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CLINICAL RESEARCH: PERIPHERAL AND PULMONARY ARTERY DISEASE

The Novel Phosphodiesterase Inhibitor NM-702 Improves Claudication-Limited Exercise Performance in Patients With Peripheral Arterial Disease

Eric P. Brass, MD, PhD^_*,_*, Richard Anthony, PhD, Frederick R. Cobb, MD, Isao Koda, PhD, Jenny Jiao, PhD and William R. Hiatt, MD^||

^_* Department of Medicine, Harbor-UCLA Medical Center, Torrance, California
Catalyst Pharmaceutical Research, Inc., Pasadena, California
Nissan Chemical America, Pasadena, California
Durham VA Medical Center, Durham, North Carolina
^|| University of Colorado, Divisions of Geriatrics and Cardiology, and the Colorado Prevention Center, Denver, Colorado

Manuscript received April 12, 2006; accepted July 23, 2006.

^_* Reprint requests and correspondence: Dr. Eric Brass, Harbor-UCLA Medical Center, Center for Clinical Pharmacology, 1124 West Carson, Torrance, California 90502. (Email: ebrass{at}ucla.edu).

OBJECTIVES: The current study tested the hypothesis that NM-702 improves treadmill exercise performance in peripheral arterial disease patients with claudication-limited exercise performance.

BACKGROUND: Patients with claudication experience significant disability, owing to their exercise limitation. Therapeutic options to improve exercise performance in these patients are limited. NM-702 is a novel drug that inhibits phosphodiesterase as well as thromboxane A₂ synthase.

METHODS: This study was a randomized, multi-center, placebo-controlled, double-blind trial. Patients were randomized to receive 24 weeks of twice-daily treatment with either placebo (intent to treat population, n = 130), 4 mg NM-702 (n = 126), or 8 mg NM-702 (n = 130).

RESULTS: After 24 weeks of treatment, 8 mg NM-702 was associated with a statistically significant increased peak walking time on a graded treadmill as compared with placebo (p = 0.004). Peak walking time after 24 weeks was increased by 17.1 ± 49.0% in the placebo arm, 22.1 ± 60.1% in the 4-mg NM-702 arm, and 28.1 ± 50.5% in the 8-mg NM-702 arm. NM-702 at the 8-mg dose for 24 weeks was associated with statistically significant improvements in the treadmill claudication onset time as compared with placebo. In addition, as compared with placebo, NM-702 improved the physical component and physical functioning scores of the Medical Outcomes Study 36-Item Short Form and the walking distance and stair climbing domains of the Walking Impairment Questionnaire. NM-702 was generally well tolerated, but adverse events typical of vasodilators were common.

CONCLUSIONS: NM-702 used for 24 weeks by patients with claudication was associated with improvements in laboratory- and ambulatory-based exercise performance.

Abbreviations and Acronyms   ABI = ankle-brachial index   ANCOVA = analysis of covariance   COT = claudication onset time   NM-702 = 4-bromo-6-[3-(4-chlorophenyl)propoxy]-5-(3-pyridylmethylamino)-3(2H)-pyridazinone hydrochloride   PAD = peripheral arterial disease   PWT = peak walking time   SF-36 = Medical Outcomes Study 36-Item Short Form   TBI = toe-brachial index   WIQ = Walking Impairment Questionnaire

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