Nasal-Spray Calcium-Channel Blocker Promising for Converting Paroxysmal SVT

Fran Lowry

July 24, 2018

Self-treatment of acute paroxysmal supraventricular tachycardia (SVT) with a nasal spray containing a short-acting calcium-channel blocker is likely to be possible with a high rate of conversion to sinus rhythm, suggests a phase 2 study.

The nasal-spray preparation used in the 104 patient, placebo-controlled trial contained etripamil (Milestone Pharmaceuticals), which is hoped to be more bioavailable, effective, and faster-acting than oral calcium-channel blockers or other medications self-administered using the "pill-in-the-pocket" approach.

SVT was induced in the study, and the nasal sprays were administered by laboratory personnel.

Still, "We have demonstrated in this trial that the new paradigm we want to develop to treat paroxysmal SVT is feasible. We showed that our drug works, that it is well tolerated, and now we can go on to phase 3 testing," Francis Plat, MD, chief medical officer of Milestone Pharmaceuticals, told theheart.org | Medscape Cardiology.

Plat is senior author of the study, called NODE-1, which has been published in the current issue of the Journal of the American College of Cardiology. Preliminary findings were presented at the Heart Rhythm Society (HRS) Scientific Sessions 2017.

"Intranasal etripamil would offer patients the ability to rapidly terminate SVT episodes without the need to visit a healthcare facility. Although this would be a niche therapy for select patients, such a treatment is long overdue," say the writers of an accompanying editorial.

"About half a million individuals suffer from SVT in the United States, which translates into about 50,000 emergency department visits a year, so it's not trivial," the editorial's lead author, Gerald V. Naccarelli, MD, Penn State University College of Medicine, Hershey, Pennsylvania, told theheart.org | Medscape Cardiology.

People with frequent episodes of SVT can often be successfully treated with ablation, but those who have occasional recurrences can be harder to treat, he said.

"There have been attempts to treat these episodes with pills, but this hasn't been very effective, partly because the pills themselves are not that effective, and also because it takes a while for the drug to get absorbed so that high enough levels are achieved," Naccarelli said.

Such patients generally end up in the emergency room, with all of the attendant costs and inconveniences. So the nasal-spray approach is "pretty potentially exciting," he said.

"With nasal delivery, you don't have to worry about oral absorption and degradation through the liver. It's basically like giving the drug intravenously because you get right through the membranes. And you get a very short duration and a big blood level very transiently because the half-life is so short," Naccarelli said.

The double-blind study performed in the electrophysiology lab included 104 patients 18 years and older with previously documented SVT due to undergo a catheter ablation.

They were randomized to receive placebo or etripamil at 35, 70, 105, or 140 mg. SVT was induced; after a minimum of 5 minutes of sustained SVT, placebo or etripamil was administered via each nostril.

The primary endpoint, conversion of SVT to sinus rhythm lasting at least 30 seconds within 15 minutes after etripamil administration, was met by 35% of those who received placebo, 65% who received etripamil 35 mg, 87% taking the drug at 70 mg; 75% taking it at 105 mg, and 95% taking it at 140 mg.

Compared with placebo, the three highest etripamil doses showed significantly higher conversion rates.

Odds Ratio (OR) for Conversion of Induced SVT at the Three Highest Etripamil Nasal-Spray Dosages

Drug Dose Conversion Rate vs Placebo OR 95% CI P value
Etripamil 140 mg 60% 37.14 3.84 – 1.65 < .0001
Etripamil 105 mg 40% 5.57 1.19 – 27.63 .0248
Etripamil 70 mg 52% 12.38 2.28 – 82.26 .0006

 

Of patients receiving etripamil 140 mg, 105 mg, or 70 mg, 50% converted to sinus rhythm in less than 3 minutes; the shortest time was in the etripamil 140 mg group (1.8 minutes).

Adverse events considered to be related to etripamil were mild or moderate and observed in 44% and 24% of patients, respectively. The most common adverse events were nasal discomfort, nasal congestion, oropharyngeal pain, rhinorrhea, and cough. 

"The highest dose, 140 mg, had a 95% efficacy, but we had a drop in blood pressure at the time of the maximum concentration. We have therefore decided to use the 70-mg dose because the benefit vs side effect ratio was best. We will be using this dose in our phase 3 study going forward," Plat said.

That trial with a projected 500 randomized patients, called NODE-301, has started randomization and is expected to last 18 months.

"We are going from the electrophysiology room to the living room. This means that patients are going to administer the drug when they feel they are having an episode," he said.

The current dose-finding study was performed in a controlled environment and excluded patients with concomitant medications and structural heart disease. Also, SVT could not be induced in almost one-half of patients considered for the study, and 87% of induced patients had atrioventricular-nodal reentrant tachycardia.

These limitations notwithstanding, Naccarelli feels that etripamil "is an exciting first step."

"Treating patients who have very rare episodes of SVT with ablation may be inappropriate, so if we had this alternative, patients could carry this with them," he said. "SVT is never going to happen at a good time. So it's pretty cool. It has the potential to minimize putting people on a medicine every day, and it would give some comfort."

The study was funded by Milestone Pharmaceuticals, of which Plat is chief medical officer. NODE-301 is sponsored by Milestone Pharmaceuticals in collaboration with Medpace. Naccarelli has reported serving as a consultant to Janssen, GlaxoSmithKline, and Omeicos, and receiving a research grant from Janssen. Disclosures for the other authors are listed in the article.

J Am Coll Cardiol. 2018;72:489-497, 498-500.

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