June 21, 2010
[Following is the text of an open letter sent on June 17 by the AIDS Treatment Activists Coalition and European AIDS Treatment Group. The letter was addressed to Susan Cox, the former senior vice president of drug development at Avexa; copies were sent to Nathan Drona, Avexa's chairman, and Stephen Kerr, the company's board secretary.]
We, the undersigned, are asking the decision makers at Avexa to reconsider the decision to stop the development of apricitabine, a nucleoside analog that has shown good efficacy in patients with the most common nucleoside mutation, M184V. Physicians and a growing number of patients with limited treatment options have been counting on the approval of this drug to enable the construction of effective regimens. Apricitabine can mean the tipping point between success and failure of a salvage regimen -- between life and death.
It is well known that the management of multidrug resistant HIV has improved dramatically with the recent approval of a number of highly effective antiretroviral drugs, including raltegravir, maraviroc, darunavir, and etravirine. Despite the impressive effectiveness of these drugs in clinical trials, a growing subset of patients continues to exhibit virologic failure in clinical practice -- even when adherence is good. Most of these treatment failures likely occur because of an inability to construct a regimen containing two to three fully effective agents for individuals with extensive prior exposure to antiretroviral drugs. Some of these patients acquired drug resistance while participating in clinical trials. Failure rates in recent phase III studies such as DUET (etravirine and darunavir), MOTIVATE (maraviroc), and BENCHMRK (raltegravir) were in the 27-40% range. Many of the patients who experienced virologic failure while participating in these studies were subsequently unable to construct suppressive regimens.
The prevalence of multidrug failure in clinical practice is not well documented, however there are signs that the number of patients in need of new options is growing. Deeks and colleagues at UCSF/SFGH have an ongoing observational cohort of patients who have developed drug resistant HIV (the SCOPE cohort). Most of these patients have been able to construct a fully suppressive regimen and are currently doing well. However, of the original 300 patients, approximately 40 now have evidence of having failed all six therapeutic drug classes. These 40 patients have a GSS of either zero or one, and have no clear options for suppressing HIV replication. Many have advanced disease (CD4 < 100) and hence may not be able to wait for the development and approval of multiple new options.
A 2009 survey of 94 responding HIV clinicians in the United States found approximately 250 patients unable to construct a viable regimen due to resistance. In contrast to a common assessment heard in 2009, several key clinicians now recognize that the latest generation of drugs has not proven as durable as they had hoped, and that resistance is slowly reemerging as a problem for some patients. Although the number of multidrug resistant patients with no treatment options may be relatively small, there is concern that this may be the tip of the iceberg and that the industry will not be prepared to meet the need for newer drugs with unique resistance profiles.
The options for constructing a three-active agent regimen for this growing population during the next four years appears to be few, which means that the chances for survival for those with lower CD4 cells counts are diminishing. Consequently, an early expanded access program that makes available current investigational agents that have progressed beyond phase II could help improve the outlook for survival for these patients in need. But the drugs must remain in development.
Other small companies developing new HIV drugs, such as TaiMed and Myriad have faced the same difficulties in finding partners that Avexa has. Of these companies drugs, though, apricitabine stands out as a member of a well-understood class, the one nearest to approval, and as an agent addressing one of the most common forms of drug resistance among all people with HIV (including those still naïve to treatment). For the salvage population, convenience in dosing is not the issue: activity is! In our recent meeting with the major HIV drug makers we have been raising awareness about the growing unmet need for new salvage options, and as they hear this message from community and clinicians, they have begun to pay attention. Researchers and statisticians are also working on creative ways to conduct registrational clinical trials in an environment when there are many effective options and a relatively small subject pool (the Forum for Collaborative HIV Research is holding a workshop on this issue in October 2010). Finally, the FDA has said it recognizes the need for new salvage therapies and appears willing to work with companies to bring new products to market in this difficult environment. The tide is turning; this is not the time to abandon apricitabine.
We the undersigned believe that apricitabine is a potentially important drug, and one of the few products currently in the pipeline that could help patients with multidrug resistance tip the balance in favor of viral suppression, health, and, for many, life itself. We ask that Avexa reconsider its decision not only based on potential sales but also on the survival of patients at risk.
The Members of the AIDS Treatment Activists Coalition -- New York , New York
The Members of the European AIDS Treatment Group -- Brussels , Belgium