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Executive Summary

Genzyme plans to submit an IND application "very soon" to FDA to begin a gene therapy trial in cystic fibrosis (CF) patients. The study protocol was unanimously approved by the National Institutes of Health's Recombinant DNA Advisory Committee (RAC) on Dec. 4. Presented by Michael Welsh, MD, Howard Hughes Medical Institute, the protocol involves the use of a recombinant adenovirus vector in which the CFTR (cystic fibrosis transmembrane conductance regulator) cDNA replaces the E1 region of a type 2 adenovirus. This Ad2/CFTR-1 vector will be administered to the nasal epithelium of three CF patients. The Welsh protocol was one of three gene therapy protocols for cystic fibrosis reviewed by the advisory committee during its two- day meeting. The three CF protocols represented the first time genetic therapy has been proposed to address the chronic and always fatal pulmonary disease. The goals of Welsh's study, according to the protocol, are to assess: the safety of the vector in human airway epithelium; the efficacy in correcting the CF chloride transport defect in vivo; and the effect of dose of recombinant adenovirus on safety and efficacy. Each patient will receive one of three doses of the gene/vector product, ranging from 2x10 and 5x10 plaque- forming units (pfus)/ml. Welsh told the advisory committee that targeting the nasal epithelium for gene transfer confers several safety and efficacy advantages. Specifically, having a defined area of application will allow the researchers to "begin to learn...about the relationship between the input virus and the biologic response." Another advantage is that frequent measurements can be made because the procedure is non-invasive. In addition, performing the therapy within a defined area of application allows the use of small doses of virus. "As a result, the patient will have a reduced risk with the virus if significant inflammation should occur or if viral replication should occur," Welsh stated. The Welsh protocol received generally favorable reaction from committee members. Commenting on the overall trial design, Ira Carmen, PhD, University of Illinois, Urbana, stated that Welsh's protocol should be approved because it is "minimalist, carefully tailored to obtain as much information as possible given the least invasive therapeutic design available." On Dec. 3, the advisory committee approved two cystic fibrosis protocols, one from NHLBI and the other from the University of Michigan. The committee also voted to defer approval for a protocol for autologous bone marrow transplants. The first CF protocol reviewed was presented by Ronald Crystal, MD, chief of the Pulmonary Branch, National Heart, Lung and Blood Institute. Crystal's protocol is an initial safety and biologic efficacy study to evaluate the use of the replication deficient recombinant adenovirus AdCFTR to transfer the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA to the respiratory epithelium of adults with cystic fibrosis. The primary goals of the protocol are to determine whether the procedure is safe in CF; the duration and extent of any correction of the biologic abnormalities of CF in the respiratory epithelium by AdCFTR; whether there is improvement in clinical parameters relevant to the disease process; and to find out if humoral immunity develops against AdCFTR sufficient to prevent repeated administrations in the future. The protocol proposes to enroll 10 adults with mild to moderate CF and lung disease typical of CF. Participants in the gene therapy trial will have to demonstrate antibodies against adenovirus type 5 in their blood as a safety precaution in the event of movement of AdCFTR or related adenoviruses into the bloodstream. Study participants also will have to show no evidence of adenovirus in their airways and airway cells should not support the replication of AdCFTR. At the committee's request, the investigators agreed to drop the requirement that participants be infertile. Under the protocol, the 10 participants will be put into five groups based on the titer of vector that will be administered. Each pair of study participants will receive an ascending dose, from 10 pfu/ml up to 10 pfu/ml, the maximum titer of adenovirus that can be repeatedly achieved in production. Following a baseline period and a vehicle control period of 35 days, the vector will be administered first to the nasal epithelium and then, after a 24-hour period demonstrating no toxic effects, to the epithelium of the large bronchi. Study participants will be required to stay at NIH's Clinical Center for two months after the vector is instilled in their lungs for post-administration evaluation, and, at various intervals following release, they will return to NIH for reevaluation. A series of bronchoscopies will be done to assess the respiratory epithelium for answers to the questions posed by the protocol. The Crystal protocol involves only one administration of AdCFTR. It is expected that any successful sustained therapy for CF will require repeated administrations in the early stages of the disease. The committee emphasized the importance of making it clear to participants that the protocol is not expected or intended to produce significant or prolonged clinical benefit. RAC member LeRoy Walters, PhD, Kennedy Institute of Ethics, Georgetown University, suggested that the disclaimer statement in the consent form, which makes it clear that long-term clinical benefit is unlikely, be moved forward from page 18 to page 1. The committee's vote to approve the protocol included these stipulations. The investigators will be looking at a variety of biological endpoints rather than treatment efficacy. The committee also considered and approved a similar protocol, entitled: "Gene Therapy of Cystic Fibrosis Lung Diseases Using E1 Deleted Adenoviruses: A Phase I Trial." Principal investigator James Wilson, MD/PhD, University of Michigan, said the protocol will enroll 12 subjects and place them in four groups receiving escalating dosages of Ad.CB-CFTR virus. Subjects will receive from 10 pfu/ml to 10 pfu/ml in 25 ml of fluid to the lung. Wilson's protocol was revised before the committee meeting to omit the performances of biopsies in response to concern over the danger of lung collapse that the procedure would pose. Post- transfection evaluation of pulmonary samples will be limited to brushing and lavage samples obtained during bronchoscopy. The approval of the three groundbreaking CF gene therapy protocols was preceded Dec. 2 by Genentech's announcement that it will implement an expanded access program for Pulmozyme (rhDNase) during or after the first quarter of 1993 when the results of an ongoing study in 80 seriously ill CF patients are analyzed. The firm reported that results of its Phase III 968-patient trial "demonstrated Pulmozyme improves lung function and reduces the rate of respiratory infection in patients with cystic fibrosis." A complete analysis of the study will be presented at the Intermountain Thoracic Society Meeting on Jan. 26 in Snowbird, Utah, the company says, and it expects simultaneous filing of the PLA in the U.S. and Canada to be finished "by March 1993." Start- up of a new facility that will produce commercial quantities of Pulmozyme "is planned to begin in first quarter 1993." The ABMT protocol reviewed by RAC was entitled: "Retroviral Mediated Transfer of the Human Multi-Drug Resistance Gene (MDR-1) into Hematopoietic Stem Cells During Autologous Transplantation after Intensive Chemotherapy for Breast Cancer." The committee voted to defer approval of the protocol until further data are available. The data should include the transduction ability of the vector to be used in the experiments and data on bone marrow recovery that will clarify what will be considered a significant improvement in recovery time. Gaithersburg, Md.-based Genetic Therapy, Inc. will supply the vectors. The investigators were also asked to give a better description of the assays for gene expression which will be used and of the methods by which this expression will be compared in tumor and in bone marrow. "Some formalization, some statement of evaluation criteria" is necessary, committee member Brigid Leventhal, MD, Johns Hopkins Hospital, said.

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