Milestone Pharmaceuticals Starts Phase 3 Trial of Etripamil for AFib With Rapid Heart Rate

First Patient Enrolled in ReVeRA-301 Study

Milestone Pharmaceuticals Inc. has enrolled the first patient in its Phase 3 ReVeRA-301 pivotal trial evaluating etripamil nasal spray as a potential treatment for adults experiencing atrial fibrillation with rapid ventricular rate, or AFib-RVR.

The study is designed to test whether patients can use etripamil themselves when an episode of AFib-RVR starts, including in settings such as their home, without needing immediate medical supervision.

Etripamil is already approved by the US Food and Drug Administration (FDA) under the brand name Cardamyst for treating acute symptomatic episodes of paroxysmal supraventricular tachycardia (PSVT) in adults.

Why Milestone Is Studying Etripamil in AFib-RVR

Atrial fibrillation, commonly called AFib, is the most common sustained heart rhythm disorder. It affects more than 6 million people in the United States.

During AFib, the heart beats irregularly. In some patients, the ventricles also begin beating very quickly. This is known as atrial fibrillation with rapid ventricular rate, or AFib-RVR.

For patients, an episode can be uncomfortable and disruptive. Symptoms can include a racing or pounding heartbeat, shortness of breath and weakness.

The problem is that there are limited options for treating an acute AFib-RVR episode outside a medical setting.

Many patients who experience these episodes need to go to an emergency department, where doctors may use intravenous medicines such as beta blockers or calcium channel blockers. Electrical cardioversion may also be considered in certain situations.

Milestone is investigating whether a self-administered nasal spray could provide another option.

ReVeRA-301 Will Evaluate Etripamil at Home

ReVeRA-301 is a multinational, multicenter, randomized, double-blind, placebo-controlled Phase 3 study.

The trial is expected to enroll approximately 150 patients with AFib-RVR.

Patients will use etripamil after they experience symptoms of AFib-RVR. The treatment will be administered in a medically unsupervised setting, such as at home.

The study uses the same 70 mg dose and repeat-dose regimen that supported the FDA approval of etripamil for PSVT.

The primary goal of the trial is to determine whether etripamil can reduce ventricular rate within 30 minutes.

Researchers will also look at symptom improvement based on patient-reported outcomes.

The Trial Uses a Repeat-Dose Approach

One important part of ReVeRA-301 is that it uses a repeat-dose regimen.

Patients will initially administer the 70 mg nasal spray when symptoms begin. If needed under the study protocol, a repeat dose can be used.

This approach is designed around the way etripamil is already used for its approved PSVT indication.

Milestone said it is currently pursuing a single-study supplemental New Drug Application, or sNDA, registration pathway for AFib-RVR based on the safety information generated so far.

Earlier Phase 2 Study Provided the Starting Point

The Phase 3 program builds on results from the earlier ReVeRA-201 Phase 2 study.

ReVeRA-201 was a multicenter, randomized controlled trial that evaluated etripamil nasal spray in patients experiencing symptomatic AFib-RVR in an emergency room setting.

The study found that a single 70 mg dose of etripamil reduced ventricular rate.

Patients also reported improvements in symptoms and treatment satisfaction.

These findings provided the basis for moving the program into Phase 3 development.

What Milestone Wants to Find Out

The main question in ReVeRA-301 is fairly simple: can etripamil safely bring down the heart's ventricular rate quickly enough when an AFib-RVR episode begins?

The study will measure ventricular rate reduction within 30 minutes as its primary endpoint.

Patient experience will also be important. Researchers will evaluate whether patients report improvement in their symptoms after treatment.

If the study produces positive results, it could support further regulatory discussions around using etripamil as an on-demand treatment for acute AFib-RVR episodes.

AFib-RVR Creates a Large Healthcare Burden

AFib is not just a problem for individual patients. It also creates a significant burden for the healthcare system.

Market research suggests that around 30% to 40% of people with AFib experience at least one RVR episode each year that requires urgent medical attention.

These episodes can result in emergency department visits and, in some cases, hospital admission.

US Healthcare Cost and Utilization Project data showed that emergency department utilization for AFib increased by 8.9% between 2015 and 2019.

Data from 2016 to 2020 also showed that AFib accounted for approximately 0.44% of all emergency department visits with a primary diagnosis of AFib. Nearly half of these visits resulted in inpatient admission.

The financial impact is also significant. Across different US studies, additional annual healthcare costs associated with AFib have been estimated at roughly $6,000 to $28,000 per patient, depending on the population and costs included.

The American Heart Association has projected that the total US economic burden of AFib could rise from $59.4 billion in 2020 to $174.8 billion by 2050.

A Self-Administered Option Could Change Acute Care

For someone experiencing an AFib-RVR episode, the current treatment process can mean leaving home, reaching an emergency department and waiting for medical evaluation before receiving treatment.

A self-administered therapy could potentially change that process if it proves safe and effective.

That is the idea behind Milestone's development strategy for etripamil.

Instead of requiring immediate IV treatment in a hospital or emergency department, patients could potentially have a portable nasal spray available for use when an eligible episode begins.

However, whether this approach can become part of routine AFib-RVR management will depend on the results of the Phase 3 study and subsequent regulatory review.

Etripamil Already Has an FDA-Approved Use

Etripamil is not an entirely new molecule.

The FDA has already approved etripamil nasal spray as Cardamyst for the conversion of acute symptomatic PSVT episodes to normal sinus rhythm in adults.

Etripamil is a calcium channel blocker designed as a rapid-response nasal spray.

Its nasal delivery is intended to allow patients to administer the medicine themselves rather than requiring immediate administration by a healthcare professional.

Milestone is now testing whether the same general approach can be extended to another acute cardiovascular condition.

The Company Is Expanding Etripamil Development

Milestone Pharmaceuticals is developing etripamil across several cardiovascular applications.

The medicine is currently being studied in Phase 2 development for PSVT in pediatric patients.

It is also now in Phase 3 development for acute AFib-RVR in adults.

The company sees the existing FDA approval for PSVT as an important foundation for the continued development of etripamil in other cardiovascular settings.

Comments From the Clinical Team

James Ip, M.D., principal investigator of ReVeRA-301 and a professor of medicine at Weill Cornell Medicine, said patients with AFib-RVR currently have no optimally effective self-administered treatment option.

He noted that many patients therefore require emergency department evaluation and treatment.

Milestone's chief medical officer, David Bharucha, M.D., PhD, said the FDA approval of etripamil for PSVT and the earlier Phase 2 findings in AFib-RVR provide a foundation for the Phase 3 program.

The company is now activating clinical trial sites across North America and internationally for the global event-driven study.

What Happens During ReVeRA-301

Patients enrolled in the study will be monitored as researchers assess how etripamil affects their heart rate and symptoms during an AFib-RVR episode.

The study will compare etripamil with placebo under controlled clinical trial conditions.

The primary measurement will focus on ventricular rate reduction during the first 30 minutes after treatment.

Researchers will also collect patient-reported information about symptom changes.

Because the trial is event-driven, the study's progress will depend on patients experiencing qualifying AFib-RVR episodes and generating the data needed for the analysis.

Looking at Patient Self-Management

The development of etripamil for AFib-RVR is centered on a different approach to acute heart rhythm management.

The goal is not simply to introduce another medicine. Milestone is looking at whether treatment can be brought closer to the patient at the moment an episode begins.

For patients who frequently experience AFib-RVR episodes, having a potential treatment that can be self-administered could provide a different way of managing these events.

Mellanie True Hills, founder and CEO of StopAfib.org, said AFib-RVR episodes can interrupt daily activities and sometimes require urgent medical care. She described the start of ReVeRA-301 as an important development for the AFib patient community.

Milestone Pharmaceuticals

Milestone Pharmaceuticals is a commercial-stage biopharmaceutical company focused on developing cardiovascular medicines.

Its lead product, Cardamyst, is based on etripamil nasal spray and is already approved in the US for acute symptomatic PSVT in adults.

The company is now advancing etripamil through Phase 3 development for AFib-RVR, with ReVeRA-301 designed to determine whether the treatment can provide rapid ventricular rate reduction and symptom improvement when administered by patients themselves.