FDA Issues Complete Response Letter for Etripamil for PSVT

Rhea-AI Summary

Milestone Pharmaceuticals (NASDAQ: MIST) received a Complete Response Letter (CRL) from the FDA regarding its New Drug Application for CARDAMYST™ (etripamil) nasal spray, a treatment for converting acute PSVT episodes to sinus rhythm in adults.

The CRL focused on two Chemistry, Manufacturing and Controls (CMC) issues: additional information needed on nitrosamine impurities based on new draft guidance, and a required inspection at a facility performing release testing that changed ownership during NDA review. Notably, the FDA raised no concerns about etripamil's clinical safety or efficacy data.

The company plans to request a Type A meeting to discuss addressing these issues in a resubmission. As of December 31, 2024, Milestone reported $69.7 million in cash, cash equivalents and short-term investments.

Positive

• No concerns raised about clinical safety or efficacy data
• Healthy cash position of $69.7M as of December 2024
• CMC issues appear addressable through additional documentation and inspection

Negative

• FDA rejection of NDA through Complete Response Letter
• Delay in potential drug approval and market entry
• Additional regulatory requirements will require time and resources to address

Insights

Pharmaceutical Regulatory Expert

The FDA's Complete Response Letter (CRL) for Milestone's etripamil represents a regulatory setback that will delay potential market approval, though the nature of the issues is relatively encouraging. The CRL focuses exclusively on Chemistry, Manufacturing and Controls (CMC) matters rather than clinical efficacy or safety concerns, which is significant.

The two specific issues - nitrosamine impurity documentation and a facility inspection requirement - are procedural hurdles rather than fundamental problems with the drug itself. Nitrosamine concerns have become a regulatory priority following discoveries of these potential carcinogens in several medications in recent years, and the FDA noted this guidance was issued after the NDA submission. The facility inspection requirement stems from an ownership change during review - essentially an administrative complication.

The company's plan to request a Type A meeting is the appropriate next step, as this high-priority meeting typically occurs within 30 days of request. For context, PSVT (Paroxysmal Supraventricular Tachycardia) is a heart rhythm disorder causing episodes of rapid heartbeat, and etripamil would be the first self-administered nasal spray for this condition, offering patients an at-home alternative to emergency room visits.

While disappointing, addressing CMC issues is typically more straightforward than clinical deficiencies. The timeline for resubmission will depend on the specific remediation requirements, but the pathway forward appears clear, albeit delayed.

Biotech Financial Analyst

This CRL creates a meaningful but manageable financial challenge for Milestone. The $69.7M cash position reported as of December 31, 2024 provides a financial cushion, but the company now faces extended pre-revenue operations and additional costs to address the FDA's requirements.

The nature of the concerns is relatively favorable from an investment perspective - CMC issues are typically resolvable without the enormous expense of additional clinical trials. However, the delay pushes back potential commercialization and revenue generation by at least several months, possibly longer depending on the complexity of addressing the nitrosamine documentation and facility inspection requirements.

For a small-cap biotech ($114M market cap) with a single lead asset, this regulatory delay increases financial pressure. The cash position will need to support operations through resubmission, review, and potential commercialization preparations. Milestone will likely provide updated cash runway guidance after their Type A meeting with the FDA once the path forward becomes clearer.

While the stock will likely experience near-term pressure, the preservation of the clinical efficacy and safety profile keeps the core investment thesis intact. This appears to be a delay rather than a derailment of etripamil's prospects, though the extended timeline increases financial risk and uncertainty. The coming Type A meeting will be crucial in determining the length of the delay and associated cash requirements.

CRL focused on CMC; no clinical issues relating to etripamil raised

$69.7M in cash, cash equivalents and short-term investments as of December 31, 2024 

MONTREAL and CHARLOTTE, N.C., March 28, 2025 (GLOBE NEWSWIRE) -- Milestone^® Pharmaceuticals Inc. (Nasdaq: MIST) today announced the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding its New Drug Application (NDA) for CARDAMYST™ (etripamil) nasal spray, a prescription medication in development for the conversion of acute episodes of PSVT to sinus rhythm in adults.

The FDA did not raise any concerns regarding etripamil clinical safety or efficacy data and highlighted two key Chemistry, Manufacturing and Controls (CMC) issues to be addressed:

• Company to submit additional information on nitrosamine impurities based on new draft guidance issued after the NDA submission; and
• An inspection is required at a facility that performs release testing for etripamil, to ensure it is in compliance with Current Good Manufacturing Practices. The facility changed ownership during the review of the NDA.

“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.”

Milestone Pharmaceuticals had $69.7M in cash, cash equivalents and short-term investments as of December 31, 2024.

About Etripamil

Etripamil is Milestone's lead investigational product. It is a novel calcium channel blocker nasal spray under clinical development for frequent and often highly symptomatic episodes of PSVT and AFib-RVR. It is designed as a self-administered rapid response therapy for patients thereby bypassing the need for immediate medical oversight. If approved, etripamil is intended to provide health care providers with a new treatment option to enable on-demand care and patient self-management. This portable, self-administered treatment may provide patients with active management and a greater sense of control over their condition. CARDAMYST™, the conditionally approved brand name for etripamil nasal spray, is well studied with a robust clinical trial program that includes a completed Phase 3 clinical-stage program for the treatment of PSVT and Phase 2 trial for the treatment of patients with AFib-RVR.

About Milestone Pharmaceuticals

Milestone Pharmaceuticals Inc. (Nasdaq: MIST) is a biopharmaceutical company developing and commercializing innovative cardiovascular solutions to improve the lives of people living with complex and life-altering heart conditions. The Company’s focus on understanding unmet patient needs and improving the patient experience has led us to develop new treatment approaches that provide patients with an active role in self-managing their care. Milestone's lead investigational product is etripamil, a novel calcium channel blocker nasal spray that is being studied for patients to self-administer without medical supervision to treat symptomatic episodic attacks associated with PSVT and AFib-RVR.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “believe,” “continue,” “could,” “demonstrate,” “designed,” “develop,” “estimate,” “expect,” “may,” “pending,” “plan,” “potential,” “progress,” “will”, “intend” and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Milestone’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this press release include statements regarding: the outcomes of future interactions with the FDA, including the potential Type A meeting; the outcome of the potential NDA resubmission; CARDAMYST’s potential as a novel treatment option to help patients with PSVT; and other statements not related to historical facts. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, but are not limited to, whether our future interactions with the FDA will have satisfactory outcomes; whether and when, if at all, our NDA for etripamil will be approved by the FDA; uncertainties related to the timing of initiation, enrollment, completion, evaluation and results of our clinical trials; risks and uncertainty related to the complexity inherent in cleaning, verifying and analyzing trial data; and whether the clinical trials will validate the safety and efficacy of etripamil for PSVT or other indications, among others, general economic, political, and market conditions, including deteriorating market conditions due to investor concerns regarding inflation, Russian hostilities in Ukraine and ongoing disputes in Israel and Gaza and overall fluctuations in the financial markets in the United States and abroad, risks related to pandemics and public health emergencies, and risks related the sufficiency of Milestone’s capital resources and its ability to raise additional capital in the current economic climate. These and other risks are set forth in Milestone’s filings with the U.S. Securities and Exchange Commission (SEC), including in its annual report on Form 10-K for the year ended December 31, 2024, under the caption “Risk Factors,” as such discussion may be updated from time to time by subsequent filings Milestone may make with the SEC. Except as required by law, Milestone assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.

Contact: 
Kim Fox, Vice President, Communications, kfox@milestonepharma.com

Investor Relations 
Kevin Gardner, kgardner@lifesciadvisors.com 

FAQ

What are the specific issues raised in FDA's Complete Response Letter for MIST's CARDAMYST?

The FDA raised two CMC issues: need for additional nitrosamine impurity information and inspection of a release testing facility that changed ownership. No clinical safety or efficacy concerns were raised.

What is MIST's financial position as of December 2024?

Milestone Pharmaceuticals reported $69.7 million in cash, cash equivalents and short-term investments as of December 31, 2024.

What are MIST's next steps following the FDA Complete Response Letter?

The company plans to request a Type A meeting with the FDA to discuss addressing the issues raised in the CRL for resubmission.

What is CARDAMYST designed to treat for MIST?

CARDAMYST (etripamil) nasal spray is designed to convert acute episodes of PSVT (Paroxysmal Supraventricular Tachycardia) to sinus rhythm in adults.