Milestone Pharmaceuticals announced Friday that the U.S. Food and Drug Administration (FDA) has issued a Complete Response Letter (CRL) rejecting its cardiovascular drug Cardamyst, a decision that sent the company's stock plummeting by more than 60%.
The FDA's rejection focused on two specific chemistry, manufacturing and controls (CMC) issues, marking another setback in the Montreal and Charlotte, N.C.-based company's efforts to bring a novel treatment to market for paroxysmal supraventricular tachycardia (PSVT), a condition affecting approximately 2 million Americans.
Regulatory Challenges Mount
This rejection follows a previous Refusal to File letter issued by the FDA in December 2023, when regulators deemed the company's application insufficient for a full review. Milestone subsequently refiled in March 2024 with additional information, including restructured data sets that better captured the timing of reported adverse events. The FDA accepted this revised application in May.
In the current CRL, regulators requested additional information on nitrosamine impurities based on new draft guidance issued after the submission of the New Drug Application (NDA). The FDA also required completion of an inspection at the facility that performs release testing for Cardamyst, which had changed ownership during the review process.
The rejection appears to have caught Milestone off guard. CEO Joe Oliveto told BioSpace in a recent interview that the company was actively "transitioning to a commercial organization" and had already hired the sales management team for Cardamyst's launch, though they were waiting for formal approval before extending offers to sales representatives.
Addressing a Significant Unmet Need
PSVT represents a significant unmet medical need, characterized by episodes of rapid heart rate often exceeding 150 to 200 beats per minute. These unpredictable episodes create substantial anxiety for patients.
"You don't know when [events are] going to come and how bad it's going to be and how long it's going to last," Oliveto explained, noting that Cardamyst would offer patients "a little bit of peace of mind."
Formulated as a nasal spray, Cardamyst is a novel calcium channel blocker designed to deliver intravenous-like potency in a convenient form, allowing patients to manage PSVT episodes wherever they occur without requiring hospitalization.
Novel Approach in an Underserved Market
PSVT treatment has seen little innovation in decades. While advances have been made in ablation procedures, where doctors use radio waves to destroy small amounts of heart tissue that might trigger PSVT, Cardamyst would represent the first new pharmacological option since adenosine, an intravenous drug used in emergency settings, received FDA approval in 1989.
"There's no one else working in the space," Oliveto noted, highlighting the orphan-like nature of the indication despite its prevalence.
Promising Clinical Data
Milestone's NDA submission included what the company described as a "comprehensive data package" from the pivotal Phase III RAPID trial. Results suggested Cardamyst was "twice as effective and three times as fast as placebo" in normalizing heart rhythm.
Beyond PSVT, Milestone is also developing Cardamyst for atrial fibrillation, with Phase II trials currently underway. According to Oliveto, while there are interventions in development for atrial fibrillation, they primarily focus on anticoagulation rather than acute episode management.
Path Forward
Despite this significant setback, Milestone remains committed to Cardamyst's development. "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," Oliveto stated.
The company plans to request a Type A meeting with the FDA to discuss the issues raised in the CRL and determine the path forward for this potentially groundbreaking treatment.
