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Milestone takes heart from NODE-301 results
MONTREAL and CHARLOTTE, N.C.—Milestone Pharmaceuticals Inc. has announced topline results from its Phase 3, multicenter, randomized, double-blind, placebo-controlled NODE-301 trial of its investigational new drug, etripamil. Etripamil is Milestone Pharmaceuticals’ novel short-acting calcium channel blocker, designed to be a rapid response therapy for episodic cardiovascular conditions. The calcium channel blocker is self-administered via a nasal spray.
Paroxysmal supraventricular tachycardia (PSVT) is a rapid heart rate condition characterized by intermittent episodes of supraventricular tachycardia (SVT) that start and stop suddenly and without warning. Episodes of SVT are often associated with symptoms including palpitations, sweating, chest pressure or pain, shortness of breath, sudden onset of fatigue, lightheadedness or dizziness, fainting and anxiety.
“PSVT places a significant burden on patients and the healthcare system, and a fast-acting therapy to resolve its symptoms when and where episodes occur would have a material impact on both,” noted Bruce Stambler, M.D., FHRS, of the Piedmont Heart Institute in Atlanta. “NODE-301 is a first-of-its-kind study, and as such encountered a number of challenges relative to studying SVT episodes outside of a controlled electrophysiology laboratory environment. The safety results support at-home use and the multiple efficacy signals show us that, with a confirmatory study, etripamil could fulfill the promise of delivering a fast-acting, patient administered therapy for PSVT.”
The NODE-301 trial, which enrolled a total of 431 patients across 65 sites in the U.S. and Canada, is an event-driven Phase 3 efficacy trial of etripamil for terminating SVT episodes in the at-home setting. Etripamil (70mg) did not achieve its primary endpoint of time to conversion of SVT to sinus rhythm (SR), compared to placebo, over the five hour period following study drug administration. Median time to conversion was 25 minutes for etripamil versus 50 minutes for placebo. Despite early activity — including the conversion of 61% of etripamil patients versus 45% of placebo patients by 45 minutes, a time period consistent with etripamil's known pharmacological activity — results from the latter part of the analysis confounded the statistical analysis of the primary endpoint.
The study demonstrated statistically significant improvements in favor of etripamil over placebo in the important secondary endpoint of patient-reported treatment satisfaction. Patient satisfaction was measured by a treatment satisfaction questionnaire for medication (TSQM-9), including global satisfaction and effectiveness scores. Questions addressed the relief of symptoms commonly associated with an episode of SVT, such as rapid pulse, heart palpitations, anxiety, shortness of breath and dizziness. There was also an improvement in the percentage of patients seeking rescue medical intervention, including in the emergency department, with etripamil and placebo patients reporting 15% and 27%, respectively.
“Efficacy signals across the earlier time points in NODE-301, in both primary and secondary endpoints, correlate directly with our understanding of the drug’s known pharmacologic activity,” said Joseph Oliveto, president and chief executive officer of Milestone Pharmaceuticals. “We are also encouraged to see very good safety and tolerability across the broad population enrolled in this study. That said, outcomes after 100 minutes, which were affected by a very small number of placebo patients remaining in the study at that time, suggest that the design and analysis plan used in NODE-301 negatively impacted the study’s outcome.”
The safety and tolerability data from the NODE-301 study are supportive of at-home use of etripamil, with adverse events (AE) consistent with those observed in prior trials. The most common AEs observed in patients were local to the nose, including nasal irritation and congestion. These events were typically transient in nature and most commonly characterized by the patient as mild in severity. There were no significant differences in incidences of severe adverse events or adverse events of interest, such as atrioventricular nodal blocks or blood pressure-related symptoms, across the etripamil and placebo groups.
“The overall results of the study reinforce our understanding of the promising profile of etripamil and meaningfully inform us how best to prove its efficacy moving forward. We will continue to execute as prudently possible on the ongoing NODE studies, including NODE-301B, and look forward to reviewing these data with regulators,” continued Oliveto. “The ongoing pandemic highlights the need for, and strengthens our commitment to, home use therapies.”
NODE-301B, which was designed to collect double-blind data from randomized patients who had not yet experienced an event after the NODE-301 trial reached its target number of adjudicated SVT events, still continues. These data will be analyzed separately as a second data set. Open-label safety studies of etripamil in subjects with PSVT — NODE-302 and NODE-303 — are ongoing, with active recruitment underway.
Milestone is conducting a comprehensive development program for etripamil, with Phase 3 trials underway in PSVT, and plans to commence a Phase 2 proof-of-concept trial in atrial fibrillation patients with rapid ventricular rate. Subsequent studies are expected in other conditions where calcium channel blockers are used.