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New data from J&J, Arrowhead mark latest step in RNAi’s hepatitis B race

Arrowhead Pharmaceuticals and partner Johnson & Johnson provided the latest update to a Phase 2 study testing their experimental RNA interference therapy in patients with chronic hepatitis B infections. Data presented at the Digital International Liver Congress showed that 39% of patients who got three doses of the drug saw sustained reductions in a key biomarker for hepatitis B 48 weeks after getting their last injection, indicative of the therapy’s potentially long-lasting effects. Presenters said the results support longer-term testing of the drug alongside antivirals, studies of which are currently underway.RNA interference, a Nobel Prize-winning method for drugmaking, has recently seen its first approvals following two decades of ups and downs. In the past few years, multiple companies have advanced programs aiming to use RNA interference, alongside other medicines, to develop a “functional cure” for patients with chronic hepatitis B infections. Four rival programs are now in clinical testing, including Arrowhead’s, which J&J licensed as part of a wide-ranging alliance in 2018.

Though a vaccine exists to prevent hepatitis B, it remains the world’s most common serious liver infection. Two million Americans are infected each year, and thousands die, according to the nonprofit Hepatitis B Foundation. It’s a disease that’s spread “silently,” through the fluids of people who don’t realize they’re infected.

While most people infected with hepatitis B clear the virus within six months, 5% to 10% of them don’t. They develop a chronic infection, need periodic, lifelong monitoring to screen for liver problems, and potentially drugs — antivirals and immune-boosting interferons — to prevent liver damage or more serious health problems. But those medications don’t cure patients; they only keep the virus under control.

RNA interference drugs, which stop a gene from making a potentially harmful protein, have long been seen as a potential solution, and in recent years their progress has picked up steam. These drugs aim to stop the production of a protein — known as a surface antigen — the hepatitis B virus uses to trick and evade the immune system. The hope is that combining an RNAi therapy, for a short time, alongside other drugs, will lead to life-long control of the virus without treatment, what’s known as a “functional cure.”

Four rival programs have come to the forefront, two of which — from Arrowhead and Dicerna — have attracted the interest of some of the world’s top pharmaceutical comapnies. J&J bought into Arrowhead’s program in 2018, while Roche grabbed rights to Dicerna’s a year later. Vir Biotechnology is advancing a program that began within Alnylam Pharmaceuticals. Pennsylvania biotech Arbutus Biopharma is also involved. All are in human testing, and three of them are in Phase 2.

It’s unclear at this point whether any of these treatments can help provide a functional cure. Thus far, the main evidence in their corner is early indications that they can meaningfully reduce levels of surface antigen in a small number of patients without side effects that would prevent further testing. It’s unknown how long those effects last.

By that measure, Wall Street analysts have said previously that J&J and Arrowhead’s program has set the bar, with an average roughly 2.0-log reduction in levels of surface antigen in early tests. Others, however, have closely followed suit, most recently Dicerna, which disclosed results from its own Phase 2 study earlier this month.

Arrowhead provided the latest look at its program at a virtual meeting of the International Liver Congress this week. In the study, chronic hepatitis B patients on antiviral drugs got three RNAi injections, each 28 days apart, while continuing their other medication. They were then evaluated at multiple time points for up to 48 weeks.

The companies said that 392 days after their first dose of JNJ-3989 — and 336 days after their last — 15 of 38 patients were still “responders,” meaning they had very low levels of surface antigen in their blood.

The most common side effects were injection site reactions, though one patient had a spike in liver enzymes, the companies said.

J&J and Arrowhead said the results are the first time an RNAi-based treatment has led to sustained reductions in surface antigen for that long, and “support the evaluation of longer durations of treatment.”

The finding “is significant as it suggests that achieving a functional cure with a finite therapy is a possibility,” wrote RBC Capital Markets analyst Luca Issi. A combination of drugs will likely be needed to achieve that, but J&J and Arrowhead’s data “reiterates our conviction that RNAi will be the base of that cocktail,” Issi added.

Phase 2b studies are underway testing the effects of monthly doses of the RNAi treatment alongside other drugs over 48 weeks.