FDA Issues CRL for Etripamil Nasal Spray (Cardamyst) in PSVT

The US Food and Drug Administration (FDA) has issued a Complete Response Letter for Milestone Pharmaceutical's application for etripamil nasal spray (Cardamyst) in the treatment of paroxysmal supraventricular tachycardia (PSVT).

Announced by Milestone Therapeutics on March 28, 2025, the FDA’s CRL did not raise any concerns regarding etripamil clinical safety or efficacy data, but cited 2 key Chemistry, Manufacturing and Controls issues to be addressed.

“We are deeply disappointed by the CRL but remain committed to the potential of CARDAMYST as a novel treatment option that can help patients with PSVT. Our team is evaluating the feedback provided and intends to request a Type A meeting to discuss the issues raised in the CRL,” said Joe Oliveto, president and chief executive officer of Milestone Pharmaceuticals. “We are appreciative of the FDA’s efforts and are confident we can collaborate with the agency with the goal of addressing these issues in a resubmission.”

According to the release from Milestone Pharmaceuticals, the FDA has requested the company submit additional information on nitrosamine impurities based on new draft guidance issued after the NDA submission and is requiring a facility inspection that performs release testing for etripamil to ensure it complies with Current Good Manufacturing Practices. The company points out the facility changed ownership during the review of the NDA.1

A novel calcium channel blocker nasal spray, etripamil was developed for elevated and often highly symptomatic heart-rate attacks associated with PSVT and atrial fibrillation with a rapid ventricular rate. The rapid-response therapy is designed to be self-administered by a patient, without the need for direct medical oversight.1

The road to the March 28, 2025 decision has been marked with twists and turns. Milestone Pharma submitted their initial New Drug Application (NDA) to the FDA on October 24, 2024. Before the close of 2024, Milestone Pharmaceuticals announced receipt of a Refusal to File Letter from the FDA, which stated the application was not sufficiently complete to permit substantive review and requested clarification about the time of data recorded for adverse events in phase 3 clinical trials. In March 2024, the company announced that, following a Type A meeting with the FDA, they had resubmitted their NDA for etripamil nasal spray in PSVT.1,2,3,4

The application for etripamil nasal spray was based on data from the RAPID trial. Part 2 of the NODE-301 study, RAPID was a multicenter, randomized, placebo-controlled trial evaluating the efficacy and safety of intranasal etripamil 70 mg as an on-demand therapy for PSVT.1,2,3,4,5

Conducted at 160 sites in North America and Europe, the study included 692 adults with a documented history of symptomatic PSVT episodes lasting at least 20 minutes. Patients who tolerated test doses were randomized in a 1:1 ratio to receive either etripamil or placebo.5

Upon experiencing PSVT symptoms, participants self-administered an initial 70 mg dose, with an optional second dose if symptoms persisted beyond 10 minutes. The primary endpoint was the time to conversion to sinus rhythm for at least 30 seconds within 30 minutes after the first dose.5

Results suggested 184, with 99 in the etripamil group and 85 in the placebo group, self-administered the study drug for confirmed atrioventricular-nodal-dependent PSVT. Kaplan-Meier estimated conversion rates within 30 minutes were significantly higher with etripamil (64%) relative to placebo (31%) (HR, 2.62; 95% CI, 1.66 to 4.15; P <.0001). The median time to conversion was 17.2 minutes (95% CI, 13.4 to 26.5) with etripamil relative to 53.5 minutes (95% CI, 38.7 to 87.3) with placebo.5

Safety data indicated etripamil was well tolerated, with treatment-emergent adverse events in 50% (68/99) of etripamil-treated patients, compared to 11% (12/85) in the placebo group. The most common adverse events were nasal discomfort (23%), nasal congestion (13%), and rhinorrhea (9%), all of which were transient and mild to moderate. No serious adverse events or deaths related to etripamil were reported in the study.5

References:

1. Milestone Pharmaceuticals. FDA Issues Complete Response Letter for Etripamil for PSVT | Milestone Pharmaceuticals, Inc. Milestone Pharmaceuticals, Inc. Published March 28, 2025. Accessed March 28, 2025. https://investors.milestonepharma.com/news-releases/news-release-details/fda-issues-complete-response-letter-etripamil-psvt

2. Milestone Pharmaceuticals, Inc. Milestone Pharmaceuticals announces submission of New Drug Application to the U.S. FDA for Etripamil. Milestone Pharmaceuticals, Inc. October 24, 2023. Accessed March 27, 2025. https://investors.milestonepharma.com/news-releases/news-release-details/milestone-pharmaceuticals-announces-submission-new-drug.

3. Milestone Pharmaceuticals, Inc. Milestone Pharmaceuticals receives refusal to file letter from U.S. FDA for New Drug Application for etripamil in the treatment of PSVT. Milestone Pharmaceuticals, Inc. December 26, 2023. Accessed March 27, 2025. https://investors.milestonepharma.com/news-releases/news-release-details/milestone-pharmaceuticals-receives-refusal-file-letter-us-fda.

4. Milestone Pharmaceuticals, Inc. Milestone Pharmaceuticals announces resubmission of New Drug Application for etripamil for treatment in paroxysmal supraventricular tachycardia. Milestone Pharmaceuticals, Inc. March 28, 2024. Accessed March 27, 2025. https://investors.milestonepharma.com/news-releases/news-release-details/milestone-pharmaceuticals-announces-resubmission-new-drug.

5. Stambler BS, Camm AJ, Alings M, et al. Self-administered intranasal etripamil using a symptom-prompted, repeat-dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia (RAPID): a multicentre, randomised trial. Lancet. 2023;402(10396):118-128. doi: 10.1016/S0140-6736(23)00776-6