Washington Editor

The FDA has permitted Targeted Genetics Corp. to resume a Phase I/II trial of its gene therapy for rheumatoid arthritis after an investigation concluded that the treatment did not cause the death of a study participant.

The trial was halted in July after 36-year-old Jolee Mohr of Illinois died of a massive infection 22 days after receiving a second dose of Targeted Genetics' tgAAC94, an investigational therapy using an adeno-associated viral vector to deliver the gene encoding a soluble form of the receptor for tumor necrosis factor (TNF)-alpha. In a conference call Monday, Targeted Genetics CEO H. Stewart Parker said that investigations of the study, which were conducted by the firm, the FDA, the National Institutes of Health Recombinant DNA Advisory Committee (RAC) and the University of Chicago, all indicated that Mohr died of disseminated histoplasmosis and a retroperitoneal hematoma.

A final report from RAC will be made public at a Dec. 3 committee meeting in Bethesda, Md.

Preliminary autopsy results made public at a September RAC meeting revealed that 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. (See BioWorld Today, Sept. 18, 2007.)

Mohr, who had a long history of rheumatoid arthritis, had been taking Humira (adalimumab, Abbott), methotrexate and prednisone, which are known to be immunosuppressive and a risk factor for the histoplasma infection. She also lived in an area of the country, Illinois, where histoplasma is highly prevalent.

Mohr had received the first dose of tgAAC94 in February and had experienced no signs of infection. She received the second dose July 2, and synovial fluid drawn that day revealed no infection.

However, five days later, Mohr experienced a 104-degree fever and was admitted on July 12 to her local hospital. She was later transferred to the University of Chicago Medical Center, where she died on July 24.

Parker noted that final molecular test results of the fatal adverse event, which were reported earlier this month, supported initial findings that no amplification of viral vector occurred in the patient's body as a result of tgAAC94, only trace amounts of vector DNA were detected in tissues outside the joint, and the level of circulating TNF-alpha antagonist protein was well within expected limits from the patient's background therapy. (See BioWorld Today, Nov. 13, 2007.)

Seattle-based Targeted Genetics is working with each of its trial sites and investigators to ensure that the company resumes its development program of tgAAC94 "in the most efficient manner possible," Parker said.

However, she noted, before it can proceed with the Phase I/II study, the company must first gain approval from an independent institutional review board of the amended protocol and revised informed consent and also must obtain the re-consent of the 35 participants who have yet to receive their second injection.

"The main amendment that we are making is to preclude patients who are coming for their second injection if they have any sign of fever at all," Parker said. "For conservative purposes, we just aren't going to treat anybody if they have a fever or any sign of infection until that's past."

Since the Phase I/II trial of tgAAC94 began in October 2005, 127 participants have received an initial dose of active drug or placebo into the knee, ankle, wrist, metacarpophalangeal or elbow and 74 have received a second dose.

Parker said that her firm anticipates completion of administration for the remaining 35 patients eligible for the second dose by early 2008.

"Subsequently, patients will be followed for 30 weeks after the second injection according to the Phase I/II protocol," she said. "We plan to provide a trial update at scientific conferences midyear and hope to have final data from the trial in the fourth quarter of 2008."

If all 35 patients do not re-consent to the study, Parker said, her firm will not seek to enroll more participants.

"We really believe that even if, frankly, the patients don't re-consent, which we don't think will be the case, we have enough data from the trial to date to really help guide us for this next design."

Based on the strength of the interim safety and dosing data from the Phase I/II trial, Parker said, Targeted Genetics is proceeding with its protocol design for a Phase II trial of tgAAC94, which the firm anticipates starting mid-2008.

That trial, she said, will be designed to evaluate efficacy and duration of response and to confirm safety in patients with inflammatory arthritis. The study will include patients with rheumatoid arthritis who are not candidates for systemic protein therapy, because either they have one or more inflamed joints or they are taking but do not fully respond to systemic anti-TNF protein therapy.

"We strongly feel that a gene therapy approach may have enormous potential to improve the treatment of [rheumatoid arthritis] and other serious diseases," Parker maintained. "We remain committed to safety of the patients in our trials and to doing our very best in developing a treatment that patients and physicians can add to their arsenal for treating this devastating disease."

Shares of Targeted Genetics (NASDAQ:TGEN) rose 7 cents Monday, to close at $2.07.