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Item 1. Business

2022-03-24 compared with 2021-03-29 · 304 added, 285 removed, 519 unchanged (53% of the section changed)

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

We are developing etripamil to treat paroxysmal supraventricular tachycardia, or PSVT, atrial fibrillation (AF) and rapid ventricular rate, or AFib-RVR, and other cardiovascular indications.

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

PSVT is a rapid heart rate condition characterized by episodes of supraventricular tachycardia, or SVT, that start and stop without warning.

Episodes of SVT are often experienced by patients with symptoms including palpitations, sweating, chest pressure or pain, shortness of breath, sudden onset of fatigue, lightheadedness or dizziness, fainting and anxiety.

Episodes of SVT are often experienced by patients with symptoms including palpitations, sweating, chest pressure or pain, shortness of brea

th, sudden onset of fatigue, lightheadedness or dizziness, fainting and anxiety.

Calcium channel blockers have long been approved for the treatment of PSVT as well as other cardiac conditions.

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

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 always with a random, irregular rhythm.

Pharmacologic treatment of PSVT focuses on terminating the arrhythmia using an agent to slow 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.

Either of these pharmacological management approaches may be administered chronically or acutely, depending on patient preference and episode frequency and/or severity.

Several rhythm control strategies exist, including electrical cardioversion, catheter 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.

Similar to PSVT, we believe that etripamil could be the first patient self-administered therapy to provide rapid rate control of episodes of AFib-RVR wherever and whenever they occur.

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.

Finally, our research with patients shows that the average patient takes two or more years to obtain a diagnosis of PSVT once they start to experience symptoms, which suggests that many more patients with PSVT are currently undiagnosed.

For our planned second indication, AFib-RVR, the American Heart Association (AHA) 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 seven million by 2030, while the Centers for Disease Control (CDC) reports this prevalence as increasing to 12 million over the same time period.

Our quantitative market research indicates that the target addressable market for etripamil in patients with atrial fibrillation and rapid ventricular rate is approximately 30% to 40% of the five to six million patients diagnosed with atrial fibrillation.

Our late-stage etripamil clinical program for the treatment of PSVT is currently executing on two ongoing Phase 3 trials, RAPID and NODE-303.

The RAPID study is our ongoing pivotal Phase 3 safety and efficacy trial.

This study enrolled its first patient in November 2020 and topline data is expected in mid-second half 2022.

NODE-303 is an open-label global safety trial enrolling patients 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 to form the basis for marketing approval.

We have also completed our first Phase 3 safety and efficacy trial of etripamil, NODE-301, and its open-label safety extension trial, NODE-302.

In addition to our PSVT clinical program, we began enrollment of patients in a Phase 2 proof-of-concept clinical trial titled ReVeRA in the first quarter of 2021 to evaluate the potential effectiveness of etripamil to reduce ventricular rate during AFib-RVR episodes.

The following table sets forth the status and initial focus of etripamil.

In March 2020, we reported topline results of the first part of the NODE-301 pivotal trial of etripamil for the treatment of PSVT, which is a placebo-controlled Phase 3 safety and efficacy trial.

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31,101) for placebo (p=0.12).

Despite early activity, including the conversion of 61% of etripamil patients compared to 45% of placebo patients within 45 minutes after study drug administration (p=0.02), a time period consistent with etripamil’s pharmacological activity, results from the latter part of the analysis confounded the statistical analysis of the primary endpoint.

The study demonstrated statistically significant differences in favor of etripamil treated patient compared to those taking placebo in the secondary endpoint of patient reported treatment satisfaction, as measured by a treatment satisfaction questionnaire for medication (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).

The most common AEs observed in patients receiving etripamil were nasal irritation (19.6%) and congestion (6.7%), and these events were typically transient in nature and most commonly characterized by patients as mild in severity.

There were no significant differences in incidences of severe adverse events or adverse events of interest, such as atrioventricular nodal blocks or blood pressure-related symptoms, across the etripamil and placebo groups.

We believe the safety and tolerability data from the first part of the NODE-301 trial is supportive of at-home use of etripamil, with adverse events, or AEs, largely consistent with those observed in prior trials.

We are continuing the second part of the NODE-301 trial, NODE-301B, which we have renamed the RAPID trial.

The RAPID trial continues to follow patients already randomized in the NODE-301 trial who did not administer a dose of the study drug before the end of the first part of the trial.

We are also expanding the RAPID trial to add more clinical study sites and more patients.

We plan to analyze the final data from the RAPID trial separately as a second efficacy data set.

In July 2020, we announced that we received guidance from the U.S.

Food and Drug Administration, or FDA, on our proposal to alter the size and design of the RAPID trial as well as the overall program based on the data from the NODE-301 trial.

Despite early activity, including the conversion of 61% of etripamil patients compared to 45% of placebo patients within 45 minutes after study drug administration (p=0.02), a time period consistent with the pharmacological activity of etripamil, results from the latter part of the analysis confounded the statistical analysis of the primary endpoint.

In July 2020, we announced that we received agreement from the U.S.

FDA, on our proposal to alter the size, design and analysis plan of a then ongoing study, NODE-301 part 2, as well as the overall program based on the data from the NODE-

We renamed the NODE-301 part 2 trial to the RAPID trial and increased the number of patients and clinical study sites.

The FDA indicated that two studies, the RAPID study and the completed NODE-301 study, could potentially fulfill the efficacy requirement for our planned NDA for etripamil in patients with PSVT.

Under an updated statistical analysis plan, or SAP, the primary efficacy endpoint for both the RAPID and NODE-301 studies will be defined as time to conversion over the first 30 minutes, with a target p-value of less than 0.05 for each study.

This endpoint supports the desire of patients to rapidly address their PSVT symptoms during an episode and ideally avoid visiting the emergency department.

Later and earlier time points will also be assessed as part of secondary analyses to fully characterize the efficacy profile of etripamil.

We believe this endpoint supports the desire of patients to rapidly address their PSVT symptoms during an episode and ideally avoid visiting the emergency department.

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

When employing the updated SAP retrospectively to the NODE-301 data, 54% of etripamil patients vs.

35% of placebo patients converted within 30 minutes (HR 1.87, p=0.02).

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

Assuming a positive outcome in the RAPID study, these data could potentially serve to fulfill the efficacy requirement for the NDA.

The RAPID trial was originally an ongoing trial named NODE-301B and was designed to collect double-blind data from randomized patients who had not yet experienced an SVT event after the NODE-301 study reached its target number of adjudicated SVT events.

After receiving guidance from the FDA on our Phase 3 program, we have amended and expanded NODE-301B and renamed it the RAPID trial.

The RAPID trial will include the 170 patients who are already enrolled in NODE-301B and is expected to enroll approximately 500 patients in total.

The trial will be completed after a total of 180 confirmed SVT events are reached.

Additional patients enrolled in the RAPID study will be randomized 1:1.

During the fourth quarter of 2020, we observed delays in our enrollment and clinical trial site startups for the RAPID study.

We believe the effects of the COVID-19 pandemic and its impact contributed to such delays.

As a result we have taken measures to increase the enrollment of patients by increasing the number of clinical trial sites, including more clinical sites planned in European countries to diversify and better protect the study recruitment against COVID’s geographical resurgences.

We are also increasing site specific support for clinical trial sites currently open.

We will continue to monitor the impact of COVID-19 on the study and expect to continue these enrollment enhancing initiatives throughout 2021.

While we monitor the effect of those initiatives, we are maintaining our guidance of achieving topline data from the RAPID trial in late 2021 or early 2022.

Based on discussions with the FDA regarding maximizing the treatment effect of etripamil, the RAPID study will allow for a repeat administration of study drug (either 70 mg of etripamil or placebo) for patients who have not experienced symptom relief within 10 minutes of the first study drug administration.

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

It is enabled by

the favorable safety data from the NODE-301 study.

We expect that the repeat administration could benefit a broader group of patients, including those with more persistent episodes.

Applying the same primary endpoint to the RAPID study, powering the study at 90% and using alpha of 0.05 to detect a 19% difference of etripamil versus placebo in 30 minute time to conversion that was observed in the NODE-301 study results in the size of 180 confirmed PSVT events.

The RAPID study is designed very similarly to NODE-301, but will introduce a new treatment regimen to the program.

Based on discussions with the FDA regarding maximizing the treatment effect of etripamil, the RAPID trial allows for repeat administration of study drug (either 70 mg of etripamil or placebo) for patients who have not experienced symptom relief within ten minutes of the first study drug administration.

This repeat dose regimen, which is similar to current PSVT treatment practices in the emergency department setting, is tailored to the pharmacokinetic profile of etripamil to deliver increased exposure over approximately the first 30 minutes following initial administration.

We believe that the repeat administration could benefit a broader group of patients, including those with more persistent episodes.

In the NODE-301 study, 32% of etripamil patients and 14% of placebo patients converted to sinus rhythm within 10 minutes.

The FDA agreed that the single and repeat administrations of etripamil could be pooled and compared to placebo for the primary analysis, resulting in no increase in the sample size.

We are in the process of initiating patient access programs that have as their primary objective providing further access to etripamil for future SVT episodes to patients who have participated in the clinical development registration trials.

These programs will be tailored to meet the regulatory requirements in the territories in which the clinical sites are located.

As with PSVT, calcium channel blockers are also approved for use in intravenous form for the treatment of some episodes of atrial fibrillation, or AF, in which patients experience rapid ventricular rates.

Our initial qualitative market research indicates that the target addressable market for etripamil in patients with atrial fibrillation and rapid ventricular rate is approximately 40% of the five to six million patients diagnosed with atrial fibrillation.

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

We began enrollment of patients in a Phase 2 proof-of-concept clinical trial titled ReVeRA in the first quarter of 2021 to evaluate the potential effectiveness of etripamil to reduce ventricular rate in AFib-RVR episodes.

The Phase 2 double blind, placebo controlled, proof-of-concept, which will be conducted in Canada in collaboration with the Montreal Heart Institute and other research centers, is expected to enroll approximately 50 patients randomized 1:1 to receive either 70 mg of etripamil nasal spray or placebo.

The primary endpoint will assess reduction in ventricular rate, with key secondary endpoints including the time to achieve the maximum reduction in rate and the duration of the effect.

The trial is to be conducted in the hospital or emergency department setting under medical supervision.We anticipate reporting data following disclosure of top line results of the RAPID trial.

As we generate more data on the safety and efficacy profile of etripamil in PSVT and assess the proof-of-concept results from the ReVeRA trial, we will continue to assess whether etripamil could be further developed in PSVT and AFib-RVR, and other areas of unmet medical need.

The following table sets forth the status and initial focus of etripamil.

Safety Studies

In addition to NODE-301 and the RAPID trial, the clinical development program for etripamil for PSVT consists of two other Phase 3 clinical trials, as well as completed Phase 2 and Phase 1 trials.

NODE-302 is our ongoing Phase 3 open-label safety extension of the NODE-301 trial.

Patients who completed NODE-301 could have enrolled in NODE-302 and received up to an additional 11 doses of etripamil.

NODE-302 is a multi- center, open label study designed to evaluate the safety of etripamil nasal spray when self-administered by patients without medical supervision for spontaneous episodes of SVT in an outpatient setting.

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

We completed NODE-302 in late 2020 with a data set of 245 episodes with 105 patients dosed at least once out of 169 patients enrolled.

Trial safety results will contribute to the etripamil safety database, and are expected to be available in 2021.

NODE-303 is a Phase 3, multi-center, open-label safety trial, evaluating the safety of etripamil when self-administered without medical supervision, and evaluating the treatment safety and efficacy of etripamil on multiple SVT episodes.

We originally designed this trial to enroll enough patients to collect data on up to 1,000 patients taking etripamil in an at-home setting.

With the expanded size of the RAPID trial, we expect the size of the NODE-303 study to be reduced.

We expect to determine a more accurate sizing of the trial following future discussions with the FDA and other regulatory authorities.

Based on a review of the NODE-301 safety data available in June 2019, the FDA and multiple European and Latin American regulatory authorities agreed to allow patient enrollment in NODE-303 without an in-office safety test dose, which is required in the RAPID trial, and in a broad patient population including patients taking concomitant beta-blockers and calcium channel blockers.

We are in the process of initiating patient access programs that have as their primary objective providing further access to etripamil to patients who have participated in the clinical development registration trials to treat future SVT episodes.

These programs will be tailored to meet the regulatory requirements in the territories in which the clinical sites are located.

Phase 1 and Phase 2 Trials

We completed our Phase 2 clinical trial of etripamil for the treatment of PSVT in the United States and Canada in the electrophysiology lab, with results published in the Journal of the American College of Cardiology.

Investigators reported an 87% termination rate of induced episodes of SVT within 15 minutes at the dose selected for our Phase 3 trials versus a 35% termination rate for placebo.

We have completed two Phase 1 clinical trials in healthy volunteers, characterizing the pharmacokinetics (PK) and pharmacodynamic (PD) effect of etripamil.

Our most recent Phase 1 trial (NODE-102) demonstrated no significant differences in etripamil plasma levels or pharmacodynamic outcomes between Caucasian volunteers and subjects of Japanese descent, which was the primary objective of the study.

In secondary analyses of all patients, the study showed that the relevant pharmacodynamic effect of 70 mg etripamil for PSVT, as measured by PR interval prolongation, is approximately in the range of 5 to 50 minutes.

This period of time is consistent with data on time to conversion of SVT observed in NODE-301.

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

The study initiated with the etripamil 70 mg single dose regimen and the 70 mg repeat dose regimen was introduced into the trial starting in the second half of 2021 following FDA acceptance of the protocol change.

The trial is designed to add to the safety data from the remainder of the development program, including both the NODE-301 and RAPID trials, in order to fulfill the safety data set needed for NDA filing.

Our plan is to ascertain the final sizing of the trial following future discussions with the FDA and other regulatory authorities.

We are conducting patient access programs to provide further access to etripamil to patients who have participated in the clinical development registration trials to treat future SVT episodes.

These programs are tailored to meet the regulatory requirements in the territories in which the clinical sites are located.

Phase 2 Proof of Concept Trial in AFib-RVR

The Phase 2 double blind, placebo controlled, proof-of-concept study, which is being conducted in Canada in collaboration with the Montreal Heart Institute and other research centers, is expected to enroll approximately 50 patients randomized 1:1 to receive either 70 mg of etripamil nasal spray or placebo.

The primary endpoint will assess reduction in ventricular rate, with key secondary endpoints including the time to achieve the maximum reduction in rate and the duration of the effect.

The trial is being conducted in the hospital or emergency department setting under medical supervision.

The COVID-19 pandemic

and its impact on emergency departments and hospital personnel has resulted in significantly slower than expected enrollment for this trial.

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.

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

We are maintaining our guidance of achieving topline data from the RAPID trial in late 2021 or

We are maintaining our guidance of achieving topline data from the RAPID trial in mid-second half 2022.

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

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

We seek to maximize our commercial opportunities by acquiring or in-licensing product candidates for indications with significant unmet need with a focus on novel treatments for cardiovascular conditions.

Our leadership team has extensive experience in developing and commercializing successful drugs.

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a slower than normal heart rate is called bradycardia.

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

Symptoms of an arrhythmia can include palpitations, lightheadedness or dizziness, chest

pain, shortness of breath or sweating.

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

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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 AF recurrences.

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

We designed and are developing etripamil, a novel, potent, rapid-onset and short-acting 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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We believe that the following attributes of etripamil make it a better treatment candidate for certain episodic cardiovascular conditions than current standards of care:

Etripamil is designed to act upon the desired target for only up to 50 minutes, with the goal of reducing long-term side effects that may occur with chronic drug therapy.

Etripamil is designed to act upon the desired target for only up to approximately 50 minutes, with the goal of reducing long-term side effects that may occur with chronic drug therapy.

Etripamil is designed to be absorbed into the bloodstream in less than 10 minutes through the inner lining of the nose.

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Etripamil is designed to be self-administered by patients via a nasal spray device.

To better understand the opportunity for etripamil in the United States and Europe, we have commissioned multiple market research studies.

In 2017, we commissioned a study that involved qualitative in-depth interviews with 121 cardiologists, electrophysiologists, emergency medicine physicians, primary care physicians, PSVT patients and private and public payors in the United States, Germany, France, United Kingdom, Italy and Spain.

In this research, cardiologists in the United States were exposed to a target product profile, or TPP, of etripamil based on our Phase 2 trial results and reported that they would use etripamil in 3.5 times as many PSVT patients as those receiving a catheter ablation, which they report as 10% of their PSVT patients.

From the same research, PSVT patients in the United States reported going to the emergency department for approximately 10% of their SVT episodes and anticipated being able to avoid 50% to 75% of these emergency department visits per year by using etripamil.

Furthermore, a majority of patients in this research expressed positive expectations for treatment with the etripamil TPP, including that it would provide peace of mind between episodes and a sense of control over the disease, by reducing anxiety in anticipation of future episodes and allowing them to perform activities that they perceived to be limited without a reliable at-home therapy.

A minority of patients expressed negative expectations for the etripamil TPP, primarily as a result of an aversion to administering medications intranasally.

When presented with hypothetical prices to the patient in the range of $30 to $60 per dose, PSVT patients in this market research also reported a desire to use etripamil for an average of approximately 50% of their SVT episodes.

We commissioned additional market research that was conducted in 2020 after the results of NODE-301 were disclosed with 15 cardiology opinion leaders and 65 clinical cardiologists and electrophysiologists.

Sixty of these physicians agreed or strongly agreed that the results of NODE-301 were clinically meaningful.

We believe these responses emphasize the need for an efficacious self-administered therapy to reduce ED visits.

These same physicians also responded favorably to a target product profile that included a repeat administration of etripamil, such as is being studied in the RAPID trial, with a hypothetical increase in conversion to sinus rhythm at 45 minutes from 60% to 75%, assuming a tolerability profile consistent with the NODE-301 trial.

We also commissioned market research that was conducted in 2019 with representatives of 20 regional and national commercial/medicare payors and pharmacy benefits managers, or PBMs.

To better understand the opportunity for etripamil in the United States and Europe, we have completed multiple market research studies and continue to conduct additional work.

In 2020, we conducted quantitative research with 250 cardiologists who .

These physicians were shown various product profiles, for etripamil reflecting different efficacy and dosing scenarios for etripamil.

In this research, cCardiologists reported a willingness to prescribe etripamil to 49% of their patients when exposed to a single administration profile commiseratecommensurate with NODEode- 301 results, and their w.

Willingness to prescribe increased to a range of ~50-55%modestly when exposed to repeat administration scenarios with higher efficacies.

We also commissioned market research in 2019 with representatives of 20 regional and national commercial/medicare payors and pharmacy benefits managers, or PBMs.

In this research, we asked these representatives to evaluate their receptivity to a product profile of etripamil, which assumes a single dose administration and a hypothetical profile of 70% conversion within 30 minutes for etripamil vs 30% for placebo.

When presented with a range of hypothetical wholesale acquisition costs to the payors and then asked about the likelihood of coverage of etripamil by commercial and medicare payors if it was approved for PSVT, the representatives on average believed etripamil was highly likely to receive broad reimbursement by both commercial and medicare payors if net pricing was

below the specialty tier pricing threshold for government managed plans, which at the time of the survey was $670 per month.

When presented with a range of hypothetical wholesale acquisition costs and asked about the likelihood of coverage of etripamil, commercial and medicare payors on average

believed it was highly likely to receive broad reimbursement if net pricing was below the specialty tier pricing threshold for government managed plans.

PSVT is a serious and recurring electrical disorder of the heart, which is caused by altered electrical conductivity over the AV node.

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In the next most common form of PSVT, called atrioventricular reciprocating tachycardia, or AVRT, there is an extra piece of electrical tissue that directly connects the atria and the ventricles.

In AVRT, the electrical signal begins like it would in a normal heart beat by traveling from the atria to the ventricles over the AV node.

In AVRT, the electrical signal begins like it would in a normal heartbeat by traveling from the atria to the ventricles over the AV node.

However, as shown in the figure above, in AVRT, the extra piece of electrical tissue allows the signal to travel back up to the atria, creating a “short circuit.” Once the signal gets back to the atria, it goes back down to the AV node and the cycle continues over and over, resulting in a rapid heart rate.

Uncertainty of the timing and duration of episodes of SVT can significantly impact patient quality of life.

In 2018, we conducted a quantitative internet survey involving 256 patients with PSVT.

The survey was designed to assess the impact of PSVT on patients prior to and after their diagnosis and explored the key patient drivers of disease burden, including episode frequency, duration, perceived severity of symptoms and emergency department visits.

The survey included both newly diagnosed PSVT patients and patients who had been diagnosed with PSVT for some time.

The previously diagnosed patients had an average time since diagnosis of seven years.

This survey indicated that it takes more than two years after first experiencing symptoms of PSVT for the average patient to receive a formal diagnosis.

In 2018, we conducted a quantitative survey involving approximately 250 patients with PSVT.

This survey indicated that it takes more than two years after first experiencing symptoms of PSVT for the average patient to receive a formal diagnosis, suggesting >600,000 undiagnosed patients given the estimated incidence rate of approximately 300,000/year.

We believe this delay in diagnosis is primarily the result of the episodic nature of the disease and the requirement for an ECG when the patient is experiencing an SVT episode to confirm the diagnosis.

We estimate that, overall, 60% of PSVT patients are women and approximately half suffer from cardiovascular comorbidities.

The figure below shows the surveyed patients’ total number of SVT episodes in the first 12 months after diagnosis.

Total Number of SVT Episodes in the First 12 Months After Diagnosis

Patients reported episode frequencies that vary from less than one per year to greater than 25 per year.

Based on this market research, we estimate that patients with PSVT experience a median of four to seven episodes of SVT per year.

These episodes can be debilitating for patients, who can be left unable to focus on family or work during an episode.

When in an episode of SVT, patients may experience symptoms including palpitations, sweating, chest pressure or pain, shortness of breath, sudden onset of fatigue, fainting and anxiety.

From this research and other corroborating sources, we estimate that, overall, 60% of patients with PSVT are women and approximately half suffer from cardiovascular comorbidities.

Patients with PSVT report that SVT episodes can be debilitating, leaving them unable to focus on family or work during an episode.

When in an episode of SVT, patients may experience symptoms including palpitations, sweating, chest pressure or chest pain, shortness of breath, sudden onset of fatigue, fainting and anxiety.

Symptoms commonly reported by patients with PSVT mimic other conditions and are often mistaken for anxiety or panic attacks, especially in women.

Researchers have noted that up to 27% of PSVT patients stopped driving for fear of temporary loss of consciousness, fainting or passing out.

Patients have reported that the duration of SVT episodes varies widely from minutes to hours, or more.

Our market research indicates that in the year of diagnosis almost 40% of patients experience two or more episodes of SVT per year that last more than 10 minutes each, and a similar percentage visit the emergency department for treatment of their PSVT at least once per year.

We also estimate that 65% of PSVT patients have used chronic medications prophylactically to reduce episode frequency.

Our market research also shows that after the first year of diagnosis the percentage of patients with SVT episodes lasting longer than 10 minutes and the percentage visiting the emergency department for treatment decreases modestly to approximately one-third of those surveyed.

Based upon our survey responses, we believe these decreases in both duration of episodes and emergency department visits are attributable to a combination of prophylactic medication use, lifestyle changes, and proper implementation of vagal maneuvers.

Researchers have noted that up to 27% of patients with PSVT stopped driving for fear of temporary loss of consciousness, fainting or passing out.

Patients have reported that the duration of SVT episodes varies widely from minutes to hours, or longer.

To further appreciate the burden of disease in PSVT, we recently completed an important patient reported outcomes (PRO) market research study that we believe establishes the disease burden for patients and the market opportunity for etripamil.

Approximately 250 patients participated in this study for on average 8.5 months and completed short surveys approximately every 12 days.

In total, over 5,000 episodes of PSVT were reported and characterized.

Patients who participated in the study demonstrated a wide range of annual SVT episode frequency (0 to >50), with a median frequency of 12-15 episodes per year.

Of these episodes, approximately 60% lasted longer than 10 minutes and 35% longer than 30 minutes.

Over 50% of episodes were reported by the study participants to be moderate or severe in intensity.

In addition, approximately 30% of patients experiencing episodes sought medical care for treatment of the episode, the majority of which were treated in the emergency department.

We believe that the results of this PRO longitudinal market research study provide increased accuracy of the true disease burden experienced by patients with PSVT that what was reported from previous patient market research.

Patients in the previous study from 2018 reported episode frequencies that varied from less than one per year to greater than 25 per year, with a calculated median of four to seven episodes of SVT per year.

The longitudinal PRO study demonstrated a higher annual SVT episode frequency of 12-15.

Qualitative research with a sample of participants who enrolled in the longitudinal PRO market research uncovered that this discrepancy is likely attributable to bias of patients to recall ‘significant’ episodes in years past (based on perceived duration/ intensity).

Specifically, the median four to seven episodes per year recalled by patients in the 2018 study were likely more memorable because they share characteristics of higher disease burden.

In the PRO study, approximately 45% of episodes were both self-described by the patient as moderate/severe in intensity and greater than five minutes in duration.

Applying this to the overall study median frequency of 12-15 episodes results in a median of five to seven ‘burdensome episodes’ per year.

Thus, we believe the results of the PRO study largely confirm prior patient market research, after accounting for recall bias associated with only remembering burdensome episodes.

In summary, we now model a target addressable market for etripamil of 60% of patients diagnosed with PSVT categorized as those who experience multiple moderate or severe 10+ minute episodes each year.

Furthermore, we believe that these target patients will use etripamil to treat a median of 4-6 episodes per year based on the projected number of self-reported longer or more intense episodes experienced by the patient as well as willingness to pay considerations.

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 PSVT patients 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 anti-arrhythmic drugs to be taken at the onset of an episode.

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 interventions are generally not acutely effective.

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

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

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.

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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.

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.

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

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

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.

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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.

In particular, we analyzed longitudinal Medicare claims data for patients age 65 and older and employer-based medical claims data for patients under age 65 with five or more years of continuous enrollment, for the years 2008 through 2016.

We identified patients who, during this time period, had either two or more PSVT codes (ICD9 427.0 or ICD10 I47.1) in the outpatient setting or one or more of these codes in the emergency department or inpatient setting.

Another prevalence analysis was published and presented at the 2018 International Academy of Cardiology’s Scientific Sessions.

Using four years of longitudinal claims data in patients under age 65, this analysis arrived at similar conclusions regarding the number of PSVT patients in the United States.

Both of these analyses were funded by us and included participation by our employees.

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

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

treated prevalence of approximately 2.1M, 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).

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

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.

From market research conducted in 2017 and 2018, we estimate a core target addressable market of approximately 40-65% of the prevalent population that we estimate has a higher burden of PSVT as measured by episode frequency and duration, emergency department visits and prophylactic use of chronic medications to reduce episode frequency.

We define this core addressable market as patients who have been diagnosed with PSVT and who are engaging the healthcare system for treatment of PSVT, as identified by insurance claims, on an annual basis.

Beyond this core addressable market, we believe that there is a significant opportunity for etripamil to help the estimated 1.4 million patients who have been diagnosed with PSVT but do not engage in the healthcare system on an annual basis.

We believe many of these patients do not seek treatment for PSVT because they are not satisfied with the current options to manage an acute episode or because they have been told by their physician that their condition is not life threatening and episodes of SVT will eventually self-terminate.

We believe that these untreated patients may reengage the healthcare system if alternative treatment options are available to them.

In addition, we believe that advances in digital health and wearable technology may lead to more rapid diagnosis of PSVT in the future, resulting in more patients seeking treatment for their symptoms.

Current treatment for PSVT consumes significant healthcare resources.

Retrospective research on claims data partly sponsored by us and published in the American Journal of Cardiology in 2020 shows that healthcare expenditures for patients rose significantly in the year prior to PSVT diagnosis, suggesting that increasing symptoms lead patients to seek more medical care.

In the year following diagnosis, mean annual healthcare expenditures nearly doubled for those less than 65 years of age and tripled for those over 65 years of age, compared to matched controls, increasing mean health care expenditures by approximately $10,000 in the less than 65 age group to approximately $20,000 per patient in the greater than 65 age group.

Significant increases in emergency department visits pre- and post-diagnosis were observed for both age groups.

For those less than 65, the average cost of hospitalizations doubled post-diagnosis as their mean number of hospitalizations quadrupled.

Of note, catheter ablations following diagnosis represented only 23% of this increased spend in this patient group.

Looking to the broader landscape of economic burden on our health system from cardiac treatments, a 2021 retrospective study of claims data partly sponsored by us and published in the American Heart Journal found patients less than 65 years of age with PSVT in the first year after diagnosis cost the health care system a comparably similar amount on a per patient basis to patients with atrial fibrillation.

This study followed patients for up to six years post-diagnosis.

Similar to the previously referenced American Journal of Cardiology study, this data showed that costs never returned to baseline, which we believe indicates a need for more treatment options in long-term PSVT management.

With regard to total healthcare costs, we estimate from the assessment of claims data that approximately $3 billion is spent each year in the United States on treatments for PSVT, with 58% or $1.9 billion of annual costs being driven by ablation procedures, and 36% or $1.2 billion resulting from emergency department visits, hospitalizations and outpatient hospital visits for 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-$30,000 per patient, significantly higher than the expenditures observed for patients without PSVT (~$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 the majority of 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 PSVT

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We believe that etripamil fills this need.

We completed a Phase 1 clinical trial, 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 those four doses in patients with PSVT.

Both trials were conducted to assess nasally- administered etripamil compared to placebo.

Based on discussions with the FDA, we initiated a pivotal 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 of 2020.

We have completed a second Phase 1 clinical trial, further characterizing the PK and PD of etripamil in

Japanese and non-Japanese healthy volunteers.

We have completed a second Phase 1 clinical trial, further characterizing the PK and PD of etripamil in Japanese and non-Japanese healthy volunteers.

We have also completed the conduct portion of 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 are in the process of analyzing the data from that trial.

We are also conducting NODE-303, which is an ongoing open label Phase 3 study that has the objective of collecting further safety data.

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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 related to nasal irritation and nasal congestion.

Tolerability areas of focus 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 reported or observed.

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

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Following nasal administration of etripamil, PK analyses demonstrated rapid absorption and elimination, a 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 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.

These findings were consistent across a range of seven doses 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.

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Pharmacokinetic Profile of Etripamil Plasma Concentrations

Prolongation of the PR interval as measured by ECGs was taken as the PD measure.

Error bars indicate standard error of the mean

Prolongation of the PR interval as measured by ECGs was taken as the pharmacodynamic (PD) measure.

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

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We believe this trial provides further justification for the selected 70 mg dose in our Phase 3 program 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 etrimpamil.

With regard to pharmacodynamics, we believe an approximately 10% increase in the PR interval is a marker of meaningful AV nodal conduction needed to terminate an episode of PSVT.

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As shown in the figure below, this regimen allowed for greater systemic exposure to etripamil in this cohort, as measured by a second maximum concentration after the second administration, as well as a total Area Under the Curve.

We believe this data supports the hypothesis underlying our RAPID trial regimen that a second administration will increase bioavailability and result in a greater therapeutic effect.

We believe this PK data supports the hypothesis underlying our RAPID trial regimen that a second administration will improve the impact of etripamil on AV nodal conduction and result in a greater therapeutic effect.

(MSP-2017-1096) -30 mg etripamil administered 10 minutes apart

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

Overall, etripamil was well tolerated, and the most common adverse events were related 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 administration.

The 70 mg dose was reported to have 48% nasal irritation and 26% nasal congestion.

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

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.

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 2 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 mmHg four minutes post dose in the 70 mg group, 17 mmHg six minutes post dose in the 105 mg group, and 20 mmHg six minutes and eight minutes post dose in the 140 mg group.

mmHg six minutes post dose in the 105 mg group, and 20 mmHg six minutes and eight minutes post dose in the 140 mg group.

(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.

There was no decrease in mean systolic blood pressure compared to baseline from 16 to 30 minutes post-study drug administration.

Ongoing and Planned Clinical Development of PSVT

In July 2020 we announced that we received guidance from the FDA on our proposal to use data from the outcome of the NODE-301 trial as well as the ongoing RAPID trial.

After discussions with the FDA, we determined that the RAPID trial will be randomized to a placebo controlled double blinded dosing regimen that will permit a second 70 mg dose of etripamil to be administered if symptoms persist for 10 minutes after the first dose.

Under an updated statistical analysis plan, the primary efficacy endpoint for both the RAPID trial and the NODE-301 trial will be defined as the difference between active drug and placebo in time to termination of an episode of PSVT and conversion to sinus rhythm within 30 minutes of study drug administration for events confirmed to have been PSVT, with a target p-value of less than 0.05 for each trial.

The FDA agreed that the single and repeat administrations of etripamil could be pooled and compared to placebo for the primary analysis, resulting in no increase in the trial’s sample size.

The FDA further indicated that the two trials, NODE-301 and RAPID, could potentially fulfill the efficacy requirement for our planned NDA for etripamil in patients with PSVT.

We also had an end of Phase 2 meeting with the FDA in September 2017 to review our Phase 2 clinical trial results and to discuss our proposed Phase 3 clinical program.

The FDA agreed with our proposal to assess the efficacy of etripamil in PSVT patients in the at home setting and suggested that we consider conducting a single pivotal trial to assess the efficacy of etripamil, followed by two open label safety trials.

The FDA further confirmed that a large outcome trial would not be required for etripamil and that the total NDA safety database could consist of up to 1,500 patients.

We also had a meeting to obtain Scientific Advice from the European Medicines Agency, or EMA, in April 2018.

The EMA agreed that our planned Phase 3 program could support a registration in the European Union but recommended additional safety data in noninduced episodes of SVT.

In summary, based on our interactions with the regulatory agencies, our planned Phase 3 clinical program includes:

Based on our interactions with the regulatory agencies, our planned Phase 3 clinical program includes:

NODE-301, a pivotal efficacy trial to assess the time to conversion of etripamil compared to placebo in the at-home setting.

RAPID Study, a confirmatory pivotal efficacy trial to assess the time to conversion of etripamil compared to placebo in the at-home setting;

NODE-302, an open-label extension of NODE301 to enroll patients who have completed NODE301 in order to collect safety data on subsequent episodes;

RAPID, a confirmatory pivotal efficacy trial to assess the time to conversion of etripamil compared to placebo in the at-home setting.

NODE-302, an open-label extension of NODE301 to enroll patients who have completed NODE301 in order to collect safety data on subsequent 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.

Phase 3 Clinical Trials

After receiving guidance from the FDA on our Phase 3 program, we have amended and expanded NODE-301B and renamed it the RAPID trial.

The RAPID trial will include the 170 patients who are already enrolled in NODE-301B and is expected to enroll approximately 500 patients.

The trial will be completed after a total of 180 confirmed SVT events are reached.

Additional patients to be enrolled in the RAPID trial will be randomized 1:1.

The RAPID trial was originally an ongoing trial named NODE-301 part 2 and was designed to collect double-blind data from randomized patients who had not yet experienced an SVT event after the NODE-301 study reached its target number of adjudicated SVT events.

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

The RAPID trial will enroll approximately 500 patients in total and will be completed after a total of 180 confirmed SVT events are reached.

Patients enrolled in the RAPID trial are 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 the repeat dose administration was fully implemented across all clinical study sites over a time period that completed in 2021.

Before the repeat dose amendment was fully implemented, a total of 33 patients dosed themselves with single dose study drug of which 31 were confirmed by the adjudication committee to be SVT (i.e.

groups C+D in the trial design graphic).

The patients in the combined groups C+D are randomized 2:1 (etripamil:placebo)

(MSP-2017-1138) RAPID – Trial Design

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(2) Wilcoxon analysis modeling from NODE-301 data

The RAPID study is planned to be conducted in North America and in multiple countries in Europe.

We believe, this endpoint supports the desire of patients to rapidly address their PSVT symptoms during an episode and ideally avoid visiting the emergency department.

When employing the updated SAP retrospectively to the NODE-301 data, 54% of etripamil patients vs.

35% of placebo patients converted within 30 minutes (HR 1.87, p=0.02).

Applying the same primary endpoint to the RAPID study and powering the study at 90% to detect a 19% difference of etripamil versus placebo in 30 minute time to conversion that was observed in the NODE-301 study results in the size of 180 confirmed PSVT events.

A total sample size of 180 patients in RAPID with a positively adjudicated PSVT episode, randomized at a range of 1:1 to 2:1 ratio (active :

control) provides

at least 90% power to detect a significant treatment difference for the primary endpoint at a two-sided significance level of 0.05.

This sample size was calculated based on internal modeling of the Part 1 data where etripamil had a higher conversion rate (54% versus 35% at 30 minutes), and also a more rapid conversion rate (32% versus 14% at 10 minutes).

Assuming a type I error rate of alpha = 0.05 and a ratio in the number of positively adjudicated episodes of PSVT etripamil placebo between 1:1 and 2:1, a minimum of 80 positive conversion events will be required.

Based on internal modeling, 180 patients with a positively adjudicated PSVT episode and 80 positive conversion events will attain greater than 90% power on the primary variable of time to conversion (using a 2-sided Wilcoxon test).

Later and earlier time points for time to conversion as well as patient reported outcomes and emergency department utilization will also be assessed as part of secondary analyses to fully characterize the efficacy profile of etripamil.

The RAPID study is being conducted in North America and in multiple countries in Europe.

The trial was initiated in North America during the fourth quarter of 2020, amidst the COVID-19 pandemic.

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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.

(MSP-2017-1138) NODE-301 Part 1 - Clinical Trial Design

In March 2020, we reported topline results of the first part of the NODE-301 trial.

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31,101) for placebo.

As shown in the top figure below, despite etripamil’s activity and separation from placebo in the first approximately sixty minutes following study drug administration, a time period consistent with etripamil’s pharmacological activity, results from the latter part of the analysis confounded the statistical analysis of the primary endpoint.

We also analyzed the first 30 minutes of the kaplain meir 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.

As shown in the top figure below, despite the activity of etripamil and separation from placebo in the first approximately sixty minutes following study drug administration, a time period consistent with the pharmacological activity of the drug, results from the latter part of the analysis confounded the statistical analysis of the primary endpoint.

We also analyzed 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.

(MSP-2017-1138) NODE-301 Part 1 Efficacy – Time to Conversion over 5 Hours

(MSP-2017-1138) NODE-301 Part 1 Efficacy – Time to Conversion up to 30 Minutes

Post-hoc analysis:

70 mg etripamil dose showed rapid time to conversion (median ~25 min)

(Post hoc analysis – Time to Conversion over 30 minutes)

The study 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 treatment satisfaction questionnaire for medication (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 Part 1

Key secondary endpoints from NODE-301 support benefit of etripamil to patients and payors

(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 study drug.

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

We designed NODE302 to 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.

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 have 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.

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We initiated NODE-302 in December 2018.

The trial completed enrollment in 2020 and data is expected to be available in 2021.The safety results will contribute to the etripamil safety database.

NODE-303 is an open-label global safety trial enrolling up to 3,000 patients who did not participate in NODE-301 or NODE-302 in order to collect data on up to 1,000 patients taking etripamil in an at-home setting.

The trial completed enrollment in 2020 and the study 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.

NODE-303 is an open-label global safety trial enrolling patients who did not participate in NODE-301 or 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 to form the basis for marketing approval.

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

The patients have the opportunity to manage up to four episodes of SVT in NODE-303.

NODE-303 was initiated in October 2019.

Based on a review of the NODE-301 safety data available in June 2019, the FDA and multiple European and Latin American regulatory authorities agreed to allow patient enrollment in NODE-303 without an in-office safety test dose and in a broad patient population, including patients taking concomitant betablockers and calcium channel blockers.

The NODE-303 trial is designed to more closely mimic the expected utilization of etripamil in the post approval setting and for example does not include an in-office safety test dose and includes a broad patient population, including patients taking concomitant betablockers and calcium channel blockers In this study, patients have 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 acceptance, 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 to date.

Atrial Fibrillation

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

During AF, 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.

AF can occur with or without symptoms, with symptoms often including heart palpitations, shortness of breath, and weakness.

Episodes of atrial fibrillation can come and go, or patients may have AF that does not resolve.

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

Additionally, AF is associated with elevated risk of embolism and stroke and

anticoagulant medications, also called blood thinners, are commonly prescribed to manage this risk.

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

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.

AFib can occur with or without symptoms, with symptoms often including heart palpitations, shortness of breath, and weakness.

Episodes of atrial fibrillation can come and go, or patients may have AFib that does not resolve.

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.

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

Classification of AF 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 AF patients based on disease progression.

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 AF episodes that resolve spontaneously within seven days of symptom onset;

persistent, which involves AF 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 AF atrial fibrillation episodes 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 AF, focusing on rate control and symptom management.

Disease progression in AF is common with approximately 25% of AF patients in the paroxysmal stage, 25% of AF patients in the persistent and long-standing persistent stage, and 50% of AF patients in the permanent stage.

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;

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.

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

Rapid, irregular, and inefficient contractility induced by rapid ventricular rate accounts for hemodynamic instability and symptoms of palpitations.

Rapid, irregular, and inefficient contractility induced by rapid ventricular rate accounts for hemodynamic

instability and symptoms of palpitations.

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

Current Treatment Options for AF

Current Treatment Options for AFib

There are currently two pharmacological 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 prevent recurrent AF episodes.

rate control to lower a rapid heart rate and rhythm control to restore and maintain a regular (sinus) rhythm and prevent recurrent AFib episodes.

Either of these pharmacological management approaches may be administered chronically or acutely, depending on patient preference and episode frequency and/or severity.

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

The decision to pursue rate and/or rhythm control for AFib 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 ablation and anti-arrhythmic drug therapy.

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Oral rate control drugs used acutely do not provide immediate ventricular rate control due to a 30-to-60-minute delayed onset of action.

Breakthrough episodes of symptomatic AF 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.

Breakthrough episodes of symptomatic AFib 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.

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.

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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 AF episodes.

PRN rate control is more prominently used in paroxysmal patients who do not tolerate chronic medications but experience symptomatic, infrequent AFib 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 – AF

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

Market Opportunity – AFib

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

We estimate that approximately 25% of these patients have paroxysmal AF, 25% have persistent AF, and 50% have permanent AF.

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

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

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 AF (ICD-10 diagnosis codes I48.0, I48.1, I48.2, I48.91).

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

Our initial qualitative market research indicates that the target addressable market for etripamil in patients with AFib-RVR is approximately 40% of the five million patients with atrial fibrillation.

We derive this percentage estimate from a 2021 market research study conducted by us that involved qualitative interviews with a total of 25 electrophysiologists, general cardiologists, and interventional cardiologists.

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

In response, physicians reported approximately 60% of paroxysmal patients, 50% of persistent patients, and 30% of permanent patients met this classification.

This research suggests the share of patients experiencing ≥1 symptomatic episode of AFib-RVR requiring treatment may constitute 40% of the prevalent atrial fibrillation 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 in the at-home setting to provide a supplemental option to the acute oral rate or rhythm control strategy their physician has already prescribed.

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 would serve as a “bridge” to the onset of acute oral agents.

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

During this time, patients may experience frightening symptoms that often prompt them to seek emergent 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-RVR out of the burdensome and costly emergency department.

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 five million patients with atrial fibrillation.

We derive this percentage estimate

from 2021 market research studies conducted by us that involved qualitative interviews and quantitative surveys with 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 atrial fibrillation 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 in the at-home setting 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 emergent 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 atrial fibrillation management consumes significant healthcare resources in the United States.

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Clinical Development Plan for Atrial Fibrillation

We began enrollment in our Phase 2 proof-of-concept clinical trial in the first quarter of 2021to evaluate the potential effectiveness of etripamil to reduce ventricular rate in patients with atrial fibrillation and rapid ventricular rate for whom IV administered calcium channel blockers have been used effectively.

The primary endpoint will assess reduction in ventricular rate, with key secondary endpoints including the time to achieve the maximum reduction in rate and the duration of the effect.The trial is to be conducted in the hospital or emergency department setting under medical supervision.

We anticipate reporting data from this study following disclosure of top line results of the RAPID trial.

We began enrollment in our Phase 2 proof-of-concept clinical trial, named 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 ReVeRA Phase 2 double blind, placebo controlled, proof-of-concept trial is conducted in Canada in collaboration with the Montreal Heart Institute and other research centers and is expected to enroll approximately 50 patients randomized 1:1 to receive either 70 mg of etripamil nasal spray or placebo.

The primary endpoint will assess reduction in ventricular rate, with key secondary endpoints including the time to achieve the maximum reduction in rate and the duration of the effect.

The trial is to be conducted in the hospital or emergency department setting under medical supervision.

The COVID-19 pandemic and its impact on emergency departments and hospital personnel has resulted in significantly slower than expected enrollment for this trial.

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 AF to other cardiac and potentially non-cardiac conditions where we believe that a rapid-onset, short-acting dihydropyridine L-type calcium channel blocker could potentially deliver significant clinical and quality of life benefits for patients.

We believe that the same 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 not only supraventricular tachycardias like PSVT or AF, but also for the treatment of chronic stable angina and angina due to coronary artery spasm.

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 to other cardiac and potentially non-cardiac conditions where we believe that a rapid-onset, short-acting 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.

Both calcium channel blockers and beta blockers are commonly used to manage not only supraventricular tachycardias like PSVT or AFib, but also for the treatment of chronic stable angina and angina due to coronary artery spasm.

Sales and Marketing

Given our stage of development, we have not yet established a commercial sales and marketing organization or distribution capabilities.

We currently have exclusive global development and commercialization rights for etripamil for all indications that 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.

Our current strategy is to market etripamil in the United States for the treatment of PSVT using a targeted direct sales force focused on clinical cardiologists, electrophysiologists, and high-volume primary care physicians who have a history of prescribing anti-arrhythmic therapies.

We believe that a majority of PSVT patients are managed by these cardiovascular specialists and that a targeted sales force will be able to reach a substantial portion of the market for etripamil.

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

If etripamil receives marketing approval, we plan to commercialize it in the United States with 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 approximately 150 to 200 field sales representatives that will call on top-prescribing clinical cardiologists, interventional cardiologists, electrophysiologists, and high-volume primary care physicians who have a history of prescribing anti-arrhythmic 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 most of the 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.

Manufacturing

We currently rely on third party contract manufacturing organizations, or CMOs, for all of our required raw materials, nasal spray device, API and finished product for our clinical trials and for our preclinical research.

We currently rely on third party contract manufacturing organizations, or CMOs, for all of our required raw materials, nasal spray device, active pharmaceutical ingredient (API) and finished product for our clinical trials and for our preclinical research.

We require all of our CMOs to conduct manufacturing activities in compliance with current good manufacturing practice, or cGMP, requirements.

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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.

We believe we can identify and establish additional CMOs to provide API and finished drug product without significant disruption to our business or clinical development timelines.

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.

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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 efficacy, safety, tolerability, dosing convenience, price, coverage and reimbursement.

Many of our existing or 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 of those product candidates in the United States and in foreign countries.

Our current and potential future competitors may also have significantly more experience commercializing drugs that have been approved for marketing.

Mergers and acquisitions in the pharmaceutical and biotechnology industries could result in even more resources being concentrated among a small number of our competitors.

Accordingly, our competitors may be more successful than us in obtaining regulatory approval for therapies and in achieving widespread market acceptance of their drugs.

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 any competitor’s product regarding efficacy, safety, tolerability, dosing convenience, price, coverage and reimbursement.

Many 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.

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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 anti-arrhythmic drugs that are used for chronic and/or acute rate control, such as metoprolol, propranolol, esmolol, pindolol, atenolol, nadolol, verapamil and diltiazem.

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 II from InCarda Therapeutics, Inc., and Gencaro (bucindolol hydrochloride), a beta blocker in Phase 2 from ARCA biopharma, Inc.

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.

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 II from InCarda Therapeutics, Inc., and Gencaro (bucindolol hydrochloride), a beta blocker in Phase 2 from ARCA biopharma, Inc.

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, Europe, Hong Kong, Japan, Mexico, Russia, South Africa, and Ukraine and corresponding patent applications in Brazil, Canada, China, Europe, Hong Kong, India, Israel, New Zealand, South Africa, and South Korea, directed to formulations including etripamil, methods of making such formulations, and uses of such formulations to treat angina or 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, China, Europe, Hong Kong, Israel, Japan, Mexico, Russia, South Africa, and Ukraine and corresponding patent applications in Brazil, Canada, 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 angina or cardiac arrhythmias, such as PSVT and atrial fibrillation.

• a patent family containing two pending U.S.

provisional patent applications and a pending Canadian patent application, which, if granted, is projected to expire in 2041, directed to uses of formulations including etripamil to treat angina, 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.

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and operate without infringing valid enforceable patents and proprietary rights of third parties.

Our ability to stop third parties from making, using, selling, offering to sell or importing our products may depend on the extent to which we have rights under valid and enforceable patents that cover these activities.

With respect to our owned intellectual property, we cannot be sure that patents will issue from any of the pending patent applications to which we own or from any patent applications that we may file in the future, nor can we be sure that any patents that may be issued in the future to us will be commercially useful in protecting etripamil or any future product candidates and methods of using or manufacturing the same.

Our ability to stop third parties from making, using, selling, offering to sell or importing our products may depend on the extent to which

we have rights under valid and enforceable patents that cover these activities.

With respect to our owned intellectual property, we cannot be sure that patents will issue from any of the pending patent applications which we own or from any patent applications that we may file in the future, nor can we be sure that any patents that may be issued in the future to us will be commercially useful in protecting etripamil or any future product candidates and methods of using or manufacturing the same.

Moreover, we may be unable to obtain patent protection for certain aspects of etripamil or future product candidates generally, as well as with respect to certain indications.

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The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources.

Failure to comply with the applicable United States requirements at any time during the drug development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve a pending New Drug Application, or NDA, withdrawal of an approval, imposition of a clinical hold, issuance of warning or untitled letters, product recalls, product seizures, total or

partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

The process required by the FDA before a drug may be marketed in the United States generally involves:

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In addition, an IRB at each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences at that institution, and the IRB must continue to oversee the clinical trial while it is being conducted.

Information about certain clinical trials must be submitted within

specific timeframes to the National Institutes of Health, or NIH, for public dissemination on their ClinicalTrials.gov website.

Information about certain clinical trials must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on their ClinicalTrials.gov website.

Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined.

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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.

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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As a condition of approval, the FDA may require a sponsor of a drug receiving accelerated approval to perform post-marketing studies to verify and describe the predicted effect on irreversible morbidity or mortality or other clinical endpoint, and the drug may be subject to accelerated withdrawal procedures.

Breakthrough therapy designation is for a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The FDA must take certain actions, such as holding timely meetings and providing advice, intended to expedite the development and review of an application for approval of a breakthrough therapy.

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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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These laws may impact, among other things, our current and future business operations, including our clinical research activities, and proposed sales, marketing and education programs and constrain the business or financial arrangements and relationships with healthcare providers and other parties through which we market, sell and distribute our products for which we obtain marketing approval.

laws include anti-kickback and false claims laws and regulations, data privacy and security, and transparency laws and regulations, including, without limitation, those laws described below.

These laws include anti-kickback and false claims laws and regulations, data privacy and security, and transparency laws and regulations, including, without limitation, those laws described below.

The federal Anti-Kickback Statute prohibits any person or entity from, among other things, knowingly and willfully offering, paying, soliciting or receiving remuneration to induce or in return for purchasing, leasing, ordering or arranging for or recommending the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs.

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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.

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), 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.

Beginning in 2022, applicable manufacturers also will be required to report such information regarding payments and other transfers of value to physician assistants, nurse practitioners, clinical nurse specialists, anesthesiologist assistants, certified registered nurse anesthetists and certified nurse midwives provided during the previous year.

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.

We may also be subject to state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures, state laws that require drug manufacturers to report information on the pricing of certain drugs, and state and local laws that require the registration of pharmaceutical sales representatives.

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.

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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At this time, we are unsure of the full impact that the PPACA will have on our business.

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.

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 December 14, 2018, a Texas U.S.

District Court Judge ruled that the PPACA is unconstitutional in its entirety because the “individual mandate” was repealed by Congress as part of the Tax Act.

Additionally, on December 18, 2019, the U.S.

Court of Appeals for the 5th Circuit

upheld the District Court ruling that the individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the PPACA are invalid as well.

The United States Supreme Court is currently reviewing this case, but it is unknown when a decision will be reached.

Although the U.S.

Supreme Court has not yet ruled on the constitutionality of the PPACA, on January 28, 2021, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through May 15, 2021 for purposes of obtaining health insurance coverage through the PPACA marketplace.

The executive order also instructs 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.

It is unclear how the Supreme Court ruling, other such litigation and the healthcare reform measures of the Biden administration will impact the PPACA.

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.

Thus, the PPACA will remain in effect in its current form.

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.

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

It is unclear how such challenges and the healthcare reform measures of the Biden 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, including the BBA, will continue through 2030 with the exception of a temporary suspension from May 1, 2020 through March 31, 2021 due to the COVID-19 pandemic, unless additional Congressional action is taken.

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, including the BBA and the Infrastructure Investment and Jobs Act, will continue through 2031 with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic, unless additional Congressional action is taken.

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 3% in the final fiscal year of this sequester.

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.

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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.

At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

At the federal level, the Trump administration used several means to propose or implement drug pricing reform, including

through federal budget proposals, executive orders and policy initiatives.

For example, on July 24, 2020 and September 13, 2020, the Trump administration announced several executive orders related to prescription drug pricing that attempted to implement several of the administration’s proposals.

As a result, the FDA also released a final rule on September 24, 2020, effective November 30, 2020, implementing a portion of the importation executive order providing guidance for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed pending review by the Biden administration until March 22, 2021.

As a result, the FDA concurrently released a final rule and guidance in September 2020 implementing a portion of the importation executive order providing pathways for states to build and submit importation plans for drugs from Canada.

Further, on November 20, 2020, the U.S.

Department of Health and Human Services, or HHS, finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed until January 1, 2026.

On November 20, 2020, CMS issued an interim final rule implementing the Trump administration’s Most Favored Nation executive order, which would tie Medicare Part B payments for certain physician-administered drugs to the lowest price paid in other economically advanced countries, effective January 1, 2021.

On December 28, 2020, the United States District Court in Northern California issued a nationwide preliminary injunction against implementation of the interim final rule.

It is unclear whether the Biden administration will work to reverse these measures or pursue similar policy initiatives.

As a result of litigation challenging the Most Favored Nation model, on December 27, 2021, CMS published a final rule that rescinded the Most Favored Nation model interim final rule.

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, 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.

No legislation or administrative actions have been finalized to implement these principles.

In addition, Congress is considering drug pricing as part of other reform initiatives.

It is unclear whether these or similar policy initiatives will be implemented in the future.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

It also possible that governmental action will be taken in response to the COVID-19 pandemic..

It is also possible that governmental action will be taken in response to the COVID-19 pandemic.

Foreign Regulation

In order to market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of our product candidates.

For example, in the EU, we must obtain authorization of a clinical trial application, or CTA, in each member state in which we intend to conduct a

clinical trial.

For example, in the EU, we must obtain authorization of a clinical trial application, or CTA, in each member state in which we intend to conduct a clinical trial.

Whether or not we obtain FDA approval for a drug, we would need to obtain the necessary approvals by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the drug in those countries.

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Employees and Human Capital

Our human capital is integral to helping us achieve our mission of developing innovative cardiovascular medicines.

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.

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

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Everything we do is with the patient in mind.

We listen to and partner with patients, and we place the patients’ well-being at the core of all our initiatives.

only through teamwork, collaboration and mentorship do we achieve our goals of developing innovative medicines for patients.

acting selflessly by putting the collective mission first.

We listen to and partner with patients and place their well-being at the core of all our initiatives.

Our patients inspire us.

Milestone 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.

Collaboration is key.

◾ Entrepreneurial Mindset:

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

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

Employees are encouraged to think like an owner.

◾ Every Idea Matters:

Sometimes the best ideas evolve from where it is least expected.

All ideas are welcome.

◾ Humility, Empathy and Integrity:

We act individually and as a team with these three attributes in mind in all we do.

We care to do what is right.

Our human capital objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees.

The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards.

As of December 31, 2020, we had 28 full-time employees, 13 of whom were primarily engaged in research and development activities and 6 of our employees had an M.D.

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

As of December 31, 2021, we had 29 full-time employees, 15 of whom were primarily engaged in research and development activities.

Seven 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.

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 with an option to terminate in November 2023.

We also have a U.S.

subsidiary in Charlotte, North Carolina that occupies 5,116 square feet of leased office space under a lease that expires in September 2022.

We believe that our facilities are adequate to meet our current needs.

subsidiary in Charlotte, North Carolina that occupies 5,116 square feet of leased office space under a lease that expires in July 2022.

We plan to expand the office space in Charlotte, NC to meet the future needs of our growing U.S.

subsidiary for preparation of commercialization.

Legal Proceedings

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Frederik-Philips Blvd., Suite 420, Montréal, Québec, Canada H4M 2X6, and our telephone number is (514) 336-0444.

Our US offices are located at 7422 Carmel Executive Park Drive, Suite 300 Charlotte, NC 28226 and our telephone number is (704) 848-5316.

Available Information

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

We also make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors

and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are provided to us by those persons.

In addition, we regularly use our website to post information regarding our business, product development programs and governance, and we encourage investors to use our website, particularly the information in the section entitled “Investors,” as a source of information about us.

We also make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% stockholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are provided to us by those persons.

In addition, we regularly use our website to post information regarding our business,

product development programs and governance, and we encourage investors to use our website, particularly the information in the section entitled “Investors,” as a source of information about us.

The information on our website is not incorporated by reference into this Annual Report on Form 10-K and should not be considered to be a part of this Annual Report on Form 10-K.

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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