Multiple Hep B Targets in Development for New Treatments
Ingrid Hein
April 18, 2019
VIENNA — Three potential approaches to the treatment of hepatitis B, each targeting a different part of the virus, attracted attention here at the International Liver Congress 2019.
To achieve a cure, "many people believe that you will not have just one mechanism," said Markus Peck-Radosavljevic, MD, from Klinikum Klagenfurt in Austria.
Because the hepatitis B virus is a highly complex, "clever" virus, several approaches at the same time might be needed to eliminate it, he told Medscape Medical News.
Current treatment options control viral replication but do not eliminate it, he explained.
An initial phase 1b trial showed that ABI-H0731, a novel core protein inhibitor from Assembly Biosciences, reduced viral activity in patients with hepatitis B over a 28-day period when administered as a standalone treatment, and was well tolerated.
Now, interim results from two ongoing double-blind, placebo-controlled phase 2a clinical trials show that the addition of ABI-H0731 to standard care reduces hepatitis B RNA to undetectable levels in patients with chronic hepatitis B and stage F0 to F2 fibrosis. Novel Core Protein Inhibitor In the first trial, the 73 participants already suppressed with nucleos(t)ide polymerase inhibitors — 47 who tested positive for the hepatitis B e-antigen and 26 who did not — were randomized to receive additional once-daily ABI-H0731 300 mg or placebo.
In the 64 patients who had completed week 12 assessments, reductions in hepatitis B RNA levels were significantly larger in the ABI-H0731 group than in the placebo group (2.34 vs 0.05 log10 IU/mL; P < .001). In patients who had completed week 24 assessment, those reductions followed a similar pattern (2.20 vs 0.15 log10 IU/mL; P = .012).
In addition, DNA viremia dropped below the limits of a highly sensitive PCR assay in the ABI-H0731 group but was persistent in the placebo.
In the second phase 2a study, 25 treatment-naive patients who tested positive for hepatitis B e-antigen were randomized to the combination of entecavir plus once-daily ABI-H0731 300 mg or to entecavir plus placebo.
Reductions in hepatitis B RNA levels were also larger in the ABI-H0731 group than in the placebo group (2.54 vs 0.61 log10 IU/mL; P < .005).
In five of six patients who received a nucleos(t)ide polymerase inhibitor plus ABI-H0731, viral DNA was eliminated over a period of 8 to 16 weeks, said Jacob Lalezari, MD, from Quest Clinical Research in San Francisco. And in the sixth patient, the virus was close to eliminated at week 24.
The results come down to the level of sensitivity of the assay. "It's not a true zero, but it's below detection," he said, adding that "this has obviously never been shown before."
This gives us a sense of what the time frame for a cure might look like, he explained. "Patients coming in fully suppressed are still taking anywhere from 2 to 6 months to get this virus closer to a true zero, but at least there's a significant reduction in the DNA."
Three patients experienced a rash that cleared, but there were no other adverse events.
Final results after the two trials are completed are expected to be even better, Lalezari said. CAR T-Cell Modification Another treatment approach presented at the meeting involves stimulating T-cells extracted from an infected patient, modifying them to express chimeric antigen receptors (CAR) or T-cell receptors that specifically target the hepatitis B virus, and then returning them to the body.
"We introduce the receptors and they are able to find infected cells, bind to them, and destroy them," said Karin Wisskirchen, PhD, from the Institute of Virology at the Technical University of Munich.
"We think we can cure the patient this way because the T-cells resemble T-cells detected in patients who are able to clear hepatitis B infection on their own by attacking infected cells and thereby eliminating covalently closed circular [ccc]DNA," she explained.
In 2017, the US Food and Drug Administration (FDA) approved two CAR T-cell therapies, as reported by Medscape Medical News: tisagenlecleucel (Kymriah, Novartis), for relapsed or refractory acute lymphoblastic leukemia for young patients; and axicabtagene ciloleucel (Yescarta, Kite Pharma), for adults with relapsed or refractory diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after two or more lines of systemic therapy.
"This therapy has huge implications; it really is a major breakthrough in medicine," said Wisskirchen. "We know it works. We see the impact on leukemia. Children who did not have any chance are now running around happily; it's amazing."
"This is the ultimate personalized medicine," Peck-Radosavljevic told Medscape Medical News.
When cells are engineered for specific patients and then infused back to that patient, "the success has been incredible," he said, although he added that this strategy is way too expensive.
Eventually, it might become possible to treat more than one patient at a time. "It could become cheaper if you find a way to generate cells that can be injected into several patients," Wisskirchen said.
Her team is working with researchers in Germany and China to perform the first human clinical trial of a CAR T-cell hepatitis B therapy.
Another study, led by Lu Gao, MD, from the Roche Innovation Center in Shanghai, looked at ccc_R08, a novel cccDNA destabilizer, to treat hepatitis B infection in a mouse model. cccDNA Destabilizer After twice-daily treatment for 2 weeks, levels of hepatitis B DNA, pregenome (pg)RNA, hepatitis B surface antigen, and hepatitis B antigen were all significantly reduced in mice that had been transduced with circular DNA to replicate the hepatitis B virus, after the establishment of a cccDNA-like molecule.
Levels of cccDNA molecules in the livers of the mice fell below the lower limit of quantification.
When evaluating ccc_R08 in human hepatocytes infected with hepatitis B, cccDNA reductions had no effect on mitochondrial DNA or toxicity, Gao told the audience.
This is the first time in the history of this research that it has been demonstrated that something like this is feasible, she said.
"Our compound is very effective. I hope we only need a short-term treatment for this complicated mechanism," she added.
However, the current destabilizer does not completely eradicate the infection, and that means it can replicate, Gao acknowledged. "If you have just one copy, it could come back. Molecule target identification is still underway." Peck-Radosavljevic reports receiving grants from Gilead and MSD, and honoraria for consulting and lectures from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Janssen, and MSD. Lalezari is a consultant for Assembly Biosciences. Wisskirchen has disclosed no relevant financial relationships. Gao is an employee of the RocheR&DCenter (China) Ltd.
International Liver Congress (ILC) 2019: Abstract LBO-06, presented April 13, 2019; abstracts FRI-155 and PS-074, presented April 12, 2019.