RAC Reviews Serious Adverse Event Associated with AAV Therapy Trial (2007)

The Recombinant DNA Advisory Committee (RAC) meeting on 17 September 2007 reviewed the serious adverse event that occurred in the adeno-associated virus (AAV) trial for rheumatoid arthritis patients. A participant in the trial died some 3 weeks after she received a second intra-articular injection of an AAV2 vector encoding a fusion of the IgG1 Fc and tumor necrosis factor-α (TNF-α) receptor. This fusion is identical to the construct utilized to manufacture the TNF-α antagonist drug etanercept (Enbrel). TNF-α, a proinflammatory mediator, is important in the pathogenesis of rheumatoid arthritis. Therapy targeting TNF-α is effective and has revolutionized treatment of severe rheumatoid arthritis. However, some patients do not respond—or respond incompletely—to systemic therapy; hence the development of the TgAAC94 vector by Targeted Genetics for local instillation into affected joints as an additional potential therapy in this disease. The presentations at the RAC have been widely commented on and with markedly different interpretations. The tragic death of Jolee Mohr, a volunteer in the study, was apparently due to disseminated infection with Histoplasma capsulatum, a fungus that is endemic in the Midwest. The volunteer was simultaneously being treated for her arthritis with systemic anti-TNF-α therapy in the form of the drug adalimumab (Humira), a TNF-α antagonist. Known serious complications of this therapy are susceptibility to infections with certain fungal organisms, including H. capsulatum. She was also taking other immunosuppressive medications. Combination therapy in rheumatoid arthritis is commonly used to attain full control of the inflammatory process, but such combinations can also increase the risk of infection with organisms that would normally be contained by a fully functional immune system. Data presented at the RAC showed that preclinical studies had documented little vector product detected systemically in rats injected intra-articularly. Thus, 4 of 102 rats analyzed had levels of the transgene product detectable at about 100-fold lower than would be found in a patient taking etanercept therapeutically. Preliminary data presented at the meeting suggested very low levels of recombinant vector in the spleen, liver, and lung of the patient at autopsy. Thus, it would seem from these data that the unfortunate demise of Mrs. Mohr is consistent with the known side effect of adalimumab and multi-agent immunosuppression. The NIH RAC will continue the review of this serious adverse event at its December meeting. According to information presented by the NIH Office of Biotechnology Activity (OBA), AAV vectors have been used in about 4% of all trials submitted to the OBA and have had a good safety record thus far. The Genetic Modification Clinical Research Information System reports slightly more than 30 adverse events in 36 trials in the United States that were unexpected and possibly related to the gene therapy trial. No patterns were identified in these adverse events, and they were not different from those in other gene therapy trials. Natural infection with AAV is prevalent in the population and without serious side effects. Two points emerged from the RAC discussions. First, Jolee Mohr's husband, Robb, noted that his wife's condition was mild and questioned why she was enrolled in the trial. The selection of candidates for early-phase human testing is complex and particularly difficult in otherwise non-life-threatening illnesses. Protection of patients depends in large part on local institutional review boards (IRBs), but in the case of gene therapy trials there is added scrutiny from the Food and Drug Administration (FDA) and the RAC itself. This trial was approved by IRB and FDA review panels and was registered with the RAC. Second, the facts that her personal physician enrolled her in the trial and that the timing of the consent process was short raised some concerns. However, as Art Nienhuis, representing the American Society of Gene Therapy (ASGT) as current president, pointed out to the RAC, “No regulations were violated in this case, but perhaps we should hold ourselves to a higher standard.” He also said that “the process for informed consent for gene therapy trials should be re-evaluated,” and he has asked the Ethics Committee of the ASGT to address this issue. As noted in an editorial in Nature Biotechnology, “2 million US citizens suffer drug interactions each year.” About 5% of these individuals die. As the editorial points out, compared with this, a large number of gene therapy trials have been done safely and the current serious adverse event is “no reason for a regulatory crackdown. Further research on the AAV platform should be encouraged and carefully monitored clinical trials continued.”1Editorial Retracing events.Nat Biotechnol. 2007; 25: 949Crossref PubMed Scopus (11) Google Scholar