West Coast Editor
The death of a patient in Targeted Genetics Inc.'s just-halted Phase I/II trial of the arthritis drug tgAAC94 might recall for some the 1999 death of Jesse Gelsinger, though the two likely have little or nothing in common - except that both cases involve gene therapy, an area still "completely misunderstood," said analyst Stephen Dunn with Dawson James in Boca Raton, Fla.
"His liver was failing," Dunn said of 18-year-old Gelsinger, who died four days after researchers at the University of Pennsylvania in Philadelphia injected genes to cure ornithine transcarbamylase deficiency, a genetic metabolic disease. "His liver panel right before the doctor injected him should have disqualified him." The physician was sued. (See BioWorld Today, Oct. 14, 1999.)
In the Gelsinger case, Penn used a high-dose adenovirus construct to deliver the genes directly into the hepatic artery. Targeted Genetics, on the other hand, uses the smaller, adeno-associated viral approach to inject TNFR:Fc fusion gene into arthritic joints.
The firm's shares (NASDAQ:TGEN), lost about 20 percent of their value Wednesday on word of the clinical hold, and fell 20.3 percent Friday, closing at $1.65, down 42 cents.
Dunn said the tgAAC94 patient who died probably was elderly, with an immune system already compromised by the likes of the anti-TNF-alpha arthritis drugs such as Enbrel (etanercept, Amgen Inc.), Remicade (infliximab, Centocor Inc.) and Humira (adalimumab, Abbott).
"If you ask the researchers [for Targeted Genetics], they're not too concerned," Dunn said, though everyone regrets the death. "They just need an answer."
The FDA will take up the issue of the patient's death during the meeting Sept. 17-19 of the NIH Recombinant DNA Advisory Committee, and said in a statement that the agency "is not aware of similar adverse events occurring in other gene therapy trials either with this specific product or with those that use other genes in AAV vectors" - but would review all ongoing trials.
Even though Targeted Genetics' drug is injected locally, "we know from other trials that you generate a flu-like response," Dunn said. "In oncology, that's nothing - the mildest of the mild, compared to side effects that you get with chemo." But in elderly arthritics, it's a much different story.
"They weren't thinking it through," he said. "I don't know how they're going to get around this."
Dunn told BioWorld Today that he believes gene therapy "at least in oncology - in very discrete uses - ultimately is going to work. But gene therapy for cystic fibrosis or things like that is going to be tough, and Targeted Genetics already got hit on that."
The firm's stock dropped 35 percent two years ago on news of its decision to stop development of the Phase IIb, mild-to-moderate CF drug, tgAAVCF, which missed the primary endpoint of a statistically significant improvement in lung function. (See BioWorld Today, March 18, 2005.)
Dunn covers Introgen Therapeutics Inc., of Austin, Texas, which at this year's meeting of the American Society of Clinical Oncology reported encouraging Phase II data in head and neck cancer with Advexin, which combines the p53 tumor suppressor gene with a nonreplicating, non-integrating adenoviral gene-delivery system.
Introgen is expected to file for approval of Advexin later this year - the first filing of a gene therapy in the Western world, though a drug similar to Advexin already is cleared for marketing in China.
Introgen's stock (NASDAQ:INGN) closed Friday at $3.51, down 11 cents.
The gene-therapy firm nearest in its approach to Targeted Genetics, in Dunn's view, is Gaithersburg, Md.-based GenVec Inc., with TNFerade, an adenovector that contains the gene for TNF-alpha, in a Phase II/III study for locally advanced pancreatic cancer.
Late last year, results for the first 51 patients enrolled in GenVec's pivotal Pancreas Cancer Clinical Trial with TNFerade study, known as PACT, showed a 42.5 percent absolute increase in overall survival when TNFerade was added to chemo-radiation, the standard of care, in pancreatic cancer. At one year, survival was 70.5 percent in the TNFerade plus standard-of-care arm vs. 28 percent for patients in the standard-of-care arm. (See BioWorld Today, Dec. 20, 2006.) GenVec's shares (NASDAQ:GNVC) closed Friday at $1.99, down 4 cents.