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Sarasar with Norvir effectively delays HDV progression, may clear virus

WASHINGTON — Combination therapy with Sarasar and Norvir in patients with hepatitis D effectively blocked hepatitis D virus production, at all tested doses of Sarasar, according to a presentation at The Liver Meeting 2017. Longer treatment duration may clear the virus from the total extracellular body fluid.

“Up to 20 million people worldwide are infected with hepatitis delta and the majority of them will develop cirrhosis within 5 to 10 years,” Harel Dahari, PhD, from the program of experimental and theoretical modeling in the division of hepatology at the Loyola University Medical Center, Illinois, said in his presentation. “Compared to HBV mono-infected patients, HDV-infected patients will have a higher risk for progression to cirrhosis, hepatic decompensation, hepatocellular carcinoma and death.”

To confirm the efficacy of Sarasar (lonafarnib, Eiger BioPharmaceuticals) combined with Norvir (ritonavir, AbbVie) for HDV, the researchers conducted a study with a mathematical model that includes hepatocyte proliferation was used to estimate HDV kinetics parameters and treatment efficacy in blocking viral production using data from the phase 2 LOWR HDV-3 study conducted at the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. The model also included hepatocyte proliferation to estimate HDV-host kinetic parameters and treatment efficacy in blocking viral production.

The researchers randomized 21 patients into six groups that received daily doses of 50, 75, or 100 mg of lonafarnib with 100 mg of ritonavirdaily for 24 weeks (n = 12) or 12 weeks of placebo followed by 12 weeks of treatment with lonafarnib and ritonavir (n = 9). Additionally, all patients received hepatitis B nucleos(t)ide analogue therapy.

Median patient age was 40 years, 60% of patients were men, and most patients were Caucasian and Asian with elevated alanine aminotransferase levels and mild fibrosis.

Analysis based on 12 patients dosed for 24 weeks with frequent sampling indicates the following viral kinetic patterns among all dosing groups:

  • a triphasic response that consisted of a rapid initial viral load decline followed by slow/constant viral load decline with a third phase of renewed viral decay;
  • a flat partial response that consisted of a rapid viral load decline followed by a lower set point of viral load;
  • a pattern of virus rebound, in which the flat partial response or the triphasic response were followed by a rebound in viral load due to a varying effectiveness of the drug; and
  • non-response (no viral load declines in which patients were excluded from modeling).

Results of the model showed a delay of HDV production (median time of 48 hours), in which viral loads remained at pre-treatment levels, and that lonafarnib with ritonavir  had a 95% efficacy in blocking HDV production, regardless of lonafarnib dose. Viral rebound was due to a decline in treatment efficacy from approximately 95% to approximately 50% at 4 to 20 weeks after treatment initiation.

In comment to Healio.com/Hepatology, Dahari said, “The model suggests that an extended treatment duration of 26 to 76 weeks in those with the triphasic response, i.e., with a continuous viral decline, will reach viral clearance (<1 HDV particle) in the entire extracellular-body fluid.”

“Lonafarnib and ritonavir treatment dosed once daily was safe and generally well-tolerated,” Dahari said. “The model was able to reproduce the observed HDV RNA, HBV surface antigen and ALT kinetics in each patient and provides an insight into viral response to the drug.” – by Talitha Bennett

Reference:

Dubey P, et al. Abstract 38. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.

Disclosure: Dahari reports he received research grants from the NIH and Eiger BioPharmaceuticals.

Editor's note: This article has been updated with clarifications and additional comment from the presenter.

WASHINGTON — Combination therapy with Sarasar and Norvir in patients with hepatitis D effectively blocked hepatitis D virus production, at all tested doses of Sarasar, according to a presentation at The Liver Meeting 2017. Longer treatment duration may clear the virus from the total extracellular body fluid.

“Up to 20 million people worldwide are infected with hepatitis delta and the majority of them will develop cirrhosis within 5 to 10 years,” Harel Dahari, PhD, from the program of experimental and theoretical modeling in the division of hepatology at the Loyola University Medical Center, Illinois, said in his presentation. “Compared to HBV mono-infected patients, HDV-infected patients will have a higher risk for progression to cirrhosis, hepatic decompensation, hepatocellular carcinoma and death.”

To confirm the efficacy of Sarasar (lonafarnib, Eiger BioPharmaceuticals) combined with Norvir (ritonavir, AbbVie) for HDV, the researchers conducted a study with a mathematical model that includes hepatocyte proliferation was used to estimate HDV kinetics parameters and treatment efficacy in blocking viral production using data from the phase 2 LOWR HDV-3 study conducted at the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, NIH. The model also included hepatocyte proliferation to estimate HDV-host kinetic parameters and treatment efficacy in blocking viral production.

The researchers randomized 21 patients into six groups that received daily doses of 50, 75, or 100 mg of lonafarnib with 100 mg of ritonavirdaily for 24 weeks (n = 12) or 12 weeks of placebo followed by 12 weeks of treatment with lonafarnib and ritonavir (n = 9). Additionally, all patients received hepatitis B nucleos(t)ide analogue therapy.

Median patient age was 40 years, 60% of patients were men, and most patients were Caucasian and Asian with elevated alanine aminotransferase levels and mild fibrosis.

Analysis based on 12 patients dosed for 24 weeks with frequent sampling indicates the following viral kinetic patterns among all dosing groups:

  • a triphasic response that consisted of a rapid initial viral load decline followed by slow/constant viral load decline with a third phase of renewed viral decay;
  • a flat partial response that consisted of a rapid viral load decline followed by a lower set point of viral load;
  • a pattern of virus rebound, in which the flat partial response or the triphasic response were followed by a rebound in viral load due to a varying effectiveness of the drug; and
  • non-response (no viral load declines in which patients were excluded from modeling).

Results of the model showed a delay of HDV production (median time of 48 hours), in which viral loads remained at pre-treatment levels, and that lonafarnib with ritonavir  had a 95% efficacy in blocking HDV production, regardless of lonafarnib dose. Viral rebound was due to a decline in treatment efficacy from approximately 95% to approximately 50% at 4 to 20 weeks after treatment initiation.

In comment to Healio.com/Hepatology, Dahari said, “The model suggests that an extended treatment duration of 26 to 76 weeks in those with the triphasic response, i.e., with a continuous viral decline, will reach viral clearance (<1 HDV particle) in the entire extracellular-body fluid.”

“Lonafarnib and ritonavir treatment dosed once daily was safe and generally well-tolerated,” Dahari said. “The model was able to reproduce the observed HDV RNA, HBV surface antigen and ALT kinetics in each patient and provides an insight into viral response to the drug.” – by Talitha Bennett

Reference:

Dubey P, et al. Abstract 38. Presented at: The Liver Meeting; Oct. 20-24, 2017; Washington, D.C.

Disclosure: Dahari reports he received research grants from the NIH and Eiger BioPharmaceuticals.

Editor's note: This article has been updated with clarifications and additional comment from the presenter.

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