For adults with chronic hepatitis B virus infection, treatment with a novel investigational capsid assembly modulator was well tolerated and showed antiviral activity against HBV, according to the results of a phase 1 study of 73 patients.
CDC/Dr. Erskine Palmer
This digitally colorized transmission electron micrograph reveals the presence of hepatitis B virions. The large round virions are known as Dane particles.
“Substantial and correlated reductions in serum HBV DNA and HBV RNA levels were observed consistently with the higher-dose cohorts and were notably greatest for combination treatment with NVR 3-778 and pegIFN [pegylated interferon],” Man Fung Yuen, MD, of the University of Hong Kong, and his associates wrote in a report published in Gastroenterology. Hence, this first-in-class capsid assembly modulator might help prolong treatment responses, “most likely as a component of new combination treatment regimens for HBV-infected patients.” However, one patient developed severe rash immediately after completing treatment that took 6 months of intensive outpatient treatment to resolve, they noted.
Chronic viral hepatitis due to HBV is a major cause of early death worldwide, and new therapies are needed to help prevent severe liver disease and liver death from this infection. Current treatments for HBV infection consist of nucleoside or nucleotide analogs or pegylated interferon. These suppress HBV replication in many patients, but most patients do not achieve durable responses. Consequently, most patients require long-term treatment with HBV nucleosides and nucleotide analogs, which they may find difficult to tolerate or adhere to and to which their infections can become resistant, the researchers said.
The HBV virion contains a viral core protein (HBc) that is required to encapsidate viral polymerase and pregenomic HBV RNA into a nucleocapsid. To target this process, researchers developed NVR 3-778, a first-in-class, orally bioavailable small molecule that binds HBc so that HBc forms a defective capsid that lacks nuclear material. Hence, NVR 3-778 is intended to stop the production of HBV nucleocapsids and keep infected cells from releasing the enveloped infectious viral particles that perpetuate HBV infection.
To assess the safety, pharmacokinetics, and antiviral activity of NVR 3-778, the researchers conducted a phase 1 study of 73 patients with chronic HBV infection who tested positive for hepatitis B e-antigen (HBeAg) and had no detectable cirrhosis. Patients were randomly assigned to receive oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1,000 mg twice daily ) or placebo for 28 days. Some patients received combination therapy with pegylated interferon plus either NVR 3-778 (600 mg twice daily) or placebo. Treatment was generally well tolerated, and adverse events were usually mild and deemed unrelated to therapy. No patient stopped treatment for adverse effects.
The only serious adverse event in the study consisted of grade 3 rash that developed in a 42-year-old male after 22 days of treatment at the lowest dose of NVR 3-778 (100 mg per day). This patient completed treatment and ultimately developed a severe papulovesicular rash with a predominantly acral distribution over the hands, arm, side of neck, and one leg (palmar plantar erythrodysesthesia), the researchers said. “There were no perioral or mucosal lesions, no ecchymotic skin involvement, no bullae, and no systemic manifestations or hematological abnormalities,” they wrote. “The rash was subsequently managed with a psoriasis-like treatment regimen of psoralen, ultraviolet light, and topical steroid ointment during outpatient follow-up and resolved after approximately 6 months.”
Another three cases of “minor” skin rash were considered probably related to treatment in the cohort that received 600 mg NVR 3-778 b.i.d. plus pegylated interferon, the investigators said. Two additional cases of mild rash were deemed unrelated to treatment.
“The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778,” the researchers concluded. “This class of compounds can also inhibit replenishment of intranuclear covalently closed circular DNA over time and may have immunomodulatory properties.” Longer treatment periods would be needed to study these mechanisms and to quantify reductions in serum HBsAg and HBeAG, they noted.
Novira Therapeutics developed NVR 3-778 and is a Janssen Pharmaceutical Company. Janssen provided funding for editorial support. Dr. Yuen disclosed relationships with AbbVie, Biocartis, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Ionis, Roche, Vir Biotechnology, and several other pharmaceutical companies. Other coinvestigators disclosed ties to pharmaceutical companies; eight reported employment by Novira or a Janssen company.
SOURCE: Yuen MF et al. Gastroenterology. 2019 Jan 5. doi: 10.1053/j.gastro.2018.12.023.