Boehringer Ingelheim/Pfizer's Spiriva demonstrates a clinically meaningful bronchodilator effect when used to treat chronic COPD patients, FDA's Pulmonary-Allergy Drugs Advisory Committee unanimously agreed Sept. 6.

"I think it has been established" that Spiriva (tiotropium) provides a benefit in treating bronchospasm in patients with chronic obstructive pulmonary disease, Committee Chair Mark Dykewicz, MD, Saint Louis University, said.

However, the committee unanimously recommended against approving the product for the treatment of dyspnea associated with COPD. No approved drugs carry the indication for the treatment of symptoms of COPD or for the disease itself.

Spiriva's efficacy in the treatment of bronchospasms was shown in six Phase III clinical trials assessing trough forced expiratory volume in one second response, the committee agreed.

Two one-year trials in the U.S. demonstrated Spiriva's superiority to placebo. In a 470-patient study, tiotropium-treated patient had an increase in trough FEV1 of .11 L versus a decrease of .03 L with placebo. Another study of 451 patients found an increase of .13 L with tiotropium versus a decrease of .01 L with placebo.

Spiriva was also superior to placebo in a six-month, multinational, 623-patient study (an increase of .11 L for tiotropium vs. a decrease of .03 L for placebo), as well as in a 584-patient, six-month, multinational study (.07 L vs. -.03 L). In two one-year trials in the Netherlands and Belgium, Spiriva had mean effect sizes of .11 to .18 L over ipratropium.

The committee agreed that trough FEV1 response is a meaningful clinical endpoint that could be used to support approval, instead of the traditional endpoint of peak FEV1 response.

"I applaud that as an endpoint because although it's been less well filled out in terms of being unconventional and therefore not having the metrics of magnitude of effect, it is from a clinical point of view...far more meaningful then...transigent peak effect," committee consultant James Stoller, MD, Cleveland Clinic Foundation, said. "Particularly in a long-acting drug such as this, [using trough FEV1 response] is a laudable and significant advance in the assessment of drug efficacy."

Committee member Polly Parsons, MD, University of Vermont, agreed and added that FDA needs to determine an adequate threshold for trough FEV1 response that would support approval.

Non-voting committee guest Michael Schatz, MD, Southern California Permanente Group, said an appropriate trough FEV1 would need to be specific to each drug. "We can't do it as a single measure," Schatz said. "We really have to take each case individually and look at the aggregate."

The committee also expressed reservations about the Spiriva safety database.

Trials excluded patients with "recent history of [myocardial infarction], cardiac arrhythmia requiring treatment, [and] hospitalization for heart failure," FDA said. In the one-year, placebo-controlled trials, 6.9% of tiotropium patients experienced chest pain versus 4.6% on placebo.

Committee member Peter Morris, MD, Wake Forest University, said he was "confident" the study data "doesn't represent an untoward risk of cardiac events," but the "unanswered question is how safely can I bring it to my patient now who might have significant underlying heart disease as well as COPD?"

BI also excluded patients with "known prostatic hypertrophy, bladder neck obstruction, [and] narrow-angle glaucoma." Urinary tract infection was reported in 7.3% of tiotropium patients versus 5.1% on placebo in the one-year studies.

Because of the elevated UTI incidence, the company should conduct "Phase IV studies on the effects of the drug on urinary obstruction," committee member Jesse Joad, MD, University of California-Davis, said.

The Spiriva NDA (21-395) was submitted Dec. 13, 2001 (¹ Also see "Pfizer's Geodon Schizophrenia Drug On 500 Hospital, 46 Medicaid Formularies" - Pink Sheet, 23 April, 2001., p. 18). COPD is the first indication sought for the drug; while BI had explored asthma as an indication, the company notified FDA in April 1999 that the research had been discontinued due to lack of efficacy.

BI/Pfizer’s Spiriva Shows Bronchodilator Effect, Not Dyspnea, Cmte. Says

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