Bulevirtide Beneficial in Hepatitis D: Phase 3 Data

LONDON — Bulevirtide may not just treat but perhaps be a potential cure for hepatitis D in some patients, as was suggested at the annual International Liver Congress.

Data from an ongoing phase 3 trial showed that, after 48 weeks of treatment, almost half of those treated with bulevirtide achieved the combined primary endpoint of reduced or undetectable hepatitis delta virus (HDV) RNA levels and normalized ALT levels.

“The good message for our patients is that the initial data of the smaller phase 2 trials will really be confirmed, so the drug works,” Heiner Wedemeyer, MD, said at a media briefing ahead of his presentation at the meeting sponsored by the European Association for the Study of the Liver.

“It induces a decline in viral load and, very importantly for us as hepatologists, liver enzymes normalize, this is really good news” added Wedemeyer, who is the clinic director of the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.

“This is really an almost historic moment for hepatology,” he said. “It’s the first time that these patients have an antiviral treatment; they are afraid of dying and now they have a hope.”

Giving his thoughts, Thomas Berg, MD, Secretary General of EASL, said: “We are entering into a golden age of hepatology science when it comes to viral hepatitis.

Berg, also of University Clinic Leipzig (Germany), added: “We have several million people worldwide living with viral hepatitis; we have a cure for hepatitis C but there’s no cure for hepatitis B or hepatitis D, so these data give me great hope that we have scientific momentum with us.”

Pivotal Phase 3 Study

The MYR301 trial is an important and pivotal study for bulevirtide, which is a first-in-class HDV entry inhibitor. While it was approved for use Europe in 2020 under the brand name Hepcludex, the drug remains investigational in the United States.

“We were really surprised that EMA [European Medicines Agency] went forward, granting approval because there was no alternative available at that time,” Wedemeyer said. That approval is conditional, however, and was based on the results of phase 2 studies with the proviso that further data needed would need to be provided. Hopefully, the phase 3 findings will mean that the drug will receive full official approval, he said.

Overall, 150 patients with chronic hepatitis D were recruited into the phase 3 study and randomized to receive one of two doses of bulevirtide (2 mg or 10 mg) for 144 weeks or delayed treatment for 48 weeks followed by the higher dose of the drug until the remainder of the treatment period. Bulevirtide was given as once-daily subcutaneous injection.

The mean age of participants was 41 years, the majority (82.7%) were White, and just under half already had liver cirrhosis. For inclusion, Wedemeyer said that they had to have compensated cirrhosis.

Just over half had received prior interferon therapy and almost two-thirds were receiving concomitant nucleos(t)ide (NUC) treatment.

Key Results

The primary endpoint was defined as a combination of decreased HDV RNA (defined as undetectable or a 2 log or greater decrease) and normalized ALT (defined as 3.1 U/L or less in women and 4.1 U/L or less in men). This was assessed after 48 weeks’ treatment and was achieved by 45% of participants given the 2-mg dose of bulevirtide, 48% of those given the 10-mg dose, and by 2% of those who had delayed treatment (P < .0001 for both doses, compared with delayed treatment).

The treatment benefit was consistent across all subgroups of patients, including those with cirrhosis, Wedemeyer reported.

Looking at some of the secondary endpoints, he reported that, when considering only decreased HDV RNA, the rate of response was over 70% with both dose of bulevirtide at week 48, compared with just 4% for delayed treatment (P < .0001), although there was no significant difference in rates of undetectable HDV RNA between the two doses. ALT normalization rates were 51%-56% versus 12% for delayed treatment (P < .0001).

A further benefit was seen in liver stiffness, with values reduced by at least three points at week 48 with either dose of bulevirtide, compared with an increase of almost 1 point for delayed treatment.

As for side effects, one of the concerns for bulevirtide is an increase in serum bile acids, but when this occurred, it occurred early and remained steady over the course of treatment, with a less pronounced effect in the 2 mg–dosed group than the 10 mg–dosed group. There were no serious adverse reactions related to bulevirtide or any adverse event that led to stopping the drug.

“There are always questions that need to be answered,” Wedemeyer acknowledged. Indeed, it’s unclear for how long patients need to be treated and if treatment with interferon is needed. In the phase 2 studies (MYR202 and MYR203), bulevirtide was given at the same time as pegylated interferon alpha (peg-IFNa) or tenofovir, whereas in the phase 3 MYR301 trial, it was given as monotherapy.

Real-World Experience

“We have already some real-world data in parallel to this phase 3 trial,” Wedemeyer said. “So, for us in the hepatitis D field, it is a really exciting time; [it’s] completely novel data and game-changing for patients.”

“The results are similar to our real life study, but in our real-life study, we have some patients treated with interferon and some not treated with interferon,” Hélène Fontaine, MD, of Hôpital Cochin in Paris, observed in an interview.

She reported preliminary results from the prospective BuleDelta cohort, which showed a virologic response rate of 58% and ALT normalization in 46% of patients.

“Virologic response was achieved in more patients receiving bulevirtide in combination with interferon,” she said. Indeed, 84% of patient who received peg-IFNa versus 39% of those who did not achieved a virologic response. However, rates of ALT normalization were more frequent in those received bulevirtide monotherapy than in combination with peg-IFN1 (54% vs. 35%).

A greater benefit of combining bulevirtide with interferon therapy was also seen in another real-world study presented by Victor de Lédinghen, MD, PhD, of Bordeaux (France) University Hospital. After 18 months of treatment, bulevirtide plus peg-IFNa was associated with undetectable HDV RNA in 57% of patients versus 33% of those given the drug as monotherapy.

“Of course, if you add interferon, it’s better than without but you cannot use interferon in all patients,” he observed in an interview.

Results are good but could be better, he suggested, noting that the results are dependent on patients injecting themselves correctly on a daily basis.

At the media briefing Wedemeyer also commented on how bulevirtide must be delivered.

“The only, let’s say, disadvantage is that it has to be injected because it’s a peptide, which requires daily injections, but patients managed very well,” Wedemeyer said.

“There is some evidence from single cases that we may stop treatment and that the virus does not come back,” he said, but stressed that patients should not stop treatment on their own as the risk is not known.

“For patients with advanced disease I consider this as a maintenance treatment,” Wedemeyer said, at least for the time being.

The MYR3201 study was funded by Gilead Sciences. The BuleDelta cohort is sponsored by the ANRS Maladies Infectieuses Emergencies. Wedemeyer acknowledged research funding, acting as a consultant to, and giving paid lectures on behalf of Gilead Sciences and MYR as well as having ties to multiple pharmaceutical and biotechnology companies. Berg, Fontaine, and de Lédinghen had no conflicts of interest to report.

This story originally appeared on MDedge.com, part of the Medscape Professional Network.

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