Bulevirtide (Hepcludex) monotherapy significantly reduces the load of hepatitis delta virus (HDV) and is safe in difficult-to-treat patients with compensated cirrhosis and clinically significant portal hypertension, according to the results of an ongoing 1-year study.
In presenting a poster with these findings at the International Liver Congress (ILC) 2022, lead author Elisabetta Degasperi, MD, from the Grand Hospital Maggiore Policlinico in Milan, Italy, said that they were important “because they confirm the safety of this drug in real life.”
Degasperi and colleagues showed that bulevirtide leads to a significant viral response in 78% of patients by week 48, which was measured using the outcome of HDV RNA ≥ 2 log decline from baseline.
Degasperi added that the research still needed to assess the longer-term benefits, but “so far the 1-year results clearly show an initial benefit that is not only a good viral response but also one of disease control and a slight improvement in liver function.”
Addressing an Immense, Unmet Therapeutic Need
HDV requires the presence of hepatitis B virus to replicate. Bulevirtide blocks the entry of HDV and hepatitis B virus into hepatocytes.
In July 2020, it was conditionally approved in the European Economic Area (EEA) for use to treat chronic HDV infection in adults with compensated liver disease upon confirmation of HDV RNA in the blood. It currently remains an investigational agent in the United States, as well as outside of the EEA.
The ongoing trial led by Degasperi is specifically conducted in patients with compensated cirrhosis who also have clinically significant portal hypertension, where safety and efficacy are unknown.
Degasperi told Medscape Medical News that although HDV was rare, there is nonetheless an “immense” need for effective therapies against it, especially in young patients with advanced liver disease.
“We have a lot of patients with hepatitis D who have not responded to other antiviral treatment. Right now, the only other available treatment is pegylated interferon,” she said. “Unfortunately, rates of sustained viral response to pegylated interferon are extremely low at around 30% of patients.”
Chronic HDV is the most severe form of viral hepatitis and can have mortality rates as high as 50% within 5 years in patients with cirrhosis.
The management of hepatitis D is also complicated by the fact that patients with advanced cirrhosis and clinically significant portal hypertension cannot be treated with pegylated interferon owing to lack of efficacy and safety reasons, including a high risk for decompensation and liver-related complications. Pegylated interferon is contraindicated in these patients.
Bulevirtide at 48 Weeks: A Closer Look at the Findings
Eighteen patients with HDV, compensated cirrhosis, and clinically significant portal hypertension were consecutively enrolled in this single-center, longitudinal study.
All received bulevirtide monotherapy at 2 mg/d and underwent monitoring every 2 months. They were also treated with nucleotide analogs for their hepatitis B virus, which was suppressed when they began bulevirtide.
Clinical and virologic characteristics were collected at baseline, at weeks 4 and 8, and then every 8 weeks thereafter.
Bulevirtide led to a significant viral response such that by week 48, HDV RNA declined by 3.1 log IU/mL (range, 0.2-4.6 log IU/mL), was undetectable in six patients (33%), and was < 100 IU/L in 50% of patients. Two patients were nonresponders. In addition, 78% of patients achieved HDV RNA ≥ 2 log decline from baseline.
There was also a normalization of biochemical response in the majority of patients.
Alanine aminotransferase normalization was seen in 89% of patients and declined by a median of 34 U/L (range, 15-76 U/L) over 48 weeks. Aspartate aminotransferase declined to 39 U/L (range, 21-92 U/L). A combined response was seen in 72% of patients, reported Degasperi.
“Previously, we only had results from a phase 2 study, so we had no idea of the results over such a long treatment period,” remarked Degasperi. “It is also the first time we have been able to treat these patients with such advanced disease that is so difficult to manage.”
“Real-world results are typically inferior to those from clinical trials, but the viral decline is comparable to phase 2 trials, and the first report of the phase 3 trial,” remarked Degasperi.
Gamma-glutamyltransferase, alpha-fetoprotein, immunoglobulin G, and gamma-globulin levels also improved, whereas hepatitis B surface antigen, hepatitis B virus RNA, hepatitis B core-related antigen, platelet, and bilirubin values did not significantly change.
“All patients were Child-Pugh score A, so well-compensated [disease]. However, they increased a little bit in liver function by week 48,” Degasperi said. “This was important for this very advanced disease population.”
She added that the safety profile was very favorable, with no adverse events, including no injection-site reactions.
There was an asymptomatic increase in serum bile acids. “No patients complained about itching or pruritus,” Degasperi said
What’s Ahead for Bulevirtide?
Commenting on the poster for Medscape Medical News was Marc Bourlière, MD, from Saint Joseph Hospital in Marseille, France, who welcomed the decrease in viral load.
“This is known to be beneficial in terms of reducing morbidity and mortality in hepatitis D,” he pointed out. “Remember that this disease is very difficult to treat, and until now, we have had no drug available. Pegylated interferon achieves cure in only 30% of patients, and half of these relapse, so actually only 15% have a meaningful response from pegylated interferon.”
“The main issue is its use as a daily subcutaneous injection. In clinical practice, it is a little bit complicated to set up, but once done, it is quite well accepted,” he said.
“I’m impressed with these results to date because there are no other compounds that have, as yet, achieved such results. This is impressive,” he added. “But whether it translates into a long-term response we don’t yet know.”
Bourlière also noted the meaningful 2-point log decline, noting that “HDV RNA negativity where treatment can be stopped would be really meaningful, but this endpoint is hard to obtain.”
Bourlière is awaiting results of the current ongoing phase 2/3 study, which would help determine a possible final treatment duration. He is also curious to settle the ongoing debate about whether bulevirtide should be used alone or in combination.
“We need to combine bulevirtide with pegylated interferon in less advanced patients, because we know it is more potent and active against the HDV RNA.”
Degasperi has previously declared she was on the advisory board for AbbVie and has spoken and taught for Gilead, MSD, and AbbVie. Bourlière declared interests with all companies involved in the R&D of liver therapies.
International Liver Congress (ILC) 2022. Abstract SAT429. Presented June 25, 2022.
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