Since the stock-jolting phase III blowup in March of Milestone Pharmaceuticals Inc.’s etripamil for paroxysmal supraventricular tachycardia (PSVT), questions have lingered regarding the short-acting channel blocker’s regulatory path forward – but no longer.

Shares of Montreal-based Milestone (NASDAQ:MIST), which in the spring plummeted to an all-time low of $1.70, made up for the loss and then some, closing at $8.91, up $5.57, or 167%, on word that the FDA has agreed to terms whereby an NDA for the nasal spray may be submitted without launching another phase III study. Gatekeepers signed off on the company’s plan to modify the ongoing experiment called Node-301b, which has been renamed Rapid, and include a primary endpoint of time to conversion within 30 minutes. The Rapid effort plus the finished Node-301 study, which will also now use a 30-minute endpoint, should fulfill efficacy requirements for an NDA, Milestone said.

Regarding the adjusted Rapid trial, Jefferies analyst Chris Howerton pointed out that patients already enrolled may have a bias to lower event rate. During Milestone’s conference call, he questioned whether that could skew results. CEO Joseph Oliveto acknowledged that subjects “already enrolled in the Rapid study and [who] are left over from, or are a part of, Node-301b are expected to have a lower event rate. They’ve been in the study longer and are still waiting for their first events, if you will. The good news is that, when we evaluated the Node-301 trial – and we evaluated across the continuum of patients, [including] those that had fast events quickly after entering the trial and those that had events after a prolonged period – we saw no difference in efficacy. As a result of that, we have confidence that even patients that are taking a little longer to have their first episode will still respond in the same manner” as those with an early one, he said.

Joseph Oliveto, CEO, Milestone

The phase III Node-301 trial in March found that a 70-mg dose of etripamil failed to achieve its primary endpoint of time to conversion of SVT to sinus rhythm compared to placebo over the five-hour period following study drug administration, with a median time to conversion of 25 minutes [95% CI: 16, 43] for etripamil vs. 50 minutes [95% CI: 31,101] for placebo (p=0.12). The company said at the time that a larger-than expected percentage of placebo patients seeking rescue therapy sooner than expected confounded the study.

Along with expanding the Rapid study, the modified design will direct patients to administer another dose of the drug 10 minutes after the first dose if they still experience signs and symptoms of an SVT episode. The dosing regimen provides a tailored approach meant to increase efficacy in patients with more persistent events and improve the overall clinical utility of etripamil. Results from Rapid are expected in late 2021 or early 2022. The company also disclosed that it raised $25 million by way of a private placement with existing shareholder RTW Investments LP, which means Milestone has enough cash to last into the second quarter of 2022.

Under an updated statistical analysis plan (SAP), the primary efficacy endpoint for Rapid and Node-301 will be defined as time to conversion over the first 30 minutes, with a target “p” value of less than 0.05 for each study. Later and earlier time points will also be checked as part of secondary analyses to best characterize the efficacy profile. When employing the new SAP, investigators said, results from Node-301 show that 54% of etripamil patients vs. 35% of placebo patients converted within 30 minutes (HR 1.87, p=0.02), which clinicians and cardiovascular thought leaders regard as a clinically meaningful outcome, given the symptomatic nature of SVT episodes and the lack of approved at-home treatments, Milestone said.

The Rapid study, originally designed to collect double-blind data from randomized patients who had not yet experienced an SVT event after the Node-301 study reached its target number of adjudicated SVT events, is being amended and expanded to serve as a pivotal efficacy and safety study. It will include the 170 patients who are already enrolled, and will be completed after a total of 180 confirmed SVT events are reached, including those that have already occurred in the study. Added patients enrolled in the Rapid study will be randomized 1-to-1. The Rapid study’s optional repeated dose, a customized approach similar to PSVT treatment practices in the emergency-room setting, was enabled by the favorable safety data from Node-301, Milestone noted. The FDA said the single and repeat administrations of etripamil can be pooled and compared to placebo for the primary analysis, thus calling for no increase in the sample size.

PSVT, which afflicts about 2 million people in the U.S., is characterized by a rapid heart rate with intermittent episodes of SVT that start and stop suddenly and without warning. Symptoms include palpitations, sweating, chest pressure or pain, shortness of breath, sudden onset of fatigue, lightheadedness or dizziness, fainting and anxiety.

Piper Sandler analyst Edward Tenthoff maintained his neutral rating on Milestone because of the Rapid data time line, but increased his price target to $8 from $3 “to reflect the clarified regulatory path and the impact of the RTW investment,” basing his move on a projected enterprise value of $211 million, up from $31 million, he wrote in a report. He predicted approval and launch in 2023. Jefferies’ Howerton said in a report that, despite the primary endpoint miss in Node-301, “etripamil shows clear efficacy at the clinically meaningful, 45-minute window.”