Lawrence Blatt, Ph.D., CEO of Aligos Therapeutics, knows a thing or two about the slow drip of progress that has defined treating viral liver infections. He was “thrilled” back in the mid-90s when a drug he co-invented at Amgen, Infergen, notched a 10% response rate in patients with hepatitis C. In 1998, ribavirin was approved as a first-line treatment, which, when combined with interferon, roughly tripled response rates.
More than a decade passed before the first direct-acting antivirals were approved, a significant breakthrough that led to the functional cure now possible for patients.
“People forget the hard labor that we all did in HCV to eventually get to 100% response,” he said.
Catherine Stehman-Breen, M.D., who leads startup Chroma Medicine, described a similar trajectory, recounting her early career in academia working on hepatitis C and chronic kidney disease. At the time, in 1993, she says roughly 1 in 5 patients on dialysis were infected with hepatitis C. It took a long while to get from those grave statistics to clinical success.
The biotechs run by Stehman-Breen and Blatt are now working to treat an equally formidable liver condition: hepatitis B. The clinical challenges both executives experienced with hepatitis C are back, and the only way through is to push past failure. Many companies have thrown in the towel along the way.
According to a database maintained by the Hepatitis B Foundation, the number of hepatitis B treatments in the clinic has risen from 26 in October 2016 to 40 in October 2023. But the number of preclinical candidates has fallen from 10 to nine, indicating few next-generation options behind the current crop of options. The overall landscape is disheartening to Chari Cohen, executive director of the foundation, who said that ultimately, pipeline prioritizations are economic decisions.
“I do think it's economic, I think it's marketplace-driven, I think it's investor-driven,” said Cohen. But she also pointed to a broader problem: Hepatitis B has never been a top infectious disease concern.
“Hepatitis B has always been a stepchild disease, it's always been a disease that is under-prioritized,” she added.
The disease affects about 296 million people worldwide, contributing to about 820,000 deaths each year, according to the Centers for Disease Control and Prevention. It causes liver damage, cirrhosis (scarring of the liver), liver failure and death.
In 2016, the World Health Organization (WHO) declared the ambitious goal of eliminating hepatitis B viral infections as a public health crisis, spurred in part by hepatitis C breakthroughs. The initiative, endorsed by all of the organization’s member states, aimed to reduce new global hepatitis infections by 90% and deaths by 65% by 2030.
Halfway to that goal, 3 million new hepatitis B and C infections are still being reported each year, according to a report from the WHO. The report estimates that only 10% of people with chronic hepatitis B infection are actually diagnosed.
Past struggles and new hope
On the research front, scientists have learned a great deal about hepatitis B in recent years, namely that the ability of the viral DNA to embed itself in the host genome makes for a biological dilemma. In other words, it’s one thing for a therapy to stomp out viral levels, but it’s another to stop the DNA from replicating.
Such has been the experience of Assembly Biosciences, which developed a first-generation core inhibitor, vebicorvir, that executives said showed “great antiviral activity.” It just wasn’t that good at the second part of the problem: the elimination of covalently closed circular DNA, the pesky DNA that rests in the nucleus. That forced the company to end development and prioritize resources elsewhere. Other companies have also had to rejig their plans, including Aligos, which cut or paused four hepatitis B programs from January 2022 to February 2023. The decision to put a pin in the second two programs spurred layoffs for 10% of employees.
Some companies have ended work entirely. Johnson & Johnson announced this year that all hepatitis drug development was ending as part of a larger wind-down of its infectious disease and vaccine unit, and RA Capital-backed Antios Therapeutics quietly shut down in February due to an insurmountable FDA clinical hold.
Melanie Paff, Ph.D., GSK’s vice president and medicine development leader for its HBV program, said the field has had a gut check in recent years.
“I think it’s made all of us quite humble at just how difficult this particular virus is,” said Paff. “[It’s] completely different from hepatitis C … and much harder to tackle.”
There are signs, however, that inroads are being made, with GSK at or near the front of the pack. The British Big Pharma’s Ionis-partnered antisense oligonucleotide, bepirovirsen, is under development as a functional cure for the disease. One phase 2 trial that’s since concluded tested the treatment as both a monotherapy and in addition to nucleos(t)ide analog therapy, while another phase 2 study tacks on pegylated interferon.
Back in June 2022, GSK reported that nearly 30% of patients in the now-finished trial had undetectable levels of the virus after 24 weeks of treatment, but further analysis reported six months later showed a much smaller undetectable rate—9% to 10% of patients. New data from the ongoing trial including pegylated interferon presented at this year’s American Association for the Study of Liver Diseases (AASLD) annual meeting showed that 9% to 15% of patients achieved undetectable status of surface antigen and DNA when given bepirovirsen followed by 24 weeks of pegylated interferon.
Barinthus Biotherapeutics—formerly known as Vaccitech—also touted data at AASLD from a couple of phase 2 trials testing its own HBV candidate, VTP-300. The first combined the asset with Bristol Myer Squibb’s Opdivo in patients on nucleos(t)ide analog (NUC) therapy, resulting in reduced surface antigen levels across all groups. The drop was most pronounced in patients with surface antigen levels under 200 IU/mL, causing the biotech to amend the trial protocol to focus on recruiting those patients moving forward. The second study found that patients with non-cirrhotic, virally suppressed chronic hepatitis B had a “robust” response when Arbutus’ imdusiran was tacked onto VTP-300. The data were available in 12 out of 40 patients who were also on stable NUC therapy.
In an interview before the data drop, Barinthus CEO Bill Enright said the company would “take the best regimen forward.”
Chroma Medicine hauled in a $135 million series B earlier this year to, in part, help finance an early hepatitis B program. At this year’s annual International HBV Meeting, the biotech presented data on the potential of its epigenetic editing technology in a hepatitis B mouse model, finding that a single dose of epigenetic editors spurred more than five months of durability. Five out of six evaluable mice had undetectable levels of the virus at the last time point evaluated.
“We really do feel that this could be needle-moving for those patients,” said Stehman-Breen.
Two recent deals have also added optimism that the larger cloud over the field could pass. The first was Gilead Sciences throwing a life raft to Assembly Biosciences, handing over $100 million in upfront cash and equity investments in exchange for first dibs at rights to all of the company’s current and future assets. Gilead also contributed two assets of its own for Assembly to take forward. That financing allowed Assembly to restart a next-generation core inhibitor program, ABI-4334, at least up to a phase 1b readout, at which point Assembly can decide whether to opt in to cost- and profit-sharing. Assembly previously paused work on that program to conserve cash.
The other was GSK’s acquisition of J&J and Arrowhead’s hep B therapy JNJ-3989, an siRNA med that shrinks the virus’s surface antigen levels but had been in limbo due to Janssen’s restructuring. The deal was worth $1 billion, with about 10% in available upfront cash, less than $10 million of which went to Arrowhead, according to a spokesperson for the biotech. GSK’s Paff hypothesized that using JNJ-3989 would get surface antigen levels down to a “sweet spot” for bepirovirsen to then limit replication.
“You need to drive S antigen down to a very, very deep, low level for it to be durable,” she said. “And we think this particular sequential combination is going to allow us to do that in a better way.”
As for the implications on the HBV marketplace as a whole, Assembly CEO Jason Okazaki said the deals put money behind the goal of reaching patients globally rather than in just select markets.
“It really solves the problem of the challenge which is ... how do you actually change patients' lives? I think now we’ve solved that problem.”
‘More money quicker’
The potential for the latest HBV-associated data and deals to spur a fresh wave of momentum comes as other liver diseases have recently risen to prominence, namely fatty liver disease and nonalcoholic steatohepatitis (NASH). Cohen feels those indications may have usurped hepatitis B interest among investors.
“What we're seeing is investors think that they can make more money quicker in other diseases,” she said.
There are no approved therapies to treat NASH, though that may soon change. Madrigal Therapeutics had a new drug application for resmetirom accepted by the FDA in September with the agency set to decide its fate by mid-March 2024. Resmetirom leads more than 80 drugs that are in clinical development to treat the disease, according to an August analysis from Global Data, more than half of which are in phase 1 development or the discovery stage.
Vantage estimates that the U.S. market for NASH could balloon to $108.4 billion in 2030, while one report estimates the global hepatitis B market size will hit $6.45 billion in 2032—a fraction of the fatty liver commercial potential. The market size may be a reflection of who’s most afflicted with hepatitis B. Of the 1.5 million new cases reported in 2019, two-thirds came from WHO’s Africa region, with an additional 17% coming from the Southeast Asia region. Less than 7% of new cases came from the Americas.
Okazaki framed the investment difference on two fronts, saying that the interest in NASH could be due to a lot of players in the space having near-term readouts. He also believed that because there’s a vaccine available for hepatitis B, the need for treatments is incorrectly downplayed.
“It’s not like this disease is under control by any means,” he said.
Aligos reported in February that its “highest priorities” would be on advancing treatments for NASH and COVID-19, the former of which is nearing a phase 2 study, while the decisions on the two hepatitis B programs would be made after seeing updated data. Evidently one of those assets, ALG-000184, has impressed enough to be pushed forward. Aligos said Friday that the therapy would advance into phase 2 based on data presented at AASLD.
Aligos' Blatt believes that U.S. HBV cases are underreported and that the size of the market is likely larger, something that researchers have previously estimated. A 2021 paper in the journal Hepatology estimated that some 2.4 million people in the U.S. were living with chronic hepatitis B, more than the 1.89 million people at the high-end of an estimate from the U.S. Health and Human Services Department.
“We're not running our company based on what trends are, we're running our company based on good science and knowing that eventually if we do what's right for patients, the rest will follow,” he said.
Editor's note: This story was updated to clarify details about Assembly Biosciences core inhibitor programs.