Today's opening sessions had a good deal of promising information. Several new drugs in development for HCV were discussed. And new data on a couple of these drugs will be presented at this meeting over the course of the next few days. In addition there was a talk today on vaccine development. The speaker presented encouraging information on the possibility for development of a preventative and a therapeutic vaccine for HCV. But he cautioned that he didn't expect a drug until 2006. He suggested that a successful vaccine would have to stimulate both a CD4 response specific for HCV and a CD8 CTL response. In animals, that type of response was promising against HCV. The same type of response appears important to responding to HIV and a vaccine has yet to be developed.
Acutely infected humans who clear HCV characteristically produce a vigorous, polyclonal, and multispecific CTL (cytotoxic lymphocyte) response. In contrast, those that progress to chronic infection fail to display HCV specific CTL or develop a narrowly focused T cell response. Obviously, most people are unable to mount an effective response upon infection because 80-85% develop chronic infection.
HCV Protease
Although the structure of the HCV protease has been characterized, this structure seems to be difficult to create a drug for. Johnson Lau, formerly with Schering Plough and now with ICN, is developing a new ribivarin type drug. In fact, at least 2 new and more effective ribivarin type drugs are in development. But Lau described why it is difficult to develop a protease inhibitor for HCV. There are multiple cavities into which a protease inhibitor would go, therefore Lau says a large molecule would be necessary to accomplish this. However, you need a small molecule for oral absorption.
It may be possible to develop a drug administered by subcutaneous injection but obviously oral administration is preferred. In addition, if you put HCV into a cell culture with a drug to see if that drug inhibits replication, HCV disappears. This is unlike HIV where you can put HIV & a drug into a cell culture and see if replication is inhibited. This makes it difficult to develop drugs for HCV and to understand a potential protease inhibitor's resistance profile. But in today's lecture series it was said that several cell culture systems are being developed and researchers seemed encouraged about this prospect.
Ribozyme
LY466700 is a ribozyme currently in human studies. A ribozyme attaches itself to the virus to prevent replication. Larry Blatt from Ribozyme Pharmacueticals discussed ongoing research in humans. He said the drug showed to be potent anti-HCV in cell culture and was synergistic with interferon. The drug will be administered by once daily subcutaneous injections. Results from a single-dose dose- escalation and safety study will be presented in a poster in the next few days. Blatt gave a preliminary report today. Itís a 28-day study using low doses. Three patients showed transient viral load reductions of about 1 log. Higher doses will be studied in combination with interferon and later with IFN+ribivarin. Since the study being presented in Dallas was not designed to chartacterize antiviral efficacy Blatt said he can't be sure whether the viral load reduction is due to the drug or not. He said it was well tolerated.
HCV Polymerase
Polymerase is part of HCV and is involved in the viral reproduction process. Blatt described today that a few companies have polymerase inhibitors in development. One of these products is in phase 1 studies in the UK. A few nucleoside analogues are being considered for development to inhibit polymerase.
Antisense
Antisense can inhibit viral replication. Gary Davis described today that major potential obstacles with antisense technologies have included delivery to the cell target. But an antisense product is in phase 1/2 studies including in HCV infected
VX-497
This is a ribivarin type drug being developed by Vertex Pharma and its in phase 1/2 studies. Vertex has said it should be more tolerable, safer and more potent than ribivarin.
Maximine
This is an immune based therapy for which 24 week data has been previously reported. It was studied at various doses in combination with interferon. Its administered by subcutaneous injection. The 24-week data is available on the NATAP web site but 48 week data will be presented in Dallas. Still, the study was not well designed enough to get a firm grip of the benefit Maximine gives. Although they previously reported 69% viral response, about 50% of the patients were genotype 2/3 and it was hard to tell how much of the benefit was from interferon or Maximine. Nonetheless, Roche has rights to study Maximine in combination with Pegasys.
Il-10
This is an inhibitory cytokine that has anti-inflammatory, antifibrotic, and immune suppressor effects. Gary Davis said today that an effect might be anticipated because patients with severe chronic HCV have lower IL-10 production while those with milder disease have higher levels of Il-10. A pilot study of daily recombinant Il-10 normalized ALT and reduced hetic inflammation on liver biopsy in 19 of 22 chronic HCV patients. This was previously reported And fibrosis decreased dramatically in 14/22. But no change in HCV viral load was seen. A large trial is underway.
Alfa Thymosin
This immune modulator has been around a while and I thought it was written off. Davis said study results have been inconsistent but felt the drug may have promise. He said a large study is planned. The drug is approved in I think Japan.