ASGCT Press Release

Breakthroughs in Gene Therapy
Recent Advances in Clinical Gene Therapy
Presented at Society Meeting

DENVER (June 1, 2000) - Experts in the field of gene therapy research presented new findings in several areas of gene therapy. This research is being presented at the American Society of Gene Therapy (ASGT) Annual Meeting in Denver.

"Gene Therapy is in its infancy as a biomedical discipline. We are already seeing preliminary results, through clinical trials, that give us glimpses of hope that we will be able to offer effective treatments for debilitating and often deadly diseases," commented ASGT President, Savio L. C. Woo, PhD, Professor and Director of the Institute for Gene Therapy and Molecular Medicine at Mount Sinai School of Medicine, NY.

At the meeting, scientists presented safety and efficacy findings from trials for several devastating diseases including, severe combined immunodeficiencies (SCID), hemophilia B, and certain forms of cancer. While all still in the clinical trial phase, thus far both the safety and efficacy results are very promising.

Participants in the panel representing recent advances in clinical gene therapy included: Alain Fischer, MD; Katherine High, MD; David Kirn, MD and Deidre Gillespie, MD. The following summaries of their findings, represent the most up-to-date information that will lead gene therapy into an exciting new future.

Gene Therapy for Severe Combined Immunodeficiency Syndrome
Alain Fischer, MD
Necker University Hospital
Paris, France

Severe combined immunodeficiencies (SCID) are a group of rare inherited diseases characterised by a profound impairment of defenses against all kinds of microorganisms. In the absence of treatment, patients die within the first year of life. The current treatment, i.e. allogenic bone marrow transplantation does not provide entirely satisfactory results. We have therefore developed a gene therapy for the most frequent form of SCID, i.e. X-linked SCID.

A normal copy of the mutated gene is inserted ex vivo into a patient's bone marrow cells using a harmless virus. The process takes 5 days and is followed by intraveinous reinjection. Five patients were treated. In 3 out of 4 patients with a follow up of 7 to 14 months, the treatment resulted in the full correction of the immunodeficiency, enabling these young children to live normally at home without any therapy. Preliminary results are encouraging in a fourth patient for whom the follow up is still short (3 months). In one patient who had severe infectious complications at time of treatment, the situation is still undecided.

Altogether, these results provide evidence for positive results of a gene therapy trial. However, further assessment of the patients is required to know how long the correction of the immunodeficiency will be observed. Extension to the treatment of other forms of severe immunodeficiencies can nevertheless now be envisaged.

Gene Therapy for Hemophilia B
Katherine High, MD
Children's Hospital of Philadelphia
Philadelphia, PA

We have been working to develop a gene-based treatment approach to hemophilia B, the severe bleeding disorder caused by a deficiency of blood coagulation factor IX. The current approach to treating hemophilia involves intravenous infusion of clotting factor protein concentrates, usually in response to bleeding episodes. This treatment is effective but has several disadvantages, including high cost and need for intravenous administration. In addition, the current approach means that bleeds are treated after they occur, rather than being prevented altogether. The goal of a gene-based treatment approach is to allow the patient to continuously produce levels of protein adequate to prevent bleeds. Studies with protein concentrates have shown that maintenance of levels of only a few percent of normal are sufficient for this purpose. Most patients with severe hemophilia have clotting factor levels of <1%.

In our work we have made use of an AAV vector expressing Factor IX. In previous work we have shown that injection of such a vector into skeletal muscle in mice and in hemophilic dogs results in sustained expression of the transgene, in mice for the lifetime of the animal (18 months) and in dogs for at least three years (duration of the experiment). Levels of F.IX expression achieved in mice were ~250-350 ng/ml at doses of 1 x 1013 vg/kg, and in dogs ~70 ng/ml at doses of 8.5 x 1012 vg/kg. In hemophilic dogs, these levels were associated with shortening of clotting assays. Toxicity studies in both species have failed to reveal any evidence of long-term toxicity at these doses. Based on these and additional studies, a clinical trial of AAV-mediated, muscle-directed gene transfer for hemophilia B has been initiated. The purpose of this Phase I/II trial is to determine the safety of this approach. To date, six subjects have been enrolled, and data are available on the first three subjects. Using tests such as Southern blots, we have shown that the donated gene is in fact transferred successfully, and that it is expressed as shown on immunoperoxidase staining of biopsied injected muscle tissue. There has been no evidence of germline transmission of vector sequences or of formation of inhibitory antibodies, two major safety concerns of the trial. There have been some detectable changes in clinical endpoints, including amount of clotting factor concentrates consumed. The goal of the planned dose escalation is to identify a safe dose that can result in an increased level of clotting factor in all subjects that receive that dose.

Cancer Treatment for the Replication Competent Adenovirus
David Kirn, MD
Imperial College School of Medicine
London, England

My presentation will cover the clinical testing of Onyx-015, a first-generation agent in a new treatment platform for cancer, and the discovery of improved second-generation viruses. This "oncolytic virus" treatment platform is based on the use of viruses that multiply in tumors and kill them, while minimizing damage to normal cells. The first-generation virus Onyx-015 is a genetically-modified adenovirus that has now been in clinical testing for over four years. I will describe the "staged development" approach we used to maximize safety to patients on trials.

In the first trials, we administered the virus directly into the tumor (e.g. head and neck cancer). Once safety was shown we moved to intracavitary (abdominal cavity) administration (ovarian cancer), followed by intra-arterial (liver metastases from colorectal cancer) and now intravenous administration (lung metastases).

Onyx-015 has been very safe at the highest doses administered following injection intravenously and into the hepatic (liver) artery, as well as intratumoral. This is critical information given the concerns raised by the patient death following adenovirus treatment at the University of Pennsylvania. Tumor infection by virus was demonstrated by all routes of administration, including intravenous injection. Unfortunately, antitumoral efficacy of Onyx-015 on its own was disappointingly low in numerous tumor types; possible reasons will be discussed.

The future of this field is very bright, however. A potential synergy has been discovered between oncolytic adenoviruses and chemotherapy which has led to initiation of phase III trial planning, the first phase III trial of its kind. In addition, new and improved viruses with potentially improved efficacy are entering clinical testing.

Advanced Clinical Trials with Non-Viral Vectors
Deirdre Gillespie, MD
Vical Inc.
San Diego, CA

Vical Incorporated (Nasdaq:VICL) reported interim data for the first 52 of 70 planned patients, in a Phase II Allovectin-7 trial for metastatic melanoma. Treatment with Allovectin-7 resulted in a reduction in total tumor burden of 50 percent or more in 10 percent of the patients (objective clinical responses) with a current median duration of response exceeding 5 months. An additional 15 percent of the patients have stable disease, some with reductions in total tumor burden that are significant but did not reach 50 percent at this time. These are patients who have failed other treatments.

Most side effects of the administration of Allovectin-7 were mild or moderate. The conclusions based on these data were that the response rate and median duration of response to date confirm the activity of Allovectin-7 in the exposed patient population, and that the safety profile of Allovectin-7 remains favorable.

Vical also reported interim data for the first 37 of 61 patients treated in a Phase II Leuvectin trial for metastatic kidney cancer. Nine of 21 patients (43 percent) with limited disease and mild symptoms ("good risk" patients) experienced clinical activity. In three patients (14 percent) tumor burden was reduced by 50 percent or more (objective clinical responses) and the duration of these responses is 12 to 19 weeks and ongoing. An additional six patients (29 percent) have stable disease lasting from 19 to 69 weeks and ongoing. In patients with multiple sites of metastatic kidney cancer and symptoms of cancer ("poor risk" patients), six of 16 (38 percent) experienced stable diseases lasting 18 to 30 weeks, but none achieved 50 percent reduction in total tumor burden. Leuvectin was safe and well-tolerated, with only four adverse events requiring overnight hospital stays. Vical has initiated a second Phase II trial for patients with limited metastatic disease and minimal symptoms using higher doses of Leuvectin.

The American Society of Gene & Cell Therapy (ASGCT) is a professional non-profit medical and scientific organization dedicated to the understanding, development and application of genetic and cellular therapies and the promotion of professional and public education in the field. For more information on ASGCT, visit its website, www.asgct.org.

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