The FDA approval of etripamil for PSVT occurred in December, 2025. Investigation about a potential role of etripamil in highly symptomatic AFib, The ReVeRA-Phase 3, trial is another test: can this self-administered nasal spray put an all-too-frequent emergency department problem back in the patient’s hands?
Atrial fibrillation with rapid ventricular rate (or AFib-RVR) is one of cardiology’s most stubborn, logistical problems. The condition is episodic, unpredictable, and intensely symptomatic, yet the standard health care provider response has been to give patients a chronic oral medication designed for a problem that arrives in bursts, or to tell them to call 911 or seek urgent care. Milestone Pharmaceuticals is betting that etripamil, a patient-administered nasal spray approved under the brand name CARDAMYST for paroxysmal supraventricular tachycardia, can change that calculus. The company’s first patient was recently enrolled in ReVeRA 301, a Phase 3 home-use trial targeting AFib-RVR. Dr. David Bharucha, MD, PhD, FACC, Milestone’s Chief Medical Officer, and a cardiac electrophysiologist with two decades of R&D experience spanning Forest, Allergan, and AbbVie, sat down with Vanguard to walk through the science and clinician rationale behind the bet, what the Phase 2 AFib study actually showed, and what a successful Phase 3 study would mean for AFib patients who have spent years planning their lives around the nearest emergency room or urgent-care facility.
Why have oral beta-blockers and calcium channel blockers failed as a real solution for acute AFib-RVR episodes?
Dr. David Bharucha: AFib-RVR is episodic, and taking a medication chronically, seven days a week, 365 days a year, is not going to give patients the bolus of drug effect they need in the moment. Even when given on an as-needed basis, what’s sometimes called pill-in-pocket, oral drugs simply don’t achieve the rapidity or the exposure level needed for adequate rate control. Physicians have been prescribing oral drugs because, currently, they’ve really had no other options.
What makes etripamil particularly novel, and makes it useful as a nasal spray for acute at-home administration and for our AFib Phase 3 trial, is that if you look at the published PK/PD curves for nasal etripamil, you would think you're looking at an IV-administered drug. What you're getting with this proprietary nasal spray formulation is IV-like action delivered through self-administration outside of medical supervision.
How does the current Phase 3 ReVeRA-301 capture reliable ventricular rate data when patients are self-administering at home without supervision?
Dr. David Bharucha: The brief answer is, exactly as we did in our extensive PSVT program. The slightly longer answer is that, with current wearable devices, which are very low-profile and can be attached directly to the chest wall to measure an EKG, we have very reliable, high-fidelity systems with which we're very experienced.
In the upcoming AFib trial, as in all of our PSVT trial experience, patients first recognize an episode purely based on symptoms. They don't have to look at a wearable to know. Based on those well-known, classic symptoms, they attach themselves to the monitor, and we obtain a high-fidelity EKG recording. Those EKG data are then transmitted to us, after the episode, and analyzed in a blinded fashion.
It's also worth noting that even in, Phase 2, where the study medication was given in the monitored setting of an emergency room, patients who were ready to be discharged after roughly an hour went home wearing a portable device. That gave us the data out to five hours post-drug.
“If you look at the published PK/PD curves for nasal etripamil, you would think you're looking at IV administration. What you're getting is IV-like action with a self-administered nasal spray.”
How did the Phase 2 ReVeRA 201 results shape the design of Phase 3?
Dr. David Bharucha: Patients in ReVeRA 201 responded very clearly to etripamil compared with placebo. What the trial showed was a very rapid and robust reduction in ventricular rate and, perhaps more importantly, a durable reduction in rate. That actually surprised us, because for a drug, etripamil, that acts quickly and is quickly metabolized, you would expect the effect to be fairly short-lived. That's not what we observed. The effect was clearly durable out to at least several hours. And that was after one dose of study drug; in Phase 3, patients will have the same repeat-dose option that they have with our approved indication in PSVT.
Beyond the Phase 2 rate data, the safety and tolerability profile was clean, and data on symptomatic reduction were compelling. Patients were given a set of standard PRO questions, and despite only 49 patients in the analysis population, we saw not only statistically significant symptom reduction, but what's recognized in PRO methodology as a clinically meaningful effect on a 7-point Likert scale.
The last piece that factored into the Phase 3 design was this Phase 2 finding: patients in the placebo arm required twice as many rescue medications in the emergency room as patients in the active treatment arm. That gives us strong optimism that, in Phase 3, we stand a very good chance of documenting not only reduced ventricular rate and improved symptoms, but also a lower rate of patients needing to go to an urgent care or emergency room facility.
Bottom-line: we have experience in this space. Both operationally in running this type of trial, and in patients’ using of etripamil nasal spray in the at-home, unsupervised setting. Also remember that these highly symptomatic episodes, of PSVT or of AFib-RVR, can occur without warning and our overarching goal, across both programs, is to prevent the need of these patients of going to an urgent care facility or ER.
How does a patient at home know when etripamil has worked, given that AFib stays in AFib and the goal is rate slowing rather than conversion?
Dr. David Bharucha: This is an important distinction to clarify. In PSVT, the expectation is conversion. In AFib-RVR, the expectation is significant rate slowing. But the commonality between the two is that they both lead to distinct symptomatic improvement. A patient who feels they're in distress, who feels their chronic medication isn't working and that they may need to go to the ER, what we’d expect with significant rate slowing in AFib is a distinct symptomatic improvement, perhaps akin to the relief patients feel upon conversion from PSVT.
Why does symptom-prompted rate control at home matter for a patient who may still eventually need ablation or cardioversion?
Dr. David Bharucha: There are several valuable potential uses here, and this is honestly what gets me enthusiastic about going to work every day.
First, it can be a standalone treatment. Sometimes all that's necessary for a patient with an episode of very rapid, highly symptomatic AFib is a cooling-off period. What tends to happen is that adrenaline starts flowing, there's a snowball effect, rapid rates lead to more adrenaline, and so on. Early and quick intervention is key in order to interrupt that cycle. So as a potential standalone treatment, this could be very valuable.
Second, this could potentially be a bridge to oral therapy. Oral medications simply take longer to produce an effect. And in the specific case of AFib, if someone is taking an oral antiarrhythmic like flecainide to try to achieve conversion at home, by the prescribing information, you need rate control first. You should not be giving flecainide, for example, to a patient who is still in rapid ventricular rates.
Third, with respect to ablation specifically, there are actually two potential windows where this could be useful. Before an ablation, patients are typically required to go off their home medications for approximately five half-lives, or close to a week. They need coverage during that interim period when they're, as I put it, naked of drug. And after an ablation, even in the most successful AFib ablation trials, there is what's called a blanking period, roughly one to several months, where the ablation is still taking hold, inflammation is settling, and all bets are off clinically and the patient often needs additional AFib suppression coverage. At-home etripamil could potentially be a useful adjunct in either of those windows.
Bottom-line: our goal for our Phase 3 AFib program is to demonstrate, similar to our PSVT trials, that self-administration of this drug is efficacious, safe, and practical for patients.
“Patients end up walking on eggshells between episodes. They say, 'Maybe I won't go on a hiking trip, or even a vacation, because I don't want to be too far away from an emergency room.'”
Why does it matter, practically and personally, for a patient living with recurrent AFib-RVR to have something they can reach for at home?
Dr. David Bharucha: It would be meaningful a lot of ways. From my experience as a practicing cardiologist and cardiac electrophysiologist, patients with episodic arrhythmias like AFib-RVR can have substantial symptoms. The palpitations can feel like one is running a marathon. Patients feel like their heart is beating out of their chest. They’re often lightheaded and can’t properly catch their breath. They sometimes think they're having a heart attack.
These episodes impose on daily life, and we also know is that the burden doesn't stop when the episode does. Patients walk on eggshells between episodes. They say, "Maybe I won't have that second cup of coffee." Or, "Maybe I won't go on a hiking trip, because I don't want to be too far away from an emergency room." We've actually presented on this very recently at the European Society of Cardiology, looking at the burden of episodic arrhythmias on patients' lives between episodes.
Beyond the patient burden, there is the growing pharmacoeconomic cost of ER visits, hospitalizations, lost work time, and all that goes with it. Our aspirations here are realistic ones: to bring this treatment not only to the approximately 2 million US patients with PSVT, but also to the even greater number patients with AFib episodes.
Dr. David Bharucha is Chief Medical Officer at Milestone Pharmaceuticals, a cardiac electrophysiologist, and a physician-scientist with more than two decades of pharmaceutical R&D leadership experience in cardiovascular and other therapeutic areas.
Moe Alsumidaie, MBA, MSF, is founder and Chief Editor of Vanguard Publications, which publishes Clinical Trial Vanguard, Pharma Vanguard and BullScope, and Head of Research at CliniBiz. He has two decades in clinical trial operations and data science, with earlier roles at Genentech, Abbott Vascular and Stanford University Medical Center, and is a guest lecturer in clinical trial sciences at Rutgers University.
