Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Double-Blind, Placebo-Controlled, Crossover Study Using a Latin Square Design to Evaluate the Safety, Tolerability, and Efficacy of NGX267 Oral Capsules in Patients with Xerostomia Associated with Sjgrens Syndrome
Yokogawa1, Naoto, Dunham1, Jonathan S., Fisher1, Lytia, Mellberg, Sue, Vivino1, Frederick B., Chase2, Walter, Kivitz3, A.
To evaluate the efficacy and safety of NGX267 oral capsules for treatment of xerostomia due to Sjögren's syndrome.
Muscarinic agonists may stimulate salivary flow and improve oral symptoms in patients with Sjögren's syndrome. However, the clinical utility of these agents is sometimes limited by dosing frequency and cholinergic side effects. NGX267 (Torrey Pines Therapeutics, Inc., La Jolla, CA) is a novel acetylcholine analog that is relatively M1 receptor selective (M1> M3>> M5> M4> M2). Prior phase I clinical studies documented increased salivary flow and tolerability of doses up to 20 mg/day in normal elderly (age >= 65 years) men and women and, in doses up to 35 mg/day in normal young adult males.
Twenty-six patients, aged 21 to 55 years with 1° or 2 ° Sjögren's syndrome, diagnosed by American European Consensus Group criteria with subjective/objective salivary gland hypofunction were enrolled at 3 different centers for this 6 week protocol. After screening, patients were randomized to one of four different treatment sequences to receive single doses of NGX267 10mg, 15mg, 20mg or placebo in four separate 24 hour treatment periods interspersed by washout periods (6±2 days). A 4 × 4 Williams Latin Square crossover design was balanced for treatment order and carryover effects. Following an overnight fast, whole mouth sialometry was performed at baseline and 0.5, 1, 2, 4, 6, 12, 14 and 24 hours post dose. Subjects remained NPO except for water for the first 4 hours post dose. Unanesthetized Schirmer's tests were measured at baseline and 2, 12, 14 and 24 hours post dose. Oral symptoms including xerostomia, dry throat, dysphonia, dysphagia, cheilosis, dry tongue, level of thirst and sensation of saliva in the mouth were assessed with 100 mm visual analog scales (VAS). Safety was monitored by vitals, labs, EKGs/Holter monitors and patient diaries. The primary outcome was the cumulative salivary flow during the first six hours post-dosing of the study drug, AUCpd 06 (g).
All doses of NGX267demonstrated a statistically significant dose-dependent f¢ salivary flow over baseline compared to placebo for AUCpd 06 (g) (p=0.0001) (Fig. 1): 10mg- 52.5 (27.577.6), 15 mg- 93 (67.9118.1), 20 mg-112.5 (87.3137.7) that persisted for 24 hours: AUCpd 024 (g) (p=0.0025). All symptoms (24 hour post dose pooled- contrast VAS data) using the 15 and 20-mg doses improved over baseline compared to placebo. Lacrimal flow did not significantly change.
There were no dropouts for adverse effects or other reasons. Side effects included headaches, cold sweats, hyperhidrosis, nausea, flushing and URI's. Only one serious adverse event was noted in a patient who developed appendicitis after protocol completion.
NGX267 is safe and efficacious in Sjögren's syndrome patients during short-term use. Further, long-term placebo controlled trials are justified.
Study Sponsor Statement:
This study was sponsored by Torrey Pines Therapeutics, Inc.
To cite this abstract, please use the following information:
Yokogawa, Naoto, Dunham, Jonathan S., Fisher, Lytia, Mellberg, Sue, Vivino, Frederick B., Chase, Walter, et al; A Double-Blind, Placebo-Controlled, Crossover Study Using a Latin Square Design to Evaluate the Safety, Tolerability, and Efficacy of NGX267 Oral Capsules in Patients with Xerostomia Associated with Sjgrens Syndrome [abstract]. Arthritis Rheum 2009;60 Suppl 10 :477