By Lisa Seachrist

Washington Editor

BETHESDA, Md. ¿ Billed as the first Gene Therapy Safety Symposium, San Diego-based UroGen/GenStar Therapeutics Corp. presented to the Recombinant DNA Advisory Committee (RAC) Wednesday its strategy for using an internally deleted, or ¿gutless,¿ adenovirus to deliver gene therapy.

The symposium is one in a series announced by the FDA and the National Institutes of Health on Tuesday to help keep the scientific community and the public informed about the safety issues facing gene therapy research. As a result, much of the discussion focused on whether the ¿gutless¿ adenovirus vector provided additional safety in comparison to current adenovirus vectors employed by gene therapy researchers.

¿The basic question is, Do we have cumulatively enough data to assume delivery of this vector is safer than adenovirus vectors,¿¿ said Philip Noguchi, director of the division of cellular and gene therapies at FDA.

Having completed a battery of preclinical tests, the company is seeking the go-ahead from FDA to take its gene therapy approach for treating hemophilia A into clinical testing. Upon request of FDA, UroGen/GenStar has agreed to get RAC approval before proceeding into a Phase I clinical trial.

¿We¿ve had discussions with FDA in developing the protocol and they¿ve had favorable comments about it,¿ said UroGen/GenStar CEO Robert Sobol. ¿We agreed not to proceed until the RAC felt comfortable with what we are doing. We haven¿t officially submitted to RAC. We will do that after further discussion with FDA and RAC.¿

The company is proposing to use gene therapy to treat hemophilia A, a hereditary disease resulting in a deficiency of the blood clotting protein Factor VIII. Sobol noted the disease was particularly amenable to a gene therapy approach since Factor VIII activity in the realm of 5 percent of normal activity has a significant clinical effect for the patient.

Hemophilia A patients currently control their bleeding with Factor VIII derived from concentrates of human plasma or a recombinant version of Factor VIII. These patients are at risk of developing inhibitory antibodies that render the Factor VIII ineffective.

UroGen/GenStar has developed a vector, which contains no adenoviral genes, to deliver the gene for Factor VIII to liver cells. Instead, the vector system relies on ¿helper¿ virus to package the Factor VIII gene in the coat of an adenovirus.

Without adenoviral genes, the UroGen/GenStar gene therapy vector is less likely to trigger an immune reaction that can lead to life-threatening disseminated intravascular coagulation (DIC) than the more commonly used adenoviral vectors. The gene therapy experiment resulting in the death of Jesse Gelsinger utilized a more standard adenoviral vector. A lessened immune response may also permit the gene to remain in the transduced liver cells and provide a long-lived source of Factor VIII.

The company presented data from mouse studies indicating the transduced Factor VIII gene could remain active for as a long as one year. While the vector didn¿t produce the same toxic effects as adenovirus, the animals experienced a transient elevation in liver enzymes and a transient decrease in the number of platelets. Dog models also showed similar toxicities.

Based on that data, UroGen/GenStar has proposed a Phase I dose-escalation study of the gene therapy vector in humans. Two groups of three patients would receive the vector in a single intravenous injection. The first group would receive a lower dose, the second a higher dose.

¿I think the data is compelling,¿ said Sobol. ¿This has a much better safety profile than adenoviral vectors and it¿s ready for clinical trials.¿

The RAC, however, was concerned that even a slight immune response would trigger inhibitors against Factor VIII, leaving the patients with less ability to respond to Factor VIII. The committee seemed eager to see animal data addressing the question of inhibitors.

¿I agree there are times when one has to study human diseases in the human,¿ said RAC member Theodore Friedmann, a professor at the Center for Molecular Genetics at the University of California in San Diego. ¿The thing that is most worrisome to me is we could render a patient unresponsive to Factor VIII. We need to be sure we derive all the information in the animal models before entering humans.¿

The RAC also raised questions about inadvertent delivery of helper virus to patients as well as the possibility of the gene integrating into the host chromosomes.

Sobol said the company needs further discussion with FDA and RAC to define what additional data are needed in order to approve the move to human clinical trials. The RAC will consider the protocol in a future meeting.

Currently known as UroGen Corp., the company is moving to be listed on either the Nasdaq or Amex exchange. Once the new listing takes place, the company will change its name to GenStar Corp.

The company¿s stock (OTCBB:UROG) closed Wednesday at $17.125, down $1.125.

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