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Investigational Therapies Show Promise in HBV (CME/CE)

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Investigational Therapies Show Promise in HBV

Agents offer early, but unsustained, antiviral activity

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  • by Contributing Writer, MedPage Today
  • This article is a collaboration between MedPage Today® and:

    Medpage Today

Action Points

  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Two investigative agents for the treatment of hepatitis B virus (HBV) demonstrated antiviral activity at 28 days, but when treatment was stopped levels of HBV DNA had returned to nearly the pre-treatment level.
  • Note that in each of these small studies, the experimental agent was relatively well-tolerated during the treatment period.

PARIS — Two investigative agents for the treatment of hepatitis B virus (HBV) demonstrated antiviral activity at 28 days, but long-term results were less promising, researchers reported here.

The core protein allosteric modulator RO7049389 exhibited robust anti-HBV activity, and was safe and well tolerated, according to Edward Gane, MBChB, MD, of the University of Auckland in New Zealand, and colleagues.

In the study, six HBV patients were treated with 200 mg twice a day of the drug for 28 days, while one other patient received placebo. Those receiving the active agent had a 2.7log10 reduction in IU/mL. Three patients who were HbeAg-negative had readings that were lower than the level of detection of the assay, he added.

In a second study, Fabien Zoulim, MD, PhD, of the Hospices Civils de Lyon in France, reported the safety and antiviral activity of JNJ-56136379, a capsid assembly modulator, in 25 HBV compared with 11 HBV patients treated with placebo.

Both studies were presented at the International Liver Congress, the annual meeting for the European Association for the Study of the Liver (EASL).

RO7049389 Study Details

RO7049389 “induces formation of abnormal … HBV core aggregates resulting in defective capsid assembly thereby suppressing HBV replication. In the AAV-HBV mouse model, robust HBV DNA declines (about 3.0 log10 copies/ml) were observed over 56 days of dosing,” Gane’s group explained.

The study has two parts, with part 1 evaluating the safety, tolerability, pharmacokinetics, and anti-HBV activity of the agent. Part 2 is evaluating the safety and pharmacokinetics of single ascending doses (SAD) of RO7049389/placebo (five dosing cohorts from 150–2,000 mg) and multiple ascending doses (five dosing cohorts from 200–800 mg BID x 14 days) in healthy volunteers, as well as anti-HBV effects of the agent in untreated chronic HBV (four planned cohorts BID x 28 days).

The authors reported that, across the dosing range, the agent was rapidly absorbed and eliminated from plasma.

“A trend of greater than dose-proportional increases in exposure from 150 to 1,000 mg, and approximately dose-proportional increases from 1,000 to 2,000 mg were observed in SAD cohorts,” they noted.

In part 1, a total of 55 adverse events were reported in 36/75 healthy volunteers. In part 2, a total of 14 adverse events were reported in three of 7 patients.

All were reported as being mild in intensity with only five being considered as related to the study drug (nausea, abdominal discomfort, rash, and two cases of headache).

No serious adverse events, or events leading to drug discontinuation, were reported and there were no clinically significant changes in ECG parameters, vital signs, or laboratory safety test.

Six untreated chronic HBV patients completed 28 days dosing period with the agent, at a dose of 200 mg BID.

“Robust and continued HBV DNA declines from pre-dosing levels were observed, with median (maximal) decline being 2.7 (3.4) log10 IU/ml and below the limits of detection in 3/6 patients,” the authors wrote.

However, Gane reported that when treatment stopped, the level of HBV DNA had returned to nearly the pre-treatment levels.

“Ongoing cohorts will explore higher doses and once daily dosing of RO7049389 and changes in other biomarkers, including HbsAg levels,” he said. “These preliminary data support the further development of RO7049389 as a potential component of a novel hepatitis B virus cure regimen.”

JNJ-56136379 Study Details

In the second study, Zoulim explained that JNJ-56136379 binds to the HBV core protein, and disrupts early and late-stage processes in the virus life cycle. JNJ-56136379 prevents the encapsidation of RNA and blocks hepatitis B virus replication.

His group enrolled treatment-naive, HBeAg-positive or HBeAg-negative chronic HBV patients, with plasma HBV DNA >2000 IU/mL, METAVIR, ALT/AST <2.5 the upper limit of normal in the phase Ib study.

Patients were randomized in a 3:1 ratio to receive JNJ-6379 or placebo for 28 days, with 8 weeks follow-up. At the time of presentation, three groups had been evaluated:

  • 25 mg QD (after 100 mg loading dose)
  • 75 mg QD
  • 150 mg QD

Evaluation of a fourth group (250 mg QD) is ongoing, they noted.

Across all 36 patients in the groups, the median age was 42.5, 83% were men, and 78% were Caucasian. A quarter of patients were HBeAg-positive.

At day 29, the authors reported substantial reductions from baseline in HBV DNA and HBV RNA in all three treatment groups. There were no notable changes in HBsAg.

Adverse events (AEs) or laboratory abnormalities ≥Grade 3 were infrequent (≤3 patients/dose), with 64% experiencing ≥1 adverse event on treatment:

  • 25 mg: n=9/12
  • 75 mg: n=6/12
  • 150 mg: n=8/12

There was one serious right frontal lobe mass unrelated to study drug; one discontinuation due to isolated ALT/AST flare with no bilirubin elevation that was likely related to study drug; and no dose-limiting toxicities.

“After repeated administration, drug exposure increased in a dose-dependent manner,” they noted.

In the 8-week follow-up period, HBV levels rebounded to nearly baseline, Zoulim said.

“All three of these dose regimens were safe and well tolerated, and displayed dose-proportional pharmacokinetics,” Zoulim said. “A phase IIa study in treatment-naive and virologically-suppressed HbsAg-positive and -negative patients has been initiated to evaluate JNJ- 56136379 alone or in combination with nucleoside analogs.”

‘Long Way to Go’

“We still have a long way to go in finding a cure regimen for patients with HBV infections that will equal our success with hepatitis C [HCV] virus,” said EASL session co-moderator Giorgina Mieli-Vergani, MD, PhD, of King’s College London.

“It is most likely that these agents will have to be combined with other classes of antivirals in order to achieve the cures that we see in HCV-infected patients,” she told MedPage Today.

She noted that the rebound effects seen in these preliminary trials were reminiscent of what happened when patients with HIV attempted to stop or interrupt medication.

The study by Gane’s Group was funded by Roche. The study by Zoulim’s group was funded by Johnson & Johnson.

Gane disclosed relevant relationships with Alios, Alnylam, Arbutus, Arrowhead, Assembly, BMS, Eiger, Gilead, Janssen, GlaxoSmithKline, Novartis, and Roche.

Zoulim and Mieli-Vergani disclosed no relevant relationships with industry.

2018-04-16T15:30:00-0400
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Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.

Medpage Today

Investigational Therapies Show Promise in HBV

Agents offer early, but unsustained, antiviral activity

MedpageToday

  • register today

    Earn Free CME Credits by reading the latest medical news in your specialty.

    sign up

  • by Contributing Writer, MedPage Today
  • This article is a collaboration between MedPage Today® and:

    Medpage Today

Action Points

  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • Two investigative agents for the treatment of hepatitis B virus (HBV) demonstrated antiviral activity at 28 days, but when treatment was stopped levels of HBV DNA had returned to nearly the pre-treatment level.
  • Note that in each of these small studies, the experimental agent was relatively well-tolerated during the treatment period.

PARIS -- Two investigative agents for the treatment of hepatitis B virus (HBV) demonstrated antiviral activity at 28 days, but long-term results were less promising, researchers reported here.

The core protein allosteric modulator RO7049389 exhibited robust anti-HBV activity, and was safe and well tolerated, according to Edward Gane, MBChB, MD, of the University of Auckland in New Zealand, and colleagues.

In the study, six HBV patients were treated with 200 mg twice a day of the drug for 28 days, while one other patient received placebo. Those receiving the active agent had a 2.7log10 reduction in IU/mL. Three patients who were HbeAg-negative had readings that were lower than the level of detection of the assay, he added.

In a second study, Fabien Zoulim, MD, PhD, of the Hospices Civils de Lyon in France, reported the safety and antiviral activity of JNJ-56136379, a capsid assembly modulator, in 25 HBV compared with 11 HBV patients treated with placebo.

Both studies were presented at the International Liver Congress, the annual meeting for the European Association for the Study of the Liver (EASL).

RO7049389 Study Details

RO7049389 "induces formation of abnormal ... HBV core aggregates resulting in defective capsid assembly thereby suppressing HBV replication. In the AAV-HBV mouse model, robust HBV DNA declines (about 3.0 log10 copies/ml) were observed over 56 days of dosing," Gane's group explained.

The study has two parts, with part 1 evaluating the safety, tolerability, pharmacokinetics, and anti-HBV activity of the agent. Part 2 is evaluating the safety and pharmacokinetics of single ascending doses (SAD) of RO7049389/placebo (five dosing cohorts from 150–2,000 mg) and multiple ascending doses (five dosing cohorts from 200–800 mg BID x 14 days) in healthy volunteers, as well as anti-HBV effects of the agent in untreated chronic HBV (four planned cohorts BID x 28 days).

The authors reported that, across the dosing range, the agent was rapidly absorbed and eliminated from plasma.

"A trend of greater than dose-proportional increases in exposure from 150 to 1,000 mg, and approximately dose-proportional increases from 1,000 to 2,000 mg were observed in SAD cohorts," they noted.

In part 1, a total of 55 adverse events were reported in 36/75 healthy volunteers. In part 2, a total of 14 adverse events were reported in three of 7 patients.

All were reported as being mild in intensity with only five being considered as related to the study drug (nausea, abdominal discomfort, rash, and two cases of headache).

No serious adverse events, or events leading to drug discontinuation, were reported and there were no clinically significant changes in ECG parameters, vital signs, or laboratory safety test.

Six untreated chronic HBV patients completed 28 days dosing period with the agent, at a dose of 200 mg BID.

"Robust and continued HBV DNA declines from pre-dosing levels were observed, with median (maximal) decline being 2.7 (3.4) log10 IU/ml and below the limits of detection in 3/6 patients," the authors wrote.

However, Gane reported that when treatment stopped, the level of HBV DNA had returned to nearly the pre-treatment levels.

"Ongoing cohorts will explore higher doses and once daily dosing of RO7049389 and changes in other biomarkers, including HbsAg levels," he said. "These preliminary data support the further development of RO7049389 as a potential component of a novel hepatitis B virus cure regimen."

JNJ-56136379 Study Details

In the second study, Zoulim explained that JNJ-56136379 binds to the HBV core protein, and disrupts early and late-stage processes in the virus life cycle. JNJ-56136379 prevents the encapsidation of RNA and blocks hepatitis B virus replication.

His group enrolled treatment-naive, HBeAg-positive or HBeAg-negative chronic HBV patients, with plasma HBV DNA >2000 IU/mL, METAVIR, ALT/AST <2.5 the upper limit of normal in the phase Ib study.

Patients were randomized in a 3:1 ratio to receive JNJ-6379 or placebo for 28 days, with 8 weeks follow-up. At the time of presentation, three groups had been evaluated:

  • 25 mg QD (after 100 mg loading dose)
  • 75 mg QD
  • 150 mg QD

Evaluation of a fourth group (250 mg QD) is ongoing, they noted.

Across all 36 patients in the groups, the median age was 42.5, 83% were men, and 78% were Caucasian. A quarter of patients were HBeAg-positive.

At day 29, the authors reported substantial reductions from baseline in HBV DNA and HBV RNA in all three treatment groups. There were no notable changes in HBsAg.

Adverse events (AEs) or laboratory abnormalities ≥Grade 3 were infrequent (≤3 patients/dose), with 64% experiencing ≥1 adverse event on treatment:

  • 25 mg: n=9/12
  • 75 mg: n=6/12
  • 150 mg: n=8/12

There was one serious right frontal lobe mass unrelated to study drug; one discontinuation due to isolated ALT/AST flare with no bilirubin elevation that was likely related to study drug; and no dose-limiting toxicities.

"After repeated administration, drug exposure increased in a dose-dependent manner," they noted.

In the 8-week follow-up period, HBV levels rebounded to nearly baseline, Zoulim said.

"All three of these dose regimens were safe and well tolerated, and displayed dose-proportional pharmacokinetics," Zoulim said. "A phase IIa study in treatment-naive and virologically-suppressed HbsAg-positive and -negative patients has been initiated to evaluate JNJ- 56136379 alone or in combination with nucleoside analogs."

'Long Way to Go'

"We still have a long way to go in finding a cure regimen for patients with HBV infections that will equal our success with hepatitis C [HCV] virus," said EASL session co-moderator Giorgina Mieli-Vergani, MD, PhD, of King's College London.

"It is most likely that these agents will have to be combined with other classes of antivirals in order to achieve the cures that we see in HCV-infected patients," she told MedPage Today.

She noted that the rebound effects seen in these preliminary trials were reminiscent of what happened when patients with HIV attempted to stop or interrupt medication.

The study by Gane's Group was funded by Roche. The study by Zoulim's group was funded by Johnson & Johnson.

Gane disclosed relevant relationships with Alios, Alnylam, Arbutus, Arrowhead, Assembly, BMS, Eiger, Gilead, Janssen, GlaxoSmithKline, Novartis, and Roche.

Zoulim and Mieli-Vergani disclosed no relevant relationships with industry.

2018-04-16T15:30:00-0400
Take Posttest Comments

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.



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