Milestone takes etripamil into Phase 3 AFib test with at-home treatment strategy

Milestone Pharmaceuticals Inc. (NASDAQ: MIST) has enrolled the first patient in ReVeRA-301, a pivotal Phase 3 trial testing etripamil nasal spray as a self-administered treatment for atrial fibrillation with rapid ventricular rate, potentially opening a much larger second cardiovascular indication for the company’s recently launched CARDAMYST franchise. Approximately 150 patients will be randomized in the multinational study and will self-administer etripamil outside a medically supervised setting when symptomatic episodes occur. Milestone is using the same 70 mg repeat-dose regimen already approved by the U.S. Food and Drug Administration for paroxysmal supraventricular tachycardia under the CARDAMYST brand. The commercial proposition is unusually straightforward for a cardiovascular drug: if etripamil can quickly slow ventricular rate at home, some patients who currently require urgent evaluation and intravenous treatment could potentially manage episodes earlier and with less dependence on emergency departments.

The opportunity also comes at a pivotal corporate moment. CARDAMYST only recently entered commercial use, generating $600,000 of product revenue in the second quarter, while Milestone held $170.6 million of cash, cash equivalents and short-term investments at June 30. Management expects that liquidity to support operations into the second half of 2027, which means ReVeRA-301 is progressing while Milestone simultaneously spends on the launch of its first approved medicine. More than half of commercially insured U.S. lives had obtained CARDAMYST coverage by August, indicating that market-access infrastructure developed for PSVT could potentially support a second indication if the AFib program succeeds.

How is Milestone Pharmaceuticals designing the ReVeRA-301 Phase 3 trial?

ReVeRA-301 is a randomized, double-blind, placebo-controlled international study expected to enroll approximately 150 people with atrial fibrillation and rapid ventricular rate. Unlike Milestone’s earlier Phase 2 study, which treated patients in emergency departments, Phase 3 participants will use the nasal spray when symptoms prompt treatment in an unsupervised setting such as their home. The primary endpoint measures reduction in ventricular rate within 30 minutes, while a key secondary endpoint assesses symptom improvement through patient-reported outcomes. Milestone says it is pursuing a single-study supplemental New Drug Application pathway based on the safety experience already accumulated with etripamil.

That trial design raises the evidentiary bar in an important way. Demonstrating heart-rate reduction under controlled emergency-department conditions is different from showing that patients can correctly recognize an episode, use the medicine without immediate medical supervision and achieve a clinically meaningful effect in everyday life. The study therefore tests both pharmacological performance and whether the self-treatment model underpinning CARDAMYST can extend into a more complex arrhythmia.

What did the earlier ReVeRA-201 trial show in AFib-RVR?

The Phase 2 ReVeRA-201 study randomized 69 patients presenting urgently with symptomatic AFib-RVR, with 56 ultimately receiving either etripamil 70 mg or placebo. Etripamil produced an adjusted mean maximum ventricular-rate reduction over the first 60 minutes that was 29.91 beats per minute greater than placebo, with a p-value below 0.0001. Two-thirds of etripamil-treated patients achieved at least a 20% ventricular-rate reduction compared with none in the placebo arm, while symptom relief and treatment satisfaction also improved. One etripamil patient experienced transient severe bradycardia and syncope that investigators attributed to hypervagotonia.

Those results established a credible biological and clinical signal, but Phase 3 must show that the effect remains reliable when patients dose themselves away from the emergency department. The larger pivotal study also uses the repeat-dose regimen that supports CARDAMYST’s approved PSVT use, rather than relying only on the single-dose approach evaluated in the earlier AFib study. That creates useful regulatory and manufacturing continuity for Milestone if the new indication is ultimately successful.

Why could AFib-RVR be commercially larger than CARDAMYST’s first indication?

Atrial fibrillation is the most common sustained cardiac arrhythmia and affects more than six million people in the United States. Milestone cites market research suggesting that 30% to 40% of AFib patients experience at least one rapid ventricular-rate episode annually that requires urgent medical attention. Current acute options can include intravenous beta blockers, intravenous calcium-channel blockers or electrical cardioversion, generally requiring direct medical care rather than a medicine patients can carry and administer themselves.

The healthcare economics make the concept attractive. Milestone cites U.S. research placing incremental annual costs associated with atrial fibrillation at roughly $6,000 to $28,000 per patient depending on the population and methodology, while American Heart Association projections place the broader U.S. AFib economic burden at $174.8 billion by 2050. A drug would not eliminate those costs, but even modestly reducing emergency-department utilization could create a payer argument alongside symptom relief.

The commercial ceiling should nevertheless be separated from the theoretical disease population. Not every AFib-RVR episode will be suitable for home treatment, some patients have cardiovascular conditions that make etripamil inappropriate, and physicians may initially remain cautious about allowing self-treatment of symptomatic rapid heart rates. The addressable market will depend heavily on final labeling, safety data and whether clinicians can define clear circumstances under which patients should self-treat versus seek immediate medical attention.

Why does CARDAMYST’s existing FDA approval reduce some development risk?

CARDAMYST is already FDA approved for converting acute symptomatic episodes of paroxysmal supraventricular tachycardia to sinus rhythm in adults. It is a fast-acting calcium-channel blocker delivered intranasally and designed specifically for patient-initiated treatment without immediate medical supervision. That approval means Milestone has already validated the formulation, device, core manufacturing system and general self-administration concept through a completed regulatory process.

The AFib-RVR program still requires independent evidence because the clinical objective is different. In PSVT, CARDAMYST is intended to terminate the arrhythmia and restore sinus rhythm. In atrial fibrillation with RVR, Milestone is trying to reduce the ventricular rate rather than convert AFib itself. Success would therefore extend one drug-delivery system across two related but clinically distinct acute cardiovascular problems.

Commercially, that could increase the value of every element Milestone is already building around CARDAMYST. The same prescriber relationships, pharmacies, reimbursement infrastructure and patient-support programs could potentially serve both indications. A second successful use would also reduce reliance on PSVT adoption alone to justify the fixed cost of the company’s commercial organization.

Can Milestone fund both the CARDAMYST launch and a pivotal Phase 3 study?

Milestone ended the second quarter with $170.6 million of cash and short-term investments, up from $106 million at the end of 2025. Management expects those resources to cover operating expenses and capital expenditure into the second half of 2027. Product revenue remains extremely early, reaching only $600,000 in the second quarter and $800,000 for the first six months, meaning the business is still dependent primarily on its balance sheet rather than internally generated cash.

That makes the timing of ReVeRA-301 material. A successful CARDAMYST launch could gradually offset operating burn while Phase 3 progresses, but a slower launch would leave Milestone funding commercialization and clinical development simultaneously. The company’s current runway provides room to execute the trial, although eventual financing needs will depend on enrollment pace, commercial spending and how quickly product revenue scales.

What does MIST stock say about investor expectations?

Milestone shares closed at about $1.04 on August 21, little changed on the day and below the approximately $1.23 closing price recorded one month earlier. The stock has also traded close to the bottom of a 52-week range that has extended to roughly $3.06, suggesting investors remain cautious despite CARDAMYST approval and the start of the AFib pivotal program.

That skepticism means ReVeRA-301 carries disproportionate strategic weight. CARDAMYST must first prove it can build meaningful PSVT revenue, while the AFib trial offers a route to a potentially much larger addressable population using substantially the same drug and delivery platform. If Phase 3 validates at-home rate control, Milestone could evolve from a single-indication launch company into a broader acute-arrhythmia franchise. If the trial fails, investors will be left valuing the company largely on how far the existing PSVT launch can scale.