- BIOETHICS FORUM ESSAY
Targeted Genetics: Response to Chris Evans
On behalf of Targeted Genetics, I wish to comment on Chris Evans’s recent essay on a patient death in our tgAAC94 arthritis clinical trial. Dr. Evans is a very respected researcher, who was also an ad hoc reviewer for the National Institutes of Health Recombinant DNA Advisory Committee on the first tgAAC94 Phase I trial, initiated in 2003. However, there are several points made by Dr. Evans that need clarification.
First, Dr. Evans points out that the NIH RAC committee stopped short of definitively ruling out any role tgAAC94 may have had in Ms. Mohr’s illness. However, every slide in the RAC presentation prior to the conclusion slides indicated that there was no data that implicated tgAAC94, in any way, in Ms. Mohr’s illness and subsequent death. The NIH RAC is a science-based committee. There is no way to scientifically prove a negative. Given this, we were not surprised at the RAC meeting outcome and the RAC’s inability to reach a definitive conclusion, even though all data suggests that this event was unrelated to the study drug.
Second, Dr. Evans questions the concept of giving intra-articular gene therapy to mitigate arthritis in joints nonresponsive to systemic anti-TNF therapy. However, small studies presented in abstract form indicate that intra-articular injections of anti-TNF proteins into joints that are nonresponsive to systemic therapy do indeed reduce inflammation and swelling in those joints.1 However, the frequency of administration that would be required to produce a sustained affect would not be acceptable to most patients: hence the desirability of a long-lasting gene therapy approach.
Third, Dr. Evans questions the lack of data on expression. At the RAC meeting, data was presented that showed no detectable systemic TNF binding in subjects not on any other TNF antagonists. Targeted Genetics is currently developing an assay that will detect anti-TNF protein binding in such a way as to answer the question of systemic expression in those subjects who are also taking other anti-TNF systemic therapies. However, the issue with measuring levels of expression in the joint is not the lack of an assay; it is the lack of available synovial fluid to extract from the treated joint. Approximately half of the patients in this clinical trial were not on concomitant anti-TNF protein therapy – a point Dr. Evans seems to have missed – and even in this group, available joint fluid post treatment has been very limited. Indeed, this may be a positive thing, since if the therapy is having a positive impact there should be little or no synovial fluid.
Finally, Dr. Evans points out that endpoints for systemic therapy are not applicable to localized therapy. We acknowledge this, and in fact the secondary objectives of this safety trial were included to explore potential endpoints appropriate for single-joint assessment. If the lack of validated endpoints had prevented earlier systemic therapies from being developed, we would not have those therapies today. Indeed, we are working closely with an international group, OMERACT (Outcomes Measures in Rheumatology) to develop a set of endpoints that could be validated. This is the same group that helped develop the ACR outcome scores for systemic therapy. But one cannot validate those endpoints until a set of biological data has been gathered in actual human clinical trials. If drug developers are faulted for being first, then no new therapies will ever be developed.
We are grateful to the NIH RAC and to the FDA for the extraordinary work done to complete the analysis showing that tgAAC94 was very unlikely to have had an impact on Ms. Mohr’s death, so that trials of this product could be resumed and moved ahead. It is only with additional clinical study that data can be generated to know whether the potential this product has to mitigate serious unmet need in the arthritis patient population will be realized.
H. Stewart Parker is president and chief executive officer of Targeted Genetics Corporation.