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Item 1. Business

2023-03-29 compared with 2022-03-24 · 334 added, 349 removed, 474 unchanged (59% of the section changed)

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

Our lead product candidate etripamil is a novel, 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 for the treatment of specific arrhythmias with a lead indication to treat PSVT, with subsequent indications to treat atrial fibrillation and rapid ventricular rate, or AFib-RVR, and other cardiovascular indications.

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

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

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

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

Calcium channel blockers available in oral form are frequently used prophylactically to control the frequency and duration of future episodes of SVT.

For treatment of episodes of SVT, approved calcium channel blockers are administered intravenously under medical supervision, usually in the emergency department.

The combination of convenient nasal-spray delivery, rapid-onset and short duration of action of etripamil has the potential to shift the current treatment paradigm for episodes of SVT away from the burdensome and costly emergency department setting.

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

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

Pharmacologic treatment of PSVT focuses on terminating the arrhythmia using an agent to slow conduction over the AV node.

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

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

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

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

For rate control, the rapid heart rate of atrial fibrillation is typically treated with AV nodal blocking drugs (for example, calcium channel blockers, beta blockers, or less commonly digoxin) to control symptoms and improve cardiac function/hemodynamic stability.

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

We believe that PSVT is a large and under-recognized market that we estimate affects approximately two million Americans and results in over 600,000 healthcare claims in the United States alone per year, including more than 150,000

emergency department visits and hospital admissions and up to 80,000 ablations.

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

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

For our planned second indication, AFib-RVR, the American Heart Association (AHA) estimates that in 2016 approximately five million people suffered from AFib in the United States.

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

the AHA suggests a prevalence of seven million by 2030, while the Centers for Disease Control (CDC) reports this prevalence as increasing to 12 million over the same time period.

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

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

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

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

NODE-303 is an open-label global safety trial enrolling patients to collect safety data that when combined with the safety data from the rest of the program will form the safety dataset to be evaluated by the FDA and other regulatory agencies to form the basis for marketing approval.

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

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

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

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

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 the pharmacological activity of etripamil, results from the latter part of the analysis confounded the statistical analysis of the primary endpoint.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Safety Studies

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.

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

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

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

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

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

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

PSVT is a highly symptomatic and impactful heart arrhythmia characterized by unpredictable attacks of a racing heart, often exceeding 150 beats per minute.

Symptoms of PSVT often arise suddenly and include palpitations, sweating, chest pressure or pain, shortness of breath, sudden onset of fatigue, lightheadedness or dizziness, fainting, and anxiety, causing many patients to interrupt their daily activities at the time of symptom-onset.

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

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

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

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

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

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

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

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

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

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

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

Regardless of the chronic approach, when faced with an episode of AFib-RVR, acute rate control is called for most commonly in the form of oral AV-nodal targeted drugs such as a beta blocker or calcium channel blockers.

However, these oral rate control drugs, when used acutely, do not adequately provide immediate ventricular rate control due to a 30- to 60-minute delayed onset of action, and, as a result, many patients seek faster and more certain rate reduction and symptom resolution by going to the emergency department for acute treatment utilizing intravenous rate control and/or electrical cardioversion of their atrial fibrillation.

Similar to PSVT, patients feel a loss of control by needing to visit the emergency department for overcoming

their atrial fibrillation attack, doctors are frustrated by the lack of options for patients to self-manage these acute rate attacks and payer organizations would prefer to treat the AFib-RVR attacks in a more cost effective and time-efficient manner.

Our objective is to develop and commercialize etripamil as a fast-acting nasal spray to be prescribed by the doctor so that the patient can carry etripamil with them for use wherever and whenever an attack occurs.

We have completed patient conduct (last patient last visit) in the Phase 3 clinical trials for the lead indication and we plan to submit a New Drug Application, or NDA, for marketing approval in the United States for etripamil for the treatment of PSVT mid-2023.

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

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

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

Etripamil is currently in Phase 2 clinical development for assessing its safety and effectiveness in AFib-RVR.

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

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

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

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

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

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

The American Heart Association estimates a prevalence for AFib 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.

According to the Healthcare and Utilization Project, AFib resulted in 660,000 patient visits to the emergency department and 465,000 admissions to the hospital in 2016.

From market research we estimate the target addressable market for etripamil in patients with AFib and rapid ventricular rate (RVR) as approximately 30 to 40% of the diagnosed prevalent population, defined as patients experiencing at least one symptomatic episode of AFib-RVR requiring treatment per year.

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

PSVT Phase 3 Program Highlights:

The RAPID, NODE-301, NODE-302, and NODE-303 Trials

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

These results were further presented shortly thereafter, on November 7, 2022, as a Late-Breaking Clinical Trial at the American Heart Association Scientific Meetings (Chicago, IL).

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

Patients were randomized 1:1 to a regimen of self-administering a first dose etripamil nasal spray, with a repeat dose 10 minutes later if symptoms persisted, or a matching placebo regimen.

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

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

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

hazard ratio, or HR, 2.62;

95% CI 1.66, 4.15;

By 90 minutes post-study drug administration, 80.6% of etripamil patients converted versus 60.7% of placebo patients (HR = 1.93;

95% CI 1.349, 2.752;

p<0.001) and statistical significance was maintained throughout the 5-hour observation window.

Statistically significant reductions in time to conversion in patients who took etripamil were evident early and persisted throughout the observation window of the study compared to placebo.

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

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

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

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

There were no serious AEs related to etripamil.

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

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

p=0.013) and had 39% fewer emergency department visits (14% vs.

p=0.035) than patients in the placebo arm.

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

After consultation with the regulatory authorities, it was concluded that the test doses procedure was an unnecessary step for the self-administration of etripamil and it was removed from the requirements of the NODE-303 safety study.

The NODE-303 trial was initiated with an etripamil 70 mg single-dose regimen and the 70 mg optional repeat-dose regimen was introduced into the trial starting in the second half of 2021 following FDA acceptance of the protocol amendment.

The trial was sized in order to add to the safety data from the remainder of the development program, including those data already obtained from the RAPID, NODE-301 and NODE-302 trials, in order to fulfill the safety and exposure dataset needed for NDA filing.

Following the results from the RAPID study, initially obtained in October 2022, and the assessment of the total exposures to etripamil in the development program to date, we believe we have the safety dataset needed for review of the NDA for PSVT and have moved to the closure stage of the NODE-303 study.

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

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

Phase 2 Proof of Concept Trial in AFib-RVR

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

The NODE-301 trial is a placebo-controlled Phase 3 safety and efficacy trial and the first trial ever conducted to treat attacks of PSVT in the at-home setting.

NODE-301 enrolled 431 patients across 65 sites in the United States and Canada.

Although the study 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 in which patients wore a cardiac monitor, both prespecified and post hoc analyses at earlier time periods, namely at 30 minutes, showed significant treatment effects in favor of etripamil.

For example, in a post hoc analysis of the NODE-301 data, 54% of etripamil patients vs.

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

The safety and tolerability data from the NODE-301 trial support the potential self-administration use of etripamil, with the most common randomized treatment emergent adverse events, or RTEAEs, adverse events, or AEs, which occurred within 24 hours of etripamil administration, being related to the nasal local administration site.

Overall, the majority of RTEAEs were reported as mild (85%) to moderate (15%).

There were no serious AEs related to etripamil.

After reviewing the data from NODE-301 with the FDA in July 2020, the Agency indicated that an analysis period shorter than 5 hours would be appropriate to measure the efficacy of etripamil.

The FDA indicated that two trials, the RAPID and NODE-301 trials could potentially fulfill the efficacy requirement for our planned NDA for etripamil in patients with PSVT, both using time to conversion over the first 30 minutes with a target p-value of less than 0.05 as the primary endpoint.

NODE-302 is a Phase 3 multi-center, open-label safety extension of the NODE-301 trial.

Patients who completed NODE-301 and enrolled in NODE-302 could administer open-label drug for up to an additional 11 episodes of PSVT.

The study’s objective is 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 over recurrent episodes.

While the primary purpose of the trial is safety, efficacy assessments were also performed.

We presented data from the NODE-302 study at a late-breaking session of the Heart Rhythm Society’s Heart Rhythm 2022 Annual conference.

Of 198 eligible NODE-301 patients, 169 (85%) enrolled in NODE-302 and 105 (62%) experienced a perceived episode of PSVT, self-administered etripamil and were included in the safety population.

Overall, the rate of conversion of PSVT to normal sinus rhythm at 30 minutes following etripamil administration was 60.2% with a median time to conversion of 15.5 minutes (95% CI, 11.3-22.1 minutes), findings consistent with those from other studies, even those of a different design, indicating robustness of results.

Among 40 patients who self-treated two separate episodes, 21 of 26 (81%) who converted on their first episode were also successfully converted on their second episode.

Moreover, the need for an external medical intervention (e.g., an intravenous therapy administered in an emergency department) to terminate a PSVT episode was low (13% of patients and 8.5% of positively adjudicated PSVT episodes).

Etripamil was generally well-tolerated, with adverse events consistent with those observed in previous trials;

most adverse events related to treatment were localized to the nasal administration site and were mild and transient.

AFIB RVR Phase 2 Proof of Concept Trial:

Reduction of Ventricular Rate in Patients with Atrial Fibrillation (ReVeRA)

The Phase 2, double-blind, placebo-controlled, proof-of-concept study, Reduction of Ventricular Rate in Patients with Atrial Fibrillation (ReVeRA), in patients with atrial fibrillation with rapid ventricular response (AFib/RVR), is being conducted in Canada and the Netherlands in collaboration with the Montreal Heart Institute, the WCN network, and other research centers.

The ReVeRA study is expected to enroll approximately 50 patients randomized 1:1 to receive either 70 mg of etripamil nasal spray or placebo to patients presenting with symptomatic AFib/RVR.

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

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

The COVID-19 pandemic

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

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, AFib-RVR, and other areas of unmet medical need.

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

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

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

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

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

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

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

We 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.

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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.

We are establishing commercialization and marketing capabilities with a focus to commercialize etripamil in the United States.

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

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

Cardiac Conduction

Cardiac and Pharmacologic Basis of Development Programs

Normal Conduction

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

The sinus node 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.

Once the signal reaches the ventricles, it causes them to contract, pumping blood out to the body.

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

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

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

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

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

A normal PR interval is 0.12-0.20 seconds.

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.

A faster than normal heat rate is called tachycardia;

a slower than normal heart rate is called bradycardia.

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

pain, shortness of breath or sweating.

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

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

A faster than normal heart rate is a tachycardia;

a slower than normal heart rate is a bradycardia.

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

these symptoms can be markedly severe, and in

advanced cases of some arrhythmias, resultant signs can include worse morbidities and even mortality.

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

Pharmacologic treatment of PSVT focuses on terminating the arrhythmia using an agent to slow conduction over the AV node.

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

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

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

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

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

Short pharmacological action is sufficient to resolve an episode of SVT.

Accordingly, long-lasting drugs that remain in the body at significant concentrations long after the episode is resolved subject patients to unnecessary risk, given the potential for prolonged adverse events.

Currently, we are in Phase 3 development for PSVT.

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.

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

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

Rapid pharmacological action is both appropriate and sufficient to resolve an episode of SVT.

We have completed Phase 3 development for PSVT.

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

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

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

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

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

We believe that the following attributes of etripamil make it a better treatment candidate for certain episodic cardiovascular conditions than current standards of care:

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

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

Etripamil is designed to be rapidly metabolized by blood-borne esterases, with the goal of reducing long-term side effects that may occur with chronic drug therapy.

• Absorption:

Etripamil is designed to be absorbed into the bloodstream in less than 10 minutes through the inner lining of the nose, yielding a rapid-onset pharmacologic pattern consistent with parenterally administered drugs.

● Administration:

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

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

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

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

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

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

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

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

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

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

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

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.

As shown in the figure below, when that extra tissue forms within or near the AV node, the signal can now travel down one part of the AV node and up the other in a small circle, sending impulses out to both the atria and ventricles along the way.

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

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 heartbeat by traveling from the atria to the ventricles over the AV node.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In the most common form of PSVT, AV nodal reentrant tachycardia, or AVNRT, there is an abnormal limb of

electrical circuitry within the AV node which represents the substrate of the tachycardia.

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

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

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

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

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

Current Treatment Options for PSVT

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

However, these interventions are generally not acutely effective.

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

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

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

Adenosine is eliminated from the body in less than one minute but cannot

be self-administered as it requires IV access.

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

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

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

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

However, they are associated with the risk of excessive slowing of the heart rate and

low blood pressure.

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

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

Market Opportunity

Market Opportunity – Paroxysmal Supraventricular Tachycardia (PSVT)

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

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

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

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

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

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

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

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

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

In the year following diagnosis, costs triple for those less than 65 years of age and double

for those over 65 years of age, compared to matched controls.

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

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

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

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

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

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

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

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

on the management of PSVT.

Our Clinical Development Program for the Treatment of PSVT

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.

Our Clinical Development Program for the Treatment of Paroxysmal Supraventricular Tachycardia

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

We believe that etripamil will fill this unmet need.

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

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

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

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

We have 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.

Both trials assessed nasally administered etripamil compared to placebo.

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

We have completed a second pivotal Phase 3 trial (RAPID) which demonstrated highly statistically significant efficacy to convert PSVT and favorable safety/tolerability of the drug We have completed additional Phase 1 clinical trials, one that further characterized the PK and PD of intranasal etripamil in Japanese and non-Japanese healthy volunteers;

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

repeated-dose approaches.

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

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

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

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

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

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

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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.

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

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

The most commonly reported side effects were related to nasal irritation and nasal congestion.

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

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

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

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

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

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

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

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

PSVT and AFib-RVR.

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

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

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

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

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

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Error bars indicate standard error of the mean

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

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

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

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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-blocking agents such as adenosine, verapamil, and tecadenoson.

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

(MSP-2017-1096) - Pharmacology

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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.

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

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

With regard to pharmacodynamics, 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.

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

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

(MSP-2017-1205) NODE-102

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

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

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

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

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

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

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

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

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

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

One dose of 70-mg etripamil vs.

repeat dose regimen administered 10 minutes apart

Error bars = standard error

Phase 2 Clinical Data

We completed a Phase 2 multicenter, randomized, double-blind, placebo controlled clinical trial in the United States and Canada 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.

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

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

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

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

70 due to inability to induce (n=42) or sustain (n=28) SVT, 5 based on physician discretion, 1 lost to follow up, 1 due to withdrawal of consent, and 18 for other reasons.

The mean age of patients was 52.2 years, with the study enrolling patients as young as 19 and as old as 85.

As shown in the figure below, SVT was induced and sustained for 5 minutes in 104 patients, who were randomized into one of five dosing cohorts.

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.

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

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

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

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

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

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

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(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.

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

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

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

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

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

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

However, these were transient.

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

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

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

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

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

however, these were transient and required no specific intervention.

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

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The incidence of adverse events was not dose-dependent.

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

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

Neither event led to sequelae or a serious classification.

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

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

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

The AV block resolved after 43 minutes, and ablation was subsequently performed.

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

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

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

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

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

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

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

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

Compared to baseline and time 0, systolic blood pressure measurements recorded from 2 minutes to 16 minutes post study drug administration showed no decrease in mean systolic blood pressure in the placebo or 35 mg groups, and maximum mean decreases of 2 mmHg four minutes post dose in the 70 mg group, 17

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

Compared to baseline and time 0, systolic blood pressure

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

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

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

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

Ongoing and Planned Clinical Development of PSVT

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

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

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

Clinical Development of Etripamil for a PSVT Indication

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

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

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

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

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

Phase 3 Clinical Trials

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

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

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

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

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

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

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

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

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

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

The graphic below shows the design of the RAPID trial.

The protocol amendment changing NODE-301 part 2 to RAPID and incorporating the repeat dose administration was fully implemented across all clinical study sites over a time period that completed in 2021.

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

groups C+D in the trial design graphic).

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

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

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

(MSP-2017-1138) RAPID – Trial Design

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

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

(2) Wilcoxon analysis modeling from NODE-301 data

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

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

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

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

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

control) provides

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

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

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

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

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

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

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

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.

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

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

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

of approved at-home treatments.

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

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

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

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

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

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

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

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

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

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

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

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

Safety outcomes were assessed.

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

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

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

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

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

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

Primary Endpoint:

Conversion of Adjudicated PSVT to NSR 30 min

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

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

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

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

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

there were no serious etripamil-related events.

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

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

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

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

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

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

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

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

Upon experiencing symptoms of an SVT episode, patients were instructed to first apply the

cardiac monitoring device to record ECG data, then attempt a vagal maneuver, and, if that was not successful in terminating the episode, to then administer the study drug.

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

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

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

In March 2020, we reported topline results of the 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.

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

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

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

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31,101) for placebo.

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

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

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

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

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

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

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

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

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

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

The study also demonstrated statistically significant improvements in patients taking etripamil compared to those taking placebo in the secondary endpoint of patient reported treatment satisfaction, as measured by a 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).

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

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

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

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

We initiated NODE-302 in December, 2018.

The trial completed enrollment in 2020 and the study is in the process of being published.

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

NODE-303 is an open-label global safety trial enrolling patients who did not participate in NODE-301 or NODE-302 or RAPID in order to collect safety data that when combined with the safety data from the rest of the program

will form the safety dataset to be evaluated by the FDA and other regulatory agencies to form the basis for marketing approval.

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

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

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

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

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

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

The NODE-303 trial is designed to closely reflect the expected utilization of etripamil in the post approval or ‘real-world’

setting and, for example, does not include an in-office safety test dose and includes a broad patient population including patients taking concomitant beta blockers and calcium channel blockers.

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

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

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

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

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

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

Atrial Fibrillation

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

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

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

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

AFib can be, and often is, highly symptomatic.

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

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

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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.

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

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

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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.

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

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

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

Current Treatment Options for AFib

There are currently two pharmacological approaches to managing atrial fibrillation:

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

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

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

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

Current Treatment Options for Atrial Fibrillation with Rapid Ventricular Rate

There are currently two major approaches to managing atrial fibrillation:

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

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

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

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

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

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

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

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

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

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

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

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

Market Opportunity – AFib

Market Opportunity – Atrial Fibrillation with Rapid Ventricular Rate

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

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

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

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

We derive this percentage estimate

from 2021 market research studies conducted by us that involved qualitative interviews and quantitative surveys with a total of 275 electrophysiologists, general cardiologists, and interventional cardiologists.

Additionally, approximately 465,000 patients were admitted to the hospital with AFib (same ICD-10 codes).Our qualitative and quantitative market research indicates that the target addressable market for etripamil in patients with AFib-RVR is approximately 30-40% of the diagnosed population of patients with atrial fibrillation.

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

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

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

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

This research

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

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

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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).

This report suggests atrial fibrillation resulted in $25 billion in direct medical costs in 2016 (approximately 7% of all cardiovascular diseases) and another $7 billion in indirect costs (i.e., $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 began enrollment in our Phase 2 proof-of-concept clinical trial, named ReVeRA, in the first quarter of 2021 to evaluate the potential effectiveness of etripamil to reduce ventricular rate in patients with atrial fibrillation and rapid ventricular rate.

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

Clinical Development Plan for Atrial Fibrillation with Rapid Ventricular Rate

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

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

The ReVeRA Phase 2 double blind, placebo controlled, proof-of-concept trial is expected to enroll approximately 50 patients randomized 1:1 to receive either 70 mg of etripamil nasal spray or placebo.

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

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

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

The expansion of study sites in Canada and the program most recently having sites in the Netherlands is anticipated to promote enrollment.

These trial data, along with data from the PSVT program, is expected to form the basis for proceeding with a full, registrational program in AFib-RVR.

Etripamil in Other Therapeutic Applications

Our goal in expanding our pipeline around etripamil is to apply the same paradigm-changing aspiration that we have for supraventricular tachycardias like PSVT and AFib 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.

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

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

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

Both calcium channel blockers and beta blockers are commonly used to manage not only supraventricular tachycardias like PSVT or AFib-RVR, and other conditions.

Sales and Marketing

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

If etripamil receives marketing approval, we plan to commercialize it in the United States with a focused, specialty sales force that could consist of our own employees, outsourced sales professionals, or a hybrid model using both internal and

external resources.

We believe that this commercial organization at the launch of etripamil will consist of approximately 150 to 200 field sales representatives that will call on top-prescribing clinical cardiologists, interventional cardiologists, electrophysiologists, and high-volume primary care physicians who have a history of prescribing anti-arrhythmic therapies.

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

We believe that this commercial organization at the launch of etripamil will consist of a field force of <100 individuals calling on primarily clinical cardiologists who treat large populations of patients with PSVT, supported by strategic

investments in digital and targeted non-personal promotion.

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

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

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

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

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

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

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

Manufacturing

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

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

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

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

of several drugs or new formulations of existing drugs under development or recently under development for atrial fibrillation, including InRhythm (flecainide), a sodium channel blocker in Phase II from InCarda Therapeutics, Inc., and Gencaro (bucindolol hydrochloride), a beta blocker in Phase 2 from ARCA biopharma, Inc.

We are aware of several drugs or new formulations of existing drugs under development or recently under development for atrial fibrillation, including InRhythm (flecainide), a sodium channel blocker in Phase 3 from InCarda Therapeutics, Inc., and 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 March 21, 2022, our patent portfolio as it pertains to etripamil included:

As of February 28, 2023, our patent portfolio as it pertains to etripamil included:

• a patent family containing six U.S.

patents, projected to expire in 2028, a pending U.S.

patent application, which, if granted, is projected to expire in 2028, as well as corresponding patents in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Mexico, New Zealand and South Korea, directed to etripamil, pharmaceutical compositions including etripamil, and uses of etripamil such as to treat angina or cardiac arrhythmias, including PSVT and atrial fibrillation;

patent application, which, if granted, is projected to expire in 2028, as well as corresponding patents in Australia, Brazil, Canada, China, Europe, Hong Kong, India, Japan, Mexico, New Zealand and South Korea, directed to etripamil, pharmaceutical compositions including etripamil, and uses of etripamil such as to treat cardiac arrhythmias, including PSVT and atrial fibrillation;

• a patent family containing one U.S.

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

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

• a patent family containing two pending U.S.

provisional patent applications and a pending Canadian patent application, which, if granted, is projected to expire in 2041, directed to uses of formulations including etripamil to treat angina, cardiac arrhythmias, such as PSVT and atrial fibrillation, or migraines.

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

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

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

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

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

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

Our ability to

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

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

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

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

Under the 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.

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

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

order for FDA to reconsider the application.

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

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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.

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.

After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, are subject to further testing requirements and FDA review and approval.

Special FDA Expedited Review and Approval Programs

The FDA has various programs, including fast track designation, accelerated approval, priority review, and breakthrough therapy designation, which are intended to expedite or simplify the process for the development and FDA review of drugs that are intended for the treatment of serious or life threatening diseases or conditions and demonstrate the potential to address unmet medical needs.

The purpose of these programs is to provide important new drugs to patients earlier than under standard FDA review procedures.

To be eligible for a fast track designation, the FDA must determine, based on the request of a sponsor, that a product is intended to treat a serious or life-threatening disease or condition and demonstrates the potential to address an unmet medical need.

The FDA will determine that a product will fill an unmet medical need if it will provide a therapy where none exists or provide a therapy that may be potentially superior to existing therapy based on efficacy or safety factors.

The FDA may review sections of the NDA for a fast track product on a rolling basis before the complete application is submitted.

If the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

The FDA may give a priority review designation to drugs that are designed to treat serious conditions, and if approved, would provide a significant improvement in treatment, or provide a treatment where no adequate therapy exists.

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.

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

In addition, products studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may be eligible for accelerated approval and may be approved on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.

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

Breakthrough therapy designation is for a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may

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

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

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

We may explore some of these opportunities for our product candidates as appropriate.

Rare pediatric disease designation by the FDA enables priority review voucher, or PRV, eligibility upon U.S.

market approval of a designated drug for rare pediatric diseases.

The RPD-PRV program is intended to encourage development of therapies to prevent and treat rare pediatric diseases.

The voucher, which is awarded upon NDA or BLA approval to the sponsor of a designated RPD can be sold or transferred to another entity and used by the holder to receive priority review for a future NDA or BLA submission, which reduces the FDA review time of such future submission from ten to six months.

Post Approval Requirements

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

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

to operate our business and our results of operations.

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

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.

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

a new Medicare Part D coverage gap discount program;

a new Medicare

Part D coverage gap discount program;

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

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

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

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

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

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

Prior to the U.S.

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

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

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

The IRA also eliminates the "donut hole"

under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

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

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

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.

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

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

through federal budget proposals, executive orders and policy initiatives.

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

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

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

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

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

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

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

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

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

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

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

At the 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.

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

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

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

These provisions will take effect progressively starting in fiscal year 2023, although they may be subject to legal challenges.

Additionally, the Biden administration released an additional executive order on October 14, 2022, directing HHS to report on how the Center for Medicare and Medicaid Innovation can be further leveraged to test new models for lowering drug costs for Medicare and Medicaid beneficiaries.

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

Foreign Regulation

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As of December 31, 2022, we had 39 full-time employees, 15 of whom were primarily engaged in research and development activities.

Seven of these employees have an M.D.

Four of these employees have an M.D.

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

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We also have a U.S.

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

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

subsidiary for preparation of commercialization.

subsidiary in Charlotte, North Carolina that occupies 13,050 square feet of leased office space under a lease that expires in September 2027.

Legal Proceedings

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

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

Our US offices are located at 6210 Ardrey Kell Rd, Suite 650, Charlotte, NC 28277 and our telephone number is (704) 848-5316.

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.

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

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

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

What changed 10-K

Item 1. Business