Project: Superinfection Therapy of Advanced Hepatitis C Virus Infection

Hepatitis C virus (HCV) persists in a chronic carrier state in about 170 million people worldwide. It serves as a reservoir for infection and gives rise to chronic hepatitis and cirrhosis. Advanced decompensated, cirrhotic hepatitis patients have no other option than liver transplantation. Unfortunately, many patients cannot survive until a suitable donor is found._x000D__x000D_It is therefore very painful to accept with resignation that in the last 10 years adult-to-adult living donor liver organ transplantations have increasingly been carried out in many countries. Why one have to wait for new drugs and put the health of living donors at risk, when the proof-of-concept of a safe and efficient therapy has already been demonstrated in preliminary clinical trials?_x000D__x000D_This proposal, therefore, is aimed at providing sufficient preclinical data for the future initiation of a new clinical trial for the viral superinfection therapy that has already been successfully tested in several advanced cirrhotic patients with life threatening conditions without significant side effects. Such results challenge the current assumption that decompensated chronic hepatitis patients are untreatable._x000D__x000D_The viral superinfection therapy is a creative and highly innovative idea, which is based on the observation that replication of two different (often unrelated) viruses may interact in co-infected patients. The dominant virus terminates the replication of the other virus. Thus, instead of targeting elusive viral antigens, viral competition should be exploited to resolve persistent viral infections._x000D_A non-pathogenic double-stranded RNA virus, the avian infectious bursal disease virus (IBDV) was chosen for superinfection. IBDV is highly resistant to low pH conditions that allows its passage through the digestive system. Importantly, from a safety point of view, IBDV is not known to be a hazard in transmitting to other species despite its worldwide distribution in domestic fowl and it has been used as a fowl vaccine for decades._x000D__x000D_Unfortunately, the previous proof-of-concept clinical studies were performed with an uncharacterized viral strain that is not acceptable for approval as a drug. _x000D_To this end a new attenuated IBDV strain (V903/78) has already been isolated and cloned. This strain was chosen because it grows exceptionally well in Vero cells allowing efficient manufacture on mammalian cell culture. Preliminary studies indicate that the virus has a unique nucleotide sequence and does not have any deleterious effects on human liver cells. _x000D_The safety of the viral competition strategy could, however, be greatly improved by using a recombinant virus to avoid the disadvantages of the conventional virus passage approaches. To this end, a recombinant vaccine candidate (R903/78) virus has been generated by reverse genetics. The recombinant IBDV technology is patent pending intellectual property for the treatment of advanced, interferon-resistant cases of chronic HCV._x000D__x000D_In the current proposal we will carry out the most important initial safety, efficacy and mechanism of action preclinical studies to develop a well-characterized recombinant viral vector. Within two years following this project a preclinical dossier will have been completed and regulatory approval obtained to take this concept to a clinical project. _x000D_We will determine whether (i) the R903/78 is reasonably safe for initial use in decompensated cirrhosis, (ii) exhibits pharmacological activity that justifies limited, early-stage clinical studies, and (iii) what is the mechanism of action of IBDV superinfection. To this end the R903/78 will be characterized in vitro and in vivo (e.g. determination of its growth, stability, cytokine induction, and neutralizing antibody generation). The bio-distribution of orally delivered R903/78 virus will be followed in mice using PCR. Mechanism of action studies will be performed in vitro and in vivo model systems respectively._x000D__x000D_Our German P will develop a cGMP-compliant manufacturing process that would enable commercial scale production for the clinical trials. In order to bring the product to the clinic within two years of this project, it is important that the preclinical characterization and the production process development of the R903/78 virus are carried out in parallel._x000D__x000D_The ultimate goal of this project is to develop an orally administered recombinant IBDV therapeutic virus, for the treatment of advanced, interferon-resistant cases of chronic HCV infections._x000D_The project consortium consists of the Corporate Values Kft and the Vibalogics GmbH meeting biological and managerial challenges respectively, in order to ensure the development of a commercially viable safe and effective drug candidate._x000D__x000D_Most relevant references:_x000D_ 1. T. Bakacs, J. N. Mehrishi, Vaccine 23, 3 (2004). _x000D_ 2. L. B. Seeff, Liver Int 29 Suppl 1, 89 (2009)._x000D_ 3. D. Lavanchy, Liver Int 29 Suppl 1, 74 (2009)._x000D_ 4. C. Upadhyay, A., et al, J Virol 85, 1408 (2011)._x000D__x000D__x000D__x000D__x000D__x000D_

Acronym	Superinfection (Reference Number: 6559)
Duration	01/12/2011 - 31/05/2014
Project Topic	This project is a radically new idea. We wish to exploit viral competition between a non-pathogenic (IBDV) and a pathogen virus (HCV) for the treatment of persistent viral infections using a recombinant virus. The proof of concept was demonstrated in clinical trial (phase I/II) in 90s in Hungary.
Project Results (after finalisation)	- Establishment of a scalable, GMP-compliant manufacturing process for Infectious Bursal Disease Virus (IBDV) strain R903/78 on adherent VERO cells using single-use, fixed bed bioreactor technology (iCELLis, PALL Corporation)_x000D_- Establishment of quality control assays for our Ps IBDV strain R903/78 enabling product characterization and release testing_x000D_- Implementation of new equipment and technologies (bioreactor, cross-flow filtraton, virus particle analyzer)_x000D_- Filing of a patent covering VERO cell cultivation in fixed-bed bioreactor system_x000D_- Supply of our P with pivotal IBDV R903/78 virus material to enable critical pre-clinical studies_x000D_- Signature of a consortium agreement that gives Vibalogics rights for manufacture of clinical phase GMP material from Phase I to Phase III
Network	Eurostars
Call	Eurostars Cut-Off 6

Project partner

Number	Name	Role	Country
2	Corporate Values Kft.	Partner	Hungary
2	Vibalogics GmbH	Coordinator	Germany