Investigational HBV core inhibitor shows early clinical promise

BARCELONA – An investigational drug that targets the hepatitis B virus (HBV) core protein is a “totally new approach” to treating chronic HBV infection according to the results of an early-phase clinical study.

In an ongoing, international, phase I study presented during the late-breaker session at the International Liver Congress, 4 weeks of treatment with NVR 3-778 was well tolerated and did not result in any drug discontinuations in chronically infected patients. There were dose-related reductions in HBV DNA and early reductions in HBeAg were observed.

“NVR 3-778 is a first-in-class HBV core inhibitor,” study investigator Dr. Man-Fung Yuen, Queen Mary Hospital, Hong Kong, said at a press briefing held at the meeting, which is sponsored by the European Association for the Study of the Liver (EASL). “The HBV core protein has many functions and is responsible for the most important pathway of the virus’ replication – nucleocapsid formation,” he explained.

The rationale behind its development is that although there are effective treatments such as nucleoside and nucleotide analogs (NAs) and pegylated interferon (peg-IFN) that can suppress the activity of HBV for many years and thus slow down damage to the liver, it is unusual to clear the virus permanently. Furthermore, as most patients require potentially life-long treatment, issues such as long-term safety, patients’ adherence, resistance, and cost of therapy come into play.

Dr. Yuen observed that achieving durable responses in patients with chronic HBV is likely to require combinations of potential agents, probably with complementary modes of action.

Preclinical data have shown that NVR 3-778 induces the rapid assembly of nonfunctional capsids and that it inhibits viral replication in a humanized mouse hepatocyte cell model. It has also been shown to reduce HBV DNA to a comparable extent as entecavir when used alone in a mouse model, with undetectable levels reached when used in combination with peg-IFN alpha-2a.

Dr. Yuen reported the preliminary results from the second part of the phase I study in 64 adults with chronic HBV, noting that the first part of the study in healthy volunteers had been completed successfully.

The aim was to examine the safety and efficacy of NVR 3-778 alone and in combination with peg-IFN alpha-2a in previously untreated patients aged between 18 and 65 years who were HBsAg- and HbeAg-positive, had HBV DNA of 20,000 or more copies per IU/mL, with no cirrhosis of the liver, as determined by liver biopsy or imaging.

Patients were randomly assigned to six groups, with four groups receiving the investigational therapy alone at four increasing doses (100, 200, 400, once daily and 600 mg twice daily). There was a staged initiation of each escalating dose of NVR 3-778 used in these groups, with the 100 mg initiated first and if, after 2 weeks, there were no interim safety concerns, the next dose groups, 200 mg, then 400 mg, then 600 mg were started. The other two groups of patients received NVR 3-788 (600 mg) with peg-IFN alpha-2a (180 microg/week) or peg-IFN alpha-2a plus placebo. Treatment for all groups was for 28 days with 28 days of follow-up.

The mean age of patients in each group ranged from 32 to 48 years, with the older patients more likely to be treated with peg-IFN alpha-2a alone or with NVR 3-788. Most of the patients studied were Chinese and the mean baseline HBV DNA was 7.5-8.3 log₁₀ IU/mL.

A total of 98 adverse events were seen in 40 of 64 patients treated, although there was not any trend for more effects with the investigational treatment versus placebo as doses escalated. There were 21 adverse events seen in 20 of 46 patients that were possibly or probably related to the study drug, of which most were grade 1 nausea. Grade 2 nausea occurred only once in a patient given the 100-mg dose. There was one serious adverse event, a grade 3 papulovesicular rash on the hands and feet that occurred in a patient in the 100-mg group, but this responded to therapy. This side effect started about 20 days after treatment and resolved over a period of 7 months.

Although generally mild, more adverse effects were seen in the patients treated with a combination of NVR 3-788 and peg-IFN alpha-2a, which Dr. Yuen noted was thought to be more likely a result of the IFN therapy.

There was not much difference in the mean change in HBV DNA from baseline for the 100-400-mg groups, but there was a 1.72-log₁₀ IU/mL decrease achieved with the 600-mg twice-daily dose. The greatest reduction, however, was seen when NVR 3-788 was combined with peg-IFN alpha-2a, with a 1.97-log₁₀ IU/mL change.

“Encouraging early reductions in HBV RNA and quantitative serum HBeAg were observed,” Dr. Yuen said. He noted that the longer-term safety and efficacy of the novel agent in combination with peg-IFN alpha-2a and first-line HBV NAs will now be further assessed in phase II studies.

“At the moment we do not have a cure for hepatitis B, only treatment,” said Dr. Frank Tacke of the University Hospital Aachen (Germany), who chaired the press briefing where Dr. Yuen first aired the findings. NVR 3-788 represents “a totally new approach to this disease that we hope will lead to a cure,” Dr. Tacke said.

In an EASL-issued press release, Dr. Tacke also noted: “The results from this study are certainly interesting and promising for the treatment of patients with hepatitis B. The medical community is always on the lookout for treatments which can cure this condition, as opposed to simply suppressing the replication of the virus. More research is needed to confirm whether NVR 3-778 could really change the treatment paradigm.”

Novira Therapeutics financed the study. Dr. Yuen has been a consultant, speaker, or both for Arrowhead, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, and Roche. Dr. Tacke did not have any relevant disclosures.

BARCELONA – An investigational drug that targets the hepatitis B virus (HBV) core protein is a “totally new approach” to treating chronic HBV infection according to the results of an early-phase clinical study.

In an ongoing, international, phase I study presented during the late-breaker session at the International Liver Congress, 4 weeks of treatment with NVR 3-778 was well tolerated and did not result in any drug discontinuations in chronically infected patients. There were dose-related reductions in HBV DNA and early reductions in HBeAg were observed.

“NVR 3-778 is a first-in-class HBV core inhibitor,” study investigator Dr. Man-Fung Yuen, Queen Mary Hospital, Hong Kong, said at a press briefing held at the meeting, which is sponsored by the European Association for the Study of the Liver (EASL). “The HBV core protein has many functions and is responsible for the most important pathway of the virus’ replication – nucleocapsid formation,” he explained.

The rationale behind its development is that although there are effective treatments such as nucleoside and nucleotide analogs (NAs) and pegylated interferon (peg-IFN) that can suppress the activity of HBV for many years and thus slow down damage to the liver, it is unusual to clear the virus permanently. Furthermore, as most patients require potentially life-long treatment, issues such as long-term safety, patients’ adherence, resistance, and cost of therapy come into play.

Dr. Yuen observed that achieving durable responses in patients with chronic HBV is likely to require combinations of potential agents, probably with complementary modes of action.

Preclinical data have shown that NVR 3-778 induces the rapid assembly of nonfunctional capsids and that it inhibits viral replication in a humanized mouse hepatocyte cell model. It has also been shown to reduce HBV DNA to a comparable extent as entecavir when used alone in a mouse model, with undetectable levels reached when used in combination with peg-IFN alpha-2a.

Dr. Yuen reported the preliminary results from the second part of the phase I study in 64 adults with chronic HBV, noting that the first part of the study in healthy volunteers had been completed successfully.

The aim was to examine the safety and efficacy of NVR 3-778 alone and in combination with peg-IFN alpha-2a in previously untreated patients aged between 18 and 65 years who were HBsAg- and HbeAg-positive, had HBV DNA of 20,000 or more copies per IU/mL, with no cirrhosis of the liver, as determined by liver biopsy or imaging.

Patients were randomly assigned to six groups, with four groups receiving the investigational therapy alone at four increasing doses (100, 200, 400, once daily and 600 mg twice daily). There was a staged initiation of each escalating dose of NVR 3-778 used in these groups, with the 100 mg initiated first and if, after 2 weeks, there were no interim safety concerns, the next dose groups, 200 mg, then 400 mg, then 600 mg were started. The other two groups of patients received NVR 3-788 (600 mg) with peg-IFN alpha-2a (180 microg/week) or peg-IFN alpha-2a plus placebo. Treatment for all groups was for 28 days with 28 days of follow-up.

The mean age of patients in each group ranged from 32 to 48 years, with the older patients more likely to be treated with peg-IFN alpha-2a alone or with NVR 3-788. Most of the patients studied were Chinese and the mean baseline HBV DNA was 7.5-8.3 log₁₀ IU/mL.

A total of 98 adverse events were seen in 40 of 64 patients treated, although there was not any trend for more effects with the investigational treatment versus placebo as doses escalated. There were 21 adverse events seen in 20 of 46 patients that were possibly or probably related to the study drug, of which most were grade 1 nausea. Grade 2 nausea occurred only once in a patient given the 100-mg dose. There was one serious adverse event, a grade 3 papulovesicular rash on the hands and feet that occurred in a patient in the 100-mg group, but this responded to therapy. This side effect started about 20 days after treatment and resolved over a period of 7 months.

Although generally mild, more adverse effects were seen in the patients treated with a combination of NVR 3-788 and peg-IFN alpha-2a, which Dr. Yuen noted was thought to be more likely a result of the IFN therapy.

There was not much difference in the mean change in HBV DNA from baseline for the 100-400-mg groups, but there was a 1.72-log₁₀ IU/mL decrease achieved with the 600-mg twice-daily dose. The greatest reduction, however, was seen when NVR 3-788 was combined with peg-IFN alpha-2a, with a 1.97-log₁₀ IU/mL change.

“Encouraging early reductions in HBV RNA and quantitative serum HBeAg were observed,” Dr. Yuen said. He noted that the longer-term safety and efficacy of the novel agent in combination with peg-IFN alpha-2a and first-line HBV NAs will now be further assessed in phase II studies.

“At the moment we do not have a cure for hepatitis B, only treatment,” said Dr. Frank Tacke of the University Hospital Aachen (Germany), who chaired the press briefing where Dr. Yuen first aired the findings. NVR 3-788 represents “a totally new approach to this disease that we hope will lead to a cure,” Dr. Tacke said.

In an EASL-issued press release, Dr. Tacke also noted: “The results from this study are certainly interesting and promising for the treatment of patients with hepatitis B. The medical community is always on the lookout for treatments which can cure this condition, as opposed to simply suppressing the replication of the virus. More research is needed to confirm whether NVR 3-778 could really change the treatment paradigm.”

Novira Therapeutics financed the study. Dr. Yuen has been a consultant, speaker, or both for Arrowhead, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, and Roche. Dr. Tacke did not have any relevant disclosures.

BARCELONA – An investigational drug that targets the hepatitis B virus (HBV) core protein is a “totally new approach” to treating chronic HBV infection according to the results of an early-phase clinical study.

In an ongoing, international, phase I study presented during the late-breaker session at the International Liver Congress, 4 weeks of treatment with NVR 3-778 was well tolerated and did not result in any drug discontinuations in chronically infected patients. There were dose-related reductions in HBV DNA and early reductions in HBeAg were observed.

“NVR 3-778 is a first-in-class HBV core inhibitor,” study investigator Dr. Man-Fung Yuen, Queen Mary Hospital, Hong Kong, said at a press briefing held at the meeting, which is sponsored by the European Association for the Study of the Liver (EASL). “The HBV core protein has many functions and is responsible for the most important pathway of the virus’ replication – nucleocapsid formation,” he explained.

The rationale behind its development is that although there are effective treatments such as nucleoside and nucleotide analogs (NAs) and pegylated interferon (peg-IFN) that can suppress the activity of HBV for many years and thus slow down damage to the liver, it is unusual to clear the virus permanently. Furthermore, as most patients require potentially life-long treatment, issues such as long-term safety, patients’ adherence, resistance, and cost of therapy come into play.

Dr. Yuen observed that achieving durable responses in patients with chronic HBV is likely to require combinations of potential agents, probably with complementary modes of action.

Preclinical data have shown that NVR 3-778 induces the rapid assembly of nonfunctional capsids and that it inhibits viral replication in a humanized mouse hepatocyte cell model. It has also been shown to reduce HBV DNA to a comparable extent as entecavir when used alone in a mouse model, with undetectable levels reached when used in combination with peg-IFN alpha-2a.

Dr. Yuen reported the preliminary results from the second part of the phase I study in 64 adults with chronic HBV, noting that the first part of the study in healthy volunteers had been completed successfully.

The aim was to examine the safety and efficacy of NVR 3-778 alone and in combination with peg-IFN alpha-2a in previously untreated patients aged between 18 and 65 years who were HBsAg- and HbeAg-positive, had HBV DNA of 20,000 or more copies per IU/mL, with no cirrhosis of the liver, as determined by liver biopsy or imaging.

Patients were randomly assigned to six groups, with four groups receiving the investigational therapy alone at four increasing doses (100, 200, 400, once daily and 600 mg twice daily). There was a staged initiation of each escalating dose of NVR 3-778 used in these groups, with the 100 mg initiated first and if, after 2 weeks, there were no interim safety concerns, the next dose groups, 200 mg, then 400 mg, then 600 mg were started. The other two groups of patients received NVR 3-788 (600 mg) with peg-IFN alpha-2a (180 microg/week) or peg-IFN alpha-2a plus placebo. Treatment for all groups was for 28 days with 28 days of follow-up.

The mean age of patients in each group ranged from 32 to 48 years, with the older patients more likely to be treated with peg-IFN alpha-2a alone or with NVR 3-788. Most of the patients studied were Chinese and the mean baseline HBV DNA was 7.5-8.3 log₁₀ IU/mL.

A total of 98 adverse events were seen in 40 of 64 patients treated, although there was not any trend for more effects with the investigational treatment versus placebo as doses escalated. There were 21 adverse events seen in 20 of 46 patients that were possibly or probably related to the study drug, of which most were grade 1 nausea. Grade 2 nausea occurred only once in a patient given the 100-mg dose. There was one serious adverse event, a grade 3 papulovesicular rash on the hands and feet that occurred in a patient in the 100-mg group, but this responded to therapy. This side effect started about 20 days after treatment and resolved over a period of 7 months.

Although generally mild, more adverse effects were seen in the patients treated with a combination of NVR 3-788 and peg-IFN alpha-2a, which Dr. Yuen noted was thought to be more likely a result of the IFN therapy.

There was not much difference in the mean change in HBV DNA from baseline for the 100-400-mg groups, but there was a 1.72-log₁₀ IU/mL decrease achieved with the 600-mg twice-daily dose. The greatest reduction, however, was seen when NVR 3-788 was combined with peg-IFN alpha-2a, with a 1.97-log₁₀ IU/mL change.

“Encouraging early reductions in HBV RNA and quantitative serum HBeAg were observed,” Dr. Yuen said. He noted that the longer-term safety and efficacy of the novel agent in combination with peg-IFN alpha-2a and first-line HBV NAs will now be further assessed in phase II studies.

“At the moment we do not have a cure for hepatitis B, only treatment,” said Dr. Frank Tacke of the University Hospital Aachen (Germany), who chaired the press briefing where Dr. Yuen first aired the findings. NVR 3-788 represents “a totally new approach to this disease that we hope will lead to a cure,” Dr. Tacke said.

In an EASL-issued press release, Dr. Tacke also noted: “The results from this study are certainly interesting and promising for the treatment of patients with hepatitis B. The medical community is always on the lookout for treatments which can cure this condition, as opposed to simply suppressing the replication of the virus. More research is needed to confirm whether NVR 3-778 could really change the treatment paradigm.”

Novira Therapeutics financed the study. Dr. Yuen has been a consultant, speaker, or both for Arrowhead, Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Novartis, and Roche. Dr. Tacke did not have any relevant disclosures.