What changed in this filing

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Item 1. Business

2024-03-21 compared with 2023-03-29 · 192 added, 138 removed, 670 unchanged (33% of the section changed)

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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.

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

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

It can be life-altering as PSVT is highly symptomatic, characterized by unpredictable attacks of a racing heart, often exceeding 150 beats per minute.

Symptoms of PSVT arise suddenly and may 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.

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

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

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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.

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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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.

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

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

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

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

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

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

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

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

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

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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.

An estimated five million Americans suffer from AFib.

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

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

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

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

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

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

New Drug Application Status

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PSVT Phase 3 Program Highlights:

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

PSVT Clinical Development Highlights

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

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

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

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

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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.

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 emergency department setting under medical supervision.

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

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

AFib-RVR Clinical Development Highlights

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

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

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

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

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

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

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

Arrhythmia and Electrophysiology .

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

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

placebo in maximum reduction from baseline:

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

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

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

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

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

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

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

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

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

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

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A normal PR interval is 0.12-0.20 seconds.

ECG Tracing Graph – Event Single Heartbeat

ECG Tracing Graph – Heartbeat

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

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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.

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.

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

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.

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

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

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

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

serum esterases.

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

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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.

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.

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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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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.

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

Both trials assessed nasally administered etripamil compared to placebo.

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

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

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.

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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.

Phase 1 Clinical Data

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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 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.

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

(MSP-2017-1096) - Pharmacology

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(MSP-2017-1205) NODE-102

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

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

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

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

Compared to baseline and time 0, systolic blood pressure

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

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.

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(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.

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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]).

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

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

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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.

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

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

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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.

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.

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

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

16, 43) compared to 50 minutes (95%

31,101) for placebo.

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(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).

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

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

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

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

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

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

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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.

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

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

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

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Atrial Fibrillation

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 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.

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

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

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

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

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

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

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

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

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

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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 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.

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

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

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

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

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

This research

suggests the share of patients experiencing ≥1 symptomatic episode of AFib requiring treatment may constitute 30-40% of the prevalent 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.

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

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

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

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

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

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

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

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

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

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

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

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

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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.

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

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

The 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 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.

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

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

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

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

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

-40.31, -19.52;

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

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

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

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

ReVeRA Primary Endpoint – Maximum Reduction in Ventricular Rate from Baseline

Primary Endpoint:

Maximum Reduction in VR from Baseline

Etripamil NS, 70 mg,

Mean (95% CI), bpm

-5.06 (-7.44, -2.67)

-34.97 (-45.13, -24.87)

Difference in means (95% CI), bpm

-29.91 (-40.31, -19.52)

1 Efficacy population (all randomized patients receiving study drug remaining in atrial fibrillation with adequately diagnostic ECG recordings for at least 60 min post drug)

2 From ANCOVA;

calculations adjust for variance in baseline

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

--------------------------------

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

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

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

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

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

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

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

The TESAEs in the etripamil arm (transient severe bradycardia and syncope, assessed as due to hyper-vagotonia occurred in a patient with a history of vagal events, and fully resolved by placing the patient supine and was without sequelae.

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

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

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

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

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

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

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

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

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

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

Etripamil in Other Therapeutic Applications

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

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

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

demonstrated clinical utility.

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

Sales and Marketing

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

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

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

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

investments in digital and targeted non-personal promotion.

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

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

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

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

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

Many of our potential competitors have substantially greater financial, technical and human resources than we do and significantly greater experience in the discovery and development of product candidates, as well as in obtaining regulatory approvals and commercializing those product candidates in the United States and in foreign countries.

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

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

United States and in foreign countries.

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

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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.

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.

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

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

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

As of December 31, 2023, our patent portfolio as it pertains to etripamil included:

• a patent family containing six U.S.

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

patent application, which, if granted, is projected to expire in 2036, as well as 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.

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

• 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.

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

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

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

effectively lost as a result of FDA regulatory review periods.

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

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

Failure to comply with the applicable United States requirements at any time during the drug development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve a pending New Drug Application, or NDA, withdrawal of an approval, imposition of a clinical hold, issuance of warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

Failure to comply with the applicable United States requirements at any time during the drug development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve an NDA, withdrawal of an approval, imposition of a clinical hold, issuance of warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

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

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

Phase 4 clinical trials, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product.

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

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

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

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

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

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

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

Coverage and Reimbursement

Medicare and Medicaid, private health insurers and other third-party payors, provide coverage of and establish adequate reimbursement levels for our product candidates.

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

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

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

Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Healthcare Reform

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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.

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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.

Moreover, prior to the U.S.

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

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

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

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.

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

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

It is unclear how such challenges and the healthcare reform measures of the Biden administration will impact the PPACA.

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

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

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

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

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

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

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

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

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

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.

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

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

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.

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

These provisions take effect progressively starting in fiscal year 2023.

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

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

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

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

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

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

While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.

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.

For example, on January 5, 2024, the FDA approved Florida’s Section 804 Importation Program, or SIP, proposal to import certain drugs from Canada for specific state healthcare programs.

It is unclear how this program will be implemented, including which drugs will be chosen, and whether it will be subject to legal challenges in the United States or Canada.

Other states have also submitted SIP proposals that are pending review by the FDA.

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

Foreign Regulation

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As of December 31, 2023, we had 47 full-time employees, 11 of whom were primarily engaged in research and development activities.

Four of these employees have an M.D.

Five of these employees have an M.D.

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

Our headquarters is currently located in Montréal (Québec), Canada and consists of 7,700 square feet of leased office space under a lease that expires in November 2025 with an option to terminate in November 2023.

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

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

We also have a U.S.

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

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

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

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.

9 unchanged sentences

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