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Question to Replicor:'
In your next clinical trial, you plan to use pegIFN and thymosin alpha 1. PegIFN has potential side effects and Thymosin alpha 1 is very expensive. Have you considered using the latest generation of HBV vaccines or therapeutic vaccines, even HBSag monoclonal antibodies, as your immunomodulator? The subcutaneous version of your NAP seems to have taken a long time to develop, clinical trials were announced and postponed. Is there anything the research communities, pharmaceutical companies, governments or patient community can do to help push development and clinical trials to happen quicker?
Reply:
It took a long time to get the scientific / medical community to accept NAPs as a legitimate antiviral technology because of their novel biochemistry and potent antiviral responses. NAPs are now well accepted and we have used our previous trials to date to move the drug product to a formulation which is now easy to self administer via subcutaneous injection (SC). The proof of this was only achieved in our last trial with REP 2139-Mg (published in 2020). As for many other companies, the SARS CoV-2 pandemic has had a negative impact on our ability to initiate new clinical development but we have gone ahead to use SC REP 2139-Mg in compassionate use patients in France with very good results (http://replicor.com/wp-content/u ... rt2021-Poster-7.pdf) so we hope to be in a position to conduct the final phase IIA trial with SC REP 2139 in the very near future. The delay with the clinical development of NAPs is not because of any problems with the drug or with our science but is due to other unrelated issues. We are working as hard as we can to get REP 2139-Mg to patients as soon as possible.
Your question about immunotherapy is good one. There are two important steps in achieving functional cure: 1) clear SVP from the blood and 2) remove HBsAg producing capacity from the liver. With NAPs (1) is easy but (2) is more difficult. In all patients, HBsAg is also produced from integrated HBV DNA (which only efficiently produces HBsAg and SVP), this reservoir of HBsAg production gradually increases throughout HBV infection. Complicating this further is the presence of 1000’s of HBV quasispecies leading to many quasispeceis of HBV DNA integration producing many quasispecies of HBsAg. A final complication is that the only way to remove this reservoir is a broad HBsAg specific T-cell response capable or efficient removal of cells containing integrated HBV DNA.
So lets look at the pros and cons of the various immunotherapies in the context of HBV functional cure:
PegIFN - strong activation of existing pools of HBsAg specific T-cells but mild side effects in HBV.
Thymosin alpha 1 - strong activation of HBsAg specific T-cells with negligible side effects (not approved in many countries)
HBV vaccines - only one strain of HBsAg! poor induction of HBsAg specific T-cells.
Therapeutic HBV vaccines - stimulate T-cells but only to a small spectrum of HBsAg quasispecies because of a single strain of HBsAg antigen
HBsAg monoclonal antibodies: - not effect on T-cell stimulation, only one strain of HBsAg.
This is why you have not seen any combination trials of NAPs with these agents. The good news is that with NAPs we are able to reduce the dose of pegIFN from 180 to 90ug without affecting antiviral response.
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