Updates on Milestone Pharmaceuticals' etripamil nasal spray application

 As of today, December 27, 2023, the specific reason for Milestone's NDA rejection for their self-administered etripamil nasal spray for paroxysmal supraventricular tachycardia (PSVT) isn't entirely clear. However, what we do know is:

• The FDA issued a "Refusal to File" letter: This means the agency deemed the NDA incomplete and not ready for substantive review.
• The issue revolves around data presentation: Specifically, the FDA requested clarification about the timing of adverse event data recorded in Phase 3 clinical trials.
• The nature or severity of adverse events wasn't a concern: This suggests the issue is technical or procedural rather than a safety red flag.

There are further details to consider:

• Timeline: The NDA was submitted in October 2023, and the Refusal to File letter was received shortly after.
• Company response: Milestone Pharmaceuticals is seeking clarification from the FDA and plans a meeting to discuss the issue further.

Based on the press release, it's likely that the rejection stems from a need for more precise or organized data presentation. This provides some optimism for Milestone's chances of resubmitting a successful NDA after addressing the requested clarifications. 

• Milestone Pharmaceuticals press release: https://www.prnewswire.com/news-releases/milestone-pharmaceuticals-announces-submission-of-new-drug-application-to-the-us-fda-for-etripamil-301965076.html
• Nasdaq article: https://seekingalpha.com/news/4050261-milestone-stock-falls-fda-rejects-new-drug-application
• Yahoo Finance article: https://finance.yahoo.com/news/milestone-pharmaceuticals-reports-third-quarter-115700022.htmlUpdate on Etripamil Nasal Spray for the At-home Treatment of Acute Paroxysmal Supraventricular Tachycardia

Etripamil is a novel intra-nasal verapamil analogue, which shows promise for the rapid outpatient treatment of PSVT. It is a short-acting non-dihydropyridine phenylalkylamine class L-type calcium channel antagonist, with a time-to-peak plasma concentration of 8 minutes, and a half-life of 20 minutes. The drug is metabolized by ubiquitous serum esterases, and its major metabolite is an inactive carboxylic acid. 

 Etripamil slows atrioventricular nodal conduction and prolongs atrioventricular nodal refractory periods via the inhibition of slow inward calcium channels. High-density electroanatomic mapping has further suggested that etripamil causes loss of voltage in the slow pathway bridge with gradual recovery, mirroring observed changes in atrioventricular block cycle length. 

The potent combination of a convenient intra-nasal mode of delivery and rapid onset of action, as well as a short half-life, make etripamil an attractive proposition for patient self-administration outside of the formal healthcare environment. The use of etripamil is directed towards the two most common subtypes of PSVT that involve the atrioventricular node: atrioventricular nodal re-entrant tachycardia (AVNRT) and atrioventricular re-entrant tachycardia (AVRT), which together account for up to 90% of PSVT cases.  

Reference: Gavin S Chu and Dhiraj Gupta, Update on Etripamil Nasal Spray for the At-home Treatment of Acute Paroxysmal Supraventricular Tachycardia Heart Int. 2021; 15(1): 2–6.