ILC: Searching for a functional cure while battling rivals, Vir and Alnylam post hep B data peek

hepatitis B virus
Hepatitis B virus (Institute for Molecular Virology - University of Wisconsin–Madison)

The battle to be the first RNAi to help cure hepatitis B is heating up as Vir Biotechnology and partner Alnylam release ongoing data and rivals line up with their own results at the International Liver Congress (ILC) 2020.

We’ve had to wait: ILC 2020 was meant to happen back in April in London, but COVID-19 chaos caused its delay and digitization until this week.

And while nonalcoholic steatohepatitis remains a key focus for investors out of this event (and Gilead Sciences is dropping some new data on Saturday), hepatitis B, a condition that affects 300 million people worldwide and can cause long-term liver damage if left untreated, still remains a major disease target.

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It’s been a tough nut to crack, with the likes of Roche and Arbutus falling to the wayside in recent years after flops and safety worries. In clinical terms, a functional cure for hep B would cut levels of the virus’s surface antigen and DNA to undetectable levels—and keep them there six months after the patient finished treatment.

What Gilead managed in hepatitis C with Sovaldi and Harvoni, both of which can effectively cure people of the disease, a number of big-name biotechs and pharmas are now aiming to achieve with hepatitis B.

There are already several antivirals approved to treat chronic hepatitis B, including Roche’s Pegasys, a pegylated interferon, but nothing as successful as what we now have to treat hepatitis C.

The new hope is coming from RNA technology and its potential to cure this disease. George Scangos’ Vir and partner Alnylam, an RNA specialist (and the first company to even have an RNA drug approved), alongside phoenix from the flames Arrowhead and partner Johnson & Johnson, are leading the hep B RNA race.

With Vir battling to find a treatment for COVID-19, its work in hep B is being largely ignored by investors, with its Alnylam partnership also now extending to COVID-19; however, it still remains a major part of the pair’s R&D pipeline.

All four companies presented at ILC 2020 today, with Vir and Alnylam unveiling a peek at their ongoing phase 2 of its RNA hopeful VIR-2218 in patients with chronic hepatitis B virus (HBV) on nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs), the current standard of care.

Their therapy is designed to target a conserved region in the HBV X gene. This drug, originally called ALN-HBV-02 before Alnylam licensed it to Vir in 2017, came as part of an infectious disease deal worth up to $1 billion.

VIR-2218 is designed to silence all HBV transcripts, from both cccDNA and integrated DNA, across all 10 HBV genotypes.

The main thrust of Vir’s study is focused on lowering the levels of a surface antigen called HBsAg, one of four hep B transcripts the virus used to duplicate and rebound.

It found that in the ongoing test of 24 patients, a subset of patients in the 50-mg dose level “have achieved maximal decline in HBsAg levels at Week 12,” with a mean decline of 1.5 log10 from baseline in VIR-2218 treated patients.

Vir said that declines in HBsAg “continue in other cohorts with at least two patterns observed: an early response and a  delayed response.” The test did not raise any safety scares.

In July, Vir also kick-started a phase 2 combo test of VIR-2218 and pegylated interferon-alpha, with these sorts of cocktails the likely best way of creating that functional cure. An initial data drop from this is “anticipated in 2021”, Vir said.

Its key rivals using a similar RNA approach are Arrowhead and partner J&J, which a few years back penned a pact with the biotech worth a few hundred million dollars upfront, but with a major $3.5 billion biobucks for the RNAi hep B program.

They both also released data at ILC 2020 today. Investigators here administered three doses of JNJ-3989 to participants in 56 days to evaluate whether giving the RNAi therapy in combination with an existing treatment can degrade viral RNA and inhibit DNA formation to reduce levels of HBsAg.

The study then tracked the subjects for 48 weeks after the administration of the final dose of JNJ-3989.

By the end of the follow-up, 15 of the 38 patients who initially responded to JNJ-3989 still had a -1.0 log10 IU/mL or greater reduction in HBsAg. The average 392-day reduction in HBsAg among the 15 sustained responders was around -2.0 log10 IU/mL.

Bigger and longer-term studies will be needed for both Vir/Alnylam and J&J/Arrowhead, but with safety seemingly not an issue and HBsAg levels generally in the right direction, all four will be hopeful bigger tests will also see positive results.

All four had also been battling another RNAi hopeful, Arbutus, but last year this biotech canned its Roivant-backed oral capsid inhibitor AB-506 in chronic hepatitis B after two healthy people in a phase 1 study ended up developing the very disease the drug was supposed to treat.

Swiss major Roche also ditched an antisense hep B drug back in January but then rebounded after it snagged a $200 million deal with Dicerna and its phase 1 effort DCR-HBVS, another RNAi therapy designed to knock down genes needed to make HBV mRNA and get the virus into liver cells.

The drug, now known as RG6346, is further behind its rivals. And Dicerna reported positive data in early August from its phase 1, with Roche now taking over for its midstage tests.

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