Washington Editor

A panel of federal experts agreed Monday that more data were needed to determine whether an investigational gene therapy agent for rheumatoid arthritis played any role in the July death of a clinical study participant.

Autopsy results of tissue samples presented at Monday's meeting left panelists perplexed as to whether the Illinois woman, 36-year-old Jolee Mohr, died of a massive infection triggered by the gene therapy agent, known as tgAAC94, or other causes.

"This is clearly a very complex case," said panel chairman Howard Federoff, executive vice president of Georgetown University Medical Center. He noted that Mohr, who had a long history of rheumatoid arthritis, had been treated with a number of disease-modifying antirheumatic drugs, including tumor necrosis factor (TNF) inhibitors.

Mohr died on July 24, 22 days after receiving a second dose of Targeted Genetics Corp.'s tgAAC94, an investigational therapy using an adeno-associated viral (AAV) vector to deliver the gene encoding a soluble form of the receptor for TNF-alpha. The TNFR:Fc protein is an inhibitor of TNF-alpha, a key mediator of inflammation.

Seattle-based Targeted Genetics, at the FDA's insistence, stopped the study in July after Mohr's death.

Pathologists had worked over the weekend to complete their analysis of postmortem tissue samples taken from Mohr. However, results of blood samples were not available for Monday's meeting of the National Institutes of Health Recombinant DNA Advisory Committee (RAC).

Federoff said the panel will discuss the results of the blood samples at a RAC meeting in December. He was uncertain whether the blood-sample results would be made public before the December meeting. Autopsy results reported at the RAC meeting was the first time any such details about Mohr's death had been made public.

John Hart, professor of pathology at the University of Chicago Hospitals, said that autopsy results revealed that disseminated histoplasmosis was present in tissue samples of Mohr's liver, lungs, bone marrow, spleen, lymph nodes, thymus, kidney and brain. Histoplama, he noted, is highly prevalent in the Mississippi River states, including Illinois where Mohr lived. At the time of her death, he said, Mohr 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.

No significant hemorrhage was found elsewhere in her body, Hart said.

Mohr had received the first dose of tgAAC94 in February. Follow-up tests revealed there was no sign of infection after she had been administered the drug by injection into her right knee. She experienced some moderate swelling and pain over the following weeks.

Mohr received the second dose of tgAAC94 on July 2. Synovial fluid drawn that day revealed no infection. However, days before that injection, Mohr had reported experiencing fatigue. The week before she also had experienced symptoms of herpes virus simplex-1 and was prescribed a five-day course of valacyclovir by phone by her primary care physician. Her gynecologist also had prescribed Mohr a seven-day course of metronidazole, of which Mohr reported that she had not completed.

There was some speculation as to whether the herpes virus played a role in Mohr's death. But Richard Whitley, professor of pediatrics, microbiology and medicine at the University of Alabama at Birmingham, told panelists it was unlikely the virus played any such role.

Mohr's physician also had prescribed her an antibiotic, levofloxicin 500 mg once daily, after she had reported having a fever the day after her second injection of tgAAC94.

On July 7, she was taken to a local emergency room with a 104-degree fever. Two days later, Mohr visited her primary care physician, who stopped the levofloxicin and started her on prochlorazine. On July 12, Mohr was admitted to her local hospital with a high fever and symptoms of possible hepatic problems. Physicians at the facility started Mohr on meropenam and again gave her levofloxicin. A CAT scan revealed a significant amount of pericholecystic fluid, which may indicate cholecystitis, but is nonspecific.

Mohr's condition continued to decline. She was transferred to the University of Chicago Medical Center, where she underwent more tests and received more medications and renal replacement therapy.

While her liver function improved, physicians were unable to stop a retroperitoneal bleed, despite massive blood transfusions, noted attending physician D. Kyle Hogarth. The physicians were unable to identify the source of the bleed, he added.

Mohr's condition continued to decline, and on July 24, she died 20 minutes after being taken off of life support.

Because Mohr had received numerous medications before her death, and had been on various therapies for rheumatoid arthritis, including high dosages of Humira (adalimumab), it is unclear what caused her death, Federoff said.

However, he told reporters after the meeting, until more data are available, the vector cannot be excluded as a cause. But, he added, the available data suggest that the vector was "unlikely to be playing a role."

Targeted Genetics plans to address the outcome of the RAC meeting during a conference call today.