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Item 1. Business

2021-03-29 compared with 2020-03-06 · 386 added, 293 removed, 418 unchanged (62% of the section changed)

Company Overview

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

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, and other cardiovascular indications.

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.

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

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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.

Our development program for etripamil for the treatment of PSVT consists of three Phase 3 clinical trials, one Phase 2 trial, and Phase 1 trials.

We believe this clinical trial program, if successful, will be sufficient to support approval in the United States and the European Union.

NODE‑301 is our ongoing, placebo‑controlled Phase 3 safety and efficacy trial, which is being conducted in North America.

NODE‑301 may serve as a single pivotal efficacy trial required for approval by the U.S.

Food and Drug Administration, or FDA.

The trial is being conducted in two parts.

NODE‑301A will continue until the trial’s adjudication committee has evaluated data from the treatment of 150 SVT events with blinded study drug (etripamil or placebo).

All pivotal efficacy analyses will be conducted on data from NODE‑301A.

NODE‑301B will follow patients already enrolled in NODE‑301 who did not take the study drug in NODE‑301A.

Data from NODE‑301B will be analyzed as a pivotal safety and supportive efficacy data set, and will contribute to potentially valuable sub‑population analyses and pharmaco‑economic assessments.

Following consultation with the FDA in 2019, we confirmed the two‑part design, along with an increase in the sample size of NODE‑301A from 100 to 150 adjudicated SVT events.

The upsize of the trial satisfies a request from the European Medicines Agency, or EMA.

NODE‑302 is our ongoing Phase 3 open‑label safety extension trial.

Patients who complete NODE‑301 may enroll in NODE‑302 and receive up to an additional 11 doses of etripamil.

We designed NODE‑302 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.

All patients randomized in NODE‑301 will be eligible for NODE‑302.

Patients who have successfully dosed with the study drug and completed a study closure visit will be eligible to enroll in NODE‑302 to manage any subsequent episodes of SVT.

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

We initiated NODE‑302 in December 2018 and the trial is ongoing.

Trial safety results will contribute to the etripamil safety database.

NODE‑303 is our ongoing Phase 3 open label safety trial, which is being conducted primarily in North America, Europe and Latin America.

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

The trial is designed to enroll up to 3,000 patients in order to collect data on approximately 1,000 patients taking etripamil in an at‑home setting.

A more accurate sizing of the trial will be determined once an overall size of the safety dataset is determined for NDA filing following future discussions with the FDA and other regulatory authorities.

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

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

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

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

We believe that PSVT is a large and under‑recognized market that we estimate affects approximately two million Americans, with over 300,000 newly diagnosed patients per year, and results in over 600,000 healthcare claims in the United States per year, including emergency department visits, hospital admissions and ablations.

We believe that, if approved, etripamil could prevent many of these healthcare encounters, saving the patient time and inconvenience, and potentially providing a cost‑effective solution for the healthcare system.

It is generally believed that patients are born with the anomaly that causes PSVT and will have life‑long episodes periodically and unpredictably.

PSVT patients experiencing an episode of SVT are usually highly symptomatic, with a rapid heart rate, often over 200 beats per minute, causing palpitations, sweating, chest pressure or pain, shortness of breath, sudden onset of fatigue, lightheadedness or dizziness, fainting and anxiety.

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

We plan to initiate in 2020 a Phase 2 proof‑of‑concept clinical trial in a controlled setting to evaluate the potential effectiveness of etripamil to reduce ventricular rate in atrial fibrillation patients who present to the clinic with rapid ventricular rate.

The trial will enroll approximately 50 patients, randomized to etripamil 70 mg versus placebo, with a primary endpoint of reduction in ventricular rate.

As we generate more data on the safety and efficacy profile of etripamil in PSVT and atrial fibrillation with rapid ventricular rate, we will continue to assess whether etripamil could be developed to potentially fulfill other areas of unmet medical need.

We currently have exclusive development and commercialization rights for etripamil for all indications that we may pursue.

The composition‑of‑matter claims for etripamil as a new chemical entity give us a strong intellectual property position with patents issued in the United Stated through 2028, and with patent term extensions possible to 2031.

In addition, we have an issued U.S.

patent that extends the exclusivity period for the commercial formulation of etripamil to 2036.

We are led by a team of executives with extensive experience in successfully developing and commercializing therapies in cardiovascular and other indications at both major pharmaceutical and emerging life sciences companies.

These therapies include Vytorin (ezetimibe & simvastatin), Ranexa (ranolazine), Effient (prasugrel), Northera (droxidopa), and Cologuard as well as several cardiac drugs in the classes of angiotensin‑converting enzyme inhibitors, angiotensin II receptor blockers, and novel oral anticoagulants.

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.

The first part of NODE-301, which enrolled a total of 431 patients across 65 sites in the United States and Canada, did not meet its primary endpoint of time to conversion of SVT to sinus rhythm compared to placebo over the five-hour period after study drug administration.

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

16, 43) compared to 50 minutes (95% CI:

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.

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.

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.

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.

* We are relying on our Phase 2 clinical trial of etripamil to support further clinical development of etripamil in PSVT, atrial fibrillation and angina.

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

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.

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

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

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

We expect top‑line data from our Phase 3 clinical trial of etripamil, which may serve as a single pivotal efficacy trial in the United States, in the middle of the first half of 2020.

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

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

Expand the scope of cardiovascular indications for etripamil beyond PSVT.

We are exploring the use of etripamil for the treatment of patients with atrial fibrillation, another condition associated with a fast heart rate.

We believe that etripamil could benefit patients with atrial fibrillation based on the approved use of intravenous, or IV, calcium channel blockers in these indications.

We are also exploring the use of etripamil for the treatment of angina, which is chest pain typically associated with an imbalance between the supply of oxygen to and the demand for oxygen by the heart.

Calcium channel blockers have already been approved for chronic management of angina.

We believe there is an opportunity to treat angina with etripamil.

We plan to test etripamil in proof‑of‑concept clinical trials with patients with atrial fibrillation and angina.

We are investigating the use of etripamil for the treatment of patients with AFib-RVR.

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

We began enrollment of our Phase 2 proof-of-concept clinical trial in patients with AFib-RVR in the first quarter of 2021 .

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

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

We currently have exclusive development and commercialization rights for etripamil for our initial indications of PSVT, atrial fibrillation and angina.

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

We plan to establish commercialization and marketing capabilities using a direct sales force to commercialize etripamil in the United States.

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Normal Conduction

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

The sinus node generates its own electrical signal, which spreads throughout both atria and is transmitted down to the lower chambers, the ventricles, and over another piece of electrical tissue called the atrio-ventricular, or AV, node, which is shown in the figure below.

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A normal PR interval is 0.12-0.20 seconds in duration.

A disruption in the heart’s normal rate or rhythm is called an arrhythmia.

ECG Tracing Graph – Event Single Heartbeat

A disruption in the heart’s normal rate or rhythm is called an arrhythmia.

With an arrhythmia, the heart can beat too quickly, too slowly or with an irregular pattern.

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

While PSVT is characterized by a faster than normal heart rate where the heart beats at regular intervals, with atrial fibrillation the heart often beats faster than normal and always with a random, irregular rhythm.

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 atrial fibrillation, there are two approaches to treatment:

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.

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Currently, we are in Phase 3 development for PSVT.

We are also developing etripamil to provide rapid rate control and associated symptom relief for patients with acute episodes of atrial fibrillation and as an acute therapy for angina.

We are also developing etripamil to provide rapid rate control for patients with acute symptomatic episodes of atrial fibrillation and are exploring other therapeutic applications where a rapid-onset and short acting non-dihydropyridine calcium channel blocking agent could provide patient benefit.

In our effort to develop potential therapies, we sought to create new chemical entities as analogs of known molecular classes with clinically validated mechanisms of action.

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

Etripamil resulted from this effort as a new chemical entity with a very short relevant pharmacodynamic effect of approximately 30‑45 minutes in humans, compared with other calcium channel blockers that have pharmacodynamic effects of several hours.

Etripamil resulted from this effort as a new chemical entity with a short relevant pharmacodynamic effect for up to 50 minutes in humans, compared with other calcium channel blockers that have pharmacodynamic effects of several hours.

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 30 to 45 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 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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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.

When asked to rank their receptivity to the etripamil TPP on a Likert scale of one to seven, where a rating of one equated to “not at all favorable”

and a rating of seven equated to “extremely favorable”, the PSVT patients surveyed provided an average (mean) rating of 6.3.

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.

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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.

In this same research, 14 medical and pharmacy directors from both national and regional health plans in the United States were surveyed to assess the attractiveness of the etripamil TPP among payors.

When asked their receptivity to the etripamil TPP, these payor representatives gave an average (mean) rating of 5.6 on the Likert scale.

When presented with hypothetical wholesale acquisition costs to the payors of $1,000 and $500 per dose and then asked about the likelihood of coverage of etripamil by payors once it was approved, the representatives reported average (mean) Likert scores of 5.8 and 6.2, respectively.

In this research, commonly reported drivers of the likelihood of covering etripamil were the lack of other approved treatment options, the potential for fast onset of action and high conversion, and the potential for effective health economic outcomes, in particular, the opportunity to offset the cost of emergency department visits and inpatient admissions.

We also commissioned a market research survey in 2018 and 2019 of 353 general cardiologists, electrophysiologists, and primary care physicians in the United States.

We asked these healthcare providers to estimate the percentage of their PSVT patients that they would prescribe a product with the etripamil TPP, assuming these patients were not contraindicated to this product.

In response, these providers reported expected prescription rates ranging from an average (mean) of 47% among electrophysiologists, or EPs, (n=50) to 58% among primary care physicians, or PCPs, (n=50), with cardiologists, or CCs, (n=253) reporting an average (mean) prescription rate of 54%.

While the average prescription rates were similar across EPs and CCs, the typical expected use case for each physician group was different, with EP expected use cases typically being for shorter periods of time.

The variability in prescription rates among all healthcare providers, including within each physician group, was high, especially among cardiologists, whose expected prescription rates ranged from 0% to 100%.

Physicians in this market research also reported that a product with a fast onset of action and high conversion rates within 30‑60 minutes of administration would be significantly better than current at‑home treatment approaches and that they were familiar with and comfortable prescribing calcium channel blockers to their PSVT patients.

However, physicians also noted that additional tests may be required prior to prescribing etripamil.

Those additional tests included administering an ECG to rule out certain arrhythmias that would likely be

contraindicated with a product with the etripamil TPP.

When asked about their receptivity to the profile of etripamil, physicians gave an average (mean) rating of 5.6 on a Likert scale.

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.

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.

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

PSVT refers to a rapid heart rate condition of the heart’s upper chambers (atria) of abrupt onset and termination.

In the most common form of PSVT called AV nodal reentrant tachycardia, or AVNRT, there is an extra piece of electrical tissue that allows the electrical signal to travel very rapidly in a circle.

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The cycle continues over and over, resulting in a rapid heart rate.

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

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.

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 the AV node and the cycle continues over and over, resulting in a rapid heart rate.

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.

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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.

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

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

While experiencing 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.

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.

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

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

Vagal maneuvers can be attempted to terminate an episode, with low to modest success rates.

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

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

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

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

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

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

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

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

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

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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 new PSVT patients are diagnosed each year in the United States.

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

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

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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.

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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 re‑engage the healthcare system if alternative treatment options are available to them.

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 approaches for PSVT consume significant healthcare resources.

One recently published longitudinal analysis in the American Journal of Cardiology has shown that mean annual total healthcare spending per PSVT patient in the year following diagnosis tripled for patients less than 65 years old (from $9,028 to $29,867) and nearly doubled for patients 65 years old and older (from $10,867 to $20,143) compared to the year prior to diagnosis.

Spending for PSVT and related cardiac arrhythmia services accounted for 67% and 47%, respectively, of the increase in expenditures in these patient groups.

A second analysis, presented at the 2018 International Academy of Cardiology’s Scientific Sessions, concluded that rates of emergency department visits and hospitalizations were 1.8 and 3.0 times higher, respectively, following diagnosis in patients less than 65 years old compared with the prior, pre‑diagnosis year.

Expenditures for ablations in patients less than 65 years old averaged $4,700 per patient (23% of the overall spending increase), as compared to $451 per patient (5% of the overall spending increase) in patients 65 years old and older, which is consistent with lower rates of ablation overall in elderly patients.

In total, we estimate from these 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 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.

Our Clinical Development Program for the Treatment of PSVT

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

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

We believe that etripamil fills this need.

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

Based on discussions with the FDA, we initiated a single pivotal Phase 3 clinical trial in July 2018 to assess the efficacy and safety of etripamil in the at‑home setting, and expect top‑line data in the middle of first half of 2020.

We have completed a second Phase 1 clinical trial, further characterizing the pharmacokinetics and pharmacodynamics of etripamil in Japanese and non‑Japanese healthy volunteers.

We are also conducting two open label Phase 3 safety trials.

The FDA agreed that our Phase 3 clinical program could support an NDA filing in the United States.

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 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.

The FDA has agreed that our Phase 3 clinical program could support an NDA filing in the United States.

Phase 1 Clinical Data

We completed a Phase 1 clinical trial in healthy volunteers, which was designed to assess the safety, pharmacokinetic, or PK, profile, and cardiac pharmacology of intra‑nasally administered etripamil in a randomized, double‑blind, placebo‑controlled, single ascending dose trial.

The primary objective of this trial was to determine the maximum

tolerated dose or maximum feasible dose of two different formulations of etripamil administered via the nasal route in healthy, adult male subjects.

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

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

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

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

We are using this Phase 1 data to support further clinical development of etripamil in three indications:

PSVT, atrial fibrillation and angina.

We are using this Phase 1 data to support further clinical development of etripamil in two indications:

PSVT and AFib-RVR.

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 six doses tested up to 140 mg, i.e., two sprays of 100 µL of solution of 35 mg of etripamil in each nostril.

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.

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

Pharmacokinetic Profile of Etripamil Plasma Concentrations in Phase 1

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

(MSP-2017-1096)

Pharmacokinetic Profile of Etripamil Plasma Concentrations

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

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

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

Such slowing of conduction has already been observed clinically with IV AV nodal agents such as adenosine, verapamil and tecadenoson.

Phase 1 Pharmacology

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

Such slowing of conduction has already been observed clinically with IV AV nodal-blocking agents such as adenosine, verapamil, and tecadenoson.

(MSP-2017-1096) - Pharmacology

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

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

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

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

(MSP-2017-1205) NODE-102

As noted in the discussion of the RAPID study below, the RAPID study will incorporate a repeat dose administration regimen of study drug (either 70 mg of etripamil or placebo).

Specifically, patients will be instructed to administer a repeat administration of study drug if they have not experienced symptom relief within 10 minutes of the first study drug administration.

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

A similar regimen, using repeat doses of 30 mg etripamil administered 10 minutes apart, was tested in one cohort of the original phase 1 trial (study MSP-2017-1096).

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.

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

Phase 2 Clinical Data

We completed a Phase 2 multi‑center, randomized, double‑blind, placebo‑controlled clinical trial in the United States and Canada to evaluate the effects of four different doses of etripamil in patients with PSVT.

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

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

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

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

There were no imbalances in

baseline characteristics across the five treatment groups.

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

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

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

Phase 2 Clinical Trial Design

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

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

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

Etripamil Conversion Rates from SVT to Sinus Rhythm in Phase 2

In a post‑hoc analysis conducted to help inform our Phase 3 trial design, the patients’

time to conversion to sinus rhythm was examined.

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

In a post-hoc analysis conducted to help inform our Phase 3 trial design, the patients’ time to conversion to sinus rhythm was examined.

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

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

Etripamil Time to Conversion from SVT to Sinus Rhythm in Phase 2

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.

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

etripamil versus none after placebo administration.

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

However, these were transient.

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Ongoing and Planned Clinical Development of PSVT

We 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.

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.

Finally, the FDA agreed that our upcoming Phase 3 program, if successful, could support efficacy claims in an NDA filing in the United States.

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 non‑induced episodes of SVT.

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 at‑home setting;

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:

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;

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Phase 3 Clinical Trials

NODE‑301 is our ongoing placebo‑controlled Phase 3 clinical trial being conducted in the United States and Canada to evaluate 70 mg of etripamil versus placebo in terminating an SVT episode in the at‑home setting.

As shown in the figure below, the primary endpoint is the time to conversion over a five‑hour monitoring period following the start of the episode.

Prior to randomization, eligible patients are administered a test dose of 70 mg of etripamil in the investigators’

office while in sinus rhythm in order to ensure tolerability.

Patients successfully completing the test dose are randomly assigned to the etripamil or placebo cohorts (2:1 randomization) and sent home with the study drug and a small portable cardiac monitor that can be used during the patient’s subsequent SVT episode.

Upon experiencing their next SVT episode, patients are instructed to first apply the cardiac monitoring device to record ECG data, then attempt a vagal maneuver, and if that is not successful in terminating the episode, to then dose the drug.

The ECG data will be reviewed by an adjudication committee to determine the type of arrhythmia during the episode and the time to conversion to sinus rhythm.

NODE‑301 will enroll up to 500 diagnosed PSVT patients meeting inclusion and exclusion criteria and will be completed when a total of 150 adjudicated SVT events are treated.

Phase 3 Clinical Trial Design

Each patient will stay in the NODE‑301 trial until one episode of SVT is treated with etripamil or placebo.

All the patients completing a study closure visit for the NODE‑301 trial will have the opportunity to continue in the open‑label NODE‑302 clinical trial and self‑manage subsequent episodes of SVT with etripamil.

NODE‑301 is being conducted in two parts.

NODE‑310A will continue until the trial’s adjudication committee has evaluated data from the treatment of 150 patients with an episode confirmed to be SVT with etripamil or placebo.

All pivotal efficacy analyses will be conducted on data from NODE‑301A.

NODE‑301B will follow patients already enrolled in NODE‑301 who did not take the study drug in NODE‑301A.

Data from NODE‑301B will be analyzed for efficacy as a secondary data set and will contribute to potentially valuable sub‑population analyses and pharmaco‑economic assessments.

In 2019, the FDA agreed to this two‑part design, along with an increase in the sample size of NODE‑301 pivotal analyses from 100 to 150 episodes confirmed to be SVT.

The upsize of the trial satisfies a regulatory request from the EMA to eliminate the use of un‑blinded, third‑party data reviews, which would have directed us when to stop the study for purposes of safeguarding against potential randomization imbalances.

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 graphic below shows the design of the RAPID trial.

(MSP-2017-1138) RAPID – Trial Design

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

(2) Wilcoxon analysis modeling from NODE-301 data

The RAPID study is planned to be 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.

The first patient was dosed in November 2020.

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

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

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

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

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

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

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

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

(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.

The first part of NODE-301 did not meet its primary endpoint of time to conversion of SVT to sinus rhythm compared to placebo over the five hour period following study drug administration.

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

16, 43) compared to 50 minutes (95% CI:

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.

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)

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

NODE302 is the open label extension trial of NODE301.

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.

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

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

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.

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

We initiated NODE302 in December 2018.

The trial is ongoing and 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 approximately 1,000 patients taking etripamil in an at‑home setting.

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.

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.

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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 beta‑blockers and calcium channel blockers.

Etripamil in Other Indications

Our goal in expanding our pipeline is to apply the same treatment paradigm‑changing aspiration that we have for PSVT to other cardiac conditions where we believe that a rapid‑onset, short‑acting 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 in which AV‑nodal blocking agents and vasodilators have demonstrated clinical utility.

Both calcium channel blockers and beta blockers are indicated to manage not only PSVT, but also to provide temporary control of rapid ventricular rate in atrial fibrillation and acute relief of angina symptoms.

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.

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 atrial fibrillation, 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.

Atrial fibrillation symptoms often include heart palpitations, shortness of breath and weakness.

Episodes of atrial fibrillation can come and go, or patients may have atrial fibrillation that does not go away and may require treatment.

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

Prevalence estimates range from four to six million patients suffering from atrial fibrillation in the United States.

Approximately 25% of these patients have paroxysmal atrial fibrillation, another 25% have persistent atrial fibrillation, while 50% have permanent atrial fibrillation.

Acute episodes of symptomatic atrial fibrillation are often treated 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.

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.

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.

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.

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.

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

A common complication of atrial fibrillation is 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.

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

Current Treatment Options for AF

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 rhythm.

For rate control, the rapid heart rate of atrial fibrillation

is often treated with calcium channel blockers or beta blockers to control symptoms and improve cardiac function.

Oral rate control drugs do not provide immediate ventricular rate control due to the delayed 30 to 60 minute onset of action by the oral route.

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

We believe that etripamil can be used by patients to rapidly reduce their heart rate in the at‑home setting on top of the oral rate or rhythm control strategy their physician has already prescribed.

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 symptomatic episodes of atrial fibrillation out of the burdensome and costly emergency department.

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

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.

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.

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

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

Pill-in-pocket rhythm control strategies are considered by physicians for patients who demonstrate favorable

outcomes to these medications in the clinic and who are thought to be reliable enough to administer them appropriately.

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

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

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

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

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.

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.

Current atrial fibrillation management consumes significant healthcare resources in the United States.

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

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

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

Clinical Development Plan for Atrial Fibrillation

We plan to initiate a Phase 2 proof‑of‑concept clinical trial in 2020 to evaluate the potential effectiveness of etripamil to reduce ventricular rate in patients with atrial fibrillation with rapid ventricular rate for whom IV‑administered calcium channel blockers have been used effectively.

The trial will be conducted in Canada in collaboration with the Montreal Heart Institute and other research centers.

The primary endpoint of the trial is reduction of ventricular rate in patients with symptomatic atrial fibrillation and elevated ventricular rate.

Angina is chest pain caused by an imbalance between the supply of oxygen to and the demand for oxygen by the heart.

It can feel like pain, pressure or squeezing in the chest, but the discomfort also can occur in the shoulders, arms, neck, jaw, or back.

Angina may be due to a number of factors, but is primarily caused by either occlusion or spasm of the coronary arteries.

The coronary arteries sit on the surface of the heart muscle and supply it with oxygen and nutrients with each heartbeat.

Coronary occlusion is most often caused by the deposition of fatty plaques that narrow the arteries and reduce blood flow, a condition known as coronary artery disease, or CAD, which can lead to a heart attack.

Coronary spasm is the sudden and involuntary tightening of the muscles within the coronary arteries, which narrows them and reduces blood flow to the heart.

It may be due to high blood pressure, high cholesterol, or certain drugs.

The coronary spasm form of angina, also known as variant or Prinzmetal’s angina, represents two out of every hundred cases of angina.

Angina from CAD is characterized as one of two forms:

stable or unstable.

Stable angina is the most common form, affecting approximately 3% of the adult population, or almost approximately nine million patients in the United States.

It manifests when the heart works harder than usual to pump blood through narrowed coronary arteries and can be triggered by physical exertion or other factors such as emotional stress.

Episodes are typically short‑lasting, five minutes or less, and disappear soon after exercise is terminated or after using angina medication.

Symptoms resolve with rest.

Unstable angina is new onset chest pain or angina that gets worse or becomes more frequent, and can be a sign of an impending heart attack.

There are several medical treatments available to treat stable angina caused by CAD, including nitrates, beta blockers and calcium channel blockers.

Only nitrates provide immediate relief, but all three classes of drug are indicated for prophylactic use.

Nitrates work by dilating or widening coronary blood vessels, allowing more blood to flow to the heart muscle.

Short‑acting nitrates are used acutely to relieve angina‑related chest discomfort, or prophylactically before doing something that normally triggers angina, such as physical exertion.

Nitroglycerin is a common form of nitrate that is available primarily in sublingual formulations for rapid symptom relief.

It is also available as a cream or patch that can be applied to the skin.

In up to 20% of patients, nitroglycerin is not tolerated and additional patients do not respond to the treatment.

For example, nitroglycerin can cause severe headaches that necessitate analgesic intervention for pain relief, the painful nature of which can have a marked negative effect on patient compliance.

Nitroglycerin also can cause severe hypotension, circulatory collapse, and death if used together with phosphodiesterase type 5 inhibitor drugs that are used for the treatment of erectile dysfunction, such as Viagra (sildenafil), Adcirca and Cialis (tadalafil), and Levitra and Staxyn (vardenafil).

In addition to their use in CAD, calcium channel blockers are also prescribed for coronary

spasm, however, they do not provide immediate relief.

We are not aware of any approved rapid‑onset, short acting treatments for coronary spasm.

We believe that etripamil could be used to rapidly reduce or relieve angina symptoms in the at‑home setting in both patients with stable angina who cannot tolerate or do not respond to nitrates, and in patients experiencing coronary spasm.

Clinical Development Plan for Angina

We are in the early stages of planning small pharmacodynamic and dose‑ranging clinical trials to test the efficacy and safety of etripamil in various forms of angina.

We expect to initiate a Phase 2 clinical trial in angina after submission of the appropriate regulatory filing (IND or equivalent) in the country where the trial is planned to be conducted.

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.

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.

Sales and Marketing

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

We currently have enough manufactured supply of etripamil to complete our ongoing NODE‑301, NODE‑302, and NODE‑303 trials.

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

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

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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.

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.

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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.

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

InCarda Therapeutics, Inc., or InCarda, is developing InRhythm, an inhaled version of flecainide, in preclinical development.

To our knowledge, there are no other treatments in development for acute episodic treatment of PSVT.

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

In the acute setting, IV treatments of generic drugs such as adenosine, verapamil and diltiazem, are routinely given.

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

However, these interventions are not acutely effective.

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

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.

There are also several drugs 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 acute relief of angina symptoms, approved drugs include short‑acting nitrates such as nitroglycerin, isosorbide dinitrate, and pentaerythritol.

We are not aware of any approved drug or drug in clinical development for rapid‑onset, short‑acting treatment for coronary spasm.

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.

Intellectual Property

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Additionally, we intend to rely on regulatory protection afforded through data exclusivity and market exclusivity, as well as patent term extensions, where available.

As of January 31, 2020, our patent portfolio as it pertains to etripamil included:

As of March 9, 2021, our patent portfolio as it pertains to etripamil included:

• a patent family containing six U.S.

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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 a corresponding patent in Europe and corresponding patent applications in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Israel, Japan, Mexico, New Zealand, Russia, South Africa, South Korea and Ukraine, 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, 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.

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

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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.

See the section entitled “Risk Factors—Risks Related to Our Intellectual Property”

for a more comprehensive description of risks related to our intellectual property.

See the section entitled “Risk Factors—Risks Related to Our Intellectual Property” for a more comprehensive description of risks related to our intellectual property.

Government Regulation and Product Approval

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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.

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:

completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s good laboratory practice, or GLP, regulations;

submission to the FDA of an IND, which must become effective before human clinical trials may begin;

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satisfactory completion of an FDA advisory committee review, if applicable;

satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with cGMP requirements, and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

satisfactory completion of an FDA inspection of selected clinical sites to assure compliance with GCPs and the integrity of the clinical data;

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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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Furthermore, the FDA or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements, or if the drug has been associated with unexpected serious harm to patients.

Marketing Approval

Assuming successful completion of the required clinical testing, the results of the preclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.

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

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing”

of a standard NDA for a new molecular entity to review and act on the submission.

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

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

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

In addition, under the Pediatric Research Equity Act, certain NDAs or supplements to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

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Once the submission is accepted for filing, the FDA begins an in-depth substantive review.

The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

The FDA may refer an application for a novel drug to an advisory committee.

An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by

the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured.

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

If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter.

An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

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, 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 and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.

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, 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 and use 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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A priority review means that the goal for the FDA to review an application is six months, rather than the standard review of ten months under current PDUFA guidelines.

Under the current PDUFA agreement, these six and ten month review

periods are measured from the “filing”

date rather than the receipt date for NDAs for new molecular entities, which typically adds approximately two months to the timeline for review and decision from the date of submission.

Under the current PDUFA agreement, these six and ten month review periods are measured from the “filing” date rather than the receipt date for NDAs for new molecular entities, which typically adds approximately two months to the timeline for review and decision from the date of submission.

Most products that are eligible for fast track designation are also likely to be considered appropriate to receive a priority review.

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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.

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.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state agencies, and are subject to periodic unannounced

inspections by the FDA and these state agencies for compliance with cGMP requirements.

Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented.

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The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market.

Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label, although physicians, in the practice of medicine, may prescribe approved drugs for unapproved indications.

Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label, although physicians, based on their independent medical judgement, may prescribe approved drugs for unapproved indications.

However, biopharmaceutical companies may share truthful and not misleading information that is otherwise consistent with the labeling.

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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.

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.

The term “remuneration”

has been broadly interpreted to include anything of value.

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.

The term “remuneration” has been broadly interpreted to include anything of value.

The federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers on the one hand and prescribers, purchasers and formulary managers on the other.

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Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor.

Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce referrals of federal healthcare covered business, the statute has been violated.

A person or entity does not need to have actual knowledge of this statute or specific intent to violate it in order to have committed a violation.

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Federal civil and criminal false claims laws, including the federal civil False Claims Act, which can be enforced by individuals through civil whistleblower and qui tam actions, and civil monetary penalties laws, prohibits any person or entity from, among other things, knowingly presenting, or causing to be presented, a false claim for payment to the federal government or knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.

A claim includes “any request or demand”

for money or property presented to the U.S.

A claim includes “any request or demand” for money or property presented to the U.S.

Several pharmaceutical and other healthcare companies have been prosecuted under these laws for allegedly providing free product to customers with the expectation that the customers would bill federal programs for the product.

Other companies have been prosecuted for causing false claims to be submitted because of the companies’

marketing of products for unapproved, and thus non‑reimbursable, uses.

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

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

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

Among other things, HITECH makes HIPAA’s security standards directly applicable to “business associates,”

defined as independent contractors or agents of covered entities, which include certain healthcare providers, healthcare clearinghouse and health plans, that create, receive, maintain or transmit individually identifiable health information in connection with providing a service for or on behalf of a covered entity.

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

Among other things, HITECH makes HIPAA’s security standards directly applicable to “business associates,” defined as independent contractors or agents of covered entities, which include certain healthcare providers, healthcare clearinghouse and health plans, that create, receive, maintain or transmit individually identifiable health information in connection with providing a service for or on behalf of a covered entity, and their covered subcontractors.

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, as defined by such law, 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.

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.

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.

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Coverage and Reimbursement

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

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

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

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Our product candidates may not be considered medically necessary or cost-effective.

A payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be approved.

Adequate third-party payor reimbursement may not be available to enable us to realize an appropriate return on our investment in product development.

Legislative proposals to reform healthcare or reduce costs under government insurance programs may

result in lower reimbursement for our product candidates, if approved, or exclusion of our product candidates from coverage and reimbursement.

Legislative proposals to reform healthcare or reduce costs under government insurance programs may result in lower reimbursement for our product candidates, if approved, or exclusion of our product candidates from coverage and reimbursement.

The cost containment measures that third-party payors and providers are instituting and any healthcare reform could significantly reduce our revenues from the sale of any approved product candidates.

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government initiatives over the past few years to fund and incentivize certain comparative effectiveness research, including creation of the Patient-Centered Outcomes Research Institute under the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the PPACA.

It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s product could adversely affect the sales of our product candidates.

The PPACA became law in March 2010 and substantially changed the way healthcare is financed by both third-party payors.

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

Additionally, the PPACA extends manufacturers’

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

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

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

There remain judicial and Congressional challenges to certain aspects of the PPACA, as well as efforts by the Trump administration to repeal or replace certain aspects of the PPACA, and we expect such challenges and amendments to continue.

Since January 2017, President Trump has signed two Executive Orders and other directives designed to delay the implementation of certain provisions of the PPACA or otherwise circumvent some of the requirements for health insurance mandated by the PPACA.

Concurrently, Congress has considered legislation that would repeal or repeal and replace all or part of the PPACA.

While Congress has not passed comprehensive repeal legislation, 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, includes 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 eliminates, 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 eliminates 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.”

In December 2018, CMS published a new final rule permitting further collections and payments to and from certain PPACA qualified health plans and health insurance issuers under the PPACA adjustment program in response to the outcome of federal district court litigation regarding the method CMS uses to determine this risk adjustment.

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.

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 ACA are invalid as well.

On March 2, 2020, the United States Supreme Court granted the petitions for writs of certiorari to review this case and has allotted one hour for oral arguments.

It is unclear when such oral arguments are to be held and when a decision

is expected to be made.

It is also unclear how such litigation and other efforts to repeal and replace the PPACA will impact the PPACA.

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.

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 2029 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, 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 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’s budget proposal for fiscal year 2020 contains further drug price control measures that could be enacted during the budget process or in other future legislation, including, for example, measures to permit Medicare Part D plans to negotiate the price of certain drugs under Medicare Part B, to allow some states to negotiate drug prices under Medicaid, and to eliminate cost sharing for generic drugs for low‑income patients.

Additionally, the Trump administration released a “Blueprint”

to lower drug prices and reduce out of pocket costs of drugs that contains additional proposals to increase manufacturer competition, increase the negotiating power of certain federal healthcare programs, incentivize manufacturers to lower the list price of their products and reduce the out of pocket costs of drug products paid by consumers.

Department of Health and Human Services, or HHS, has solicited feedback on some of these measures and has implemented others under its existing authority.

For example, in May 2019, CMS issued a final rule to allow Medicare Advantage plans the option to use step therapy for Part B drugs beginning January 1, 2020.

This final rule codified CMS’s policy change that was effective January 1, 2019.

Although a number of these and other measures may require additional authorization to become effective, Congress and the Trump administration have each indicated that it will continue to seek new legislative and/or administrative measures to control drug costs.

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.

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.

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..

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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Regulatory approval in one country does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country may negatively impact the regulatory process in others.

As of December 31, 2019, we had 30 full‑time employees, 14 of whom were primarily engaged in research and development activities and 9 of whom had an M.D.

Employees and Human Capital

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

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

Patients first:

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.

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.

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 2020.

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.

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

Corporate Information

Our principal executive offices are located at 1111 Dr.

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

Available Information

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

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

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.

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.

Our website address is included in this Annual Report on Form 10-K as an inactive technical reference only.

Investors and others should note that we announce material information to our investors using one or more of the following:

SEC filings, press releases and our corporate website, including without limitation the “Investors” and “Events and Presentations” sections of our website.

We use these channels, as well as social media channels such as LinkedIn, in order to achieve broad, non-exclusionary distribution of information to the public and for complying with our disclosure obligations under Regulation FD.

It is possible that the information we post on our corporate website or other social media could be deemed to be material information.

Therefore, we encourage investors, the media, and others interested in our company to review the information we post on the “Investors” and “Events and Presentations” sections of our corporate website and on our social media channels.

The contents of our corporate website and social media channels are not, however, a part of this Annual Report.

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