Etripamil

Milestone Pharmaceuticals’ nasal spray failed for a second time to secure US approval to treat an arrhythmia disorder called paroxysmal supraventricular tachycardia. The FDA’s complete response letter identified two CMC issues, according to Friday’s release . Milestone said it has to provide more information about “nitrosamine impurities,” saying the FDA issued new draft guidance after it filed its NDA. It also said the facility that conducts release testing for etripamil will need to be inspected after a change in ownership during the review period. Milestone said the agency didn’t raise any concerns about drug efficacy or safety. Even so, the company’s shares $MIST plummeted about 60% on Friday morning. Milestone’s path to the FDA has been filled with setbacks. It previously tried to file for approval of etripamil in 2023 but received a refuse-to-file letter from the FDA at the end of that year. The agency requested more information about the “time of data recorded for adverse events” in the company’s registrational studies. In 2020, etripamil failed a Phase 3 trial in PSVT. Milestone’s latest NDA was based on results from two Phase 3 studies called RAPID and NODE-301. In the RAPID trial, almost 65% of patients given etripamil switched to sinus rhythm — or a regular heartbeat — within 30 minutes of treatment, versus 31.2% of placebo patients, according to topline results shared by Milestone in 2022. The data were statistically significant. Etripamil is a calcium channel blocker formulated as a self-administered nasal spray. Patients with paroxysmal supraventricular tachycardia, or PSVT, who have a sudden onset of rapid heartbeats often need immediate medical attention, which may include a trip to the emergency room. Milestone’s drug is meant to treat patients quickly and help them avoid an ER visit. The company had been preparing for a “staged launch” of etripamil in PSVT starting in the middle of this year, according to TD Cowen analysts in February. The plan had been to initially target 10,000 to 12,000 physicians, mostly cardiologists. The disease is estimated to have a prevalence of less than 1% in the US. That said, the company believes that atrial fibrillation represents a much larger market opportunity for the drug, Milestone CEO Joseph Oliveto said at the TD Cowen Health Care Conference in Boston in February. Etripamil is currently in Phase 2 development for atrial fibrillation. In September of last year, the drug passed a Phase 3 test in patients in China with PSVT, setting the stage for a filing by Milestone’s China partner Ji Xing.

iStock, Tymofii Riabets Milestone Pharmaceuticals hit another bump in the road in its quest to get Cardamyst approved for paroxysmal supraventricular tachycardia when the FDA issued a Complete Response Letter on Friday. Milestone Pharmaceuticals revealed on Friday that the FDA has rejected its cardiovascular drug Cardamyst, sending the company’s shares down by more than 60%. The complete response letter, which focused on two key chemistry, manufacturing and controls (CMC) issues, is the latest knock in the Montreal and Charlotte, N.C.–based company’s quest to get Cardamyst approved for paroxysmal supraventricular tachycardia (PSVT), a type of abnormal heart rhythm affecting around 2 million people in the U.S. In December 2023, the FDA hit Milestone with a Refusal to File letter for the nasal spray, saying the company’s application was not sufficient to warrant a full review. Milestone refiled its application in March 2024 with additional information, including restructured data sets that captured the timing of reported adverse events. The FDA accepted the application in May of that year. The rejection may have come as a surprise to Milestone, which had been actively preparing for the drug’s launch. In an interview earlier this week, CEO Joe Oliveto told BioSpace the company was “transitioning to a commercial organization” and had already hired the sales management team for Cardamyst’s rollout but was waiting for formal approval before issuing offers to sales representatives. In its CRL, the FDA requested that Milestone submit additional information on nitrosamine impurities based on a new draft guidance issued after the new drug application was submitted and complete an inspection at the facility that performs release testing for Cardamyst. The facility had changed ownership during the review process, according to Milestone. There is high unmet need for patients with PSVT, which is characterized by episodes of rapid heart rate often exceeding 150 to 200 beats per minute. The condition instills a lot of fear in patients because “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 said. Cardamyst offers patients “a little bit of peace of mind.” A novel calcium channel blocker, Cardamyst is formulated to deliver IV-like potency in the convenience of a nasal spray, Oliveto explained, so patients can manage PSVT events wherever they occur without needing to go to the hospital. PSVT is somewhat of an orphan indication, as “there’s no one else working in the space,” Oliveto said. There have been advances in an ablation procedure where doctors use small radio waves to destroy a small amount of heart tissue that might trigger PSVT, he noted. However, Cardamyst would be the first new drug for the condition since adenosine , an intravenous drug used in emergency rooms, was approved by the FDA in 1989. In its NDA submission, Milestone touted a “comprehensive data package” from the pivotal Phase III RAPID trial that suggested the drug was “twice as effective and three times as fast as placebo” in normalizing heart rhythm. Cardamyst is also in Phase II development for another cardiovascular disease, atrial fibrillation. In this indication, “there are interventions in development, but they’re really more for anticoagulants,” Oliveto said. There are “none to actually treat the episode in the moment like [Cardamyst] will be.” Responding to the rejection, Oliveto said in a statement: “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.” The company intends to request a Type A meeting with the FDA to discuss the issues raised in the CRL, he added.