The Food and Drug Administration (FDA) approved Hepcludex on Friday for the treatment of chronic hepatitis D, ending decades in which patients had no approved treatment options for this indication. The drug had already been approved for use in Europe at a lower dose.
The injectable drug, developed by Gilead Sciences, is the first antiviral therapy approved by the FDA for a disease considered the most severe form of viral hepatitis. It works by blocking the receptor used by both HBV and HDV (hepatitis B and hepatitis D). Several clinical trials have shown that prolonged use suppresses HDV replication, improves markers of chronic liver inflammation and leads to regression of liver scarring in a significant proportion of patients. However, stopping treatment typically leads to relapse in most cases. Gilead’s stock rose about 3% following the announcement.
Hepatitis D has a unique and particularly dangerous profile: it is a satellite virus, the smallest known virus that infects humans, and cannot infect cells without hepatitis B, which provides the envelope proteins it needs to enter liver cells. As a result, patients with hepatitis D are simultaneously dealing with two viral liver infections, each with its own monitoring requirements and treatment complexity. Risk factors include unprotected sex, injection drug use and occupational exposure to blood, such as among healthcare workers. The hepatitis B vaccine, available for decades, also protects against hepatitis D.
Co-infection is significantly more dangerous than hepatitis B alone. The disease progresses rapidly to liver cirrhosis, liver cancer and liver failure, with mortality rates among cirrhotic patients reaching up to 50% within five years. Globally, at least 12 million people are estimated to live with co-infection. In the United States alone, there are between 40,000 and 80,000 carriers.
“Hepcludex is the first antiviral drug approved for hepatitis D in three decades,” said Professor Ziv Ben-Ari, head of the Assuta's Liver Center of Excellence. “It significantly reduces viral load in about 58% of patients and has a strong safety profile. This is very important news for patients in Israel who need it.”
She added: “Hepatitis D is the most severe viral liver disease, progressing rapidly in 70% of patients within 5 to 10 years to cirrhosis, with complications including liver cancer.” She described the previous treatment gap: “Until this drug was approved there was no effective antiviral therapy. Pegylated interferon had limited efficacy and severe side effects and is no longer available. In practice, there is nothing to offer patients today.”
Dr. Ira Jacobson of NYU Grossman School of Medicine said: “For patients, an HDV diagnosis means managing two distinct viral liver diseases — hepatitis B and hepatitis D — each contributing to disease progression, monitoring demands, and treatment complexities. The approval of Hepcludex for chronic HDV represents a critical advancement, introducing a long-awaited option that begins to address a significant unmet medical need and has the potential to meaningfully alter the course of this devastating disease for people living with HDV in the United States.”
A new mechanism: a drug that blocks entry
Hepcludex belongs to a new class of drugs known as entry inhibitors. It works by blocking the entry of both hepatitis D and hepatitis B viruses into liver cells, thereby slowing the spread of infection. It is a subcutaneous injection given once daily at a dose of 8.5 mg.
The approval was based on a phase 3 randomized controlled clinical trial called MYR301, conducted at 19 medical centers across five countries: the United States, Germany, Italy, Sweden and Russia. The study included 150 patients aged 18 to 65. Participants were randomly assigned to two groups: an immediate-treatment group receiving the drug for 144 weeks and a control group observed for 48 weeks before also starting treatment.
The primary endpoint was a composite response combining a significant reduction in viral load and normalization of ALT liver enzyme levels. After 48 weeks, 48% of patients receiving Hepcludex achieved this response compared with just 2% in the control group. The proportion of patients with undetectable virus increased over time: 20% after 48 weeks, 36% after 96 weeks and 50% after 144 weeks. The trial also included elastography measurements, an imaging method used to assess liver stiffness as a marker of fibrosis, to evaluate long-term impact on liver condition.
It is important to note that approval was granted based on virologic and biochemical markers, and a direct proven improvement in clinical outcomes such as survival or prevention of complications has not yet been demonstrated in this study.
Accelerated approval pathway
The FDA added a black box warning, its most serious type of warning, stating that stopping treatment may cause severe acute flare-ups of both hepatitis D and hepatitis B, with risk of serious liver damage. Patients who discontinue treatment must therefore undergo close medical monitoring for at least six months, including laboratory tests and viral load measurements. Common side effects include injection-site reactions, headache, abdominal pain, fatigue and itching. Rare cases of hypersensitivity reactions, including severe anaphylaxis, have also been reported.
The drug was approved under the FDA’s Accelerated Approval pathway, intended for serious diseases with limited treatment options. It also received Breakthrough Therapy Designation and Orphan Drug Designation. Gilead has committed to conducting a long-term confirmatory trial, which is already underway.
The U.S. approval comes three years after the European Union approved a lower-dose version (2 mg) for patients in Europe. “This reflects years of close engagement with the FDA and the application of rigorous science to address a serious disease with long-standing unmet need.,” said Dr. Dietmar Berger, chief medical officer at Gilead Sciences. “With Hepcludex, we now have the opportunity to deliver a meaningful clinical advancement that has the potential to change the trajectory of HDV for patients in the U.S.”
In Israel, several patients are already receiving the drug under compassionate use, and it is expected to be submitted again for inclusion in the national health basket, this time with FDA approval.