Hi @Stephenw,
Indeed there has been a delay in the initiation of new phase II trials and we hope to have these underway soon. Issues in the field surrounding the NAP technology have been driven by a lack of understanding of phosphorothioate oligonucleotide chemistry, how NAPs work, their biochemical effects in the liver and how these impact safety, especially in view of the high prevalence of host mediated flares which routinely accompany NAP therapy (and the establishment of functional cure with other approved agents). These safety concerns in the community are best addressed by deploying REP 2139-Mg in very sick patients with very advanced liver disease (something which is very difficult to do in a phase II trial). The compassionate use of REP 2139-Mg in patients with compensated and decompensated cirrhosis provides a unique safety assessment which more effectively expands the safety envelope and addresses these safety concerns than additional assessments in patient populations we have already examined where liver disease is less advanced. REP 2139-Mg to date is the only antiviral agent other than NUCs which is proving to be safe and effective in patients with decompensated cirrhosis. These compassionate use cases are also quickly demonstrating the efficacy of once weekly SC administration of REP 2139-Mg which will be the mode of administration moving forward. You should look for the data from the compassionate access program to expand to a MUCH greater number of patients from many different countries and well known investigators during the spring / summer cycle of meetings. Of course phase II trials are on the way and if you are not already subscribed to our newsletter, please ask to be subscribed at info@replicor.com to get the latest news.
With regards to HBV quasispecies, some important corrections are needed to your comments. While prophyactic vaccination against horizontal transfer is highly effective, there is a significant percentage of vaccine breakthrough following birth dose vaccination in vertical (maternal) transfer (up to 30% in some populations) see here, here, here and here. The rapid evolution in HBV quasispecies is the reason for this breakthrough see here and here.
It is important to note that the most recent therapeutic vaccine trial with VBI-2601 / BRI-179 (see here) failed to achieve any reduction of HBsAg despite the induction of anti-HBsAg titers > 1000 mIU/mL, again due to quasispecies escape. This will be the fundamental challenge of all therapeutic vaccines in development for chronic HBV.
It is also important to understand that later generation NUCs such as ETV, TDF and TAF have well characterized ability to stimulate the innate immune response by stimulation of TLR7 by guanosine (ETV) or stimulation of the purine P1 receptor by tenofovir (TDF / TAF) which are well characterized and the effects of which have been observed in clinical trials here, here and here which drive declines in HBV RNA and HBcrAg see here, here and here. This additional effect of ETV and TDF/TAF is the underlying mechnism for the lack of vifral breakthrough which occurred with earlier generation NUCs (ADV and 3TC) which have far weaker immunostimulatory properties.
Recombinant monoclonal antibodies (like VIR-3434) do have immediate reductions of HBsAg but with finite effect, leaving significant amounts of HBsAg present despite the presence of uncomplexed free VIR-3434, even though they are designed to be “broadly reactive”. This VIR-3434 escape HBsAg is certainly a function of HBsAg quasispecies. In addition, IV infusion of IgG is known to alter immune function and this has not yet been considered in the antiviral responses to VIR-3434.