Washington Editor

BETHESDA, Md. - The July death of a gene therapy clinical trial participant was primarily the result of disseminated histoplasmosis with subsequent bleeding complications and multiorgan failure, federal advisers said Monday.

However, the National Institutes of Health Recombinant DNA Advisory Committee (RAC) could not completely rule out Targeted Genetics' tgAAC94 as a possible contributor in the death of the 36-year-old Illinois woman.

"Despite every effort that was conceivable, we are still missing key pieces of information that would allow us to draw a definitive conclusion," said RAC Chairman Howard J. Federoff, executive vice president of Georgetown University Medical Center.

Jolee Mohr died 22 days after receiving the second dose of tgAAC94, an investigational therapy using an adeno-associated viral (AAV) vector to deliver the gene encoding a soluble form of the receptor for tumor necrosis factor (TNF)-alpha. The product is being investigated as a treatment for rheumatoid arthritis.

Mohr's systemic use of TNF-antagonists, which are known to be immunosuppressive, placed her at risk for the histoplasma infection, Federoff noted.

On the day of her second injection of tgAAC94, Mohr had a slight fever of 99 degrees, but tests showed no other signs of infection.

Within 12 hours of the injection, Mohr experienced fevers, chills, and abdominal pain. She was admitted to the hospital 10 days later. Her condition rapidly deteriorated, and on July 24, Mohr died.

An autopsy revealed disseminated histoplasmosis was present in tissue samples of Mohr's liver, lungs, bone marrow, spleen, lymph nodes, thymus, kidney and brain. She also had a 3.5 kg retroperitoneal hemorrhage, which had displaced her abdominal organs to the right, shifted the diaphragm upward, and had enveloped her left kidney.

The etiology of the large retroperitoneal bleed, according to RAC, was never determined.

Federoff said that sterility tests of tgAAC94 showed no evidence of contamination of the product. Postmortem tests showed that the majority of vector remained in Mohr's knee at the injection site, with only "extremely low levels" of vector present in tissues outside the knee, he added.

AAV2 rep gene, which may indicate replication competent AAV, only was found in very low levels in Mohr's heart and trachea, but tgAAC94 was not detected at those sites, Federoff explained.

There had been some speculation that transgene production led to excessive systemic levels of TNF-antagonist. However, Federoff said, declining serum levels of TNF antagonist in Mohr's blood samples did not support that theory.

But, he said, "the fact that this does not appear to have been a factor in this case does not diminish the importance of having an assay to specifically detect levels of the transgene product." He noted that the degree of functional TNF inhibition could not be determined because of the lack of such assays.

In addition, Federoff said, the absence of significant vector in Mohr's liver and spleen at autopsy and the high anti-AAV titers "does not exclude an immune response."

The committee noted that an immunologic response to the AAV vector capsid has been hypothesized to have been the cause of an asymptomatic elevation in liver enzymes in a gene transfer trial for hemophilia in which the AAV vector encoding factor IX was injected into the hepatic artery.

But Barrie Clark, chief scientific officer for Targeted Genetics, called the factor IX hypothesis "speculation" because it is based on "unresolved" data that are and "not yet understood."

In Mohr's case, Federoff said, blood samples from before and after administration of tgAAC94 were not available for CD8+ capsid specific T-cell assays.

"In the absence of these data, an immune response cannot be definitively ruled out," he said. However, Federoff added, if such a response occurred, it was "not the primary factor" in Mohr's death.

"The inability to exclude an immune reaction to the vector underscores the importance of obtaining samples for T-cell assays," Federoff said, calling on Targeted Genetics and other gene therapy firms to monitor for anti-capsid T-cells during clinical trials.

"This may help both in interpretation of adverse events and shed light on the safety of AAV vectors generally," Federoff contended.

Targeted Genetics, Clark told BioWorld Today, will in the future conduct such monitoring for immune response.

However, he argued, in Mohr's case, "there's no clinical reason, there's no scientific reason, there's no data coming from this patient to lead you to believe there was such a response. They are trying to exclude a speculative hypothesis."

The FDA last week told Targeted Genetics that it could resume its Phase I/II clinical trial of tgAAC94, which has been on hold since July. (See BioWorld Today, Nov. 27, 2007.)

But at Monday's meeting, Daniel Takefman, chief of gene therapy at the FDA, said that the agency agreed with RAC panelists that it could not "absolutely rule out that the gene transfer product may have contributed to the serious and unfortunate adverse event in some currently unknown way. However, the information available does not suggest that the therapy played a direct role."

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