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Antiviral Therapeutics: Cambridge Healthtech Associates (CHA): Do you think that the emergence of resistance will be a continuing problem with all classes of agent, or do you think that some of the entry blocker approaches may not be so prone to the development of resistance (in light of suggestions of the role of mutant chemokine receptors in providing natural resistance to infection)? Dr. Cordingley: Yes, more or less. There is no good evidence that thenew targets will not encounter drug resistance, but the altering of the treatment paradigm, better drugs and new targets, should reduce the rate of development of resistance. For example, Kaletra [lopinavir/ritonavir] is less prone to the development of drug resistance [than older treatments], but resistance still develops. CHA: Do you envision an effective HIV vaccine ever becoming widely used in Western markets? Dr. Cordingley: Not for the foreseeable future, and its use would be influenced by other issues. In about 25 years’ time, there might be a greater incentive to use vaccines. If vaccines are developed with improved coverage, they might start to be employed in conjunction with HAART [highly active antiretroviral therapy]. CHA: Are there other potential molecular targets for new drugs for treatment that are not currently being pursued by any company? Dr. Cordingley: Success to date has relied on a limited number of targets. HIV is like an iceberg in which only the (small) proportion above the surface has been exploited to date, but that under the surface is being explored (to varying degrees). To an extent this relates to the tractability of the targets and the assessment of whether they are exploitable. Maturation appears to be one of these less tractable, and less well-defined, targets, which should be played out over the next 5 years as a better molecular understanding is obtained of how the Panacos maturation inhibitors work. CHA: Is a once-daily oral treatment, the gold standard for most modern drug discovery efforts, a realistic goal for new anti-HIV therapies? Dr. Cordingley: Ideally yes, and it would clearly be used if it were both available and effective. However, I cannot envision the availability of such agents for a long time. Line extensions and fixed-dose combinations will go some way in addressing these uses, and there will be a gradual shift in patients’ expectations. CHA: Why is it proving so difficult to make good progress in developing HCV [hepatitis C virus] protease inhibitors? Dr. Cordingley: The target molecule contains a flat featureless site against which inhibitors are targeted. Enhancing affinity results in the attachment of additional groups leading to larger molecules. The high molecular weight results in poorer DMPK [drug metabolism and pharmacokinetics] properties. Despite this the NS3 protease still appears to be a better target than polymerase inhibition. CHA: Do you consider that the preferred treatment options will eventually be the use of new antiviral agents plus interferons? Or should the aim be the use of antivirals (e.g., HCV protease inhibitors) alone? Dr. Cordingley: The issue is complex and might be addressed at three levels: (1) Interferon remains required because of the inadequate efficacy of the antivirals, but the combination of oral antivirals and interferon should give better effects and may provide a short-term cure; (2) oral antiviral may be effective in those patients who are nonresponders to interferon or who cannot tolerate current interferon treatments; and (3) available evidence suggests that a better response rate is achieved with combinations. In addition, it remains to be seen whether being “cured” of viral infection (i.e., negligible viral titers) results in a reduction in liver inflammation or whether interferon treatment is still necessary to treat that symptom. CHA: Considerable interest has been shown in developing longeracting interferon products. What treatment interval would you consider most desirable for such agents? Dr. Cordingley: The optimal treatment interval will be that which provides the best control of plasma levels of interferon, minimizing peak-to-trough variations, and, it is hoped, providing better tolerability. However, the lack of understanding of interferon toxicity makes it difficult to be absolute on that point. HGS’ Albuferon [albumin–interferon-alpha-2b] looks very promising with respect to regulating plasma concentrations of interferon. CHA: There is increasing interest in the development of antiviral agents for the treatment of hepatitis B infection. Do you envision any of these becoming widely used in Western markets? Dr. Cordingley: While such treatments are likely to be widely used in Far Eastern markets, it appears unlikely that there will be much demand for such drugs in Western markets. Problems of enforcing patent rights in some Eastern markets provide a disincentive for major investment in this area. CHA: Which viruses other than HIV and hepatitis do you consider to have a significant medical need for improved treatments, and which represent major commercial opportunities? Dr. Cordingley: HPV [human papilloma virus] represents a clear opportunity, but vaccines offer the logical approach to treatment. RSV [respiratory syncytial virus] is an interesting disease, but a number of issues render it a poor commercial opportunity. Diagnosis is generally slow and probably too late for effective antiviral treatment; the pharmacoeconomic case looks unpromising; and the small size of the potential market makes the disease commercially unattractive. Tropical diseases such as West Nile virus appear unlikely to offer sufficient commercial opportunities. CHA: In your opinion, will the current concerns about the development of a flu pandemic be a transitory issue? Dr. Cordingley: It will remain an area of concern, but avian influenza of the H5N1 type is not a new phenomenon. This was emphasized in a review by Palese,1 who highlighted how this basic strain has been around since the 1950s. However, the potential pandemic will be a continuing concern for some time. CHA: Will the concerns about a flu pandemic be sufficient to evoke significant interest in the identification and development of novel neuraminidase inhibitors? Dr. Cordingley: The available agents are the result of considerable optimization, and it is difficult to see how significantly better enzyme inhibitors could be achieved with further efforts. CHA: Apart from the development of a prophylactic vaccine against HPV infection, do you envision the widespread development of such vaccines against other viruses? Dr. Cordingley: Vaccine production is a specialty business, with significant entry barriers, so I do not expect additional big pharma companies to enter this field. There are no easy respiratory virus targets left. Vaccines could be potentially useful in treating CMV and HSV infections if the vaccines have sufficient efficacy. Vaccines for West Nile virus and dengue virus are clearly desirable, but is there a sufficient market for such vaccines? CHA: Do you think enough advantage has yet been taken of developments in formulation and delivery technology to improve the effectiveness of antiviral drugs? Dr. Cordingley: The generally poor pharmacokinetic properties of antiviral agents are substantially attributable to the difficult targets pursued. The modifications required to enhance activity, for example, due to the flat nature of the HCV protease site, tends to worsen absorption. However, taking advantage of the boosting effect that can be seen when using agents in combination with ritonavir, due to its inhibition of P450, has been exploited to great effect in Kaletra (ritonavir plus lopinavir), which enhances the activity of lopinavir. This effect is now being explored for other combination treatments. CHA: Other than your own, which companies do you see becoming major players in the antiviral market? Dr. Cordingley: I think that Novartis is going to become a significant player. Its agreement with Idenix and its internal R&D will deliver new therapeutics, and the acquisition of Chiron strengthens its position.
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