GlobeImmune has revealed an investigational therapeutic vaccine being developed to treat chronic hepatitis B virus (HBV) infection has suffered a setback in its Phase II clinical trial. Results from the GS-US-330-0101 trial showed the vaccine, GS-4774, failed to meet itsprimary endpoint of reducing the serum levels of HBV surface antigen (HBsAg) in virally-suppressed patients. Analysts from GlobalData agree the results may hurl the future of the GS-4774 vaccine into serious doubt. The failure of GS-4774 underscores the difficulty in developing an effective vaccine,despite thehigh demand for novel treatments within the medical community.

The GS-4774 vaccine comprises of heat-inactivated yeast cells that express well-conserved regions of the HBV core antigen (HBcAg, the HBV X protein (HBx), and HBsAg. The vaccine, which GlobeImmune is developing in collaboration with Gilead Sciences, is primarily designed to induce HBV-specific host T-cell response.This is a mechanism of action (MOA) that differs from oral nucleoside analogues (NAs) and recombinant human interferon (IFN)-type treatments currently in the market.

The results of a Phase I clinical trial showed that GS-4774, at a dose equivalent to the highest dose used in the GS-US-330-0101 trial, achieved immune responses in 90% of the healthy participants. Encouraged by these results, GlobeImmune and Gilead initiated two Phase II studies, with the aim of investigating the safety and efficacy of GS-4774 in two distinct patient populations: in virally-suppressed patients, and in treatment-naïve patients in combination with NAs. The trial in treatment-naïve patients (GS-US-330-1401) is ongoing, with the initial results expected in mid-2016.

The first of these two studies to report top-line results, GS-US-330-0101, recruited 178 patients with chronic HBV infection who were using NAs to control the disease. This was a randomized, open-label trial with four arms: NA only; and NA plus GS-4774 at two, 10, or 40 yeast units (YU; 1 YU = 10 million yeast cells), administered via subcutaneous injection every four weeks, for a total of six doses. However, even the highest dose of GS-4774 failed to produce any improvement in the HBsAg level compared with the NA-only group at 24 weeks. Although it showed a numerical decrease in the HBsAg serum levels at 48 weeks, the observed reduction was not statistically significant.

The current treatment landscape for chronic HBV is dominated by NAs and IFN-type treatments, so agents with novel MOAs, such as GS-4774, are the primary focus of R&D efforts in this area. Although the available drugs are able to control the disease in many patients, experts interviewed by GlobalData stated that the immediate targets for the future management of chronic HBV infection include improving treatment outcomes and achieving a cure.

Treatment success in chronic HBV infection is measured in a number of stages. The main effects of the available NAs are a reduction in and maintenance of HBV DNA and alanine aminotransferase (ALT) levels, and limitation on liver injuries. However, they can rarely achieve the loss of HBsAg, which is an indication of HBV clearance. IFN-type treatments offer a better long-term outcome than NAs, but they have poor adverse reaction profiles and are only effective in and used by a small proportion of patients. Thus, the reduction or clearance of serum HBsAg is an important measure of improvement in the treatment outcome in chronic HBV infection. Many pipeline products aim to address these clinical unmet needs, such as Arrowhead’s experimental RNA interference (RNAi) treatment, ARC-520, and Gilead’s investigational toll-like receptor 7 (TLR7) agonist, GS-9620. Currently, many such products are being tested as adjuncts to oral NAs, and aim for serum HBsAg reduction. This strategy, if successful, could improve the outcome of NA treatments and avoid long-term — or in many cases, lifelong — treatment, while providing comparable efficacy to the IFN-type treatments, to most patients and with reduced adverse effects.

The future plan for GS-4777 lies largely in the hands of Gilead, which will likely base its decision whether to continue this collaboration on the data gleaned from the two aforementioned Phase II studies. The US-based pharmaceutical giant is already a major player in the chronic HBV marketplace, with two marketed NAs, Hepsera (adefovir dipivoxil) and the first-line option, Viread (tenofovirdisoproxil fumarate [TDF]). The company also has an active late-stage chronic HBV pipeline that consists of tenofovir alafenamide fumarate (TAF), which is in Phase III of clinical development, and GS-4774 and GS-9620, which are both in Phase II. Further analysis of the data from the completed GS-US-330-0101 trial is underway. In addition, the results of the ongoing GS-US-330-1401 trial may also bring fresh prospects for the vaccine candidate. Despite this setback for GS-4774, the diversity of the chronic HBV pipeline provides an optimistic outlook for the future treatment landscape.


*This article first appeared on GlobalData on 29th May 2015