Core protein inhibitor, nuc combination shows promise in HBV
VIENNA — A combination of a core protein inhibitor and nucleos(t)ide analogue therapy brought hepatitis B virus RNA and DNA below levels of quantification, pointing toward the possibility of a cure, according to a presenter at the International Liver Congress.
“In both study 201 and 202, we are seeing the same story – very significant declines in viral nucleic acids,” Jacob Lalezari, MD, from Quest Clinical Research in San Francisco, said during his presentation. “The end game in all of this obviously is not the nucleic acids. It’s cure for hepatitis B, elimination of the cccDNA and elimination of the viral proteins. We expect the elimination of viral proteins to follow elimination of viral nucleic acids.”
Lalezari presented the interim results of two phase 2a studies where ABI-H0731 (Assembly Biosciences) was given in combination with nucleos(t)ide analogue (nuc) therapy. In the 201 cohort, Lalezari and colleauges looked at patients who were already suppressed on nucs (n = 73) and then received ABI-HO731 300 mg as a daily add-on therapy or placebo. In the 202 study, the same dosage of ABI-HO731 was delivered to patients (n = 25) who were treatment-naive but HBeAg-positive; in combination with ABI-HO731 or placebo, patients started entecavir.
The interim analysis of cohort 201 included 64 participants who completed 12 weeks of the study and nine who reached week 24. The interim analysis of cohort 202 included 24 participants who completed week 12 and 12 who completed week 24.
In discussing safety of the novel treatment, Lalezari showed a “smattering” of abnormal lab results but no signals and mentioned rash in two patients.
“Bottom line, the drug was safe and well tolerated and I don’t see a safety issue,” he said.
In the 202 cohort of treatment-naive, but high viral load participants, Lalezari said the combination arm showed quick impact.
“What we see is superior DNA reductions with the combination vs. the nuc alone starting at week 2. ... Faster and deeper declines with DNA that persist out to week 12 and to week 24,” he said. “With the DNA, so with the RNA. ... There were faster and deeper declines in RNA that again were manifest at week 2 and persisted out to week 12 and 24.”
At week 12, HBV DNA declines in the combination arm were 4.54 log10 IU/mL compared with 3.29 log10 IU/mL in the placebo plus encetevir group (P < .011). HBV RNA declined 2.27 log10 IU/mL in the combination arm and 0.44 log10 IU/mL in the placebo group (P < .005). Week 24 saw DNA declines of 5.94 log10 IU/mL vs. 3.99 log10 IU/mL (P < .005) and RNA declines of 2.54 log10 IU/mL vs. 0.61 log10 IU/mL (P < .005).
Lalezari explained that the nuc-suppressed group in the 201 cohort lend themselves to thinking more about a cure for HBV.
“There is a persistence of PCR positive virus below the 20 IU threshold,” he said. “That virus is infectious virus. That virus can infect hepatocytes.”
What he showed was the new combination therapy gets lower than previously seen.
“If you add the core inhibitor to the nuc therapy, you see resolution and elimination of the virus in five of six subjects over 8 to 16 weeks,” Lalezari said. “This is not elimination of virus but elimination down to the level of sensitivity of this assay.”
At week 12, participants receiving the combination therapy had reductions in HBV RNA levels of 2.34 log10 IU/mL compared with 0.05 log10 IU/mL in the group receiving nuc and placebo (P < .001). At week 24, combination therapy reduced 2.20 log 10 IU/mL vs. 0.15 log 10 IU/mL with placebo (P = .012).
“On the nuc for the 24 weeks, none of the subjects go undetectable, but then in contrast on the combination arm, 50% 60% of subjects are going below the level of quantification,” Lalezari said.
DNA persisted in the nuc plus placebo.
“You only see this elimination below the current threshold in the combination arm,” he said. “It’s giving us a sense of the time frame involved of what cure might look like in that subjects who are coming in fully suppressed are Still taking 2 to 6 months to get this virus closer to a true 0, at least in DNA.” – by Katrina Altersitz
Lalezari J. LB-06. Presented at: International Liver Congress; April 10-14, 2019; Vienna, Austria.
Disclosures: Lalezari reports serving as a consultant to Assembly Biosciences.