Targeted Genetics Aims To Reinitiate Arthritis Gene Therapy Trial By December

Data reviewed by NIH Recombinant DNA Advisory Committee suggest it is unlikely the experimental therapy contributed to a patient’s death in July, CEO says.

Targeted Genetics plans to restart a trial of its experimental inflammatory arthritis therapy tgAAC94, on hold since July, after an NIH advisory committee review determined it is unlikely the death of a patient in the study was caused by the biologic, CEO H. Stewart Parker told investors during a Sept. 18 conference call.

While the Recombinant DNA Advisory Committee has asked to review additional data at its Dec. 3-4 meeting, "the specific discussion was about reporting on the conclusions ... but not necessarily tied to a delay on our part," Parker said. "Our goal is to start the trial before the RAC meeting in December, and we're certainly going to do everything we can to try to make that happen," she explained.

NIH's RAC, which, along with FDA, originally reviewed the tgAAC94 Phase I/II trial design, met in Bethesda, Md., Sept. 17 to take a critical look at the clinical case and gain insight into the cause of the subject's death. Targeted Genetics said during its second-quarter earnings call Aug. 7 that it had put the trial on hold after consulting with FDA concerning the event on July 20 (¹ (Also see "Targeted Genetics To Examine Safety of Recombinant AAV Technology Following Patient Death" - Pink Sheet, 7 Aug, 2007.)).

"Additional items needed to get this trial back up and running ... involve molecular tests [and] additional PCR tests on tissue samples," Stewart Parker said. "Then obviously we will need to revise the consent form to include a description of this SAE and a few other procedural details, but we're optimistic that we certainly will be able to move ahead."

"We are pleased that molecular tests completed on several tissue samples suggest that there was no replication of vector, and only trace amounts of vector DNA were found in tissues outside the [knee] joint. These data suggest that it is unlikely that tgAAC94 contributed to the conditions that caused the patient's death," Stewart Parker said.

Data presented at the meeting indicate that disseminated histoplasmosis, a fungal infection, played a significant role in the death. The exec also noted that other medications the patient was on at the time of enrollment and during the trial "are recognized to have immunosuppressant effects which may predispose patients to serious invasive opportunistic infections, such as histoplasmosis."

The patient, who met trial inclusion and exclusion criteria, was experiencing persistent inflammation in her knee "despite being on a cocktail of systemic methotrexate, prednisone and adalimumab [Abbott's Humira ] and in spite of a total of ten interarticular steroid injections in her affected knee prior to enrolling in this trial," Stewart Parker explained.

Amendments to the study's informed consent form likely will include a caution about immunosuppression. "Certainly there have been cases in the literature of histoplasmosis in patients who are on the anti-TNF systemic protein therapies, but I think the overriding factor was that heavily immunosuppressed patients have a high chance of coming down with histoplasmosis, and it really needs to be monitored," Stewart Parker said.

TgAAC94 uses a recombinant adeno-associated virus-derived vector to deliver a gene encoding the protein TVFR:Fc, a soluble form of the tumor necrosis factor alpha receptor, to reduce inflammation and disease in patients with active inflammatory arthritis who have one or more joints that do not fully respond to systemic protein therapy. Direct injection of tgAAC94 into affected joints "leads to the localized production of secreted TNFR:Fc within joint cells, reducing the activity of TNF-alpha within the joint and, potentially, leading to a decrease in the signs and symptoms" of disease, according to Targeted Genetics.

The Phase I/II study was designed to evaluate three different doses of tgAAC94 administered directly to affected sites, including knee, ankle, wrist, metacarpophalangeal or elbow, the exec explained.

Phase I is a dose escalation study, while Phase II is an open-label study in which all subjects receive two doses of the product.

The study began enrolling in October 2005. At the time it was halted, enrollment had closed, with 127 patients having received an initial dose of active drug or placebo and 74 of the 127 subjects having received a second dose of active drug. Of the 74, 55 have received two doses of active drug, she said.

The second dose timing occurs at the latter of 12 weeks or when signs and symptoms of disease reappear, Stewart Parker said. Based on that signal, "We'll just dose the second dose and then follow them out and see how long it lasts," the exec said. "I don't think [the hold will] jeopardize the study, really."

Targeted Genetics is also studying its AAV-derived vector in tgAAC09, a vaccine against HIV/AIDS, and in MYDICAR, a congestive heart failure candidate it is developing in a collaboration with Celladon. MYDICAR uses an AAV vector to deliver the SERCA2a gene to the heart muscle of patients with congestive heart failure.

More than 300 patients have been treated with AAV-based product candidates, and the "naturally occurring virus has never been associated with any pathology in humans, which is a key attribute in our decision to use AAV-based vectors as a platform for developing novel therapies," Stewart Parker asserted during the second-quarter call.

-Shirley Haley ([email protected])