New Agent Shows Promise in HBV/HDV Co-infected Patients

FigureVIENNA, Austria—An investigative agent appears to rapidly and dramatically reduce both hepatitis B virus surface antigen and hepatitis D virus infection in co-infected individuals, researchers reported here at the International Liver Congress, sponsored by the European Association for the Study of the Liver. The reduction in the hepatitis B surface antigen is the key action of the nucleic acid polymer with a catchy name of REP 2139-Ca because without that surface antigen being available, hepatitis D virus cannot infect its host, explained Andrew Vaillant, PhD, Chief Science Officer of Replicor, a Montreal-based company that is developing the product, who presented the preliminary findings of the late-breaker study at a plenary session. “Nucleic acid polymer-based antiviral therapy may become an important new treatment option for patients with hepatitis B virus and hepatitis D virus co-infection,” he said about the early trial that reviewed how well REP 2139-Ca worked in a small group of Caucasian patients with co-infection. Earlier trials showed effectiveness in Asian patients. He reported on 12 patients who completed the first 15 weeks of therapy with REP 2139-Ca. “Therapy is continuing in all the patients, so the researchers do not have any follow-up data—such as whether there is a viral rebound when treatment ends—in this population.” At baseline, patients had about 10,000 IU/mL of surface antigen. “We observed at the start of treatment a rapid decline with a fall of 4 to 5 log10 which is the same kind of profound clearance already observed in our Asian trials,” he said. All the patients responded, but the response in some was muted, even though, he said, the reduction in surface antigens fell by 1 to 2 log10.DAVID BERNSTEIN, MD. DAVID BERNSTEIN, MD: “A high percentage of people co-infected go on to develop cirrhosis and cancer.”“As we observed in previous trials, we saw an initial increase in serum anti-hepatitis B levels and then when we added interferon we began to see rapid increases in the levels of antibodies. In the hepatitis D levels, we again show that at the beginning of treatment we see reductions of hepatitis D RNA, falling 7 log10, falling all the way down to undetectable. All of the patients are responding very well. Most of them have reached below the limit of quantification on this assay. It represents a very robust response.” REP 2139-Ca is able to simultaneously reduce hepatitis B surface antigen and hepatitis D virus RNA in patients with chronic co-infection, he continued. “The pharmacologic effect on serum hepatitis B surface antigen observed in Asian patients is replicated in Caucasians and gives us confidence that these results can be replicated in a wide-range of infected patients.” ‘One of the Better Presentations’ Asked for his perspective, David Bernstein, MD, Chief of the Division of Hepatology at North Shore University Hospital in Manhasset, N.Y., said: “I found this presentation very interesting. I think the new concept that they are looking at is intriguing. It is novel, and I think one of the better presentations at the meeting. “To me, what is more important is that it lowers the level of hepatitis B surface antigen. I think there is a much larger potential market for its impact on hepatitis B than for its use in co-infected patients in this country. This is extremely important for patients with hepatitis B in this country, and worth pursuing.” Co-infection with the two viruses is uncommon in the United States, Bernstein said. “In other parts of the world, it is more common. It is more commonly seen in the Mediterranean areas. We may see this co-infection in individuals who are recent immigrants from Northern Africa and southern Europe, but not often in people living here with ancestry from those areas. “Hepatitis D is sort of unique because in order for it to survive, the patient has to already have hepatitis B. A high percentage of people co-infected go on to develop cirrhosis and cancer,” he said. Actually as many as 20 million people worldwide may be infected with hepatitis D, Vaillant said in his presentation. He said his company went to Chisinau, Moldova, to recruit patients for the Caucasians study. “Because of the issues with genetic diversity it is very important to validate these results in different populations.” Samples in the study group were analyzed by two independent laboratories, finding similar results in most of the patients, but different findings in two individuals, emphasizing the diversity of the viral strains. “Co-infection is a real challenge because these patients progress most quickly through cirrhosis to hepatocellular carcinoma,” Vaillant said. “It is an urgent unmet medical need because there is no approved therapy although interferon-based treatment can infrequently achieve functional cures with long exposure.”ANDREW VAILLANT, PHD. ANDREW VAILLANT, PHD: “All of the patients are responding very well. Most of them have reached below the limit of quantification on this assay. It represents a very robust response.”Nucleic Acid Polymer In developing the nucleic acid polymer, the researchers leveraged the relationship of hepatitis B surface antigen and hepatitis D, he explained. “Hepatitis B surface antigen is a critical component of the Hepatitis D life cycle. Both hepatitis B and hepatitis D have the same entry mechanisms because they both share the surface antigen protein.” Hepatitis B surface antigen is not produced by hepatitis D, but it is required for its assembly. Hence, hepatitis D infection can occur only in patients who are infected with hepatitis B. Hepatitis D assembly may be linked to the assembly of hepatitis B subviral particles. The researchers suggested that nucleic acid polymers could impact co-infection by blocking hepatitis B entry into cells, and by blocking subviral particles. This type of mechanism leads to the clearance of hepatitis B surface antigen in patients and can lead “to very profound reductions in surface antigens,” he said. “We have also found that when you reduce hepatitis B surface antigen, we also get substantial amounts of anti-hepatitis B surface antigens which may directly attack the hepatitis D virus.” Study Details Patients in the trial were required to have compensated liver disease, with mild to moderate fibrosis, but they could not have disease that had progressed to cirrhosis. Participants received REP 2139-Ca at a dose of 500 mg a week intravenously for 15 weeks. Vaillant explained that this 15-week run-in phase was done to validate the pharmacology of REP 2130-Ca. The patients were then transitioned into combination therapy at a dose of 250 mg a week intravenously for another 15 weeks, and at the same time were receiving pegylated Interferon alfa-2a at a dose of 180 micrograms a week by subcutaneous injection. After the 15 weeks of combination therapy, the patients finished out the usual 48 weeks of interferon treatment. Previous clinical trials have shown that the addition of pegylated interferon “dramatically improves the efficacy of the new agent and we expected to see similar evidence of that in the new trial,” he said. Patients will be followed at four 12, and 24 weeks. In the preliminary safety profile, all adverse events were Grades 1-2—mainly fever, redness, or headache, which were associated with intravenous infusion, Vaillant said. The adverse events typically became less frequent as the dosing regimens progressed. The reactions tended to self-resolve within two to three hours after completion of the intravenous infusion, infrequently requiring supportive treatment. The researchers attributed the reaction to the presence of phthalate plasticizers in the intravenous tubing. The use of non-phthalate tubing in the Asian trials conducted in Bangladesh tended to eliminate these reactions, he said. Clinical serology was monitored weekly, “and there have been no clinically significant findings.” Vaillant said that the expectation is for the drug to be introduced as a once-weekly subcutaneous injection—use as an intravenous agent in the clinical trials, he noted, is to control administration.

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