Abstract 19713: The Electrocardiographic Effects of Intranasal Formulations of a New Calcium Channel Blocker, MSP-2017, are Consistent With a Potential Treatment of Paroxysmal Supraventricular Tachycardia: Results of a Phase I Dose Escalation Study

Abstract

Introduction: MSP-2017 is a new L-type calcium channel antagonist developed to be self-administered intranasally to convert episodes of PSVT into sinus rhythm. Hypothesis: This phase 1 study was designed to determine safety, tolerability of two formulations (A and B) of MSP-2017 and to test whether the effects on ECG intervals (PR, QTc) and HR were significantly different from placebo. Methods: A double-blind, dose-escalation, placebo-controlled study was conducted in healthy males, consisting of 7 cohorts each including 6 subjects on active drug and 2 on placebo. Cohorts 1 to 5 subjects received 2 single doses of 3.5, 7, 14, 30, 60 mg of MSP-2017 formulations A and B, 3 days apart, and cohorts 6 and 7 subjects received a single dose of 105 and 140 mg of MSP-2017 formulation B only due to lack of PK differences compared to formulation A. Twenty-four hour Holter recordings were performed at screening and on dosing Days 1 and 3. ECGs were analyzed prior to dosing and at 0.5, 1.5, 3, 5, 7, 10, 15 min post-dose and less frequently until 1440 min post-dose. Results: The intranasal administration of MSP-2017 was safe and well tolerated. The largest mean placebo-corrected PR increase was observed early, with a peak effect of 20 msec (90% CI: 14.9 to 25.1) at 12 minutes with 60 mg, 19.5 msec (90% CI: 8.4 to 30.5) at 10 min with 105 mg, and 24 msec (90% CI: 15.3 to 32.7) at 12 min with 140 mg of MSP-2017. At lower doses the peak effect was lower and time to onset longer. MSP-2017 did not have a notable effect on QRS intervals but had a dose-related effect on HR. HR increase with both formulations of MSP-2017 was different from placebo at all dose levels. Seven minutes post-dose mean HR increase reached 7, 21.4, 32.2 and 37.4 bpm at 30, 60, 105 and 140 mg doses, respectively. MSP-2017 caused a shortening of the QT duration corrected for individual heart rate (QTcI) at high doses but without dose-dependence. Conclusions: MSP-2017 caused significant PR prolongation at early time points after dosing, with 20 msec at higher doses (60, 105 and 140 mg) and smaller effects beyond 50 min post-dose. The HR increase and the QTcI shortening suggest a sympathetic stimulation may have contributed to these ECG changes. These results are consistent with a potential positive clinical effect to be tested in patients with PSVT.