Milestone Pharmaceuticals Inc. (NASDAQ:MIST) is a biopharmaceutical company focused on the development and commercialization of innovative cardiovascular medicines. The company's lead product candidate, etripamil, is a novel, potent rapid-onset calcium channel blocker that Milestone has designed and is developing as a rapid-onset nasal spray to be administered by patients. Milestone is developing etripamil to treat paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation with rapid ventricular rate (AFib-RVR), and other cardiovascular indications.

Recent Developments

In the first quarter of 2024, Milestone resubmitted the New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval to sell and market etripamil for the treatment of PSVT. The NDA was resubmitted based on guidance from the FDA after receipt of a Refusal to File (RTF) letter from the FDA in December 2023. The FDA had determined that the original NDA was not sufficiently complete to permit substantive review, primarily requesting clarification about the data recorded for the time of adverse events in the Phase 3 clinical trials. Milestone held a Type A Meeting with the FDA in February 2024 and was able to address the Agency's concerns, leading to the resubmission of the NDA.

Clinical Development Program

Milestone's PSVT clinical development program has yielded promising results. In October 2022, the company announced positive and statistically significant topline efficacy and safety data from its Phase 3 RAPID clinical trial evaluating etripamil in patients with PSVT. The RAPID trial achieved its primary endpoint, with etripamil demonstrating a highly statistically significant and clinically meaningful difference in time to PSVT conversion as compared to placebo. Specifically, a Kaplan Meier analysis showed that 64.3% of patients who took etripamil converted to sinus rhythm within 30 minutes, compared to 31.2% of patients who took placebo. By 90 minutes post-study drug administration, 80.6% of patients taking etripamil converted to sinus rhythm compared to 60.7% of patients taking placebo.

In addition to the PSVT program, Milestone is also developing etripamil for the treatment of AFib-RVR. In the first quarter of 2024, the company met with the FDA in a Type C meeting, where the Agency reiterated its prior guidance regarding the availability of a supplemental NDA (sNDA) pathway for the marketing approval of etripamil for the AFib-RVR indication. The FDA concurred with the key proposed study elements, including powering, inclusion criteria, patient population, and statistical analyses, and provided clarification on the endpoints to guide the design of the Phase 3 study.

Milestone presented positive Phase 2 data from the ReVeRA study for etripamil in AFib-RVR in November 2023. The randomized, placebo-controlled trial showed that etripamil significantly and rapidly reduced ventricular rate, with patients experiencing a ventricular rate reduction of 29.91 beats per minute (bpm) compared to placebo. The maximum reduction in rate reported by a patient taking etripamil was 34.97 bpm, and the median time to maximum reduction in ventricular rate was 13 minutes. Furthermore, a greater number of patients taking etripamil achieved a ventricular rate of less than 100 bpm (58.3%) than those taking placebo (4%).

Financials

For the three months ended March 31, 2024, Milestone reported no revenue, compared to $1.0 million in revenue for the same period in 2023. The 2023 revenue was the result of a milestone payment received under the company's license agreement with Ji Xing Pharmaceuticals Limited for the successful initiation of a Phase 1 clinical trial of a product that uses etripamil in China.

Research and development expenses decreased by $6.6 million, or 64.5%, for the three months ended March 31, 2024, compared to the same period in 2023. This decrease was primarily driven by lower clinical expenses as a result of the completion of Phase 3 studies for etripamil in PSVT. General and administrative expenses remained consistent, while commercial expenses increased by $0.5 million, or 22.4%, due to additional personnel costs, professional costs, and other operational expenses related to commercialization.

For the full year 2023, Milestone reported an annual net loss of $59.7 million, annual revenue of $1.0 million, annual operating cash flow of -$46.4 million, and annual free cash flow of -$46.5 million.

Liquidity

As of March 31, 2024, Milestone had cash, cash equivalents, and short-term investments of $89.5 million and an accumulated deficit of $336.4 million. In February 2024, the company raised $31.9 million in net proceeds from an underwritten public offering, including the exercise of the underwriters' option to purchase additional shares. Additionally, in March 2023, Milestone closed a $50 million private placement of convertible senior notes.

Milestone's liquidity position and recent financing activities provide the company with the resources to continue the development of etripamil for PSVT and AFib-RVR, as well as potentially pursue other cardiovascular indications. The company expects its operating plan, existing cash and cash equivalents, and short-term investments to be sufficient to fund its operations for at least the next 12 months.

Market Opportunity

The PSVT market represents a significant opportunity for Milestone, with an estimated 2 million Americans affected by the condition and over 150,000 emergency department visits and hospital admissions per year. Milestone believes that etripamil has the potential to shift the current treatment paradigm away from the burdensome and costly emergency department setting, as the company's market research suggests that cardiologists are willing to prescribe etripamil to approximately 50% of their PSVT patients.

In the AFib-RVR market, the company estimates that there are 5 million Americans suffering from AFib, with nearly 800,000 patients admitted to the emergency department due to AFib symptoms in 2016. Milestone believes that etripamil's ability to rapidly reduce ventricular rate could provide a valuable treatment option for these patients, who often seek acute care to resolve their symptoms.

Risks and Challenges

Milestone faces several risks and uncertainties in its pursuit of regulatory approval and commercialization of etripamil. These include the inherent risks associated with drug development, the ability to obtain regulatory approvals, the successful scale-up of manufacturing, and the company's ability to effectively commercialize the product, if approved. Additionally, Milestone may be impacted by general economic, political, and market conditions, including the recent trends towards rising inflation and interest rates.

Conclusion

Overall, Milestone Pharmaceuticals is well-positioned to continue its progress in the development of etripamil for the treatment of PSVT and AFib-RVR. The company's recent financing activities, coupled with its promising clinical data and the significant market opportunities, suggest that Milestone is navigating the cardiovascular landscape with a clear strategic vision and the necessary resources to potentially bring innovative treatment options to patients in need.