Death halts Targeted Genetics gene therapy trial

STORY UPDATE

SEATTLE—December 3, 2007—Targeted Genetics reported on the findings of the NIH Recombinant DNA Advisory Committee's review of the fatal serious adverse event in the company's Phase I/II trial of tgAAC94 for inflammatory arthritis. The Committee held that the participant's death was the result of complications from an opportunistic infection and was unlikely to be related to the experimental drug. As such, the FDA has released the trial from clinical hold.

SEATTLE—An article in the August 6 issue of the Washington Post about the death of a patient, 36-year-old Jolee Mohr, in a Targeted Genetics gene therapy trial for the treatment of arthritis promptly sent the biotech firm's shares down more than 6.5 percent. But looking beyond the immediate fallout, this story on the second known death in a gene therapy trial may put a dark cloud over gene therapy in general, which has yet to log enough success to offset numerous treatment failures. The specter of the 1999 death of a teenager in another gene therapy trial—18-year old Jesse Gelsinger in a University of Pennsylvania study on an inherited liver disease—hasn't helped, particularly since there is an indirect connection between Targeted Genetics and that earlier case.

The 1999 UPenn trial was led by Dr. James Wilson, whose company, Genovo, licensed the technology used in the trial. Targeted Genetics acquired Genovo in 2000 for $66 million in stock. However, Targeted Genetics has reported that no Genovo technology was used in the inflammatory-arthritis drug used on Mohr or her fellow study participants.

Adding to the intrigue of the situation is the fact that Alan Milstein, a New Jersey attorney who is representing Mohr's husband, Robb Mohr, in a possible civil lawsuit, also represented the Gelsinger family after the UPenn fatality.

After discussions with the U.S. Food and Drug Administration (FDA) following the Mohr death, Targeted Genetics promptly put the development program for tgAAC94, an investigational therapy for the treatment of inflammatory arthritis, on clinical hold.

The FDA hasn't flagged any of the company's other gene therapy trials or preclinical efforts, notes Targeted Genetics spokesperson Stacie D. Byars. Those other efforts, like the arthritis one, use adeno-associated virus (AAV) derived vectors, but the disease areas are completely different—such as HIV/AIDS, congestive heart failure and Huntington's disease. Also, the arthritis trial had a novel delivery method, with the therapy injected directly into affected joints.

"Our other clinical trials are still underway, so I wouldn't say there's a long-term impact from this case for our overall efforts," she says. "However, our No. 1 priority is to find out the cause of death and find out what, if any, connection there is to the therapy. But at this point, it's too early to even speculate on that."

Although officials at the FDA are not aware of similar adverse events in gene therapies using AAV vectors, they say that as a precaution, the agency will perform further review of all ongoing trials involving any use of AAV.

Researchers in the field, however, are skeptical that AAV itself will turn out to be the culprit. Terence Flotte of the University of Massachusetts Medical School in Worcester, Mass., for example, who has been a principal investigator in several clinical trials of AAV-based gene therapies, notes that AAV vectors have been used in hundreds of patients over more than a decade without any associations to acute toxicity.

Targeted Genetics responded immediately to the original Washington Post article with a criticism that the piece seemed "designed to agitate as opposed to inform" and H. Stewart Parker, president and CEO of Targeted Genetics, noted in a release that "Patient safety is of paramount importance and we have designed and conducted all of our trials with that in mind. We are confident in the safety of our product and platform and look forward to the opportunity to complete the clinical trials, which is the only way to determine the efficacy and safety profile of this or any other drug candidate."

Subjects already enrolled in the study will continue to be followed and monitored, Byars notes. Since the trial began in October 2005, 127 subjects have received an initial dose of active drug or placebo, and 74 subjects out of the total 127 have received a second dose of active drug.

"More than 100 subjects have been enrolled in the trial…without known similar serious events," the FDA noted in a statement about the clinical hold. "However, the patient's illness was related in time to the receipt of a second injection of the product. Upon being alerted to the adverse event, FDA immediately began its investigation to determine whether the illness was related to the treatment. The investigation into the cause of the patient's illness and subsequent death is intensive and ongoing."

While the Mohr death has put a spotlight on gene therapy and possibly AAV as a platform, it may not put much of a dent in public confidence in clinical trials. In a recent study by Thomson CenterWatch, more than 90 percent of study volunteers say their experiences were good enough in a clinical trial that they would participate again and, despite some of the recent bad press about the pharmaceutical industry, study volunteers remain strong in their support of trial participation.