New tiotropium formulation for COPD moves closer to approval

SILVER SPRING, MD. – Reassured by the cardiovascular safety data in a large randomized study, the majority of a Food and Drug Administration advisory panel supported the approval of an inhaled liquid spray formulation of tiotropium bromide in a new delivery device for the long-term maintenance treatment of chronic obstructive pulmonary disease.

At the Aug. 14 meeting of the FDA Pulmonary-Allergy Drugs Advisory Committee, the panel voted 10-3 that the safety and efficacy data supported the approval of tiotropium bromide inhalation spray, at a dose of 5 mcg/day, administered via a device that contains 30 doses, for the long-term, once-daily maintenance treatment of bronchospasm associated with COPD and for reducing COPD exacerbations.

If the FDA approves the product, Boehringer Ingelheim plans to market it as Spiriva Respimat. It has been available outside of the United States since 2007 and is now available in more than 85 countries, according to the company.

The panel unanimously voted that the available data supported the efficacy of the Respimat device for the indication. This is the same indication approved for the dry powder formulation of tiotropium in the single dose, breath-actuated HandiHaler device, marketed as Spiriva HandiHaler by Boehringer Ingelheim, approved in 2004 by the FDA. A capsule is inserted into the HandiHaler device for each dose.

Like others voting for approval, Dr. Francis McCormack agreed the data had met the criteria for safety and efficacy required for approval and that the new tiotropium product, Spiriva Respimat, was comparable to the existing Spiriva HandiHaler product. “I’m enthusiastic about being able to offer this delivery device to my patients,” commented Dr. McCormack, professor of medicine and director of the division of pulmonary, critical care, and sleep medicine at the University of Cincinnati.

The Respimat device delivers a 5-mcg dose, and the HandiHaler device delivers an 18-mcg dose, with similar pharmacokinetic effects and systemic exposure, according to the company. Panelists agreed that treatment with the Respimat device was not shown to be more effective than with the HandiHaler, and the company did not have any data showing that compliance was better with the Respimat device.

Those voting in favor of approval were reassured by the results of a large study that addressed concerns about a cardiovascular mortality signal in earlier studies associated with tiotropium Respimat.

Boehringer Ingelheim filed for approval of tiotropium Respimat almost 7 years ago. At that time, the FDA requested more data from the company to support the exacerbation claim and to address the mortality imbalance among those treated with tiotropium Respimat in 48-week, placebo-controlled studies, and concerns over cardiovascular safety raised during the review.

The randomized, double-blind, parallel group study, the Tiotropium Safety and Performance in Respimat (TIOSPIR) trial of more than 17,000 patients with COPD followed for at least 2 years adjudicated the cause of deaths, comparing 2.5 mg and 5 mg of tiotropium in the Respimat device to the tiotropium HandiHaler device. All-cause mortality in the three groups was similar.

Fatal MACE (major adverse cardiovascular events) rates were similar between the treatment groups, noted Dr. Robert Lim, a clinical reviewer in the FDA’s division of pulmonary, allergy, and rheumatology products. While there were numerical differences in two fatal MACE components – cardiac disorders and fatal myocardial infarction – the differences were small.

Panelists said that the imbalance in fatal MIs could be a random finding and was not strong enough to vote against approval. However, some panelists cited lingering concerns about a cardiovascular safety signal in different studies.

Although she voted in favor of approval, Erica H. Brittain, Ph.D., a biostatistician at the National Institute of Allergy and Infectious Diseases, Bethesda, Md., said that she had “lingering unease” about a cardiovascular safety signal cropping up in several studies. But she was confident with the all-cause mortality finding and the “clear-cut” efficacy. However, if the ease-of-use feature of the Respimat inhaler was not important to a patient, Dr. Brittain noted that she would probably recommend the HandiHaler product.

A cardiologist on the panel, Dr. Philip Sager, said that he was reassured by the data, and that overall safety, cardiovascular safety, and “clear efficacy in treating patients with COPD has been demonstrated.” Breaking the MACE endpoint down by subgroups gets complicated, and the MI finding could be “statistical noise,” added Dr. Sager, chair of the scientific programs committee of the Cardiac Safety Research Consortium, San Francisco.

Voting against approval, Sean Hennessy, Pharm.D., director of the Center for Pharmacoepidemiology Research and Training, University of Pennsylvania, Philadelphia, said he remained concerned about cardiac safety and the absence of data showing Respimat provided benefits over the HandiHaler. He referred to the consistent finding of an increased rate of fatal MIs in multiple randomized clinical trials.