is the likely primary endpoint needed for approval, said Locarnini. Targeting the capsid would stop HBV replication by interfering with HBV RNA, which would have an impact on HBsAg production, Lampertico explained.

Capsid inhibition/modulation also seems to be potent in inducing viral DNA reduction, which is not observed with NUCs, Yuen added. Capsid inhibitors/modulators having a viral target may lead to a positive safety profile, said Lampertico and Yuen.

However, with at least five capsid inhibitors/modulators under investigation, this makes it a crowded field, Locarnini said. Companies may differentiate their compounds by highlighting different inhibitor/modulator classes, but they all still target the capsid, Lampertico said.

As any available data is only from early stage trials, it is hard to differentiate capsid inhibitors/modulators, Lampertico added. The longest data collection has so far been 28 days and longer follow-up is needed, Yuen added. Although they all show promising animal model data, this may not translate to humans as seen with TLR agonists, which showed positive efficacy in woodchucks but failed in human trials, Kennedy noted.

Nonetheless, Locarnini said capsid inhibitors/modulators may not provide a central role in HBV therapy in the long term as they may not be ideal as the backbone for a functional cure. Whilst they may be able to deliver enough HBsAg loss for approval, capsid inhibitors may lack overall potency to turn off many viral covalently closed circular DNA or allow host immune system to recover to clear the virus, he said.

New immunomodulator shows promise

On the other hand, Spring Bank’s inarigivir may provide a promising alternative to peg-interferon, as it is an immunomodulator without associated side effects, Locarnini said. Inarigivir can help reach functional cure as immunological enhancement is needed, said Locarnini, an investigator in the virology aspect of the inargivir Phase II trial.

Inarigivir is an RIG I agonist that activates innate and adaptive immunity plus has an antiviral effect via inhibition of encapsidation of pgRNA and HBV DNA polymerase, which is a unique approach, Yuen added.

Data from the first two Phase II cohorts presented at EASL is promising for more positive data, as it shows HBV DNA and RNA reduction, noted Yuen, a trial investigator.Of note, after 12 weeks of inarigivir monotherapy, patients were switched to tenofovir for another 12 weeks, where HBsAg levels kept on decreasing, Yuen noted. Tenofovir by itself typically does not reduce HBsAg, Yuen noted.

But Lampertico said inarigivir’s data is still preliminary to peg hopes on potentially replacing peg-interferon. Spring Bank did not respond to a request for comment.

Finally, delivering a unique approach in reducing HBsAg is Replicor’s REP2139, as it reduces detectable HBsAg by preventing it to burst out of infected cells, said Lampertico. HBsAg absence in the blood could help reactivate the immune system for a functional cure with the addition of NUCs and peg-interferon, he added.

Its early Phase II data is also profound, with some patients having an 80% HBsAg loss (more than 4logs), the best reported in human HBV trials thus far, Lampertico and Yuen noted. HBsAg decrease is observed during and after therapy, which also draws enthusiasm for a functional cure, Lampertico noted.

But there are still mechanism gaps, which draws some safety reservations. For example, if HBsAg is trapped it is unclear if it is degraded or accumulates, potentially damaging the cell, Yuen said.

A Replicor spokesperson said HBsAg inhibition is not accompanied by increase of intracellular HbsAg according to preclinical studies. There is a constant and rapid HBsAg turnover, which stabilises when incorporated into a virus, he added. In clinical trials, REP2139 is well-tolerated with no signs/symptoms of liver dysfunction even in combination with tenofovir and peg-interferon, he added.

ALT flares were observed in human trials, and it is unclear if this is a safety issue or helps clear HBsAg, Lampertico added. The flares appear to be due to removal of HBsAg burden and not therapy-related, the spokesperson noted.

But Lampertico noted, with the human trials staged in Pakistan and Moldavia, result replicability could be an issue. The spokesperson noted REP2139’s antiviral effects have been highly reproducible in preclinical studies as well as in different patient populations from different geographical regions.

by Reynald Castaneda in London

Reynald Castaneda is part of GlobalData’s investigative journalism team. GlobalData provides unique and market-leading data and insights into the global pharmaceutical industry and is’s parent company. To access more investigative news like this article, visit GlobalData .