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Item 1. Business

2025-03-13 compared with 2024-03-21 · 254 added, 523 removed, 339 unchanged (70% of the section changed)

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We are a biopharmaceutical company focused on the development and commercialization of innovative cardiovascular medicines.

Our lead product candidate etripamil is a novel and potent calcium channel blocker that we designed as a rapid-onset nasal spray to be self-administered by patients.

We are developing etripamil for the treatment of specific heart arrhythmias with a lead indication to treat paroxysmal supraventricular tachycardia, or PSVT, and a subsequent indication to treat atrial fibrillation with rapid ventricular rate, or AFib-RVR.

Our objective is to commercialize and develop CARDAMYST (also known as etripamil) in the United States as a fast-acting, portable nasal spray treatment for use by patients anywhere, anytime an attack of supraventricular tachycardia, or “SVT” occurs.

We are also developing etripamil for the indication of atrial fibrillation with rapid ventricular rate, or “AFib-RVR.”

CARDAMYST TM (etripamil) nasal spray

We are currently focused on obtaining marketing approval of CARDAMYST for the treatment of paroxysmal supraventricular tachycardia, or “PSVT” from the U.S.

Food and Drug Administration, or “FDA.” We expect that the FDA will make their final decision regarding the marketing approval of CARDAMYST for PSVT by March 27, 2025, which is also known as the Prescription Drug User Fee Act, or “PDUFA,” review goal date.

We are also developing etripamil nasal spray for a subsequent indication to treat patients with AFib-RVR.

Similar to our approach for PSVT, we believe that etripamil has the potential to help the person experiencing a symptomatic episode of AFib-RVR to self-treat themselves and to conveniently, reliably, and quickly, reduce their elevated heart rate, with the goal of reducing the need for emergency department utilization.

We completed a successful Phase 2 study in patients presenting urgently with AFib-RVR, i.e., to an emergency department.

We publicly presented these positive Phase 2 data in November 2023, which demonstrated that patients receiving etripamil nasal spray experienced rapid and statistically superior ventricular rate reduction and improved symptom-relief compared to placebo, with safety and tolerability findings generally consistent with those observed in our PSVT program.

This data supports the development of etripamil, self-administered in the medically unmonitored setting, for the treatment of AFib-RVR and, following dialogue with FDA, have finalized a Phase 3, potentially registrational study.

PSVT Market Overview

PSVT is a condition that causes a patient’s heart to suddenly start beating faster than normal.

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The impact and morbidity from an episode of PSVT can be especially detrimental in patients with underlying cardiovascular or medical conditions, such as heart failure, obstructive coronary disease, or dehydration.

The uncertainty of when such an attack of PSVT will strike or how long it will persist is often anxiety-provoking, reduces patients’ quality of life and prevents participation in many desired activities.

Drugs approved for the treatment of PSVT attacks include adenosine, verapamil, and diltiazem, with all being administered intravenously under medical supervision, usually in the emergency department.

The uncertainty of when such an attack of PSVT will strike or how long it will persist is often anxiety-provoking, reducing patients’ quality of life and preventing participation in many desired activities.

Drugs approved for the treatment of attacks of PSVT include adenosine, verapamil, and diltiazem, with all being administered intravenously under medical supervision, usually in the emergency department.

Other oral drugs are sometimes used to treat attacks in a concept called “pill in the pocket.” However, those drugs have never been proven effective or safe and are not approved for this use.

Doctors are frustrated by the lack of effective treatment options besides a prolonged, unpleasant, and costly trip to the emergency department or, for some patients, an invasive ablation procedure.

PSVT is traumatic for patients, frustrating for healthcare providers, and costly for payors.

With no pharmaceutical innovation in the treatment of PSVT for more than 30 years and a movement in the healthcare system to enable patient centered care, there is an opportunity to help patients living with PSVT to take greater control over their PSVT attacks.

Atrial Fibrillation, or AFib, is a common form of arrhythmia with an irregular and often rapid heart rate that is often markedly symptomatic and, without proper treatment, can increase the risk of stroke, heart failure, and other cardiovascular complications.

A common complication of AFib is a rapid ventricular rate, or AFib-RVR, which is frequently defined as a heart rate ≥ 110 beats per minute.

The occurrence of a rapid ventricular rate in patients with atrial fibrillation increases the likelihood of marked symptoms including heart palpitations, shortness of breath and weakness.

Doctors are often frustrated by the lack of effective treatment options besides a prolonged, unpleasant, and costly trip to the emergency department or, for some patients, an invasive ablation procedure.

PSVT can be traumatic for patients, frustrating for healthcare providers, and costly for payors.

With no pharmaceutical innovation in the treatment of PSVT for more than 30 years and a movement in the healthcare system to enable patient-centered care, we believe there is an opportunity to help patients living with PSVT to take greater control over their PSVT.

We believe that PSVT is a large and under-recognized market which we estimate affects more than two million Americans.

From this diagnosed population, we define the immediate target addressable market for CARDAMYST as approximately 60% of patients who are actively managed by clinical cardiologists, interventional cardiologists and electrophysiologists.

The remaining patients with PSVT can become addressable over time, as they are inconsistently managed (cycling in and

out of the healthcare system) and/or being managed less frequently by primary care healthcare providers.

Furthermore, PSVT is expected to increase in prevalence in coming years as wearable electrocardiogram, or “ECG,” technology (e.g., smartphone, watches) becomes both more adept at diagnosing PSVT and more widely used by patients and clinical practitioners, in turn shortening the current two to three year average time to diagnosis.

Following the release of data from the RAPID clinical study in market research, cardiologists reported a willingness to prescribe CARDAMYST to approximately 50% of the patients with PSVT in their care, which suggests approximately 500,000 to 800,000 patients can potentially be treated with CARDAMYST in peak years.

Additionally, we believe that this cardiology-identified group of patients may use CARDAMYST to treat a median of three to five episodes per year, based on the projected number of self-reported longer and more intense episodes experienced by patients, as well as the patient utilization experience in our Phase 3 clinical trials.

This implies a peak demand potential in the United States for CARDAMYST of 2.5 million to 4 million episodes treated per year.

Current treatment for PSVT also consumes significant healthcare resources.

Research published in the American Journal of Cardiology in 2020 shows that total healthcare expenditures in the year following a diagnosis of PSVT ranged from $20,000 to $30,000 per patient which were significantly higher than the expenditures observed for patients without PSVT.

These significant increases included increased emergency department visits and hospitalization costs.

Of note, catheter ablations following diagnosis represented only 23% of this increased spend, meaning most costs were unrelated to ablations.

Recent data from the Healthcare Cost and Utilization Project (HCUP) database indicate that in 2019 there were approximately 140,000 emergency department, or “ED,” visits for PSVT when coded in the primary diagnostic position, and a total of approximately 525,000 ED visits when PSVT was coded in any diagnostic position.

Of these, approximately 25% of ED admissions for PSVT resulted in a hospital admission.

HCUP estimates a total of approximately 40,000 to approximately 120,000 inpatient admissions for PSVT in 2019 (based again if PSVT were found in the primary v.

any diagnostic position).

Despite the effectiveness of catheter ablation, claims data suggests that only approximately 15% of patients with PSVT are ablated over a three-year period, leading to a total of approximately 100,000 catheter ablations annually.

In total, at least $5 billion is spent annually in the United States on the management of PSVT.

AFib-RVR Market Overview

Atrial Fibrillation, or “AFib,” is a common cardiac arrhythmia with an irregular and often rapid heart rate that is often markedly symptomatic and, without proper treatment, can increase the risk of stroke, heart failure, and other cardiovascular complications.

A common complication of AFib is a rapid heart rate, also referred to as AFib-RVR, which is frequently defined as a heart rate ≥ 110 beats per minute.

The occurrence of a rapid ventricular rate, or “RVR,” in patients with atrial fibrillation increases the likelihood of marked symptoms including heart palpitations, shortness of breath and weakness.

There are two commonly used pharmacological approaches to chronically manage AFib, rhythm control and rate control.

Regardless of the chronic approach, when faced with a sudden episode of AFib-RVR, acute rate control is needed, and most treatments are oral AV-nodal targeted drugs such as a beta blocker or calcium channel blockers.

However, these oral rate control drugs, when used acutely, do not adequately provide immediate or adequate ventricular rate control due to a 30- to 90-minute delayed onset of action, and, as a result, many patients need faster and more certain rate-reduction and symptom-resolution and so seek acute-medical care by going to the emergency department for treatment utilizing intravenous rate control and/or electrical cardioversion of their atrial fibrillation.

Similar to PSVT, patients feel a loss of control by needing to visit the emergency department for overcoming their atrial fibrillation attack and the unpredictable nature of RVR episodes;

doctors are frustrated by the lack of options for patients to self-manage these acute rate attacks;

Regardless of the chronic approach, break-through episodes of rapid heart rate occur frequently;

and when faced with a sudden episode of AFib-RVR, acute rate control is needed, with most treatments being AV-nodal targeted drugs such as a beta blocker or calcium channel blocker.

These treatments can be given intravenously;

however, this requires a burdensome trip to an emergency department which may lead to a hospital admission.

Acute treatment can be attempted by administration of an oral rate control drug;

however, such drugs do not adequately provide immediate or adequate ventricular rate control due to a 30- to 90-minute delayed onset of action, and, as a result, many patients need faster and more certain rate-reduction and symptom-resolution and so seek acute-medical care by going to the emergency department for treatment utilizing intravenous rate control and/or electrical cardioversion of their atrial fibrillation.

Furthermore, the chronic administration of oral rate-control drugs does not broadly prevent episodes of AFib-RVR.

Similar to PSVT, patients may feel a loss of control by needing to visit the emergency department for overcoming their AFib-RVR episode and the unpredictable nature of these episodes, which can occur anytime and anywhere.

Doctors have expressed frustration at the lack of options for patients to self-manage these acute rate attacks;

and payor organizations would prefer to treat the AFib-RVR attacks in a more cost effective and time-efficient manner.

Our objective is to develop and commercialize etripamil as a fast-acting, portable nasal spray treatment to be prescribed by a physician or appropriate health-care professional such that the patient with the indicated arrhythmia can carry etripamil with them for use wherever and whenever an attack of the arrhythmia occurs.

If approved, we believe that etripamil will provide the patient with a portable treatment to stop an attack at-home and to reduce the reliance on the emergency department.

We believe that this may help patients to live their lives with less concern over when their next PSVT attack will occur.

For health care providers, etripamil could represent a new tool they can offer to their patients to better self-manage their PSVT attacks resulting in fewer calls to their office, a more efficient use of healthcare resources, and more empowered, satisfied patients.

Our recently completed and reported data from a Phase 2 clinical trial for assessing the safety and effectiveness of etripamil in AFib-RVR.

Similar to our approach for PSVT, we believe that etripamil has the potential to help the patient experiencing a symptomatic episode of AFib-RVR to self-manage their condition by conveniently, reliably and quickly reducing their elevated heart rate wherever and whenever the episode occurs, thereby reducing the need for emergency department utilization that many patients currently seek.

On November 11, 2023, we announced and publicly presented positive Phase 2 data reflecting that patients with AFib-RVR receiving etripamil nasal spray experienced rapid and statistically superior ventricular rate reduction and improved symptom-relief compared to placebo.

Safety and tolerability reported in the 56-patient safety population who received etripamil was generally consistent with that observed in our PSVT program discussed above.

We believe these data support the further development of self-administered etripamil for the treatment of AFib-RVR and are in dialogue with FDA concerning Phase 3 development for this indication.

We believe that PSVT is a large and under-recognized market that we estimate affects approximately two million Americans and results in over 150,000 emergency department visits and hospital admissions and up to 80,000 ablations per year.

From this diagnosed population, we define the target addressable market for etripamil as 40% to 60% of patients who experience frequent and longer, moderate to severe episodes each year.

After being exposed to the data from the RAPID clinical study in market research, Cardiologists reported a willingness to prescribe etripamil to approximately 50% of the patients with PSVT in their care, which suggests 500,000 to 800,000 patients can potentially be treated with etripamil in the peak year.

Additionally, we believe that these target patients will use etripamil to treat a median of five episodes per year based on the projected number of longer or more intense episodes (self-reported) experienced by the patient.

This implies demand in the US for etripamil of 2.5 million to 4 million episodes treated in the peak year.

An estimated five million Americans suffer from AFib.

The incidence of AFib is expected to grow to approximately 10 million by 2025 and up to about 12 million by 2030.

A subset of patients with AFib experience episodes of abnormally high heart rate most often accompanied by palpitations, shortness of breath, dizziness, and weakness.

While these episodes, known as AFib-RVR, may be treated by oral calcium channel blockers and/or beta blockers, patients frequently seek acute care in the emergency department to address symptoms.

In 2016, nearly 800,000 patients were admitted to the emergency department due to AFib symptoms.

An estimated 10 million Americans suffer from AFib.

The prevalence of AFib is expected to grow to greater than 12 million by 2030.

A subset of patients with AFib experiences episodes of abnormally high heart rate, most often

accompanied by palpitations, shortness of breath, dizziness, and weakness.

While these episodes, known as AFib-RVR, may be treated by oral calcium channel blockers and/or beta blockers, patients frequently seek acute care in the ED to address symptoms.

In 2019, nearly 1.1 million patients were admitted to the ED due to AFib symptoms.

Initial data suggests that approximately 60% of all AFib ED visits were attributable to AFib-RVR, as symptoms driving patients to seek care generally become more pronounced at higher heart rates.

Treatment for such symptoms typically includes medically supervised intravenous administration of calcium channel blockers or beta blockers, or electrical cardioversion.

With little available data for AFib-RVR, we believe based on our initial market research that 30% to 40% of patients with AFib experience one or more symptomatic episodes of RVR per year that require treatment, suggesting a target addressable market of approximately three to four million patients in 2030 for etripamil in patients with AFib-RVR.

With little available data for AFib-RVR, we believe, based on our initial market research, that 30% to 40% of patients with AFib experience one or more symptomatic episodes of RVR per year that require treatment, suggesting a target addressable market of up to approximately four to five million patients by 2030 for etripamil in patients with AFib-RVR.

We believe that etripamil has the potential to be developed such that it can be used by patients to rapidly reduce their heart rate at home, self-administered, to provide a supplemental option to either the acute oral rate or rhythm control strategy their physician would use.

When presented with a target product profile reflecting this potential use case, cardiologists and electrophysiologists in a 2021 market research study perceived utility in the product profile and indicated that they would prescribe to approximately 67% of their patients that experience episodes of AFib-RVR.

They further indicated that a rapidly-acting intranasal calcium channel blocker could serve as a “bridge” to the longer onset times of acute oral agents.

According to physicians, it can take hours for patients to feel an alleviation of symptoms using acute oral rate or rhythm control.

During this time, patients may experience concerning symptoms that often prompt them to seek emergency care.

We believe that the combination of convenient delivery, potency, rapid onset and short duration of action of etripamil has the potential to move the current treatment setting for some acute episodes of AFib out of the burdensome and costly emergency department.

Current AFib management consumes significant healthcare resources in the United States.

The American Heart Association published a report in 2016 summarizing the current and projected cost burden of cardiovascular diseases in the United States.

This report suggests atrial fibrillation resulted in $25 billion in direct medical costs in 2016 (approximately 7% of all cardiovascular diseases) and another $7 billion in indirect costs (i.e., up to $32 billion in total costs).

Additionally, the forecasted growth in atrial fibrillation prevalence is anticipated to result in healthcare expenditures of $46 billion in direct costs and $10 billion in indirect costs in the United States by 2030.

New Drug Application Status

In October 2023 we submitted a New Drug Application, or NDA, for marketing approval in the United States for etripamil for the treatment of PSVT.

On December 26, 2023 we announced that we received a refuse-to-file, or RTF, letter from the FDA.

Upon preliminary review, the FDA determined that the NDA was not sufficiently complete to permit substantive review.

The FDA requested clarification about the time of data recorded for adverse events in our Phase 3 clinical trials;

FDA did not express concerns about the nature or severity of adverse events, or AEs.

In February 2024, we held a Type A Meeting with the FDA to determine next steps for the filing for marketing approval.

The FDA indicated that the timing of AEs in question had minimal impact on the overall characterization of the etripamil safety profile, based on the FDA’s review of the affected data which was mainly related to AEs associated with local drug administration site tolerability and, importantly, did not appear to affect the assessment of serious adverse events and/or AEs of special interest for a calcium channel blocker.

To align with the FDA’s guidance in preliminary response to our questions presented to the FDA in our Type A Meeting request, we plan to restructure the data sets that capture timing of reported AEs, reformat certain data files to facilitate FDA’s analyses, and resubmit the NDA.

Based on the guidance received during the Type A Meeting, we expect that this approach will address the RTF from the FDA.

The FDA has not requested that we complete additional clinical efficacy or safety trials prior to resubmitting the NDA.

We expect a standard NDA review period following resubmission of the NDA for etripamil for PSVT.

The NDA resubmission is planned for the second quarter of 2024.

In connection with the revised timeline for NDA submission, we have undertaken certain cash conservation measures to reduce spend through program deferrals and team restructuring and expect that our existing cash resources will fund operations into 2026, including through the expected Prescription Drug User Fee Act date for the NDA resubmission.

We expect the implementation of these cash conservation measures to be substantially completed in the first quarter of 2024.

If FDA approval is granted, we expect to receive a $75 million payment under an existing royalty agreement, which is intended to fund the potential commercial launch of etripamil for PSVT.

The figure below sets forth the status and focus of etripamil:

In May 2024, we announced that the FDA accepted our New Drug Application, or “NDA,” for CARDAMYST (etripamil) for the treatment of PSVT.

The Company continues to engage the FDA throughout the NDA review process in the form of responses to FDA requests for information, as well as audits of manufacturing facilities and testing labs, clinical sites, clinical study support services and of our headquarters.

The PDUFA goal date for action on the NDA is March 27, 2025.

If approved, we believe that CARDAMYST will be the first and only self-administered therapy for the rapid termination of episodes of SVT wherever and whenever they occur.

PSVT Clinical Development Highlights

On October 17, 2022, we announced positive and statistically significant topline efficacy and safety data from the Phase 3 RAPID clinical trial of etripamil in patients with PSVT.

These results were further presented shortly thereafter, on November 7, 2022, as a Late-Breaking Clinical Trial Session at the American Heart Association Scientific Sessions 2022 (Chicago, IL) and subsequently published in The Lancet (June 2023) .

In April 2024, we announced new clinical data demonstrating real-world application of etripamil, an investigational new drug, for conversion of recurrent PSVT.

Conducted in North and South America, an open label, Phase 3 study of etripamil in PSVT (the NODE-303 study) was presented at The American College of Cardiology Scientific Sessions.

NODE-303 evaluated self-administered etripamil (70 mg, nasal spray) in an outpatient setting for up to four episodes of PSVT per patient.

Other key characteristics of the NODE-303 study that distinguish the study from earlier Phase 3 studies, include the removal of the in-office test dose as well as the use of a broader inclusion exclusion study entry criteria.

For example, NODE-303 did not exclude patients with a history of co-morbid AFib or atrial flutter.

The results demonstrated that symptom-prompted treatment with etripamil restored sinus rhythm with a median time-to-conversion of 17 minutes and was generally well tolerated.

The conversion of PSVT to sinus rhythm was similar among multiple episodes of PSVT and the frequency of treatment-emergent adverse events within 24 hours decreased with successively treated episodes.

Adverse events, or “AEs,” were predominantly localized to the drug’s nasal administration site, consistent with prior trial findings.

The protocol was amended during the trial to allow for a repeat dose of drug if

symptoms persisted 10 minutes following the first dose, however most of the clinical trial was conducted prior to the amendment and used the 70 mg single dose.

Efficacy of etripamil for PSVT conversion (restoration of sinus rhythm) in NODE-303 was 60.0% by 30 minutes after drug self-administration, and 69.9% by 60 minutes after drug self-administration;

these rates of conversion are similar to those demonstrated in double-blinded and other open-label etripamil studies.

This data supports a potentially significant shift in the management approach for recurrent PSVT.

In October 2022, we announced positive and statistically significant topline efficacy and safety data from the Phase 3 RAPID clinical trial of etripamil in patients with PSVT.

These results were further presented shortly thereafter, in November 2022, as a Late-Breaking Clinical Trial Session at the American Heart Association Scientific Sessions 2022 (Chicago, IL) and subsequently published in The Lancet (June 2023) .

RAPID, our multi-center, randomized, double-blind, placebo-controlled, event-driven Phase 3 trial, enrolled 706 patients across clinical sites in North America and Europe.

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Self-administration was prompted by a patient’s customary symptoms and was performed in the at-home setting without medical supervision.

The RAPID trial achieved its primary endpoint, with patients taking the etripamil regimen demonstrating a highly statistically significant and clinically meaningful difference in time to SVT conversion as compared to placebo.

The RAPID trial achieved its primary endpoint, with patients taking the regimen with etripamil demonstrating a highly statistically significant and clinically meaningful difference in time to SVT conversion as compared to placebo.

A Kaplan Meier analysis demonstrated a significantly greater proportion of patients who took etripamil converted within thirty minutes compared to placebo (64.3% vs.

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The median time to conversion for patients in RAPID who self-administered etripamil was 17.2 minutes compared to 53.3 minutes for patients on placebo.

The safety and tolerability data from the RAPID trial continue to support the potential self-administration use of etripamil, with findings consistent with those observed in prior trials.

The most common randomized-treatment emergent adverse events, or RTEAEs, adverse events, or AEs, which occurred within 24 hours of etripamil administration, were related to the nasal local administration site.

The safety and tolerability data from the RAPID trial continues to support the potential self-administration use of etripamil, with findings consistent with those observed in prior trials.

The most common randomized-treatment emergent adverse events, or “RTEAEs,” and AEs which occurred within 24 hours of administration of etripamil, were related to the nasal local administration site.

Overall, the majority of RTEAEs were reported as mild (68%) or moderate (31%).

There were no serious AEs related to etripamil.

The use of additional medical interventions and emergency department utilization were important secondary measures of efficacy for both the RAPID and NODE-301 studies, although with the understanding that neither study was individually powered to expect statistical differences.

In March 2023, we completed NODE-303, a Phase 3, multi-center, open-label safety trial, evaluating the safety of etripamil when self-administered without medical supervision over multiple, separate episodes of SVT.

Data from the completed NODE-303 open-label safety and RAPID extension studies are included in the PSVT NDA submission for etripamil to the FDA.

The use of additional medical interventions and visits to an emergency department were important secondary measures of efficacy for both the RAPID and NODE-301 studies, although with the understanding that neither study was individually powered to expect statistical differences.

In a pre-planned analysis across both studies, patients who self-administered etripamil sought additional medical interventions 43% less frequently (15% vs.

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p=0.035) than patients in the placebo arm.

In March 2023, we completed NODE-303 a Phase 3, multi-center, open-label safety trial, evaluating the safety of etripamil when self-administered without medical supervision over multiple, separate SVT episodes.

Data from the completed NODE-303 open-label safety and RAPID extension studies are included in the etripamil PSVT NDA submission to the FDA.

In September 2024, our licensing partner, Corxel (formerly Ji Xing Pharmaceuticals Limited, JIXING), a clinical-stage biopharmaceutical company announced positive topline data from the Phase 3 JX02002 clinical trial of etripamil nasal spray in patients with PSVT in China.

The 500-patient Phase 3 trial (JX02002) met its primary endpoint, with a Kaplan Meier analysis shows a statistically significantly greater proportion of patients who self-administered etripamil converted from PSVT to sinus rhythm within 30 minutes compared to placebo (40.5% vs.

15.9%, respectively;

hazard ratio [HR] = 3.00;

95% CI 1.58-5.71;

Statistically significant (p<0.05) results were also shown for the secondary efficacy endpoints for percent of patients’ PSVT converted to sinus rhythm by 10, 15, 45 and 60 minutes after self-administration of study drug.

Corxel further reported that, overall, treatment emergent adverse events were comparable between treatment groups, and there were no reported serious adverse events related to etripamil.

The safety and tolerability data from the JX02002 trial

were consistent with previous clinical studies.

This important study further expands the etripamil global development program to more than 2,000 unique patients treated with etripamil.

AFib-RVR Clinical Development Highlights

In mid-2023, we held a pre-IND meeting with FDA and received guidance indicating that we could follow a supplemental NDA, or sNDA, regulatory pathway for the marketing approval for etripamil for the indication of AFib-RVR.

The sNDA pathway potentially permits a single pivotal efficacy study to be sufficient for filing for marketing approval if etripamil is already approved for PSVT.

In the first quarter of 2024, we met with the FDA in a Type A meeting.

In this meeting FDA reiterated its prior guidance regarding the availability of an sNDA pathway.

FDA further concurred with respect to key study elements including powering, inclusion criteria, patient population, and statistical analyses, and offered clarification with respect to the endpoints to guide the design of the Phase 3 study.

We anticipate progressing to an End of Phase 2 meeting in mid-2024 as an important step to finalize the registrational study protocol.

On November 11, 2023, we presented positive Phase 2 data from the ReVeRA study, as a Featured Science Presentation at the American Heart Association Scientific Meetings (Philadelphia, PA) and as simultaneously published in Circulation:

In November 2023, we presented positive Phase 2 data from the ReVeRA study as a Featured Science Presentation at the American Heart Association Scientific Meetings (Philadelphia, PA) and as simultaneously published in Circulation:

Arrhythmia and Electrophysiology .

The data reflected that patients with AFib-RVR receiving etripamil nasal spray experienced rapid and statistically superior ventricular rate reduction and improved symptom-relief compared to placebo.

In summary, the data demonstrated that etripamil NS was effective in patients with AF-RVR in substantially reducing VR (difference between etripamil vs.

placebo in maximum reduction from baseline:

The median time to maximum reduction in VR was 13 min, and the duration of effect (reduction in VR from baseline) was at least 150 min.

The median duration of maintaining a VR <100 bpm was 45.5 min in the first 60 min following drug in the etripamil arm.

Etripamil treatment was associated with significant improvement in symptom relief and in treatment satisfaction as measured by the Treatment Satisfaction Questionnaire 9, or TSQM-9, patient-reported outcome instrument.

Safety and tolerability reported in the 56-patient safety population who received etripamil was generally consistent with that observed in our PSVT program.

The majority of common AEs were localized to the drug-administration site, and there was a low incidence of serious adverse events.

Our goal is to identify, develop and commercialize innovative cardiovascular medicines, including etripamil for the treatment of PSVT, AFib-RVR and other cardiovascular indications, and additional clinical stage compounds for other cardiovascular conditions.

The randomized, double-blinded, placebo-controlled ReVeRA trial of etripamil nasal spray enrolled 87 patients and dosed 56 patients aged 18 years and older with AFib who urgently presented experiencing AFib and a ventricular rate of 110 or more beats per minute, or “bpm.” The trial was designed to assess the magnitude, rapidity, and duration of reduction and the patient satisfaction with treatment using an established patient reported outcome, or “PRO,” tool.

Data showed that delivery of etripamil nasal spray (70 mg) significantly and rapidly reduced ventricular rate, in a pattern consistent with the drug’s pharmacologic profile.

Etripamil achieved the primary endpoint with a high degree of statistical significance;

patients experienced a ventricular rate reduction of 29.91 bpm (95% confidence interval:

-40.31, -19.52;

p<0.0001) in the etripamil arm relative to placebo.

The absolute maximum reduction in rate in the etripamil arm was 34.97 bpm.

Using the Treatment Satisfaction Questionnaire 9 (TSQM-9) PRO, compared to placebo, patients treated with etripamil demonstrated significant improvements in two satisfaction ratings:

effectiveness (p<0.0001) and relief of symptoms (p=0.0002), with the degrees of improvement consistent with those customarily described as clinically meaningful.

Treatment-emergent serious adverse events, or “TESAEs,” were rare and the most common (≥ 5%) adverse events were mild or moderate in intensity and included nasal discomfort, rhinorrhea, increased lacrimation, throat irritation and dizziness.

Further trial details are below in this document.

During 2024, we met with the FDA on the ReVeRA study, during which the FDA confirmed its guidance from our Pre-IND meeting (2023) regarding the availability of a supplemental new drug application, or “sNDA,” pathway for the marketing approval of etripamil for the indication of AFib-RVR.

The sNDA pathway potentially permits a single pivotal efficacy study to be sufficient for filing for marketing approval if etripamil is already approved for PSVT.

FDA further concurred with respect to key proposed study elements including powering, inclusion criteria, patient population, and statistical analyses, and offered clarification with respect to the endpoints to guide the design of the Phase 3 study.

In our mid-2023 Pre-IND meeting, the FDA provided guidance that our primary endpoint can be the reduction of ventricular rate, and the primary analysis would be performed on the intent to treat, or “ITT,” population.

In addition, the study would have to show statistical significance (p<0.05) on the key secondary endpoint of symptom relief as a patient benefit, also in the ITT population.

The secondary endpoint could use a PRO measure, and the application of a seven-point anchored scale was discussed with the FDA.

We have finalized the Phase 3 study protocol following FDA’s review, obtained concurrence with the FDA to proceed, are operationally starting the study, and anticipating enrolling patients in 2025.

The Phase 3 study will be conducted in a medically unmonitored setting (e.g., at-home) in a manner very similar to the conduct of our Phase 3 development program for PSVT.

The Phase 3 AFib-RVR study will enroll patients with a history of symptomatic AFib episodes, and will use a self-administered, repeat-dose regimen of 70 mg per dose (the dose and dosing approach that was studied in the RAPID trial in patients with PSVT).

The Phase 3 study’s target population will be patients with verified history of AFib-RVR, and the ITT population will be all patients self-administering the study drug for perceived AFib-RVR.

The primary endpoint is the mean change from baseline ventricular rate to nadir ventricular rate for patients treated with etripamil versus placebo, as was studied in the ReVeRA trial in AFib-RVR.

The key secondary endpoint will be based on a PRO of symptomatic improvement, discussed with the FDA, which is similar to the PRO questions utilized in our PSVT and AFib-RVR programs.

The study has been powered and sized based upon approximately 150 events from 150 unique patients with a history of symptomatic episodes of AFib-RVR.

compounds for other cardiovascular conditions.

The key elements of our business strategy to achieve this goal include the following:

Successfully complete development and obtain regulatory approval of etripamil for the treatment of PSVT.

We are focused on efficiently developing and obtaining approval for etripamil to treat patients with PSVT.

We intend to first seek regulatory approval in the United States, followed by Europe and other major markets.

• Maximize the value of our programs by launching CARDAMYST in the United States.

If approved by the FDA, we intend to launch CARDAMYST by primarily targeting cardiology and high value primary care healthcare providers who we believe treat the majority of patients with a diagnosis of PSVT.

We intend to pursue retail distribution and target most of our launch year marketing mix on driving healthcare professional, or “HCP,” awareness and trial of CARDAMYST as well as ensuring that patients who are prescribed CARDAMYST have good experiences with the drug.

• Expand the scope of cardiovascular indications for etripamil beyond PSVT.

We are investigating, in a Phase 2 proof of concept study, the use of etripamil for the treatment of patients with AFib-RVR.

We are investigating, through a Phase 2 study and an upcoming Phase 3 study, the use of etripamil for the treatment of patients with AFib-RVR.

We believe that etripamil could benefit patients with AFib-RVR based on the approved use of intravenous, or “IV,” calcium channel blockers in this indication.

We are also exploring the additional cardiovascular opportunities for the use of etripamil.

Maximize the value of our programs by maintaining flexibility to commercialize our product candidates independently or through collaborative partnerships.

We currently have exclusive development and commercialization rights for etripamil for our initial indications of PSVT and AFib-RVR.

We have commercialization plans and are establishing commercialization and marketing capabilities in order to commercialize etripamil in the United States.

Outside of the United States, we are considering commercialization strategies that may include collaborations with other companies.

We also intend to explore additional cardiovascular opportunities for the use of etripamil.

• Successfully complete development and obtain regulatory approval of etripamil for the treatment of PSVT.

We are focused on efficiently developing and obtaining approval for etripamil to treat patients with PSVT.

In addition to potential regulatory approval in the United States, we are seeking regulatory approvals in China through our partner.

We intend to seek regulatory approvals in other major markets through strategic partnerships.

• Leverage our expertise and experience to expand our pipeline of product candidates.

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We intend to leverage the collective talent within our organization and our network to guide our development plans and pipeline expansion.

Cardiac and Pharmacologic Basis of Development Programs

Normal Conduction

Within the right atrium, one of the heart’s upper chambers, sits a specialized structure called the sinus node.

The sinus node, serving as the heart’s intrinsic pacemaker, generates an electrical signal which spreads throughout both atria and then is transmitted down to the lower chambers, the ventricles, via another specialized electrical tissue, the atrio-ventricular, or AV, node, which is shown in the figure below.

Upon reaching the ventricles, the electrical signal them to contract, pumping blood out to the lungs and the rest of the body.

Another heartbeat does not occur until a new signal is generated from the sinus node and the cycle repeats.

Under normal conditions, passage from the sinus node over the AV node is the only way for the electrical impulse to travel from the atria down to the ventricles.

The electrical signal of each heartbeat can be detected by placing sensors known as electrodes over the skin, and recorded over time in a tracing known as an electrocardiogram, or ECG.

The ECG measures signal voltage and duration.

To the trained interpreter, an ECG conveys a large amount of information about the structure and function of the heart, including among other things, heart rate and rhythm.

Under normal physiologic conditions, an ECG has a characteristic pattern of waves corresponding to the electrical activity, contraction and relaxation of each heart chamber.

This normal functioning is referred to as sinus rhythm and occurs at a heart rate of between 60 and 100 beats per minute at regular intervals.

As seen in the figure below, the various waves of an ECG tracing corresponding to the events of a single heartbeat are named with the letters P, Q, R, S and T.

The interval between the P wave and the R wave, known as the PR interval, is a measure of conduction over the AV node.

A normal PR interval is 0.12-0.20 seconds.

ECG Tracing Graph – Heartbeat

A disruption in the heart’s normal rhythm or conduction of electrical signals is called an arrhythmia.

An arrhythmia can take the form of the heart beating too quickly, too slowly, or with an irregular pattern.

A faster than normal heart rate is a tachycardia;

a slower than normal heart rate is a bradycardia.

Symptoms of an arrhythmia can include palpitations, lightheadedness or dizziness, chest pain, shortness of breath, or sweating;

these symptoms can be markedly severe, and in advanced cases of some arrhythmias, resultant signs can include worse morbidities and even mortality.

PSVT and atrial fibrillation are two of the most commonly occurring arrhythmias.

While PSVT is characterized by a faster than normal heart rate where the heart beats at regular intervals, with AFib-RVR the heart often beats faster than normal and with an irregularly irregular rhythm.

Pharmacologic treatment of PSVT focuses on terminating the arrhythmia using an agent to prolong the refractoriness (the recovery time between consecutive activations) of the AV node or to prolong conduction over the AV node.

With AFib-RVR, there are two approaches to treatment:

rate control to reduce the heart rate and rhythm control to restore sinus rhythm and prevent AFib recurrences.

CARDAMYST TM (etripamil) nasal spray

We designed the molecule of etripamil, and we are developing the drug, a novel, potent and rapid-onset calcium channel blocker, as a nasal spray to be administered by the patient to terminate episodes of transient cardiovascular conditions as they occur.

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Our goal was to preserve the beneficial pharmacology of existing molecules while altering their pharmacokinetic profile with focused medicinal chemistry to produce drugs that are fast acting.

As a result, we created a series of novel non-dihydropyridine, L-type calcium channel blockers containing chemical ester moieties that preserved the desired pharmacology on the heart but that could be rapidly metabolized in the blood by

serum esterases.

Etripamil resulted from this effort as a new chemical entity with a fast pharmacodynamic effect in humans, relative to oral calcium channel blockers.

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Etripamil is designed, and has been investigated, to empower patients to self-administer treatment outside of a medical setting and as prompted by a patient’s symptoms.

PSVT is a serious, markedly symptomatic, and recurring cardiac arrhythmia, which is caused by altered electrical conduction within the heart, involving the AV node and over an abnormal electrical circuit in the substantial majority of cases.

In the most common form of PSVT, AV nodal reentrant tachycardia, or AVNRT, there is an abnormal limb of electrical circuitry within the AV node which represents the substrate of the tachycardia.

This abnormal circuitry is the basis for a reentrant arrhythmia which results in excessively rapid beating of both the atria and ventricles.

PSVT is a serious, markedly symptomatic, and recurring cardiac arrhythmia, caused by altered electrical conduction within the heart involving the AV node and over an abnormal electrical circuit in most cases.

The common form of PSVT, AV nodal reentrant tachycardia, or “AVNRT,” has an abnormal limb of electrical circuitry within the AV node that is the substrate of the tachycardia and forms the basis for a reentrant arrhythmia, resulting in excessively rapid beating of both the atria and ventricles.

In the next most common form of PSVT, atrioventricular reciprocating tachycardia, or “AVRT,” there is an abnormal limb of electrical tissue, or bypass tract, that directly connects the atria and the ventricles.

In AVRT, the bypass tract allows the signal to travel between the atria and ventricles as a “short circuit.” AVRT involves the AV node, in addition to the bypass tract.

Thus, for both AVNRT and AVRT – two PSVT types that require the AV node as a part of their abnormal circuit, or AV-nodal dependent PSVTs – a drug which targets the AV node can represent a potential treatment.

Non-dihydropyridine calcium channel blockers are a class of drugs that target the AV node, reflecting why etripamil has been an excellent therapeutic candidate for AVNRT and AVRT termination.

In AVRT, the bypass tract allows the signal to travel between the atria and ventricles as a “short circuit.” AVRT also involves the AV node, in addition to the bypass tract.

Thus, for both AVNRT and AVRT – two PSVT types that require the AV node as a part of their abnormal circuit (i.e., AV-nodal dependent PSVTs) – a drug which targets the AV node can represent a potential treatment.

Non-dihydropyridine calcium channel blockers are a class of drugs that target the AV node, reflecting why etripamil has been an excellent therapeutic candidate for AVNRT and AVRT disruption and termination.

Current Treatment Options for PSVT

Treatment for PSVT depends on the frequency, duration, and severity of the episodes as well as patient preference.

Current options for patients with PSVT to terminate an episode of SVT include vagal maneuvers, IV medication or external shock delivered in the emergency department.

Additionally, some practitioners prescribe oral medications, such as calcium channel blockers, beta blockers and antiarrhythmic drugs to be taken at the onset of an episode.

However, these oral medications interventions are generally not acutely effective.

Long-term strategies include chronic drug therapy to reduce the frequency of episodes and cardiac ablation to potentially cure the disease.

Patients may also elect to not treat their symptoms and simply endure episodes of SVT when they occur.

Vagal maneuvers are commonly attempted to terminate an episode, with low to modest success rates.

These are physiological maneuvers that stimulate the vagus nerve, which can terminate an SVT episode.

These include gagging, massaging one carotid artery, holding one’s breath and bearing down (Valsalva maneuver), immersing one’s face in ice-cold water, or coughing.

Currently approved acute pharmacological therapy for the treatment of an acute episode of SVT includes IV administration of approved AV nodal-blocking agents in an acute care setting.

The current standard of care for treatment of episodes of SVT is adenosine, but prior to its approval in 1990, episodes of SVT were treated with IV calcium channel blockers, such as verapamil or diltiazem.

When given as a rapid IV bolus, adenosine blocks conduction over the AV node, thereby interrupting the arrhythmia circuit and restoring the heart back to sinus rhythm.

Adenosine temporarily stops the heart and patients have reported experiencing chest tightness, flushing and a sense of impending death.

Physicians report that patients tell them that they feel like they are going to die.

Adenosine is eliminated from the body in less than one minute but cannot be self-administered as it requires IV access.

In-hospital IV administrations are associated with higher healthcare costs and are also unsettling and inconvenient for the patient.

IV calcium channel blockers also slow conduction over the AV node during the course of several minutes.

However, they are associated with the risk of excessive slowing of the heart rate and low blood pressure.

According to treatment guidelines, patients in the acute care setting who fail pharmacologic treatment for PSVT could then receive direct current cardioversion, where an electric shock is applied to the heart to return it to sinus rhythm.

In an attempt to prophylactically control the frequency and duration of future SVT episodes, many patients will take chronic daily oral medications that modulate AV nodal conduction, such as beta blockers, L-type non-dihydropyridine calcium channel blockers, or antiarrhythmic drugs.

Despite chronic daily oral medication, breakthrough SVT episodes that require visits to the emergency department may still occur, albeit for some patients at a reduced frequency.

Chronic medication can lead to side effects such as sexual dysfunction or fatigue in the case of beta blockers and constipation in the case of verapamil.

Treatment for PSVT depends on the frequency, duration, and severity of the episodes, as well as patient preference for pharmacologic or invasive treatment.

Current options for patients with PSVT to acutely terminate an episode of arrhythmia include IV medication (e.g., IV adenosine, IV calcium channel blockers), administered in an emergency department, which transiently alter electrical conduction over the AV node leading to termination of AV-dependent arrhythmias and restoration of sinus rhythm;

or an external shock delivered in the emergency department.

Of note, IV adenosine temporarily causes complete heart block and patients have reported experiencing chest tightness, flushing and a sense of impending doom.

Two other modalities, though of low effectiveness, are vagal maneuvers or oral medications administered at the onset of an episode (e.g., calcium channel blockers, beta blockers).

Long-term, preventative strategies include chronic drug therapy to reduce the frequency of episodes, though patients exhibit break-through episodes of PSVT and emergency department visits for the same, despite chronic medications, and cardiac ablation to potentially cure the disease.

Patients may also elect not to treat their PSVT and simply endure episodes of SVT when they occur.

Of note, chronic medication can lead to side effects such as sexual dysfunction or fatigue in the case of beta blockers and constipation in the case of verapamil.

Some patients discontinue chronic oral medication due to intolerable side effects.

Based on our market research, we estimate that approximately two thirds of patients with PSVT have been prescribed chronic medications such as beta blockers or calcium channel blockers to prevent SVT episodes or to treat other concomitant conditions such as hypertension.

The only potentially curative treatment available at the present time for PSVT is ablation, an invasive procedure, which works by directly cauterizing or freezing the short circuit that is the cause of the abnormal rhythm.

This is achieved in an electrophysiology lab via catheters that are run through the patient’s groin vessels and into the heart and uses burning or freezing techniques to destroy the heart’s abnormal electrical tissue.

Based on our market research, we estimate that approximately two thirds of patients with PSVT have been prescribed chronic medications such as beta blockers or calcium channel blockers to prevent episodes of SVT or to treat other concomitant conditions such as hypertension.

Ablations, a potentially curative treatment for PSVT, is an invasive procedure, which works by directly cauterizing or freezing the short circuit that is the substrate for the abnormal rhythm.

This is achieved in an electrophysiology lab via catheters that enter the patient’s heart through the blood vessels and that deliver burning or freezing to ablate the abnormal electrical tissue.

Ablation single-procedure success rates for PSVT are reported to be 91% to 96%.

However, we estimate that less than 10% of patients with PSVT per year choose this option, which we believe is due primarily to anxiety related to the procedure.

However, we estimate that less than 10% of eligible patients with PSVT per year choose this option, which we believe is due primarily to anxiety related to the procedure.

Although ablations are generally considered to be safe by the treating community, as with any invasive procedure there are potential complications, which include bleeding, blood clots, pericardial tamponade, and transient or permanent heart block, with the latter requiring permanent pacemaker implantation.

Market Opportunity – Paroxysmal Supraventricular Tachycardia (PSVT)

We believe that PSVT is a large and under-recognized market that we estimate affects approximately two million Americans and results in over 600,000 healthcare claims in the United States alone per year, including more than 150,000 emergency department visits and hospital admissions and up to 80,000 ablations.

Furthermore, we estimate that approximately 300,000 people are diagnosed with PSVT each year in the United States.

We derive these estimates from the analysis of longitudinal claims data, which we believe is the most accurate method available to estimate the epidemiology of PSVT.

A study in the Journal of Clinical Electrophysiology published in 2021 concluded that excluding patients with comorbid Atrial Fibrillation or Atrial Flutter, or AFib/AFL, leads to a conservative estimate of PSVT treated prevalence in the U.S.

of approximately 1.3 million, while including those with comorbid AFib/AFL suggests a U.S.

treated prevalence of approximately 2.1 million, with approximately 190,000 to 310,000 corresponding new cases each year.

Other published sources that attempt to quantify the epidemiology of PSVT, such as the MESA study published in the Journal of the American College of Cardiology in 1998, and the PREEMPT study published in the Journal of the American Heart Association in 2018, provide important demographic and clinical characteristic data on patients with PSVT.

For example, in the MESA study, fewer than 40% of the adjudicated incident cases of PSVT would have been detected had the investigators limited their screening to those patients identified by the PSVT ICD9 Code (427.0).

In addition, 21% of the incident patients with PSVT in the MESA study also had a diagnosis of atrial fibrillation (18%) or atrial flutter (6%).

As an epidemiology tool, however, we believe these studies underestimate the incidence and prevalence of PSVT due to the episodic nature of the disease as well as the variability in the duration of the episodes, as the investigators in both studies relied only on data from patients presenting to healthcare settings acutely, with the episode confirmed on ECG during the encounter, to estimate the incidence and prevalence of PSVT.

Current treatment for PSVT also consumes significant healthcare resources.

Research published in the American Journal of Cardiology in 2020 shows that costs for patients rose significantly in the pre-diagnosis year due to the difficulty of obtaining an accurate diagnosis.

In the year following diagnosis, costs triple for those less than 65 years of age and double for those over 65 years of age, compared to matched controls.

Total healthcare expenditures in the year following PSVT diagnosis ranged from $20,000 to $30,000 per patient, significantly higher than the expenditures observed for patients without PSVT (approximately $6,500 per patient).

Significant increases for both age groups were noted for emergency department visits.

For those less than 65, the average cost of hospitalizations doubled as their inpatient rates quadrupled.

Of note, catheter ablations following diagnosis represent only 23% of this increased spend, meaning most costs are unrelated to ablations.

In total, approximately $3 billion is spent annually in the U.S.

on the management of PSVT.

Our Clinical Development Program for the Treatment of Paroxysmal Supraventricular Tachycardia

Current treatments do not address the medical need for a rapidly acting, effective, safe and patient-administered treatment that can be taken outside of a hospital or acute care setting at the onset of an SVT episode to restore the heart back to sinus rhythm.

We believe that etripamil will fill this unmet need.

We completed a Phase 1 clinical trial (study MSP-2017-1096), which supported the selection of four doses of etripamil for Phase 2 development, followed by a Phase 2 clinical trial in adult patients to evaluate the effects of four doses in patients with PSVT.

Both trials assessed nasally administered etripamil compared to placebo.

Based on discussions with the FDA, we initiated a major Phase 3 clinical trial (NODE-301) in July, 2018 to assess the efficacy and safety of etripamil in the at-home setting and released topline data in March 2020.

We have completed a second pivotal Phase 3 trial (RAPID) which demonstrated highly statistically significant efficacy to convert PSVT and favorable safety/tolerability of the drug.

We have completed additional Phase 1 clinical trials, one that further characterized the PK and PD of intranasal etripamil in Japanese and non-Japanese healthy volunteers;

a second that further characterized pharmacokinetics and safety of administering the drug in single- vs.

repeated-dose approaches.

We have also completed an open label Phase 3 safety trial (NODE-302), which provided further drug access to patients that had previously participated in the NODE-301 trial.

The primary objective of the NODE-302 trial is to assess the safety of etripamil 70 mg in patients over multiple episodes.

We completed a third Phase 1 clinical trial, assessing the impact of a repeat-dose regimen, in which patients take a second 70 mg dose of etripamil 10 minutes after a first dose of 70 mg, on the PK and safety of etripamil.

We have completed NODE-303, which is an open label Phase 3 study that has the objective of collecting further safety data.

Phase 1 Clinical Data

We completed a Phase 1 clinical trial (MSP-2017-1096), in healthy volunteers, which was designed to assess the safety, PK profile, and cardiac pharmacology of intranasally administered etripamil in a randomized, double-blind, placebo controlled, single ascending dose trial.

The trial’s primary objective was to determine the maximum tolerated dose or maximum feasible dose of two different formulations of etripamil administered via the nasal route in healthy, adult male subjects.

All doses of etripamil were generally well tolerated, and there was no difference in the safety profile and PK between the two formulations of etripamil, referred to as MSP2017A and MSP2017B.

The most commonly reported side effects were localized to the administration site, e.g., nasal irritation and nasal congestion.

Potential concerns such as syncope, pre-syncope, lightheadedness, or decreases in systolic blood pressure below 90 mmHg or AV nodal blocks of second degree or worse were not observed.

The study of formulation MSP2017A was stopped at 60 mg and MSP2017B was further studied at higher doses (105 mg and 140 mg).

The Phase 1 results supported the selection of four doses of etripamil for Phase 2 development.

We are using these Phase 1 data, and resultant Phase 2 data, to support further clinical development of etripamil in two indications:

PSVT and AFib-RVR.

PK analyses have demonstrated rapid absorption and elimination following nasal administration of etripamil, as well as dose proportional systemic exposure, or area under the curve, and maximum plasma concentration for etripamil and its primary inactive metabolite.

These findings were consistent across a range of seven doses of drug tested up to 140 mg.

The 140 mg dose was the maximal feasible dose because neither the concentration (350 mg/mL) nor the volume (200 µL) of solution administered in each nostril could be increased.

Due to these characteristics of formulation and delivery, a maximum tolerated dose of etripamil was not established.

The figure below shows the rapid absorption via the nasal route and the rapid decrease in plasma concentration of etripamil.

(MSP-2017-1096)

Pharmacokinetic Profile of Etripamil Plasma Concentrations

Error bars indicate standard error of the mean

Prolongation of the PR interval as measured by ECGs, which reflects the impact of drug on AV-nodal conduction, was utilized as the pharmacodynamic, or PD, measure.

A linear relationship was observed between the dose of etripamil and prolongation of the PR interval.

The 60 mg, 105 mg, and 140 mg doses demonstrated a 10% or greater PR prolongation, which is shown in the figure below.

This correlates with the reported slowing of conduction over the AV node that is necessary to convert an SVT episode to sinus rhythm.

Such slowing of AV-nodal conduction, reflected by PR interval prolongation, has been observed clinically and through investigations with known intravenous AV-nodal targeted agents such as verapamil, adenosine, and tecadenoson.

(MSP-2017-1096) - Pharmacology

We completed a second Phase 1 trial, NODE-102, comparing the PK and PD of etripamil 35 mg, 70 mg, and 105 mg versus placebo in Japanese and non-Japanese healthy volunteers.

Once we determined there was no difference in PK and PD of etripamil between Japanese and non-Japanese participants, we pooled the data from the overall populations into a single dataset.

We believe this trial provides further justification for the selected 70 mg dose in our Phase 3 program broadly and may be used to support further clinical development of etripamil in Japan.

As shown in the figure below, we observed a correlation between the PK profile of etripamil 70 mg, measured by change in PR interval from baseline over time, and the plasma concentrations of etripamil.

With regard to pharmacodynamics, an approximate 10% increase in the PR interval has been reported to be a marker of meaningful prolongation in AV-nodal conduction that is needed to terminate an episode of PSVT.

The data as demonstrated on the blue line on the graph below indicates that etripamil 70 mg is potentially impacting AV nodal conduction at meaningful levels for a period up to approximately 50 minutes.

(MSP-2017-1205) NODE-102

The Phase 3 RAPID study incorporated a repeat-dose administration regimen of the study drug (70 mg of etripamil or placebo).

Specifically, patients were instructed to administer a repeat administration of study drug if they did not experience relief from symptoms of PSVT within 10 minutes of the first administration of study drug.

This tailored, staged drug regimen utilizes a repeat-dose similar to current PSVT treatment practices with intravenous drugs in the emergency department setting.

Pharmacologic data supporting a repeat-dose approach were obtained from a Phase 1 study.

A repeat dose regimen (two doses of 70 mg etripamil administered 10 minutes apart) was tested in study NODE-103.

As shown in the figure below, this regimen resulted in greater systemic exposure to etripamil, as measured by an apparently increased second maximum concentration after the second administration, as well as an elevated total Area Under the Curve, compared to single-dose administration of 70 mg.

Furthermore, from visual inspection of the data, the intended two-bolus PK plot can be observed.

We believe these PK data supports the hypothesis underlying our RAPID trial regimen that a second administration will augment etripamil exposure, while maintaining safety, and will improve impact of the drug on AV-nodal conduction thereby resulting in a greater therapeutic effect.

One dose of 70-mg etripamil vs.

repeat dose regimen administered 10 minutes apart

Error bars = standard error

Phase 2 Clinical Data

We completed a Phase 2 multicenter, randomized, double-blind, placebo controlled clinical trial in the United States and Canada, NODE-1, to evaluate the effects of four doses of etripamil in patients with PSVT.

In order to demonstrate the effectiveness and safety of etripamil to terminate SVT in a controlled setting, we conducted the study in the electrophysiology, or EP, laboratory setting, where an SVT episode could be induced in patients scheduled to undergo an EP study and ablation.

The primary objective of this trial was to demonstrate the superiority of at least one dose of etripamil over placebo in terminating SVT.

The secondary objectives were to determine the minimally effective dose of etripamil, to establish a dose related efficacy trend for etripamil, and to evaluate the safety of etripamil in a clinical setting.

The trial was statistically powered at more than 80% to show a 50% absolute difference of etripamil versus placebo.

The trial enrolled 199 patients, of which 95 withdrew prior to dosing:

70 due to inability to induce (n=42) or to sustain (n=28) SVT, five based on physician discretion, one lost to follow up, one due to withdrawal of consent, and 18 for other reasons.

The mean age of patients was 52.2 years (range, 19 to 85 years).

As shown in the figure below, SVT was induced and sustained for five minutes in 104 patients, who were randomized into one of five dosing cohorts.

Four cohorts received intranasal doses of etripamil (35 mg, 70 mg, 105 mg, or 140 mg) and one cohort received matching placebo.

All doses of study drug were delivered in a double-blind fashion in which healthcare providers administered four 100 µL sprays from four different single-spray devices.

There were no imbalances in baseline characteristics across the five treatment groups.

The mean heart rate in SVT at time = 0 was 177 bpm in the placebo group and 168 bpm, 173 bpm, 180 bpm, and 155 bpm in the etripamil 35-mg, 70-mg, 105-mg and 140-mg groups, respectively.

(MSP-2017-1109) NODE 1 – Clinical Trial Design

The primary endpoint in this clinical trial was the conversion of SVT to sinus rhythm within 15 minutes after administration of etripamil or placebo.

As shown in the figure below, the percentage of patients in whom SVT converted to sinus rhythm within 15 minutes of study drug administration was 65% with 35 mg etripamil, 87% with 70 mg, 75% with 105 mg and 95% with 140 mg, compared with 35% in the placebo arm.

The three highest doses of etripamil showed statistically significant conversion rates compared with placebo.

Statistical significance expresses the probability that the results of a particular study could have occurred purely by chance.

Statistical significance is assessed by the FDA and other health regulatory agencies in evaluating marketing approval applications.

FDA and other regulatory agencies review the strength of the statistical evidence and whether it supports the claims of the applicant.

The primary endpoint, statistical methods for the trial and a p-value boundary for achieving statistical significance for a clinical trial are typically defined before the trial begins.

If the probability of observing the calculated statistic is smaller than the p-value boundary, the primary endpoint is considered statistically significant.

P-value is a conventional statistical method for measuring the statistical significance of clinical results.

A p-value of 0.05 or less represents statistical significance, meaning there is a less than 1in 20 likelihood that the observed results occurred by chance.

The FDA utilizes statistical significance, as measured by p-value, as an evidentiary standard of efficacy and typically requires a p-value of 0.05 or less to demonstrate statistical significance.

(MSP-2017-1109) NODE 1 - Etripamil Conversion Rates from SVT to Sinus Rhythm

In a post-hoc analysis conducted to inform our Phase 3 trial design, the patients’ times to conversion of SVT to sinus rhythm were examined.

As shown in the following Kaplan Meier plot, patients successfully converting to sinus rhythm during the 15-minute study window, the three highest doses of etripamil (140 mg, 105 mg, and 70 mg) demonstrated statistically significant shorter time to conversion of SVT compared with placebo.

The 70-mg dose showed a rapid onset of action with a median time to conversion of less than three minutes after nasal administration of etripamil.

Doses of drug above 70 mg, given as single-dose administrations in this study, did not yield meaningfully greater degrees of conversion of SVT.

These data contributed greatly to selection of etripamil dose for the Phase 3 program.

(MSP-2017-1109) NODE 1 – Etripamil Time to Conversion from Supraventricular Tachycardia to Sinus Rhythm

Overall, etripamil was well tolerated, and the most common adverse events were localized to the nasal route of administration, e.g., nasal irritation or nasal congestion, reported by up to 60% and 45% of patients, respectively, after etripamil (versus none after placebo).

Specifically, the 70-mg dose was reported to have 48% nasal irritation and 26% nasal congestion;

however, these were transient and required no specific intervention.

Most adverse events were mild (44.2%) or moderate (24.0%) across all treatment groups.

At least one adverse event considered related to the study drug, according to the investigator assessment, was reported in 17 (85.0%) patients in the etripamil 35-mg group, 18 (78.3%) in the 70-mg group, 15 (75.0%) in the 105-mg group, 20 (95.2%) in the 140-mg group and 4 (20.0%) in the placebo group.

The incidence of adverse events was not dose-dependent.

Hypotension, or low blood pressure, was reported as an adverse event in two patients, one in the 105-mg group and one in the 140-mg group.

Neither event led to sequelae or a serious classification.

A total of three patients experienced severe adverse events that were considered possibly related to etripamil.

One patient who received a 35-mg dose of etripamil experienced facial flushing, shortness of breath, and chest discomfort.

One patient who received a 105-mg dose of etripamil had nausea and vomiting, as well as a severe and serious cough.

One patient who received a 140-mg dose of etripamil experienced a severe adverse event of second-degree AV block with relative hypotension, beginning five minutes after conversion to sinus rhythm;

the AV block resolved after 43 minutes, was without sequelae observed, and ablation was subsequently performed.

There were no adverse events that led to study discontinuation or death.

Calcium channel blockers have the potential to cause hypotension as a side effect.

Thus, in our Phase 2 clinical trial, we recorded vital signs, including heart rate and blood pressure, before induction of SVT and every two minutes for 30 minutes after study drug was given (see figure below).

We observed no meaningful reduction in mean blood pressure in the 35 mg or 70 mg etripamil cohorts but observed a transient decrease in the mean blood pressure in the two highest cohorts, 105 mg, and 140 mg.

Due to the induction of SVT, the mean systolic blood pressure decreased at time 0 compared to the average at 20 and 10 minutes before SVT induction.

Compared to baseline and time 0, systolic blood pressure measurements recorded from two minutes to 16 minutes post study drug administration showed no decrease in mean systolic blood pressure in the placebo or 35-mg groups, and maximum mean decreases of 2 mm Hg four minutes post dose in the 70-mg group, 17 mm Hg six minutes post dose in the 105-mg group, and 20 mm Hg six minutes and eight minutes post dose in the 140-mg group.

As illustrated in the figure below, mean blood pressure reductions in these two groups were transient.

(MSP-2017-1109) NODE 1 – Etripamil Systolic Blood Pressure Over Time

* p < 0.05 vs baseline.

Baseline is defined as the average of the -20 and -10 minutes pre-dose measurements.

Time 0 is defined as the average of the measurements during SVT between -5 and 0 minutes before study drug administration.

Mean and standard error (SEs) values were calculated based on available data at the relevant time point.

MSP-2017 means etripamil.

Error bars indicate standard error of the mean.

Based on the combination of efficacy and safety data from our Phase 2 trial, we selected the 70 mg dose of etripamil for our subsequent clinical trials.

Clinical Development of Etripamil for a PSVT Indication

In accordance with on our interactions with regulatory agencies, our Phase 3 clinical program has included:

RAPID, a confirmatory pivotal efficacy trial to assess the time to conversion of PSVT to sinus rhythm due to treatment with etripamil compared to placebo in the at-home setting and, in this trial, utilizing an optional repeat-dose regimen.

NODE-301 part 1, a pivotal efficacy trial to assess the time to conversion of PSVT to sinus rhythm due to treatment with etripamil compared to placebo in the at-home setting.

NODE-302, an open-label extension of NODE-301 that enrolled patients who completed NODE-301 in order to collect safety data on subsequent (recurrent) episodes in the at-home setting, and.

NODE-303, an open-label global safety trial to complete the safety assessment of etripamil in the at-home setting to support an NDA and other regulatory filings.

Phase 3 Clinical Trials

The RAPID trial was a placebo-controlled, double-blinded, randomized, event-driven Phase 3 clinical trial conducted in the United States, Canada, and Europe to evaluate 70 mg of etripamil (with an optional repeat dose of drug) versus placebo in terminating an SVT episode in the at-home setting.

RAPID, also named NODE-301 part 2, was originally intended 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.

After receiving guidance from the FDA on our Phase 3 program, we amended and expanded NODE-301 part 2 and renamed it the RAPID trial;

and, with regulatory agreement, RAPID is inferentially separate from NODE-301 part 1.

The RAPID trial, an event-driven trial like the prior Phase 3 one, was projected to enroll approximately 500 patients and was defined to be completed after a total of 180 confirmed SVT events occurred.

Patients enrolled in the RAPID trial were randomized 1:1 (etripamil:placebo).

The graphic below shows the design of the RAPID trial.

The protocol amendment changing NODE-301 part 2 to RAPID, and incorporating an important repeat-dose treatment regimen, was implemented across all clinical study sites over 2021.

Prior to the RAPID / repeat-dose amendment being fully implemented, a total of 34 patients dosed themselves with single dose study drug of which 29 were confirmed by the adjudication committee to be SVT (i.e., groups C+D in the trial design graphic, which had been randomized 2:1, etripamil:placebo).

(MSP-2017-1138) RAPID – Trial Design

(1) Arms C and D (single-dose regimen) will be only the patients enrolled under NODE-301 who have had an episode prior to the RAPID Study protocol amendment

(2) Wilcoxon analysis modeling from NODE-301 data

Under the RAPID statistical analysis plan (SAP), the primary efficacy endpoint for the study was defined as time to conversion over the first 30 minutes, with a target p-value of less than 0.05.

(This endpoint was agreed upon with FDA and other regulatory bodies because it, when assessed in either a prespecified or in a post hoc analysis for NODE-301 part 1, was statistically significant and showed a compelling treatment effect.) This endpoint supports the desire and need of patients to address their PSVT symptoms rapidly during an episode and have a normal cardiac rhythm restored during a time-window that would avoid additional medical intervention and visiting an emergency department.

Based on interactions with PSVT-treating physicians and cardiovascular thought leaders, it is clear that a 50% conversion rate within 60 minutes would be a clinically meaningful outcome given the highly symptomatic nature of SVT episodes and the lack of approved at-home treatments.

In addition to its clinical relevance, primary assessment by 30 minutes is a time aligned with the drug’s known pharmacologic characteristics.

The design of the RAPID study was based on power calculations utilizing NODE-301 Part-1 study data.

The Kaplan–Meier probabilities of conversion to sinus rhythm by 30 minutes as 54% under etripamil treatment and 35% under placebo were the basis for effect-size assumptions, and indicated that 180 patients, each with a PSVT event confirmed by adjudication, would provide 90% power to detect a 19% relative-reduction treatment difference for the primary endpoint at a 2-sided-significance level of 0·05.

It was anticipated that ≥500 patients would be randomized to accrue requisite confirmed PSVT events.

Later and earlier time point data from NODE-301 part 1 for time to conversion, for patient reported outcomes, and for emergency department utilization were used to define assessments for secondary analyses in RAPID;

these secondary analyses were pre-planned to fully characterize the efficacy profile of etripamil.

RAPID was performed at approximately 160 study sites in North America and Europe and enrolled patients with similar inclusion and exclusion criteria as the prior randomized Phase 3 study.

Key eligibility criteria included, similar to the prior Phase 3 study:

patients were aged ≥18 years with electrocardiogram-documented history of PSVT with sustained, symptomatic episodes (≥20 minutes).

In the RAPID study, as prompted by PSVT symptoms, patients self-administered a first 70-mg etripamil or placebo dose and, if symptoms persisted beyond 10 minutes, a repeat dose of study drug (70-mg etripamil or placebo).

Continuously recorded electrocardiographic data were blindly adjudicated for the primary endpoint, time-to-conversion of PSVT to sinus rhythm for ≥30 seconds by 30 minutes of first dose.

Pre-defined secondary endpoints assessed the robustness of the primary findings and measured use of additional medical interventions and emergency department use for episodes of PSVT.

Safety outcomes were assessed.

This trial was registered at www.clinicaltrials.gov (NCT03464019).

Among the 692 patients randomized, 184 self-administered the study drug for confirmed PSVT.

Kaplan–Meier estimates of conversion rates by 30 minutes were 64.3% with etripamil and 31.2% with placebo (hazard ratio=2.62;

P<0.001), and statistically significant differences were observed by 300 minutes as well (hazard ratio=1.70;

Median time-to-conversion was 17.2 minutes (etripamil) versus 53.5 minutes (placebo).

The Kaplan–Meier plot of cumulative incidence of conversion by 30 minutes is in the below figure.

Primary Endpoint:

Conversion of Adjudicated PSVT to NSR 30 min

There were reduced rates of additional medical interventions and emergency-department visits following etripamil administration compared to placebo in the RAPID study, and these rates are consistent with those observed in NODE-301 part-1.

Neither trial was sized to detect significantly different rates between treatment groups in need of additional acute care.

Thus, a predefined analysis was performed on a dataset pooled between RAPID and NODE-301 part-1, confirming alignment between the studies’ findings, and showing reduced rates of additional medical interventions (25.4% under placebo versus 14.6% under etripamil [P=0.013]) and emergency-department visits (22.4% under placebo versus 13.6% under etripamil [P=0.035]).

Risk-reductions observed in RAPID indicate that the number-needed-to-treat with etripamil to convert an episode of PSVT within 30 minutes of drug administration is 3.0 and to prevent an emergency visit for PSVT is 14.1, within the range for effectiveness of a treatment for a symptomatic condition.

The majority of adverse events were localized at the administration site and mild;

there were no serious etripamil-related events.

A blinded, independent examination of ECG data by expert adjudicators showed no instances of AV block or significant pauses during randomized drug administration or in the hours following that.

Results from the RAPID trial demonstrate that intranasal etripamil, self-administered in an at-home setting, with initial- and repeat-dosing prompted by symptoms, was superior to placebo for rapid PSVT conversion and well-tolerated.

This symptom-prompted treatment approach was further supported by findings of improvement in patient-defined symptoms of PSVT.

Reduced rates of additional medical interventions and emergency-department visits observed with etripamil potentially support this drug regimen for lessening the healthcare burden of PSVT.

NODE-301 is a placebo-controlled, double-blinded, randomized, event-driven Phase 3 clinical trial conducted in the United States and Canada to evaluate 70 mg of etripamil versus placebo in terminating an SVT episode in the at-home setting.

As shown in the figure below, the primary endpoint is the time to conversion over a five-hour monitoring period following the administration of the study drug.

Prior to randomization, eligible patients administered a test dose of 70 mg of etripamil in the investigator’s office while in sinus rhythm in order to assess tolerability.

Patients successfully completing the test dose were randomly assigned to the etripamil or placebo cohorts (2:1 randomization) and sent home with the study drug and a small portable electrocardiographic cardiac monitor to be used during patients’ subsequent SVT episodes.

Upon experiencing symptoms of an SVT episode, patients were instructed to first apply the cardiac monitoring device to record ECG data, then attempt a vagal maneuver, and, if that was not successful in terminating the episode, to then administer the study drug.

Patients’ ECG data were recorded using the electrocardiographic cardiac monitoring device for a period of five hours after study drug administration.

Patients returned to the clinic for a follow up visit within one week following their SVT event for collection of further information.

NODE-301 enrolled 431 patients across 65 sites in the United States and Canada, with 156 patients (107 etripamil, 49 placebo) receiving etripamil for an adjudicated true PSVT episode.

In March 2020, we reported topline results of the NODE-301 trial, referred to as NODE-301 part 1.

The first part of NODE-301 did not meet its primary endpoint of time to conversion of SVT to sinus rhythm compared to placebo over the five-hour period following study drug administration, however, prespecified and post hoc assessments at 30 minutes were significant.

The median time to conversion for etripamil was 25 minutes (95% CI:

16, 43) compared to 50 minutes (95%

31,101) for placebo.

As shown in the top figure below, despite the activity of etripamil to convert PSVT and its separation from placebo in the first approximately 30 to 60 minutes following study drug administration, results from the latter part of the analysis confounded the statistical analysis of the primary endpoint.

Analysis of the first 30 minutes of the Kaplan Meier curve, shown in the bottom graph below, and the post hoc results at that time point were a 54% rate of conversion for the etripamil patients and 35% for the placebo patients.

The results were statistically significant with a hazard ratio of 1.87 and a p-value of 0.02.

Prespecified landmark analyses were aligned with these post hoc findings and also significant.

(MSP-2017-1138) NODE-301 Part 1 Efficacy – Time to Conversion over 5 Hours (Primary analysis) and Time to Conversion over 30 minutes (post hoc analysis, aligned with prespecified analyses at 30 minutes)

The study also demonstrated statistically significant improvements in patients taking etripamil compared to those taking placebo in the secondary endpoint of patient reported treatment satisfaction, as measured by a TSQM-9, including global satisfaction (p=0.0069) and effectiveness scores (p=0.0015).

Additionally, there was a trend towards improvement in the percentage of patients seeking rescue medical intervention, including in the emergency department, with 15% and 27% etripamil and placebo patients, respectively, reporting such intervention (p=0.12).

(MSP-2017-1138) NODE-301 Key Secondary Efficacy Endpoints

Overall, etripamil was well tolerated when self-administered as a test dose during sinus rhythm or as a post-randomization dose during symptomatic PSVT.

The most common (≥5%) adverse events occurring within 24 hours of a test dose or those occurring more frequently with etripamil within 24 hours of a randomized dose were nasal discomfort, nasal congestion, epistaxis, rhinorrhea, throat irritation, and increased lacrimation, all of which were related to the nasal route of administration.

The incidence of all other adverse events, including those related to abnormal vital signs, laboratory results, and ECG findings, was balanced between the 2 groups.

No serious adverse events were observed within 24 hours of taking the study drug.

NODE-302 is the open label extension trial of NODE-301.

We designed NODE-302 to primarily evaluate the safety of etripamil when self-administered without medical supervision and to monitor the safety and efficacy of etripamil for the treatment of multiple episodes of SVT.

Patients who had successfully dosed with the study drug in NODE-301 and completed a study closure visit were eligible to enroll in NODE-302 to manage any subsequent episodes of SVT.

Eligibility was also contingent on satisfying all inclusion and exclusion criteria, including not experiencing a serious adverse event related to the study drug or the study procedure that precludes the self-administration of etripamil.

We initiated NODE-302 in December 2018.

The trial completed enrollment in 2020 and the study was presented at the Heart Rhythm Society Scientific Sessions as a late-breaking clinical trial in May 2022, and is in the process of being published.

Overall, the safety and tolerability profile of etripamil 70 mg was favorable and generally consistent with what was observed in the NODE-301 study including for patients experiencing recurrent episodes.

NODE-303 is an open-label global safety trial enrolling patients who did not participate in NODE-301, NODE-302, or RAPID in order to collect safety data that, when combined with the safety data from the rest of the program, will form the safety dataset to be evaluated by the FDA and other regulatory agencies, forming the basis for marketing approval.

We designed NODE-303 to evaluate the safety of etripamil when self-administered as prompted by symptoms and without medical supervision, and to evaluate the safety and efficacy of etripamil over multiple episodes of SVT.

The NODE-303 trial is designed to closely reflect the expected utilization of etripamil in the post approval or ‘real-world’ setting and, for example, does not include an in-office safety test dose and includes a broad patient population including patients taking concomitant beta blockers and calcium channel blockers.

In this study, patients had the opportunity to manage up to four episodes of SVT.

NODE-303 was initiated in October 2019 utilizing the single 70 mg etripamil administration.

In 2021, following FDA’s agreement, we initiated the change from the single 70 mg etripamil administration to the 70 mg repeat-dose treatment regimen.

The FDA’s acceptance was based on initial safety data of the repeat-dose regimen experience gained in the RAPID study and the overall safety data from the etripamil clinical program.

Atrial Fibrillation

AFib is a common arrhythmia with an irregular and often rapid heart rate that can increase the risk of stroke, heart failure, and other heart-related complications.

AFib can be, and often is, highly symptomatic.

AFib is a common arrhythmia with an irregular and often rapid heart rate that can increase the risk of stroke, embolism, heart failure, and other cardiac morbidities.

AFib is often highly symptomatic, particularly when episodes have rapid heart rates.

Symptoms include heart palpitations, shortness of breath, fatigue, and weakness, and underlying cardiac disorders can be worsened.

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Although the heart arrhythmia in AFib itself usually is not life-threatening, it is a serious medical condition that sometimes requires emergency treatment.

Additionally, AFib is associated with elevated risk of embolism and stroke and anticoagulant medications, also called blood thinners, are commonly prescribed to manage this risk.

Because AFib is associated with elevated risk of embolism and stroke, anticoagulant medications, also called blood thinners, are commonly prescribed to manage this risk.

Uncertainty around symptom timing and episode length may impact a patient’s quality of life.

During AFib, the heart’s two upper chambers, the atria, beat chaotically and irregularly—out of coordination with the two lower chambers, the ventricles, of the heart, as shown in the figure below.

Classification of AFib is used to determine the appropriate treatment modality for patients.

The American Heart Association, or AHA, and the American College of Cardiology, or ACC, categorize AFib patients based on disease progression.

These categories are defined as follows:

paroxysmal, which involves AFib episodes that resolve spontaneously within seven days of symptom onset;

persistent, which involves AFib episodes that fail to terminate within seven days of symptom onset and require treatment to convert back to sinus rhythm;

long-standing persistent, which involves atrial fibrillation episodes that last longer than one year despite continued attempts to restore sinus rhythm;

Categorization of AFib is customarily defined as:

paroxysmal, which involves episodes of AFib that resolve spontaneously within seven days of symptom onset;

persistent, which involves episodes that fail to terminate within seven days of symptom onset and require treatment to convert back to sinus rhythm;

long-standing persistent, which involves episodes of atrial fibrillation that last longer than one year despite continued attempts to restore sinus rhythm;

and permanent, which involves a joint decision by the treating provider and patient to no longer pursue cardioversion and leave the patient in AFib, focusing on rate control and symptom management.

Disease progression in AFib is common with approximately 40% of AFib patients in the paroxysmal stage, 30% of AFib patients in the persistent and long-standing persistent stage, and 30% of AFib patients in the permanent stage.

For purposes of simplicity, we do not differentiate the long-standing persistent classification from the persistent classification as the clinical impact of this differentiation has not been characterized.

Prevalence of categories includes approximately 40% of patients with AFib as paroxysmal stage, 30% as persistent and long-standing persistent stage, and 30% as permanent.

Concomitant structural heart irregularities including valvular dysfunction and the presence of active symptoms may also help to characterize patients and influence treatment decisions.

A common complication of atrial fibrillation is a rapid ventricular rate which can be defined as a heart rate of ≥110 beats per minute.

Rapid, irregular, and inefficient cardiac pumping function induced by a rapid ventricular rate accounts for hemodynamic instability and many of the arrhythmia’s symptoms.

Frequently, new-onset patients with atrial fibrillation present with symptoms related to rapid ventricular rate.

Current Treatment Options for Atrial Fibrillation with Rapid Ventricular Rate

There are currently two major approaches to managing atrial fibrillation:

rate control to lower a rapid heart rate, and rhythm control to restore and maintain a regular (sinus) rhythm and to prevent recurrent atrial fibrillation.

Either of these management approaches, often performed by pharmacological means, may be given chronically or acutely, depending on patient preference and episode frequency and severity.

The decision to pursue rate and/or rhythm control for atrial fibrillation episodes is dependent on a variety of factors, including episode severity, episode frequency, patient preference, and safety and tolerability of treatments.

Several rhythm control strategies exist, including electrical cardioversion, catheter-based cardiac ablation, and anti-arrhythmic drug therapy.

For rate control, the rapid heart rate of atrial fibrillation is typically treated with AV nodal blocking drugs (for example, calcium channel blockers, beta blockers, or less commonly

digoxin) to control symptoms and improve cardiac function/hemodynamic stability.

A common complication of AFib is an RVR which can be defined as a heart rate of ≥110 beats per minute.

Irregular and inefficient cardiac pumping function caused by a RVR accounts for hemodynamic instability and many of the arrhythmia’s symptoms.

There are currently two major approaches to managing AFib:

rate control to lower a RVR or upward excursions in rate, and rhythm control to both restore and maintain normal sinus rhythm and to prevent recurrent AFib.

Either of these treatment approaches, often performed by pharmacological means, may be given chronically or acutely, depending on patient preference and episode frequency and severity, though each has limitations.

The decision to pursue rate or rhythm control for episodes of AFib is dependent on factors including episode severity, episode frequency, patient preference, and safety and tolerability of treatments.

Several rhythm control strategies exist, including electrical cardioversion, catheter-based cardiac ablation, and antiarrhythmic drug therapy.

For rate control, the rapid heart rate of AFib is can be treated with chronically administered AV nodal acting drugs (e.g., calcium channel blockers, beta blockers, digoxin) to control RVR and symptoms from RVR, and to improve cardiac function/hemodynamic stability.

Oral rate control drugs used acutely do not provide immediate ventricular rate control due to a 30-to-120-minute delayed onset of action.

Breakthrough episodes of symptomatic atrial fibrillation often require urgent medical treatment with IV calcium channel blockers and beta-blockers under medical supervision, usually in the emergency department to quickly reduce heart rate before transitioning a patient back to oral therapy.

The “pill-in-pocket” anti-arrhythmic strategy is described by the AHA and ACC guidelines as the utilization of an oral dose of flecainide or propafenone as an attempt to restore sinus rhythm shortly after the onset of symptomatic atrial fibrillation.

Neither drug referenced in the guideline is approved by any regulatory agency for the use outlined in the guideline.

Pill-in-pocket rhythm control strategies are considered by physicians for patients who demonstrate favorable outcomes to these medications in the clinic and who are thought to be reliable enough to administer them appropriately.

Initial administration of pill-in-pocket medication is recommended in a monitorable setting due to potential AV node dysfunction or a proarrhythmic response and may be preceded by beta-blocker or calcium channel blocker therapy if the patient is not chronically rate controlled.

Rate controlling agents (for example, calcium channel blockers and beta blockers) may also be administered acutely on an as needed (or PRN) basis.

Though the AHA and ACC guidelines do not explicitly acknowledge this approach, participants in market research conducted by us indicate a significant share of patients are managed this way.

PRN rate control is more prominently used in paroxysmal patients who do not tolerate chronic medications but experience symptomatic, infrequent atrial fibrillation episodes.

Our patient market research from 2018 estimated that approximately 40% of patients use an additional rate control medication to manage acute symptoms of atrial fibrillation.

Additionally, our physician market research commissioned in 2021 suggests that both clinical/interventional cardiologists and electrophysiologists prescribe PRN rate control for some of their paroxysmal and persistent patients.

Market Opportunity – Atrial Fibrillation with Rapid Ventricular Rate

The American Heart Association estimates that in 2016 approximately five million people suffered from AFib in the United States.

This estimate is projected to increase over the next ten years;

the AHA suggests a prevalence of 12 million by 2030, while the Centers for Disease Control (CDC) reports this prevalence as increasing to 12.1 million over the same time period, representing an approximately 6% annual growth rate.

From market research with treating physicians, we estimate that approximately 40% of these patients have paroxysmal AFib, 30% have persistent AFib, and 30% have permanent AFib.

Acute episodes of symptomatic AFib are often treated with the approaches described above.

However, due to the concerning nature of AFib symptoms, patients often present to the emergency department.

In the ED, patients are treated with IV calcium channel blockers or beta-blockers to quickly reduce heart rate and/or anti-arrhythmic or electrical cardioversion before transitioning a patient back to oral therapy.

According to the Healthcare and Utilization Project, 660,000 patient visits to the emergency department in 2016 were attributed to AFib (ICD-10 diagnosis codes I48.0, I48.1, I48.2, I48.91).

Additionally, approximately 465,000 patients were admitted to the hospital with AFib (same ICD-10 codes).

Our qualitative and quantitative market research indicates that the target addressable market for etripamil in patients with AFib-RVR is approximately 30-40% of the diagnosed population of patients with atrial fibrillation.

We derive this percentage estimate from 2021 market research studies conducted by us that involved qualitative interviews and quantitative surveys that included a total of 275 electrophysiologists, general cardiologists, and interventional cardiologists.

The physicians in the two studies were asked to estimate the share of patients experiencing ≥1 symptomatic episode of AFib-RVR requiring treatment per year.

In response, physicians in the quantitative survey reported approximately 40% of paroxysmal patients, 40% of persistent patients, and 30% of permanent patients met this classification.

This research suggests the share of patients experiencing ≥1 symptomatic episode of AFib requiring treatment may constitute 30-40% of the prevalent AFib population on a weighted average basis.

We believe that etripamil has the potential to be developed such that it can be used by patients to rapidly reduce their heart rate at home to provide a supplemental option to the acute oral rate or rhythm control strategy their physician would use.

When presented with a target product profile reflecting this potential use case, approximately two thirds of the physicians in the 2021 market research study perceived utility in the product profile, which could serve as a “bridge” to the onset of acute oral agents.

According to physicians, it can take hours for patients to feel an alleviation of symptoms using acute oral rate and rhythm control.

During this time, patients may experience concerning symptoms that often prompt them to seek emergency care.

We believe that the combination of convenient delivery, potency, rapid onset

and short duration of action of etripamil has the potential to move the current treatment setting for some acute episodes of AFib out of the burdensome and costly emergency department.

Current AFib management consumes significant healthcare resources in the United States.

The American Heart Association published a report in 2016 summarizing the current and projected cost burden of cardiovascular diseases in the United States.

Breakthrough episodes of symptomatic atrial fibrillation often require urgent medical treatment with IV calcium channel blockers and IV beta blockers under medical supervision in an emergency department to quickly reduce heart rate before transitioning a patient back to oral therapy.

Of note, AHA and ACC guidelines do not explicitly acknowledge the as needed (PRN) approach to acutely administering oral rate control agents, however, market research conducted by us indicates a significant share of patients are managed this way.

This market research, from 2018, estimated that approximately 40% of patients use acutely administered rate control medication to manage symptoms of atrial fibrillation.

Additionally, our physician market research, from 2021, suggests that both clinical/interventional cardiologists and electrophysiologists prescribe PRN rate control for some of their patients with AFib.

Clinical Development Plan for Atrial Fibrillation with Rapid Ventricular Rate

The Phase 2, double-blind, placebo-controlled, study, Reduction of Ventricular Rate in Patients with Atrial Fibrillation (ReVeRA), in patients with AFib-RVR, was conducted in Canada and the Netherlands in collaboration with the Montreal Heart Institute, the WCN network, and other research centers.

We began enrollment in ReVeRA in the first quarter of 2021 to evaluate the potential effectiveness of etripamil to reduce ventricular rate in patients with atrial fibrillation and rapid ventricular rate.

The randomized, placebo-controlled Phase 2 ReVeRA trial enrolled 87 patients aged 18 years and older with symptomatic AFib, and dosed 56 patients with blinded study drug.

Patients exhibited a ventricular rate of 110 or more beats per minute (bpm) prior to receiving study drug (etripamil nasal spray or placebo NS).

The trial was designed to assess the reduction in ventricular rate (primary endpoint), the time to achieve maximum reduction in ventricular rate, duration of effect, and patient satisfaction with treatment using TSQM-9 patient reported outcome, or PRO, tool (key secondary endpoints).

Data from ReVeRA trial showed that delivery of etripamil nasal spray significantly and rapidly reduced ventricular rate, with a time course consistent with the drug’s pharmacologic profile.

The Phase 2, double-blind, placebo-controlled, study, Reduction of Ventricular Rate in Patients with Atrial Fibrillation (ReVeRA), was conducted in patients presenting urgently (e.g., to an emergency department) with AFib-RVR.

ReVeRA’s objectives included evaluation of the potential effectiveness of etripamil NS to reduce RVR and to improve symptoms in patients with AFib and evaluation of the drug’s safety.

The trial enrolled 87 patients and dosed 56 patients with blinded study drug (the latter having a ventricular rate of ≥110 bpm) prior to receiving study drug.

Data showed that delivery of etripamil nasal spray significantly and rapidly reduced ventricular rate, with a time course consistent with the drug’s pharmacologic profile.

Etripamil achieved the primary endpoint with high statistical significance with patients experiencing a ventricular rate reduction of 29.91 bpm (95% confidence interval:

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p<0.0001) in the etripamil arm compared to placebo.

The maximum reduction in rate reported by a patient taking etripamil was 34.97 bpm.

The median time to maximum reduction in VR was 13 minutes in patients taking etripamil, and the duration of effect (reduction in VR from baseline) was at least 150 min.

The maximum absolute reduction in rate in the etripamil arm was 34.97 bpm.

The median time to maximum reduction in VR was 13 minutes in patients taking etripamil, and the duration of effect (reduction in VR from baseline and from placebo) was at least 150 min.

The median duration of maintaining a VR <100 bpm was 45.5 min in the first 60 min following drug in the etripamil arm.

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calculations adjust for variance in baseline

Bpm = beats per minute, CI = confidence interval, NS = nasal spray, VR = ventricular rate

Bpm = beats per minute, ECG = electrocardiogram, CI = confidence interval, NS = nasal spray, VR = ventricular rate

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A greater number of patients taking etripamil achieved a ventricular rate of less than 100 bpm (58.3%) than those taking placebo (4%).

Furthermore, 67% of patients taking etripamil achieved ventricular rate reductions of more than 20% and 96% of patients receiving etripamil achieved more than 10% in ventricular rate reductions in the first 60 minutes compared to 0% and 20% in patients taking placebo, respectively.

Etripamil treatment was associated with significant improvement in symptom relief and in treatment satisfaction as measured by the TSQM-9 patient-reported outcome instrument.

Using the TSQM-9, compared to placebo, patients treated with etripamil demonstrated significant improvements in satisfaction ratings in the effectiveness domain (p<0.0001).

As well, patient reported outcomes on the Relief of Symptoms Question from the Effectiveness Domain showed statistically significant greater scores (greater satisfaction) with a p = 0.0002 for patients treated with etripamil compared to those treated with placebo, and with a treatment effect (delta) of 1.55 units.

In ReVeRA, safety and tolerability reported in the 56-patient safety population who received etripamil was generally consistent with that observed in our PSVT program.

Etripamil treatment was associated with significant improvement in symptom relief and in treatment satisfaction as measured by the TSQM-9 PRO instrument.

Patients treated with etripamil, compared to those treated with placebo, demonstrated significant improvements in satisfaction ratings in the TSQM-9 Effectiveness Domain (p<0.0001) and on

the Relief of Symptoms Question from the Effectiveness Domain (p = 0.0002, with a treatment effect of 1.55 units).

Moreover, patients in the placebo arm were given additional AFib-RVR treatments during the window of 60 minutes to 24 hours after study drug to an approximately two-fold greater degree than patients in the etripamil arm.

In ReVeRA, safety and tolerability data were generally consistent with that observed in our PSVT program.

Treatment-emergent serious adverse events, or “TESAEs,” were rare, with two occurring in one patient in the etripamil arm (3.7%) and four occurring in two patients in the placebo arm (6.9%).

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The most common (≥ 5%) adverse events were mild or moderate in intensity and included nasal discomfort, rhinorrhea, increased lacrimation, throat irritation and dizziness.

In mid-2023, we held a pre-IND meeting with FDA and received guidance indicating a potential development path for etripamil in AFib-RVR.

The FDA agreed that to gain a labelled indication via supplemental NDA, or sNDA, a Phase 3, randomized, placebo controlled, double blind clinical trial using a dosing regimen with self-administration of etripamil in an at-home setting could be acceptable with the support of the already existing safety database from our PSVT trials.

The primary endpoint can be the reduction of ventricular rate, and the primary analysis would be on the intent to treat, or ITT, population.

In addition, the study would have to show statistical significance (p<0.05) on the key secondary endpoint of symptom relief as a patient benefit, also in the ITT population.

The secondary endpoint could use a PRO measure and the application of a 7-point anchored scale was discussed with the FDA.

In the first quarter of 2024, we met with the FDA in a Type A meeting.

In this meeting we confirmed prior FDA guidance on a single-study sNDA pathway.

We anticipate progressing to an End of Phase 2 meeting in mid-2024 as an important step to finalize the registrational study protocol.

These positive Phase 2 data have supported interactions with the FDA (as summarized in “AFib-RVR Clinical Development Highlights”) that have established a path to potential approval for an indication for etripamil in patients with AFib-RVR.

As also summarized above, the protocol of a Phase 3, potentially registrational study has been finalized and study start-up has commenced.

The Phase 3 study is expected to use an optional repeat-dose, self-administration approach of etripamil nasal spray, outside of the medically supervised setting, that is similar to that used in the PSVT development program.

Etripamil in Other Therapeutic Applications

Our goal in expanding our pipeline around etripamil is to apply the same paradigm-changing aspiration that we have for supraventricular tachycardias, like PSVT and AFib-RVR, to other cardiac and potentially non-cardiac conditions where we believe that a rapid-onset dihydropyridine L-type calcium channel blocker could potentially deliver significant clinical and quality of life benefits for patients.

We believe that the insights that led to the development of etripamil for the treatment of PSVT are relevant in other indications where AV-nodal blocking agents with blood vessel widening activity have

demonstrated clinical utility.

We believe that the insights that led to the development of etripamil for the treatment of PSVT are relevant in other indications where AV-nodal blocking agents with blood vessel widening activity

have demonstrated clinical utility.

Both calcium channel blockers and beta blockers are commonly used to manage supraventricular tachycardias like PSVT or AFib-RVR, and other conditions.

Sales and Marketing

Given our stage of development, we have commercialization plans but have not yet established a commercial organization or distribution capabilities.

If etripamil receives marketing approval, we plan to commercialize it in the United States leveraging industry trends regarding staged deployment of resources, digital/omnichannel investments, and a focused, specialty sales force that could consist of our own employees, outsourced sales professionals, or a hybrid model using both internal and external resources.

We believe that this commercial organization at the launch of etripamil will consist of a field force of <100 individuals calling on primarily clinical cardiologists who treat large populations of patients with PSVT, supported by strategic investments in digital and targeted non-personal promotion.

As we establish reimbursement for etripamil with commercial and Medicare payors, we anticipate that this investment in omnichannel promotion will grow, targeting both prescribers and patients.

Aligned to this expansion, our field force could grow to 150 to 200 field sales representatives calling on top-prescribing clinical cardiologists, interventional cardiologists, electrophysiologists, and high-volume primary care physicians who have a history of prescribing cardiovascular therapies.

We believe an organization of this size would allow us to reach prescribers that collectively care for a substantial portion of patients diagnosed with PSVT in the United States.

Given the importance of increasing awareness and educating patients with PSVT, we also anticipate deploying focused direct-to-patient marketing campaigns for etripamil.

We anticipate that our sales force could also support the commercialization of additional product candidates treating cardiovascular diseases.

We would expect to conduct the initial buildout of our commercial organization following NDA submission for etripamil.

At this time, we may pursue and believe that we can maximize the value of etripamil by retaining commercialization rights in the United States and entering into collaboration agreements for certain territories outside the United States, including the European Union.

If CARDAMYST receives marketing approval, we plan to commercialize it in the United States leveraging industry trends regarding staged deployment of resources, digital/omnichannel investments, and a focused, specialty sales force.

Specifically, we plan for the launch of CARDAMYST to be led by a field force calling on between 10,000 and 15,000 primarily clinical cardiologists who treat large populations of patients with PSVT, supported by strategic investments in medical affairs and digital/targeted non-personal promotion.

Although we will initially focus on obtaining broad commercial insurance coverage from large Pharmacy Benefit Managers, or “PBMs,” and targeted national and regional commercial payors, as we expand reimbursement for CARDAMYST to include government payors and targeted integrated delivery networks we anticipate that this investment in omnichannel promotion will grow, targeting both prescribers and patients.

Aligned to this expansion, our field force could grow to call on up to 30,000 clinical cardiologists, interventional cardiologists, electrophysiologists, and high-volume primary care physicians who have a history of prescribing cardiovascular therapies.

We believe an organization of this size would allow us to reach prescribers that collectively care for most patients diagnosed with PSVT in the United States.

Given the importance of increasing awareness and educating patients with PSVT, as we establish favorable broad payor reimbursement, we also anticipate deploying focused direct-to-patient marketing campaigns for CARDAMYST.

We anticipate that our sales force could also support the commercialization of additional product candidates treating cardiovascular diseases through partnerships and/or co-promotion deals.

In addition, we may pursue and believe that we can maximize the value of etripamil by entering into collaboration agreements for certain territories outside the United States, including the European Union, while retaining commercialization rights in the United States.

Manufacturing

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We have assembled a team of experienced employees and consultants to provide the necessary technical, quality and regulatory oversight over our CMOs and have implemented a comprehensive plan for audits of our CMOs.

Currently, we have development contracts and quality agreements with our CMOs for the manufacturing of etripamil drug substance and drug product.

We currently have enough manufactured supply of etripamil to complete our ongoing registration trials.

Currently, we have contracts and quality agreements with our CMOs for the manufacturing of etripamil drug substance and drug product.

We believe we currently have enough manufactured supply of etripamil to support our potential commercial launch.

We also may elect to pursue additional CMOs for manufacturing supplies of regulatory starting materials in the future and for the filling of the nasal spray device, labeling, packaging, storage and distribution of investigational drug products.

We plan to continue to rely on third party manufacturers for any future trials and commercialization of etripamil, if approved.

We anticipate that these CMOs will have capacity to support commercial scale production, but we do not have any formal agreements at this time with these CMOs to cover commercial production.

If etripamil is approved by any regulatory agency, we intend to enter into agreements with a third-party contract manufacturer and one or more backup manufacturers for the commercial production of etripamil.

We anticipate that these CMOs will have capacity to support commercial scale production.

Drug development is highly competitive and subject to rapid and significant technological advancements.

Our ability to compete will significantly depend upon our ability to complete necessary clinical trials and regulatory approval processes, and effectively market any drug that we may successfully develop.

Our ability to compete will significantly depend upon our ability to complete necessary clinical trials, regulatory approval processes, and effectively market any drug that we may successfully develop.

Our current and potential future competitors include pharmaceutical and biotechnology companies, academic institutions and government agencies.

The primary competitive factors that will affect the commercial success of etripamil or any other product candidate for which we may receive marketing approval, include differentiation of any competitor’s product regarding efficacy, safety, tolerability, dosing convenience, price, coverage and reimbursement.

A number of our potential competitors have substantially greater financial, technical and human resources than we do and significantly greater experience in the discovery and development of product candidates, as well as in obtaining regulatory approvals and commercializing those product candidates in the

United States and in foreign countries.

It is also possible that a competitor may develop a cure or more effective treatment method for the diseases we are targeting, which could render our current or future product candidates non-competitive or obsolete, or reduce the demand for our product candidates before we can recover our development and commercialization expenses.

obsolete, or reduce the demand for our product candidates before we can recover our development and commercialization expenses.

We are not aware of any approved drug or any drug candidate in clinical development for a patient with PSVT to self-administer treatment to terminate SVT episodes.

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However, these interventions are not acutely effective and are not approved by the FDA or other regulatory agencies for this use.

For atrial fibrillation, there are a number of marketed generic antiarrhythmic drugs that are used for chronic and/or acute rate control, such as metoprolol, propranolol, esmolol, pindolol, atenolol, nadolol, verapamil and diltiazem.

For AFib, there are a number of marketed generic antiarrhythmic drugs that are used for chronic and/or acute rate control, such as metoprolol, propranolol, esmolol, pindolol, atenolol, nadolol, verapamil and diltiazem.

For acute rate control, the intravenous forms of these drugs are the ones most often used.

We are aware of several drugs or new formulations of existing drugs under development or recently under development for atrial fibrillation, including InRhythm (flecainide), a sodium channel blocker in Phase 3 from InCarda Therapeutics, Inc., and an IV and potentially oral small-molecule SK channel inhibitor being developed by Acesion Pharma for acute conversion and chronic maintenance of sinus rhythm, respectively, in patients with AFib.

Acesion’s lead asset, AAP30663, is the IV-formulated short acting AFib conversion therapy for hospital use that has successfully completed a Phase 2 trial.

Rapiblyk (landiolol) is an intravenous beta blocker approved for the short-term reduction of ventricular rate with supraventricular tachycardia including atrial fibrillation and atrial flutter.

Intellectual Property

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patent, projected to expire in 2036, a pending U.S.

patent application, which, if granted, is projected to expire in 2036, as well as corresponding patents in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, Japan, Mexico, Russia, South Africa, and Ukraine and corresponding patent applications in China, Europe, Hong Kong, India, New Zealand, South Africa, and South Korea, directed to formulations including etripamil, methods of making such formulations, and uses of such formulations to treat cardiac arrhythmias, such as PSVT and atrial fibrillation.

patent application, which, if granted, is projected to expire in 2036, as well as corresponding patents in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, Japan, Macau, Mexico, Russia, South Africa, South Korea and Ukraine and corresponding patent applications in China, Europe, Hong Kong, India and New Zealand, directed to formulations including etripamil, methods of making such formulations, and uses of such formulations to treat cardiac arrhythmias, such as PSVT and atrial fibrillation.

• a patent family containing pending applications in the United States, Canada, and Europe, which, if granted, is projected to expire in 2041, directed to uses of formulations including etripamil to treat cardiac arrhythmias, such as PSVT and atrial fibrillation, or migraines.

The terms of individual patents may vary based on the countries in which they are obtained.

Generally, patents issued for applications filed in the United States are effective for 20 years from the earliest effective non-provisional filing date in the absence, for example, of a terminal disclaimer shortening the term of the patent or patent term adjustment increasing the term of the patent.

In addition, in certain instances, a patent term can be extended to recapture a portion of the term

effectively lost as a result of FDA regulatory review periods.

the term of the patent.

In addition, in certain instances, a patent term can be extended to recapture a portion of the term effectively lost as a result of FDA regulatory review periods.

The restoration period cannot be longer than five years and the total term, including the restoration period, must not exceed 14 years following FDA approval.

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In most cases, the submission of an NDA is subject to a substantial application user fee.

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

Under the PDUFA guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

This review typically takes twelve months from the date the NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision.

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Additionally, before approving an NDA, the FDA will typically inspect one or more clinical trial sites to assure compliance with GCP requirements.

The testing and approval process for an NDA requires substantial time, effort and financial resources, and takes several years to complete.

Data obtained from preclinical and clinical testing are not always conclusive and may be susceptible to varying interpretations, which could delay, limit or prevent regulatory approval.

The FDA may not grant approval of an NDA on a timely basis, or at all.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter, or, in some cases, a complete response letter.

A complete response letter generally contains a statement of specific conditions that must be met in order to secure final approval of the NDA and may require additional clinical or preclinical testing in order for FDA to reconsider the application.

A complete response letter generally contains a statement of specific conditions

that must be met in order to secure final approval of the NDA and may require additional clinical or preclinical testing in order for FDA to reconsider the application.

Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

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There also are continuing annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as application fees for supplemental applications with clinical data.

Even if the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings or precautions be included in the product labeling, including a boxed warning, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.

The FDA may prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs.

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The FDA and other agencies actively enforce the laws and regulations prohibiting their promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant civil, criminal and administrative liability.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act, or PDMA, which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states.

Both the PDMA and state laws limit the distribution of prescription pharmaceutical product samples and impose requirements to ensure accountability in distribution.

In addition, the distribution of prescription pharmaceutical products is subject to the Drug Supply Chain Act, which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states.

Federal and State Fraud and Abuse, Data Privacy and Security, and Transparency Laws and Regulations

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Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of products for unapproved, and thus non-reimbursable, uses.

The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

The federal Health Insurance Portability and Accountability Act of 1996, or “HIPAA,” created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit

program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.

Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.

In addition, we may be subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

In addition, we are subject to data privacy and security regulation by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, or “HITECH,” and their respective implementing regulations, impose specified requirements on certain types of individuals and entities relating to the privacy, security and transmission of individually identifiable health information.

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HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce HIPAA and seek attorney’s fees and costs associated with pursuing federal civil actions.

In addition, state laws govern the privacy and security of health information in certain circumstances, many of which are not pre-empted by HIPAA, differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

In addition, state laws govern the privacy and security of health information in certain circumstances, many of which are not preempted by HIPAA, differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services, or “CMS,” information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, and applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians and their immediate family members.

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Because of the breadth of these laws and the narrowness of available statutory exceptions and regulatory safe harbors, it is possible that some of our business activities could be subject to challenge under one or more of such laws.

If our operations are found to be in violation of any of the federal and state laws described above or any other governmental

regulations that apply to us, we may be subject to significant criminal, civil and administrative penalties including damages, fines, imprisonment, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, reputational harm, diminished profits and future earnings, disgorgement, exclusion from participation in government healthcare programs and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

If our operations are found to be in violation of any of the federal and state laws described above or any other governmental regulations that apply to us, we may be subject to significant criminal, civil and administrative penalties including damages, fines, imprisonment, additional reporting requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, reputational harm, diminished profits and future earnings, disgorgement, exclusion from participation in government healthcare programs and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti-fraud and abuse laws, implementation of corporate compliance programs, reporting of payments or transfers of value to healthcare professionals, and additional data privacy and security requirements.

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The future commercial success of our, or any of our collaborators’, product candidates, if approved, will depend in part on the extent to which third-party payors, such as governmental payor programs at the federal and state levels, including Medicare and Medicaid, private health insurers and other third-party payors, provide coverage of and establish adequate reimbursement levels for our product candidates.

Third-party payors generally decide which products they will pay for and establish reimbursement levels for those products.

Third-party payors generally decide which products they will pay for

and establish reimbursement levels for those products.

In particular, in the United States, no uniform policy for coverage and reimbursement exists.

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Among other measures that may have an impact on our business, the PPACA establishes an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;

a new Medicare Part D coverage gap discount program;

a new Medicare

Part D coverage gap discount program;

and a new formula that increases the rebates a manufacturer must pay under the Medicaid Drug Rebate Program.

Additionally, the PPACA extends manufacturers’ Medicaid rebate liability, expands eligibility criteria for Medicaid programs, and expands entities eligible for discounts under the Public Health Service Act.

There have been executive, judicial and Congressional challenges to certain aspects of the PPACA.

While Congress has not passed comprehensive repeal legislation, several bills affecting the implementation of certain taxes under the PPACA have been signed into law.

The Tax Cuts and Jobs Act of 2017, or Tax Act, included a provision that repealed, effective January 1, 2019, the tax-based shared responsibility payment imposed by the PPACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” In addition, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the PPACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminated the health insurer tax.

The Bipartisan Budget Act of 2018, or the BBA, among other things, amended the PPACA, effective January 1, 2019, to increase from 50% to 70% the point-of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug plans, commonly referred to as the “donut hole.” On June 17, 2021, the U.S.

Supreme Court dismissed a challenge on procedural grounds that argued the PPACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress.

Moreover, prior to the U.S.

Supreme Court ruling, on January 28, 2021, President Biden issued an executive order that initiated a special enrollment period for purposes of obtaining health insurance coverage through the PPACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the PPACA.

Further, on August 16, 2022, President Biden signed the Inflation Reduction Act of 2022, or IRA, into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in PPACA marketplaces through plan year 2025.

There have been amendments to, and executive, judicial and Congressional challenges to certain aspects of the PPACA.

For example, on August 16, 2022, the Inflation Reduction Act of 2022, or “IRA”, was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in PPACA marketplaces through plan year 2025.

The IRA also eliminates the "donut hole" under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and through a newly established manufacturer discount program.

It is possible that the PPACA will be subject to judicial or Congressional challenges in the future.

It is unclear how additional healthcare reform measures of the Biden administration will impact the PPACA.

It is unclear how additional healthcare reform measures of the second Trump administration will impact the PPACA.

In addition, other legislative changes have been proposed and adopted since the PPACA was enacted.

In August 2011, the President signed into law the Budget Control Act of 2011, as amended, which, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which began in 2013 and, following passage of subsequent legislation, will continue until 2032 unless additional Congressional action is taken.

Additionally, on March 11, 2021, President Biden signed the American Rescue Plan Act of 2021 into law, which eliminates the statutory Medicaid

drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

In January 2013, the American Taxpayer Relief Act of 2012 was enacted and, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Additionally, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminated the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024

Further, there has been increasing legislative and enforcement interest in the United States with respect to drug pricing practices.

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Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

For example, in July 2021, the Biden administration released an executive order, “Promoting Competition in the American Economy,” with multiple provisions aimed at prescription drugs.

In response to Biden’s executive order, on September 9, 2021, the Department of Health and Human Services, or HHS, released a Comprehensive Plan for Addressing High Drug Prices that outlines principles for drug pricing reform and sets out a variety of potential legislative policies that Congress could pursue as well as potential administrative actions HHS can take to advance these principles.

In addition, the IRA, among other things (i) directs HHS to negotiate the price of certain single-source drugs and biologics covered under Medicare and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions take effect progressively starting in fiscal year 2023.

On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges.

It is currently unclear how the IRA will be implemented but is likely to have a significant impact on the pharmaceutical industry.

In response to the Biden administration’s October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act.

For example, the IRA, among other things (i) directs the U.S.

Department of Health and Human Services, or “HHS” to negotiate the price of certain high expenditure, single-source drugs that have been on the market for at least 7 years covered under Medicare, or the “Medicare Drug Price Negotiation Program,” and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions began to take effect progressively in fiscal year 2023.

On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations, although the Medicare Drug Price Negotiation program is currently subject to legal challenges.

On January 17, 2025, HHS selected fifteen additional products covered under Part D for price negotiation in 2025.

Each year thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

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Any such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs.

Additional health reform measures may continue and affect our business in unknown ways, particularly given the recent changes in administration.

The current Trump administration is pursuing policies to reduce regulations and expenditures across government including at HHS, the FDA, CMS and related agencies.

These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business.

These actions may include, for example, directives to reduce agency workforce, rescinding a Biden administration executive order tasking the Center for Medicare and Medicaid Innovation to consider new payment and healthcare models to limit drug spending and eliminating the Biden administration’s executive order that directed HHS to establishing an AI task force and developing a strategic plan.

Additionally, in its June 2024 decision in Loper

Bright Enterprises v.

Raimondo, or “Loper Bright”, the U.S.

Supreme Court overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes.

The Loper Bright decision could result in additional legal challenges to current regulations and guidance issued by federal agencies applicable to our operations, including those issued by the FDA.

Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program created under the IRA.

Foreign Regulation

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Patients inspire all we do.

Milestone employees are passionate about creating a solution for patients who suffer from PSVT and other related illness as we work together on our mission to develop innovative cardiovascular medicines.

Our employees are passionate about creating a solution for patients who suffer from PSVT and other related illnesses as we work together on our mission to develop innovative cardiovascular medicines.

We have built a culture of high performance based on our core values:

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Our patients inspire us.

Milestone employees support, challenge and care for each other.

Our employees support, challenge and care for each other.

Employees engage with one another through their teams, but also through our weekly gatherings, outings and friendly competitions and challenges.

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• Entrepreneurial Mindset:

Milestone places a high value on grit, courage and resolve.

Milestone’s organizational energy has the sense of a startup.

We place a high value on grit, courage and resolve.

Our organizational energy has the sense of a startup.

Employees are encouraged to think like an owner.

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As of December 31, 2024, we had 33 full-time employees, 12 of whom were primarily engaged in research and development activities.

Five of these employees have an M.D.

Four of these employees have an M.D.

None of our employees is represented by a labor union and we consider our employee relations to be excellent.

In the first quarter of 2024, we underwent a reduction in force resulting in 27 full-time employees remaining with the Company.

Our headquarters is currently located in Montréal (Québec), Canada and consists of 7,700 square feet of leased office space under a lease that expires in November 2025.

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From time to time, we may become involved in legal proceedings arising in the ordinary course of our business.

We are not currently a party to any material legal proceedings, and we are not aware of any pending or threatened legal proceeding against us that we believe could have an adverse effect on our business, operating results or financial condition.

We are not currently a party to any material legal proceedings, and we are not aware of any pending or threatened legal proceedings against us that we believe could have an adverse effect on our business, operating results or financial condition.

Corporate Information

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We maintain an internet website at www.milestonepharma.com and make available free of charge through our website our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act of 1934, or the “Exchange Act”.

We make these reports available through our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the Securities and Exchange Commission (“SEC”).

You can review our electronically filed reports and other information that we file with the SEC on the SEC’s website at http://www.sec.gov.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business