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Inhaled cyclosporine for lung transplant assessed.

ROCKVILLE, MD. -- The FDA's Pulmonary-Allergy Drugs Advisory Committee voted 8-8 last month on whether treatment with inhaled cyclosporine was behind the improved survival in a small study of lung transplant recipients. The advisory panel's vote is now being considered by the Food and Drug Administration in its review of the product for approval.

Chiron Corp., which acquired the rights to develop inhaled cyclosporine from the University of Pittsburgh in 2003, has proposed that it be approved for increasing survival and preventing chronic rejection in patients receiving allogeneic lung transplants who are on standard immunosuppressive therapy.

If approved, it would be the first treatment indicated for lung transplant recipients. The FDA, which usually follows the advice of its advisory panels, could decide either to approve inhaled cyclosporine with a postmarketing study or to defer approval until another study answers unresolved questions about efficacy and safety.

If the FDA approves the product, Chiron has said it would conduct a 5-year multinational postmarketing study with 250 treated and 250 control patients, Stephen Dilly, M.D., chief medical officer at Chiron, told the panel.

The 5-year survival rate among lung transplant patients is 50%, with bronchiolitis obliterans--chronic rejection--as the primary cause of poor survival, said Jeffrey A. Golden, M.D., medical director of lung transplantation at the University of California, San Francisco. Most lung transplant patients eventually develop chronic rejection, said Dr. Golden, who spoke on behalf of Chiron at the meeting.

The pivotal trial, a phase II, randomized, double-blind, placebo-controlled study, enrolled 56 patients within 7-42 days after a single or double lung transplant at the University of Pittsburgh. They were on standard systemic immunotherapy and were followed for 24-56 months; 26 patients received an inhaled cyclosporine formulation, titrated to a dose of 300 mg administered with a nebulizer three times a week, and 30 received placebo.

There was no difference in the acute rejection rate, the study's primary end point (71% of patients in both groups had at least one episode of acute rejection). But the use of inhaled cyclosporine was associated with a 79% reduced risk of death and a 72% reduced risk of chronic rejection or death, compared with placebo.

There were no increases in renal toxicity, infections, neoplasms, or other systemic toxicities among those on inhaled cyclosporine, who did have a significant increase in mild to moderate local respiratory tract irritation and bronchospasm, similar to the effects of other inhaled drugs.

The panelists who did not support approval said they were uncertain whether other factors might explain why survival was higher in treated patients. For example, more patients in the treated arm had double lung transplants, which are associated with better long-term survival and freedom from bronchiolitis obliterans syndrome than single lung transplants.

Although the survival effect was statistically significant, "it's not clear that the drug itself was responsible," remarked Roslyn B. Mannon, M.D., medical director of transplantation in the transplantation and autoimmunity branch at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.

But those voting for approval said this issue could be addressed in a postmarketing study, and there was enough evidence to show a survival benefit that justified approval. Some said inhaled cyclosporine offers promise for patients with few options.

The vote on safety was more favorable, with 11 panelists agreeing that there was adequate information on the safety of inhaled cyclosporine for its intended use, although they also said that longer-term safety data would be needed.

FDA officials said they were puzzled about the lack of a correlation between acute rejection and chronic rejection. Arturo Hernandez, M.D., a medical officer in the FDA's division of special pathogen and immunologic drug products, said that this was disturbing, since acute rejection is a major risk factor for the development of chronic rejection.

In a statement issued after the meeting, Dr. Dilly reiterated Chiron's commitment to a large postapproval study of the product, which would be marketed under the trade name Pulminiq if approved.

BY ELIZABETH MECHCATIE

Senior Writer
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Title Annotation:Pulmonary Medicine
Author:Mechcatie, Elizabeth
Publication:Internal Medicine News
Geographic Code:1U5MD
Date:Jul 1, 2005
Words:666
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