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We are a biopharmaceutical company focused on the development and commercialization of innovative cardiovascular medicines.
−Removed: Our objective is to commercialize and develop CARDAMYST (also known as etripamil) in the United States as a fast-acting, portable nasal spray treatment for use by patients anywhere, anytime an attack of supraventricular tachycardia, or “SVT” occurs.
+Added: Our approved product CARDAMYST TM (etripamil) nasal spray is available in the United States and is the first and only FDA approved self-administered treatment for use by patients anywhere, anytime an attack of PSVT occurs.
+Added: We continue to seek, either directly or through collaboration with our partners, marketing approval from regulatory agencies responsible for regions outside the United States.
We are also developing etripamil for the indication of atrial fibrillation with rapid ventricular rate, or “AFib-RVR.”
−Removed: CARDAMYST TM (etripamil) nasal spray
−Removed: We are currently focused on obtaining marketing approval of CARDAMYST for the treatment of paroxysmal supraventricular tachycardia, or “PSVT” from the U.S.
−Removed: Food and Drug Administration, or “FDA.” We expect that the FDA will make their final decision regarding the marketing approval of CARDAMYST for PSVT by March 27, 2025, which is also known as the Prescription Drug User Fee Act, or “PDUFA,” review goal date.
−Removed: We are also developing etripamil nasal spray for a subsequent indication to treat patients with AFib-RVR.
−Removed: Similar to our approach for PSVT, we believe that etripamil has the potential to help the person experiencing a symptomatic episode of AFib-RVR to self-treat themselves and to conveniently, reliably, and quickly, reduce their elevated heart rate, with the goal of reducing the need for emergency department utilization.
−Removed: We completed a successful Phase 2 study in patients presenting urgently with AFib-RVR, i.e., to an emergency department.
−Removed: We publicly presented these positive Phase 2 data in November 2023, which demonstrated that patients receiving etripamil nasal spray experienced rapid and statistically superior ventricular rate reduction and improved symptom-relief compared to placebo, with safety and tolerability findings generally consistent with those observed in our PSVT program.
−Removed: This data supports the development of etripamil, self-administered in the medically unmonitored setting, for the treatment of AFib-RVR and, following dialogue with FDA, have finalized a Phase 3, potentially registrational study.
−Removed: PSVT Market Overview
−Removed: PSVT is a condition that causes a patient’s heart to suddenly start beating faster than normal.
−Removed: It can be life-altering as PSVT is highly symptomatic, characterized by unpredictable attacks of a racing heart, often exceeding 150 beats per minute.
−Removed: 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.
−Removed: 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.
−Removed: The uncertainty of when such an attack of PSVT will strike or how long it will persist is often anxiety-provoking, reducing patients’ quality of life and preventing participation in many desired activities.
−Removed: Drugs approved for the treatment of attacks of PSVT include adenosine, verapamil, and diltiazem, with all being administered intravenously under medical supervision, usually in the emergency department.
−Removed: 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.
−Removed: Doctors are often frustrated by the lack of effective treatment options besides a prolonged, unpleasant, and costly trip to the emergency department or, for some patients, an invasive ablation procedure.
−Removed: PSVT can be traumatic for patients, frustrating for healthcare providers, and costly for payors.
−Removed: With no pharmaceutical innovation in the treatment of PSVT for more than 30 years and a movement in the healthcare system to enable patient-centered care, we believe there is an opportunity to help patients living with PSVT to take greater control over their PSVT.
−Removed: We believe that PSVT is a large and under-recognized market which we estimate affects more than two million Americans.
−Removed: From this diagnosed population, we define the immediate target addressable market for CARDAMYST as approximately 60% of patients who are actively managed by clinical cardiologists, interventional cardiologists and electrophysiologists.
−Removed: The remaining patients with PSVT can become addressable over time, as they are inconsistently managed (cycling in and
−Removed: out of the healthcare system) and/or being managed less frequently by primary care healthcare providers.
−Removed: Furthermore, PSVT is expected to increase in prevalence in coming years as wearable electrocardiogram, or “ECG,” technology (e.g., smartphone, watches) becomes both more adept at diagnosing PSVT and more widely used by patients and clinical practitioners, in turn shortening the current two to three year average time to diagnosis.
−Removed: Following the release of data from the RAPID clinical study in market research, cardiologists reported a willingness to prescribe CARDAMYST to approximately 50% of the patients with PSVT in their care, which suggests approximately 500,000 to 800,000 patients can potentially be treated with CARDAMYST in peak years.
−Removed: Additionally, we believe that this cardiology-identified group of patients may use CARDAMYST to treat a median of three to five episodes per year, based on the projected number of self-reported longer and more intense episodes experienced by patients, as well as the patient utilization experience in our Phase 3 clinical trials.
−Removed: This implies a peak demand potential in the United States for CARDAMYST of 2.5 million to 4 million episodes treated per year.
−Removed: Current treatment for PSVT also consumes significant healthcare resources.
−Removed: Research published in the American Journal of Cardiology in 2020 shows that total healthcare expenditures in the year following a diagnosis of PSVT ranged from $20,000 to $30,000 per patient which were significantly higher than the expenditures observed for patients without PSVT.
−Removed: These significant increases included increased emergency department visits and hospitalization costs.
−Removed: Of note, catheter ablations following diagnosis represented only 23% of this increased spend, meaning most costs were unrelated to ablations.
−Removed: Recent data from the Healthcare Cost and Utilization Project (HCUP) database indicate that in 2019 there were approximately 140,000 emergency department, or “ED,” visits for PSVT when coded in the primary diagnostic position, and a total of approximately 525,000 ED visits when PSVT was coded in any diagnostic position.
−Removed: Of these, approximately 25% of ED admissions for PSVT resulted in a hospital admission.
−Removed: HCUP estimates a total of approximately 40,000 to approximately 120,000 inpatient admissions for PSVT in 2019 (based again if PSVT were found in the primary v.
−Removed: any diagnostic position).
−Removed: Despite the effectiveness of catheter ablation, claims data suggests that only approximately 15% of patients with PSVT are ablated over a three-year period, leading to a total of approximately 100,000 catheter ablations annually.
−Removed: In total, at least $5 billion is spent annually in the United States on the management of PSVT.
−Removed: AFib-RVR Market Overview
−Removed: Atrial Fibrillation, or “AFib,” is a common cardiac arrhythmia with an irregular and often rapid heart rate that is often markedly symptomatic and, without proper treatment, can increase the risk of stroke, heart failure, and other cardiovascular complications.
−Removed: A common complication of AFib is a rapid heart rate, also referred to as AFib-RVR, which is frequently defined as a heart rate ≥ 110 beats per minute.
−Removed: The occurrence of a rapid ventricular rate, or “RVR,” in patients with atrial fibrillation increases the likelihood of marked symptoms including heart palpitations, shortness of breath and weakness.
−Removed: There are two commonly used pharmacological approaches to chronically manage AFib, rhythm control and rate control.
−Removed: Regardless of the chronic approach, break-through episodes of rapid heart rate occur frequently;
−Removed: and when faced with a sudden episode of AFib-RVR, acute rate control is needed, with most treatments being AV-nodal targeted drugs such as a beta blocker or calcium channel blocker.
−Removed: These treatments can be given intravenously;
−Removed: however, this requires a burdensome trip to an emergency department which may lead to a hospital admission.
−Removed: Acute treatment can be attempted by administration of an oral rate control drug;
−Removed: however, such drugs do not adequately provide immediate or adequate ventricular rate control due to a 30- to 90-minute delayed onset of action, and, as a result, many patients need faster and more certain rate-reduction and symptom-resolution and so seek acute-medical care by going to the emergency department for treatment utilizing intravenous rate control and/or electrical cardioversion of their atrial fibrillation.
−Removed: Furthermore, the chronic administration of oral rate-control drugs does not broadly prevent episodes of AFib-RVR.
−Removed: Similar to PSVT, patients may feel a loss of control by needing to visit the emergency department for overcoming their AFib-RVR episode and the unpredictable nature of these episodes, which can occur anytime and anywhere.
−Removed: Doctors have expressed frustration at the lack of options for patients to self-manage these acute rate attacks;
−Removed: and payor organizations would prefer to treat the AFib-RVR attacks in a more cost effective and time-efficient manner.
−Removed: An estimated 10 million Americans suffer from AFib.
−Removed: The prevalence of AFib is expected to grow to greater than 12 million by 2030.
−Removed: A subset of patients with AFib experiences episodes of abnormally high heart rate, most often
−Removed: accompanied by palpitations, shortness of breath, dizziness, and weakness.
−Removed: While these episodes, known as AFib-RVR, may be treated by oral calcium channel blockers and/or beta blockers, patients frequently seek acute care in the ED to address symptoms.
−Removed: In 2019, nearly 1.1 million patients were admitted to the ED due to AFib symptoms.
−Removed: Initial data suggests that approximately 60% of all AFib ED visits were attributable to AFib-RVR, as symptoms driving patients to seek care generally become more pronounced at higher heart rates.
−Removed: Treatment for such symptoms typically includes medically supervised intravenous administration of calcium channel blockers or beta blockers, or electrical cardioversion.
−Removed: With little available data for AFib-RVR, we believe, based on our initial market research, that 30% to 40% of patients with AFib experience one or more symptomatic episodes of RVR per year that require treatment, suggesting a target addressable market of up to approximately four to five million patients by 2030 for etripamil in patients with AFib-RVR.
−Removed: We believe that etripamil has the potential to be developed such that it can be used by patients to rapidly reduce their heart rate at home, self-administered, to provide a supplemental option to either the acute oral rate or rhythm control strategy their physician would use.
−Removed: When presented with a target product profile reflecting this potential use case, cardiologists and electrophysiologists in a 2021 market research study perceived utility in the product profile and indicated that they would prescribe to approximately 67% of their patients that experience episodes of AFib-RVR.
−Removed: They further indicated that a rapidly-acting intranasal calcium channel blocker could serve as a “bridge” to the longer onset times of acute oral agents.
−Removed: According to physicians, it can take hours for patients to feel an alleviation of symptoms using acute oral rate or rhythm control.
−Removed: During this time, patients may experience concerning symptoms that often prompt them to seek emergency care.
−Removed: 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.
−Removed: Current AFib management consumes significant healthcare resources in the United States.
−Removed: The American Heart Association published a report in 2016 summarizing the current and projected cost burden of cardiovascular diseases in the United States.
−Removed: This report suggests atrial fibrillation resulted in $25 billion in direct medical costs in 2016 (approximately 7% of all cardiovascular diseases) and another $7 billion in indirect costs (i.e., up to $32 billion in total costs).
−Removed: 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.
−Removed: New Drug Application Status
−Removed: In May 2024, we announced that the FDA accepted our New Drug Application, or “NDA,” for CARDAMYST (etripamil) for the treatment of PSVT.
−Removed: The Company continues to engage the FDA throughout the NDA review process in the form of responses to FDA requests for information, as well as audits of manufacturing facilities and testing labs, clinical sites, clinical study support services and of our headquarters.
−Removed: The PDUFA goal date for action on the NDA is March 27, 2025.
−Removed: If approved, we believe that CARDAMYST will be the first and only self-administered therapy for the rapid termination of episodes of SVT wherever and whenever they occur.
−Removed: PSVT Clinical Development Highlights
−Removed: In April 2024, we announced new clinical data demonstrating real-world application of etripamil, an investigational new drug, for conversion of recurrent PSVT.
−Removed: Conducted in North and South America, an open label, Phase 3 study of etripamil in PSVT (the NODE-303 study) was presented at The American College of Cardiology Scientific Sessions.
−Removed: NODE-303 evaluated self-administered etripamil (70 mg, nasal spray) in an outpatient setting for up to four episodes of PSVT per patient.
−Removed: Other key characteristics of the NODE-303 study that distinguish the study from earlier Phase 3 studies, include the removal of the in-office test dose as well as the use of a broader inclusion exclusion study entry criteria.
−Removed: For example, NODE-303 did not exclude patients with a history of co-morbid AFib or atrial flutter.
−Removed: The results demonstrated that symptom-prompted treatment with etripamil restored sinus rhythm with a median time-to-conversion of 17 minutes and was generally well tolerated.
−Removed: The conversion of PSVT to sinus rhythm was similar among multiple episodes of PSVT and the frequency of treatment-emergent adverse events within 24 hours decreased with successively treated episodes.
−Removed: Adverse events, or “AEs,” were predominantly localized to the drug’s nasal administration site, consistent with prior trial findings.
−Removed: The protocol was amended during the trial to allow for a repeat dose of drug if
−Removed: symptoms persisted 10 minutes following the first dose, however most of the clinical trial was conducted prior to the amendment and used the 70 mg single dose.
−Removed: Efficacy of etripamil for PSVT conversion (restoration of sinus rhythm) in NODE-303 was 60.0% by 30 minutes after drug self-administration, and 69.9% by 60 minutes after drug self-administration;
−Removed: these rates of conversion are similar to those demonstrated in double-blinded and other open-label etripamil studies.
−Removed: This data supports a potentially significant shift in the management approach for recurrent PSVT.
−Removed: In October 2022, we announced positive and statistically significant topline efficacy and safety data from the Phase 3 RAPID clinical trial of etripamil in patients with PSVT.
−Removed: These results were further presented shortly thereafter, in November 2022, as a Late-Breaking Clinical Trial Session at the American Heart Association Scientific Sessions 2022 (Chicago, IL) and subsequently published in The Lancet (June 2023) .
−Removed: 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.
−Removed: 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.
−Removed: Self-administration was prompted by a patient’s customary symptoms and was performed in the at-home setting without medical supervision.
−Removed: The RAPID trial achieved its primary endpoint, with patients taking the regimen with etripamil demonstrating a highly statistically significant and clinically meaningful difference in time to SVT conversion as compared to placebo.
−Removed: A Kaplan Meier analysis demonstrated a significantly greater proportion of patients who took etripamil converted within thirty minutes compared to placebo (64.3% vs.
−Removed: hazard ratio, or “HR,” 2.62;
−Removed: 95% CI 1.66, 4.15;
−Removed: By 90 minutes post-study drug administration, 80.6% of etripamil patients converted versus 60.7% of placebo patients (HR = 1.93;
−Removed: 95% CI 1.349, 2.752;
−Removed: p<0.001) and statistical significance was maintained throughout the 5-hour observation window.
−Removed: 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.
−Removed: 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.
−Removed: The safety and tolerability data from the RAPID trial continues to support the potential self-administration use of etripamil, with findings consistent with those observed in prior trials.
−Removed: The most common randomized-treatment emergent adverse events, or “RTEAEs,” and AEs which occurred within 24 hours of administration of etripamil, were related to the nasal local administration site.
−Removed: Overall, the majority of RTEAEs were reported as mild (68%) or moderate (31%).
−Removed: There were no serious AEs related to etripamil.
−Removed: In March 2023, we completed NODE-303, a Phase 3, multi-center, open-label safety trial, evaluating the safety of etripamil when self-administered without medical supervision over multiple, separate episodes of SVT.
−Removed: Data from the completed NODE-303 open-label safety and RAPID extension studies are included in the PSVT NDA submission for etripamil to the FDA.
−Removed: The use of additional medical interventions and visits to an emergency department were important secondary measures of efficacy for both the RAPID and NODE-301 studies, although with the understanding that neither study was individually powered to expect statistical differences.
−Removed: In a pre-planned analysis across both studies, patients who self-administered etripamil sought additional medical interventions 43% less frequently (15% vs.
−Removed: p=0.013) and had 39% fewer emergency department visits (14% vs.
−Removed: p=0.035) than patients in the placebo arm.
−Removed: In September 2024, our licensing partner, Corxel (formerly Ji Xing Pharmaceuticals Limited, JIXING), a clinical-stage biopharmaceutical company announced positive topline data from the Phase 3 JX02002 clinical trial of etripamil nasal spray in patients with PSVT in China.
−Removed: The 500-patient Phase 3 trial (JX02002) met its primary endpoint, with a Kaplan Meier analysis shows a statistically significantly greater proportion of patients who self-administered etripamil converted from PSVT to sinus rhythm within 30 minutes compared to placebo (40.5% vs.
−Removed: 15.9%, respectively;
−Removed: hazard ratio [HR] = 3.00;
−Removed: 95% CI 1.58-5.71;
−Removed: Statistically significant (p<0.05) results were also shown for the secondary efficacy endpoints for percent of patients’ PSVT converted to sinus rhythm by 10, 15, 45 and 60 minutes after self-administration of study drug.
−Removed: Corxel further reported that, overall, treatment emergent adverse events were comparable between treatment groups, and there were no reported serious adverse events related to etripamil.
−Removed: The safety and tolerability data from the JX02002 trial
−Removed: were consistent with previous clinical studies.
−Removed: This important study further expands the etripamil global development program to more than 2,000 unique patients treated with etripamil.
−Removed: AFib-RVR Clinical Development Highlights
−Removed: In November 2023, we presented positive Phase 2 data from the ReVeRA study as a Featured Science Presentation at the American Heart Association Scientific Meetings (Philadelphia, PA) and as simultaneously published in Circulation:
−Removed: Arrhythmia and Electrophysiology .
−Removed: The randomized, double-blinded, placebo-controlled ReVeRA trial of etripamil nasal spray enrolled 87 patients and dosed 56 patients aged 18 years and older with AFib who urgently presented experiencing AFib and a ventricular rate of 110 or more beats per minute, or “bpm.” The trial was designed to assess the magnitude, rapidity, and duration of reduction and the patient satisfaction with treatment using an established patient reported outcome, or “PRO,” tool.
−Removed: Data showed that delivery of etripamil nasal spray (70 mg) significantly and rapidly reduced ventricular rate, in a pattern consistent with the drug’s pharmacologic profile.
−Removed: Etripamil achieved the primary endpoint with a high degree of statistical significance;
−Removed: patients experienced a ventricular rate reduction of 29.91 bpm (95% confidence interval:
−Removed: -40.31, -19.52;
−Removed: p<0.0001) in the etripamil arm relative to placebo.
−Removed: The absolute maximum reduction in rate in the etripamil arm was 34.97 bpm.
−Removed: Using the Treatment Satisfaction Questionnaire 9 (TSQM-9) PRO, compared to placebo, patients treated with etripamil demonstrated significant improvements in two satisfaction ratings:
−Removed: effectiveness (p<0.0001) and relief of symptoms (p=0.0002), with the degrees of improvement consistent with those customarily described as clinically meaningful.
−Removed: Treatment-emergent serious adverse events, or “TESAEs,” were rare and the most common (≥ 5%) adverse events were mild or moderate in intensity and included nasal discomfort, rhinorrhea, increased lacrimation, throat irritation and dizziness.
−Removed: Further trial details are below in this document.
−Removed: During 2024, we met with the FDA on the ReVeRA study, during which the FDA confirmed its guidance from our Pre-IND meeting (2023) regarding the availability of a supplemental new drug application, or “sNDA,” pathway for the marketing approval of etripamil for the indication of AFib-RVR.
−Removed: 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.
−Removed: FDA further concurred with respect to key proposed study elements including powering, inclusion criteria, patient population, and statistical analyses, and offered clarification with respect to the endpoints to guide the design of the Phase 3 study.
−Removed: In our mid-2023 Pre-IND meeting, the FDA provided guidance that our primary endpoint can be the reduction of ventricular rate, and the primary analysis would be performed on the intent to treat, or “ITT,” population.
−Removed: 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.
−Removed: The secondary endpoint could use a PRO measure, and the application of a seven-point anchored scale was discussed with the FDA.
−Removed: We have finalized the Phase 3 study protocol following FDA’s review, obtained concurrence with the FDA to proceed, are operationally starting the study, and anticipating enrolling patients in 2025.
−Removed: The Phase 3 study will be conducted in a medically unmonitored setting (e.g., at-home) in a manner very similar to the conduct of our Phase 3 development program for PSVT.
−Removed: The Phase 3 AFib-RVR study will enroll patients with a history of symptomatic AFib episodes, and will use a self-administered, repeat-dose regimen of 70 mg per dose (the dose and dosing approach that was studied in the RAPID trial in patients with PSVT).
−Removed: The Phase 3 study’s target population will be patients with verified history of AFib-RVR, and the ITT population will be all patients self-administering the study drug for perceived AFib-RVR.
−Removed: The primary endpoint is the mean change from baseline ventricular rate to nadir ventricular rate for patients treated with etripamil versus placebo, as was studied in the ReVeRA trial in AFib-RVR.
−Removed: The key secondary endpoint will be based on a PRO of symptomatic improvement, discussed with the FDA, which is similar to the PRO questions utilized in our PSVT and AFib-RVR programs.
−Removed: The study has been powered and sized based upon approximately 150 events from 150 unique patients with a history of symptomatic episodes of AFib-RVR.
−Removed: 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 potentially including additional clinical stage
−Removed: compounds for other cardiovascular conditions.
−Removed: The key elements of our business strategy to achieve this goal include the following:
−Removed: • Maximize the value of our programs by launching CARDAMYST in the United States.
−Removed: If approved by the FDA, we intend to launch CARDAMYST by primarily targeting cardiology and high value primary care healthcare providers who we believe treat the majority of patients with a diagnosis of PSVT.
−Removed: We intend to pursue retail distribution and target most of our launch year marketing mix on driving healthcare professional, or “HCP,” awareness and trial of CARDAMYST as well as ensuring that patients who are prescribed CARDAMYST have good experiences with the drug.
−Removed: • Expand the scope of cardiovascular indications for etripamil beyond PSVT.
−Removed: We are investigating, through a Phase 2 study and an upcoming Phase 3 study, the use of etripamil for the treatment of patients with AFib-RVR.
−Removed: 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.
−Removed: We also intend to explore additional cardiovascular opportunities for the use of etripamil.
−Removed: • Successfully complete development and obtain regulatory approval of etripamil for the treatment of PSVT.
−Removed: We are focused on efficiently developing and obtaining approval for etripamil to treat patients with PSVT.
−Removed: In addition to potential regulatory approval in the United States, we are seeking regulatory approvals in China through our partner.
−Removed: We intend to seek regulatory approvals in other major markets through strategic partnerships.
−Removed: • Leverage our expertise and experience to expand our pipeline of product candidates.
−Removed: We seek to maximize our commercial opportunities by acquiring or in-licensing product candidates for indications with significant unmet need with a focus on novel treatments for cardiovascular or other conditions.
−Removed: Our leadership team has extensive experience in developing and commercializing successful drugs.
−Removed: We intend to leverage the collective talent within our organization and our network to guide our development plans and pipeline expansion.
−Removed: CARDAMYST TM (etripamil) nasal spray
−Removed: 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.
−Removed: Rapid pharmacological action is both appropriate and sufficient to resolve an episode of SVT.
−Removed: We have completed Phase 3 development for PSVT.
−Removed: 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.
+Added: We are currently focusing our efforts and financial resources on (i) the commercialization of CARDAMYST TM (etripamil) nasal spray for the treatment of PSVT, (ii) the development of etripamil for the treatment of AFib-RVR and (iii) corporate development activities that have the potential to increase company value through strategic collaborations.
+Added: CARDAMYST TM (etripamil) nasal spray for the Treatment of PSVT
+Added: On December 12, 2025, we announced that the FDA approved our first commercial product, CARDAMYST (etripamil) nasal spray, a prescription medication for the conversion of acute symptomatic episodes of PSVT, to sinus rhythm in adults.
+Added: We are focused on the commercialization of CARDAMYST, which became available in retail pharmacies in the first quarter of 2026.
+Added: We manufacture CARDAMYST with a global supply chain that produces the active pharmaceutical ingredient, etripamil, and then formulates and assembles it into the delivery device, a nasal spray, before completing packaging of the saleable product which is then distributed via a third party logistics provider to wholesalers for delivery to retail pharmacies once prescriptions are received.
+Added: To create demand, our sales team of approximately 60 representatives expects to engage healthcare providers who we believe will treat around 500,000 patients with a diagnosis of PSVT in 2026.
+Added: We designed the molecule of etripamil, and we are commercializing and further 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.
+Added: Rapid pharmacological action is both appropriate and sufficient to resolve an episode of supraventricular tachycardia, or “SVT.” 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.
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We believe that the following attributes of etripamil make it a better treatment candidate for certain episodic cardiovascular conditions than current standards of care:
−Removed: 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.
+Added: Etripamil is designed to be rapidly metabolized by blood-borne esterases, with the goal of reducing either the duration of side effects that may occur with acute treatment or the long-term side effects that may occur with chronic drug therapy.
• Absorption:
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Etripamil is designed, and has been investigated, to empower patients to self-administer treatment outside of a medical setting and as prompted by a patient’s symptoms.
−Removed: PSVT is a serious, markedly symptomatic, and recurring cardiac arrhythmia, caused by altered electrical conduction within the heart involving the AV node and over an abnormal electrical circuit in most cases.
+Added: PSVT is a serious, markedly symptomatic, and recurring cardiac arrhythmia, caused by altered electrical conduction within the heart involving the atrioventricular, or “AV,” node and over an abnormal electrical circuit in most cases.
The common form of PSVT, AV nodal reentrant tachycardia, or “AVNRT,” has an abnormal limb of electrical circuitry within the AV node that is the substrate of the tachycardia and forms the basis for a reentrant arrhythmia, resulting in excessively rapid beating of both the atria and ventricles.
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Treatment for PSVT depends on the frequency, duration, and severity of the episodes, as well as patient preference for pharmacologic or invasive treatment.
−Removed: Current options for patients with PSVT to acutely terminate an episode of arrhythmia include IV medication (e.g., IV adenosine, IV calcium channel blockers), administered in an emergency department, which transiently alter electrical conduction over the AV node leading to termination of AV-dependent arrhythmias and restoration of sinus rhythm;
+Added: Current options for patients with PSVT to acutely terminate an episode of arrhythmia include intravenous, or “IV,” medication (e.g., IV adenosine, IV calcium channel blockers), administered in an emergency department, which transiently alter electrical conduction over the AV node leading to termination of AV-dependent arrhythmias and restoration of sinus rhythm;
or an external shock delivered in the emergency department.
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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.
+Added: PSVT Market Overview
+Added: PSVT is a condition that causes a patient’s heart to suddenly start beating faster than normal.
+Added: It can be life-altering as PSVT is highly symptomatic, characterized by unpredictable attacks of a racing heart, often exceeding 150 beats per minute.
+Added: 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.
+Added: 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.
+Added: The uncertainty of when such an attack of PSVT will strike or how long it will persist is often anxiety-provoking, reducing patients’ quality of life and preventing participation in many desired activities.
+Added: Drugs approved for the treatment of attacks of PSVT include adenosine, verapamil, and diltiazem, with all being administered intravenously under medical supervision, usually in the emergency department.
+Added: 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.
+Added: Doctors are often frustrated by the limited effective treatment options with the only approved options involving prolonged, unpleasant, and costly trips to the emergency department or, for some patients, an invasive ablation procedure.
+Added: PSVT can be traumatic for patients, frustrating for healthcare providers, and costly for payors.
+Added: With no pharmaceutical innovation in the treatment of PSVT for more than 30 years and a movement in the healthcare system to enable patient-centered care, we believe there is an opportunity to help patients living with PSVT to take greater control over their PSVT.
+Added: We believe that PSVT is a large and under-recognized market which we estimate affects more than two million Americans.
+Added: From this diagnosed population, we define the immediate target addressable market for CARDAMYST as approximately 50% of patients with PSVT who have sufficient disease burden that they are compelled to seek care for their condition and are primarily managed by approximately 40,000 healthcare providers composed primarily of clinical cardiologists, interventional cardiologists and electrophysiologists.
+Added: The remaining patients with PSVT can become addressable over time, as they are inconsistently managed (cycling in and out of the healthcare system).
+Added: Furthermore, PSVT is expected to increase in diagnosed prevalence in coming years as wearable electrocardiogram, or “ECG,” technology (e.g., smartphone, watches) becomes both more adept at diagnosing PSVT and more widely used by patients and clinical practitioners, in turn shortening the time to diagnosis.
+Added: Following the release of data from the RAPID clinical study, in market research, cardiologists reported a willingness to prescribe CARDAMYST to approximately 50% of the patients with PSVT in their care, which suggests approximately 500,000 to 800,000 patients can potentially be treated with CARDAMYST in peak years.
+Added: Additionally, we believe that this cardiology-identified group of patients may use CARDAMYST to treat a median of three to five episodes per year, based on the projected number of self-reported longer and more intense episodes experienced by patients, as well as the patient utilization experience in our Phase 3 clinical trials.
+Added: This implies a peak demand potential in the United States for CARDAMYST of 2.5 million to 4 million episodes treated per year.
+Added: Current treatment for PSVT also consumes significant healthcare resources.
+Added: Research published in the American Journal of Cardiology in 2020 shows that total healthcare expenditures in the year following a diagnosis of PSVT ranged from $20,000 to $30,000 per patient which were significantly higher than the expenditures observed for patients without PSVT.
+Added: These significant increases included increased emergency department visits and hospitalization costs.
+Added: Of note, catheter ablations following diagnosis represented only 23% of this increased spend, meaning most costs were unrelated to ablations.
+Added: Recent data from the Healthcare Cost and Utilization Project, or “HCUP,” database indicate that in 2019 there were approximately 140,000 emergency department, or “ED,” visits for PSVT when coded (for billing) in the primary diagnostic position, and a total of approximately 525,000 ED visits when PSVT was coded in any diagnostic position.
+Added: Of these, approximately 25% of ED admissions for PSVT resulted in a hospital admission.
+Added: HCUP estimates a total of approximately 40,000 to approximately 120,000 inpatient admissions for PSVT in 2019 (based again if a PSVT billing code was found in the primary v.
+Added: any diagnostic position).
+Added: Despite the effectiveness of catheter ablation, claims data suggests that only approximately 15% of patients with PSVT are ablated over a three-year period, leading to a total of approximately 100,000 catheter ablations annually.
+Added: In total, up to $15.0 billion is spent annually in the United States on the management of PSVT.
+Added: PSVT Continued Development Highlights
+Added: In November 2025, we submitted our marketing authorization application, or “MAA,” to the European Medicines Agency, or “EMA,” for review for approval to market etripamil nasal spray, under the trade name TACHYMIST TM , in European Union.
+Added: The MAA utilizes much of the clinical, manufacturing and quality data package that was submitted in the NDA which lead to the US FDA approval.
+Added: In January 2025, our licensing partner, Corxel (formerly Ji Xing Pharmaceuticals Limited, JIXING), announced that the Center for Drug Evaluation, or “CDE,” of the National Medical Products Administration, or “NMPA,” of the People’s Republic of China has accepted the New Drug Application, or “NDA,” for etripamil nasal spray for the treatment of PSVT.
+Added: The NDA to the NMPA included data from the successful Phase 3 JX02002 clinical trial of etripamil nasal spray in patients with PSVT in China in addition to data included in the NDA that Milestone submitted to the FDA.
+Added: The 500-patient Phase 3 trial (JX02002) met its primary endpoint, with a Kaplan Meier analysis shows a statistically significantly greater proportion of patients who self-administered etripamil converted from PSVT to sinus rhythm within 30 minutes compared to placebo (40.5% vs.
+Added: 15.9%, respectively;
+Added: hazard ratio [HR] = 3.00;
+Added: 95% CI 1.58-5.71;
+Added: Statistically significant (p<0.05) results were also shown for the secondary efficacy endpoints for percent of patients’ PSVT converted to sinus rhythm by 10, 15, 45 and 60 minutes after self-administration of study drug.
+Added: Corxel further reported that, overall, treatment emergent adverse events were comparable between treatment groups, and there were no reported serious adverse events related to etripamil.
+Added: The safety and tolerability data from the JX02002 trial were consistent with previous clinical studies.
+Added: This important study further expands the etripamil global development program to more than 2,000 unique patients treated with etripamil.
+Added: Etripamil Nasal Spray for the Treatment of AFib-RVR
+Added: Similar to our approach for PSVT, we believe that etripamil has the potential to help people experiencing a symptomatic episode of AFib-RVR to self-treat and to conveniently, reliably, and quickly reduce their elevated heart rate, with the goal of reducing the need for emergency department utilization.
+Added: We completed a successful Phase 2 study, named “ReVeRA” or the “ReVeRA study”, in patients presenting urgently with episodes of AFib-RVR to the emergency department.
+Added: We have published the ReVeRA study and results, which demonstrated that patients receiving etripamil nasal spray experienced rapid and statistically superior ventricular rate reduction and improved symptom-relief compared to placebo, with safety and tolerability findings generally consistent with those observed in our PSVT program.
+Added: We believe these data support the continued development of etripamil, self-administered in the medically unmonitored setting, for the treatment of AFib-RVR.
+Added: Incorporating FDA’s guidance, we have developed a Phase 3 registrational program to evaluate self-administered etripamil as a potential treatment for patients with AFib-RVR.
+Added: We intend to pursue a supplemental new drug application, or “sNDA,”
+Added: regulatory approval pathway for a potential second indication for etripamil in Afib-RVR.
+Added: As such, we will leverage the PSVT indication and PSVT program data, along with a single pivotal Phase 3 study in patients with AFib-RVR.
Atrial Fibrillation
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Oral rate control drugs used acutely do not provide immediate ventricular rate control due to a 30-to-120-minute delayed onset of action.
−Removed: Breakthrough episodes of symptomatic atrial fibrillation often require urgent medical treatment with IV calcium channel blockers and IV beta blockers under medical supervision in an emergency department to quickly reduce heart rate before transitioning a patient back to oral therapy.
+Added: episodes of symptomatic atrial fibrillation often require urgent medical treatment with IV calcium channel blockers and IV beta blockers under medical supervision in an emergency department to quickly reduce heart rate before transitioning a patient back to oral therapy.
Of note, AHA and ACC guidelines do not explicitly acknowledge the as needed (PRN) approach to acutely administering oral rate control agents, however, market research conducted by us indicates a significant share of patients are managed this way.
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Clinical Development Plan for Atrial Fibrillation with Rapid Ventricular Rate
−Removed: The Phase 2, double-blind, placebo-controlled, study, Reduction of Ventricular Rate in Patients with Atrial Fibrillation (ReVeRA), was conducted in patients presenting urgently (e.g., to an emergency department) with AFib-RVR.
+Added: In November 2023, we presented positive Phase 2 data from the ReVeRA study as a Featured Science Presentation at the American Heart Association Scientific Meetings (Philadelphia, PA) and as simultaneously published in Circulation:
+Added: Arrhythmia and Electrophysiology .
+Added: The Phase 2, double-blind, placebo-controlled, study, Reduction of Ventricular Rate in Patients with Atrial Fibrillation, or “ReVeRA”, was conducted in patients presenting urgently (e.g., to an emergency department) with AFib-RVR.
ReVeRA’s objectives included evaluation of the potential effectiveness of etripamil NS to reduce RVR and to improve symptoms in patients with AFib and evaluation of the drug’s safety.
−Removed: The trial enrolled 87 patients and dosed 56 patients with blinded study drug (the latter having a ventricular rate of ≥110 bpm) prior to receiving study drug.
+Added: The trial enrolled 87 patients and dosed 56 patients with blinded study drug (the latter having a ventricular rate of ≥110 beats per minute, or “bpm”) prior to receiving study drug.
Data showed that delivery of etripamil nasal spray significantly and rapidly reduced ventricular rate, with a time course consistent with the drug’s pharmacologic profile.
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The maximum absolute reduction in rate in the etripamil arm was 34.97 bpm.
−Removed: The median time to maximum reduction in VR was 13 minutes in patients taking etripamil, and the duration of effect (reduction in VR from baseline and from placebo) was at least 150 min.
+Added: The median time to maximum reduction in ventricular rate, or “VR,” was 13 minutes in patients taking etripamil, and the duration of effect (reduction in VR from
+Added: baseline and from placebo) was at least 150 min.
The median duration of maintaining a VR <100 bpm was 45.5 min in the first 60 min following drug in the etripamil arm.
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−Removed: Etripamil treatment was associated with significant improvement in symptom relief and in treatment satisfaction as measured by the TSQM-9 PRO instrument.
−Removed: Patients treated with etripamil, compared to those treated with placebo, demonstrated significant improvements in satisfaction ratings in the TSQM-9 Effectiveness Domain (p<0.0001) and on
−Removed: the Relief of Symptoms Question from the Effectiveness Domain (p = 0.0002, with a treatment effect of 1.55 units).
+Added: Etripamil treatment was associated with significant improvement in symptom relief and in treatment satisfaction as measured by the TSQM-9 patient reported outcome, or “PRO,” instrument.
+Added: Patients treated with etripamil, compared to those treated with placebo, demonstrated significant improvements in satisfaction ratings in the TSQM-9 Effectiveness Domain (p<0.0001) and on the Relief of Symptoms Question from the Effectiveness Domain (p = 0.0002, with a treatment effect of 1.55 units).
Moreover, patients in the placebo arm were given additional AFib-RVR treatments during the window of 60 minutes to 24 hours after study drug to an approximately two-fold greater degree than patients in the etripamil arm.
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These positive Phase 2 data have supported interactions with the FDA (as summarized in “AFib-RVR Clinical Development Highlights”) that have established a path to potential approval for an indication for etripamil in patients with AFib-RVR.
−Removed: As also summarized above, the protocol of a Phase 3, potentially registrational study has been finalized and study start-up has commenced.
The Phase 3 study is expected to use an optional repeat-dose, self-administration approach of etripamil nasal spray, outside of the medically supervised setting, that is similar to that used in the PSVT development program.
+Added: AFib-RVR Clinical Development Highlights
+Added: During 2024, we met with the FDA on the ReVeRA study, during which the FDA confirmed its guidance from our Pre-IND meeting (2023) regarding the availability of a sNDA pathway for the marketing approval for etripamil for the indication of AFib-RVR.
+Added: 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.
+Added: FDA further concurred with respect to key proposed study elements including powering, inclusion criteria, patient population, and statistical analyses, and offered clarification with respect to the endpoints to guide the design of the Phase 3 study.
+Added: In our mid-2023 Pre-IND meeting, the FDA provided guidance that our primary endpoint can be the reduction of ventricular rate, and the primary analysis would be performed on the intent to treat, or “ITT,” population.
+Added: 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.
+Added: The secondary endpoint could use a PRO measure, and various PROs were discussed with the FDA.
+Added: We have finalized the Phase 3 study protocol following FDA’s review and obtained concurrence with the FDA to proceed.
+Added: The Phase 3 study will be conducted in a medically unmonitored setting (e.g., at-home) in a manner very similar to the conduct of our Phase 3 development program for PSVT.
+Added: The Phase 3 AFib-RVR study will enroll patients with a history of symptomatic AFib episodes, and will use a self-administered, repeat-dose regimen of 70 mg per dose (the dose and dosing approach that was studied in the RAPID trial in patients with PSVT).
+Added: The Phase 3 study’s target population will be patients with verified history of AFib-RVR, and the ITT population will be all patients self-administering the study drug for perceived AFib-RVR.
+Added: The primary endpoint is the mean change from baseline ventricular rate to nadir ventricular rate for patients treated with etripamil versus placebo, as was studied in the ReVeRA trial in AFib-RVR.
+Added: The key secondary endpoint will be based on a PRO of symptomatic improvement, discussed with the FDA, which is similar to the PRO questions utilized in our PSVT and AFib-RVR programs.
+Added: The study has been powered and sized based upon approximately 150 events from 150 unique patients with a history of symptomatic episodes of AFib-RVR.
+Added: AFib-RVR Market Overview
+Added: Atrial Fibrillation, or “AFib,” is a common cardiac arrhythmia with an irregular and often rapid heart rate that is often markedly symptomatic and, without proper treatment, can increase the risk of stroke, heart failure, and other cardiovascular complications.
+Added: A common complication of AFib is a rapid heart rate, also referred to as AFib-RVR, which is frequently defined as a heart rate ≥ 110 beats per minute.
+Added: The occurrence of a rapid ventricular rate, or “RVR,” in patients with atrial fibrillation increases the likelihood of marked symptoms including heart palpitations, shortness of breath and weakness.
+Added: There are two commonly used pharmacological approaches to chronically manage AFib, rhythm control and rate control.
+Added: Regardless of the chronic approach, break-through episodes of rapid heart rate occur frequently;
+Added: and when faced with a sudden episode of AFib-RVR, acute rate control is needed, with most treatments being AV-nodal targeted drugs such as a beta blocker or calcium channel blocker.
+Added: These treatments can be given intravenously;
+Added: however, this requires a burdensome trip to an emergency department which may lead to a hospital admission.
+Added: Acute treatment can be attempted by administration of an oral rate control drug;
+Added: however, such drugs do not adequately provide immediate or dependable enough ventricular rate control due to a 30- to 90-minute delayed onset of action, and, as a result, many patients need faster
+Added: 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.
+Added: Furthermore, the chronic administration of oral rate-control drugs does not broadly prevent episodes of AFib-RVR.
+Added: Similar to PSVT, patients may feel a loss of control by needing to visit the emergency department for overcoming their AFib-RVR episode and the unpredictable nature of these episodes, which can occur anytime and anywhere.
+Added: Doctors have expressed frustration at the lack of options for patients to self-manage these acute rate attacks;
+Added: and payor organizations would prefer to treat the AFib-RVR attacks in a more cost effective and time-efficient manner.
+Added: An estimated 10 million Americans suffer from AFib.
+Added: The prevalence of AFib is expected to grow to greater than 12 million by 2030.
+Added: A subset of patients with AFib experiences episodes of abnormally high heart rate, most often accompanied by palpitations, shortness of breath, dizziness, and weakness.
+Added: While these episodes, known as AFib-RVR, may be treated by oral calcium channel blockers and/or beta blockers, patients frequently seek acute care in the ED to address symptoms.
+Added: In 2019, nearly 1.1 million patients were admitted to the ED due to AFib symptoms.
+Added: Initial data suggests that approximately 60% of all AFib ED visits were attributable to AFib-RVR, as symptoms driving patients to seek care generally become more pronounced at higher heart rates.
+Added: Treatment for such symptoms typically includes medically supervised intravenous administration of calcium channel blockers or beta blockers, or electrical cardioversion.
+Added: 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 current target addressable market of approximately three to four million patients for etripamil in patients with AFib-RVR.
+Added: We believe that etripamil has the potential to be developed such that it can be used by patients to rapidly reduce their heart rate to provide a supplemental option to either the acute oral rate or rhythm control strategy their physician would use.
+Added: When presented with a target product profile reflecting this potential use case, cardiologists and electrophysiologists, in a 2021 market research study perceived utility in the product profile and indicated that they would prescribe to approximately two-thirds of their patients that experience episodes of AFib-RVR.
+Added: They further indicated that a rapidly-acting intranasal calcium channel blocker could serve as a “bridge” to the longer onset times of acute oral agents.
+Added: According to physicians, it can take hours for patients to feel an alleviation of symptoms using acute oral rate or rhythm control.
+Added: During this time, patients may experience concerning symptoms that often prompt them to seek emergency care.
+Added: 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.
+Added: Current AFib management consumes significant healthcare resources in the United States.
+Added: The American Heart Association published a report in 2016 summarizing the current and projected cost burden of cardiovascular diseases in the United States.
+Added: This report suggests atrial fibrillation resulted in $25 billion in direct medical costs in 2016 (approximately 7% of all cardiovascular diseases) and another $7 billion in indirect costs (i.e., up to $32 billion in total costs).
+Added: 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.
+Added: 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 potentially including additional clinical stage compounds for other cardiovascular conditions.
+Added: The key elements of our business strategy to achieve this goal include the following:
+Added: • Maximize the value of our launch of CARDAMYST in the United States.
+Added: We have launched CARDAMYST by building out our sales team of approximately 60 sales representatives who will be targeting cardiology and high value primary care healthcare providers who we believe will treat up to an estimated 500,000 patients with a diagnosis of PSVT during 2026.
+Added: We have implemented retail distribution and target most of our launch year marketing mix on increasing healthcare professional, or “HCP,” awareness and the number of trials of CARDAMYST.
+Added: • Expand the scope of cardiovascular indications for etripamil beyond PSVT.
+Added: We are investigating, through a completed Phase 2 study and an upcoming Phase 3 study, the use of etripamil for the treatment of patients with AFib-RVR.
+Added: We believe that etripamil could benefit patients with AFib-RVR based on the approved use of IV calcium channel blockers in this indication.
+Added: We also intend to explore additional cardiovascular opportunities for the use of etripamil.
+Added: • Successfully complete development and obtain regulatory approval of etripamil in other major markets.
+Added: We are currently seeking regulatory approval in China through our partner, Corxel.
+Added: We intend to seek regulatory approvals in other major markets through additional strategic partnerships.
+Added: • Leverage our expertise and experience to expand our pipeline of product candidates.
+Added: We seek to maximize our commercial opportunities by acquiring or in-licensing product candidates for indications with significant unmet need with a focus on novel treatments for cardiovascular or other conditions.
+Added: Our leadership team has extensive experience in developing and commercializing successful drugs and has developed a deep understanding of the PSVT and Atrial Fibrillation markets.
+Added: We intend to leverage the collective talent within our organization and our network to guide our development plans and pipeline expansion.
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.
−Removed: 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
−Removed: have demonstrated clinical utility.
+Added: We believe that the insights that led to the development of etripamil for the treatment of PSVT are relevant in other indications where AV-nodal blocking agents with blood vessel widening activity have demonstrated clinical utility.
Both calcium channel blockers and beta blockers are commonly used to manage supraventricular tachycardias like PSVT or AFib-RVR, and other conditions.
Sales and Marketing
−Removed: If CARDAMYST receives marketing approval, we plan to commercialize it in the United States leveraging industry trends regarding staged deployment of resources, digital/omnichannel investments, and a focused, specialty sales force.
−Removed: Specifically, we plan for the launch of CARDAMYST to be led by a field force calling on between 10,000 and 15,000 primarily clinical cardiologists who treat large populations of patients with PSVT, supported by strategic investments in medical affairs and digital/targeted non-personal promotion.
+Added: We are commercializing CARDAMYST in the United States by targeting high volume healthcare providers, primarily cardiologists, with a focused specialty sales force supported by digital/omnichannel investments and robust reimbursement and patient support.
+Added: Specifically, the launch of CARDAMYST is being led by a focused national field force calling on approximately 8,000 clinical/interventional cardiologists, 1,500 electrophysiologists, and 500 primary care physicians who treat large populations of patients with PSVT, supported by strategic investments in medical affairs, digital/targeted non-personal promotion, and robust reimbursement and patient support programs.
Although we will initially focus on obtaining broad commercial insurance coverage from large Pharmacy Benefit Managers, or “PBMs,” and targeted national and regional commercial payors, as we expand reimbursement for CARDAMYST to include government payors and targeted integrated delivery networks we anticipate that this investment in omnichannel promotion will grow, targeting both prescribers and patients.
−Removed: Aligned to this expansion, our field force could grow to call on up to 30,000 clinical cardiologists, interventional cardiologists, electrophysiologists, and high-volume primary care physicians who have a history of prescribing cardiovascular therapies.
−Removed: We believe an organization of this size would allow us to reach prescribers that collectively care for most patients diagnosed with PSVT in the United States.
+Added: As we expand, we believe our field force could potentially grow to call on up to 25,000 clinical cardiologists, interventional cardiologists, electrophysiologists, and high-volume primary care physicians/advanced practice providers who have a history of prescribing cardiovascular therapies.
+Added: We believe an organization of this size could potentially allow us to reach prescribers that collectively care for most patients diagnosed with PSVT in the United States.
Given the importance of increasing awareness and educating patients with PSVT, as we establish favorable broad payor reimbursement, we also anticipate deploying focused direct-to-patient marketing campaigns for CARDAMYST.
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In addition, we may pursue and believe that we can maximize the value of etripamil by entering into collaboration agreements for certain territories outside the United States, including the European Union, while retaining commercialization rights in the United States.
−Removed: Manufacturing
−Removed: 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.
+Added: Manufacturing of Commercial Supply
+Added: We do not have any manufacturing facilities.
+Added: We rely on, and expect to continue to 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 commercial product, 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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Currently, we have contracts and quality agreements with our CMOs for the manufacturing of etripamil drug substance and drug product.
−Removed: We believe we currently have enough manufactured supply of etripamil to support our potential commercial launch.
−Removed: We also may elect to pursue additional CMOs for manufacturing supplies of regulatory starting materials in the future and for the filling of the nasal spray device, labeling, packaging, storage and distribution of investigational drug products.
−Removed: We plan to continue to rely on third party manufacturers for any future trials and commercialization of etripamil, if approved.
+Added: We believe we currently have enough manufactured supply of etripamil to support our commercial launch.
+Added: We also may elect to pursue additional CMOs for manufacturing supplies of regulatory starting materials in the future and for the filling of the nasal spray device, labeling, packaging, storage, and distribution of investigational and commercial drug products.
+Added: We plan to continue to rely on third party manufacturers for any future trials and commercialization of etripamil.
We anticipate that these CMOs will have capacity to support commercial scale production.
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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.
−Removed: 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
−Removed: obsolete, or reduce the demand for our product candidates before we can recover our development and commercialization expenses.
−Removed: We are not aware of any approved drug or any drug candidate in clinical development for a patient with PSVT to self-administer treatment to terminate SVT episodes.
+Added: 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.
+Added: We are not aware of any approved drug or any drug candidate in clinical development for a patient with PSVT to self-administer treatment to terminate PSVT episodes.
In the acute setting, IV treatments of generic drugs such as adenosine, verapamil, and diltiazem, are routinely given.
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We have filed numerous patent applications pertaining to etripamil and possible future product candidates, formulations containing etripamil, methods of making such formulations, and clinical use.
−Removed: We strive to protect and enhance the proprietary technology, invention and improvements that are commercially important to the development of our business by seeking, maintaining, and defending our intellectual property.
+Added: We strive to protect and enhance the
+Added: proprietary technology, invention, and improvements that are commercially important to the development of our business by seeking, maintaining, and defending our intellectual property.
We also rely on know-how, continuing technological innovation and potential in-licensing opportunities to develop, strengthen, and maintain our position in the field of cardiac arrhythmias, such as PSVT, and immediate rate control in atrial fibrillation, as well as other medical conditions affecting the cardiovascular system.
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patent, projected to expire in 2036, a pending U.S.
−Removed: patent application, which, if granted, is projected to expire in 2036, as well as corresponding patents in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, Japan, Macau, Mexico, Russia, South Africa, South Korea and Ukraine and corresponding patent applications in China, Europe, Hong Kong, India and New Zealand, directed to formulations including etripamil, methods of making such formulations, and uses of such formulations to treat cardiac arrhythmias, such as PSVT and atrial fibrillation.
−Removed: • 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.
+Added: patent application, which, if granted, is projected to expire in 2036, as well as corresponding patents in Australia, Brazil, Canada, China, Europe, Hong Kong, Israel, Japan, Macau, Mexico, Russia, South Africa, South Korea and Ukraine and corresponding patent applications in China, Europe, Hong Kong, and New Zealand, directed to formulations including etripamil, methods of making such formulations, and uses of such formulations to treat cardiac arrhythmias, such as PSVT and atrial fibrillation.
+Added: • a patent family containing one U.S.
+Added: patent, projected to expire in 2042, a pending U.S.
+Added: application which, if granted, is projected to expire in 2042, and pending applications in Canada and Europe, which, if granted, are projected to expire in 2041 in Canada and 2042 in Europe, 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.
−Removed: 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
−Removed: the term of the patent.
+Added: Generally, patents issued for applications filed in the United States are effective for 20 years from the earliest effective non-provisional filing date in the absence, for example, of a terminal disclaimer shortening the term of the patent or patent term adjustment increasing the term of the patent.
In addition, in certain instances, a patent term can be extended to recapture a portion of the term effectively lost as a result of FDA regulatory review periods.
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In the United States, the FDA regulates drugs under the Federal Food, Drug, and Cosmetic Act, or “FDCA,” and its implementing regulations.
−Removed: 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.
+Added: The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require 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 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.
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Preclinical studies include laboratory evaluation of product chemistry, toxicity, and formulation, as well as animal studies to assess potential safety and efficacy.
−Removed: An IND sponsor must submit the results of the nonclinical tests, together with manufacturing information, analytical data and any available clinical data or literature, among other things, to the FDA as part of an IND.
+Added: An IND sponsor must submit the results of the nonclinical tests, together with
+Added: manufacturing information, analytical data, and any available clinical data or literature, among other things, to the FDA as part of an IND.
Some nonclinical testing may continue even after the IND is submitted.
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In addition, under the Pediatric Research Equity Act, certain NDAs or supplements to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
−Removed: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
+Added: The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some
+Added: or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.
Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.
14 unchanged sentences
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.
−Removed: A complete response letter generally contains a statement of specific conditions
−Removed: 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.
+Added: 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.
6 unchanged sentences
Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, advertising, and promotion and reporting of adverse experiences with the product.
−Removed: After approval, most changes to the approved product, such as adding new indications, manufacturing changes or other labeling claims, are subject to further testing requirements and prior FDA review and approval.
+Added: After approval, most changes to the approved product, such as adding new indications, manufacturing changes or other labeling claims, are
+Added: subject to further testing requirements and prior FDA review and approval.
There also are continuing annual user fee requirements for any marketed products and the establishments at which such products are manufactured, as well as application fees for supplemental applications with clinical data.
6 unchanged sentences
Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in mandatory revisions to the approved labeling to add new safety information;
−Removed: imposition of post-market studies or clinical trials to assess new safety risks;
−Removed: or imposition of distribution or other restrictions under a REMS program.
+Added: imposition of post-market studies or clinical trials to assess new safety risks, or imposition of distribution or other restrictions under a REMS program.
Other potential consequences include, among other things:
5 unchanged sentences
The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market.
−Removed: Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label, although physicians, based on their independent medical judgement, may prescribe approved drugs for unapproved indications.
−Removed: However, biopharmaceutical companies may share truthful and not misleading information that is otherwise consistent with the labeling.
+Added: Drugs may be promoted only for the approved indications and in accordance with the provisions of the approved label, although physicians, based on their independent medical judgement, may prescribe approved drugs for unapproved (or “off-label”) indications.
The FDA and other agencies actively enforce the laws and regulations prohibiting their promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant civil, criminal and administrative liability.
−Removed: In addition, the distribution of prescription pharmaceutical products is subject to the Drug Supply Chain Act, which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states.
+Added: In addition, the distribution of prescription pharmaceutical products is subject to the Drug Supply Security Chain Act, which regulates the distribution of drugs and drug samples at the federal level, and sets minimum standards for the registration and regulation of drug distributors by the states.
Federal and State Fraud and Abuse, Data Privacy and Security, and Transparency Laws and Regulations
In addition to FDA restrictions on marketing of pharmaceutical products, federal and state healthcare laws and regulations restrict business practices in the biopharmaceutical industry.
−Removed: These laws may impact, among other things, our current and future business operations, including our clinical research activities, and proposed sales, marketing and education programs and constrain the business or financial arrangements and relationships with healthcare providers and other parties through which we market, sell and distribute our products for which we obtain marketing approval.
−Removed: These laws include anti-kickback and false claims laws and regulations, data privacy and security, and transparency laws and regulations, including, without limitation, those laws described below.
+Added: These laws regulate, among other things, our current and future business operations, including our clinical research activities, sales, marketing, and education programs.
+Added: These laws may also constrain the business or financial arrangements and relationships with healthcare providers and other parties through which we market, sell, and distribute our products for which we obtain marketing approval.
+Added: These laws include
+Added: anti-kickback and false claims laws and regulations, data privacy and security laws and regulations, and transparency laws and regulations, including, without limitation, those laws described below.
The federal Anti-Kickback Statute prohibits any person or entity from, among other things, knowingly and willfully offering, paying, soliciting, or receiving remuneration to induce or in return for purchasing, leasing, ordering, or arranging for or recommending the purchase, lease, or order of any item or service reimbursable under Medicare, Medicaid, or other federal healthcare programs.
1 unchanged sentence
The federal Anti-Kickback Statute has been interpreted to apply to arrangements between pharmaceutical manufacturers, on the one hand, and prescribers, purchasers, and formulary managers on the other.
−Removed: Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly.
+Added: There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.
Practices that involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor.
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In addition, the government may assert that a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act or the civil monetary penalties laws.
−Removed: Federal civil and criminal false claims laws, including the federal civil False Claims Act, which can be enforced by individuals through civil whistleblower and qui tam actions, and civil monetary penalties laws, prohibits any person or entity from, among other things, knowingly presenting, or causing to be presented, a false claim for payment to the federal government or knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.
+Added: Federal civil and criminal false claims laws, including the federal civil False Claims Act, which can be enforced by individuals through civil whistleblower and qui tam actions and civil monetary penalties laws, prohibit any person or entity from, among other things, knowingly presenting, or causing to be presented, a false claim for payment to the federal government or knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government.
A claim includes “any request or demand” for money or property presented to the U.S.
1 unchanged sentence
Other companies have been prosecuted for causing false claims to be submitted because of the companies’ marketing of products for unapproved, and thus non-reimbursable, uses.
−Removed: The federal Health Insurance Portability and Accountability Act of 1996, or “HIPAA,” created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit
−Removed: program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.
+Added: The federal Health Insurance Portability and Accountability Act of 1996, or “HIPAA,” created additional federal criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit program, including private third-party payors and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious, or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services.
Also, many states have similar fraud and abuse statutes or regulations that apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payor.
4 unchanged sentences
In addition, state laws govern the privacy and security of health information in certain circumstances, many of which are not preempted by HIPAA, differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.
−Removed: The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to the Centers for Medicare & Medicaid Services, or “CMS,” information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, and applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians and their immediate family members.
−Removed: We may also be subject to state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures, state laws that require drug manufacturers to report information on the pricing of certain drugs, and state and local laws that require the registration of pharmaceutical sales representatives.
−Removed: 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.
+Added: The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with
+Added: specific exceptions, to report annually to the Centers for Medicare & Medicaid Services, or “CMS,” information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), other healthcare professionals (such as physician assistants and nurse practitioners), and teaching hospitals, and applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians and their immediate family members.
+Added: We may also be subject to state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, state laws that require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare providers or marketing expenditures, state laws that require drug manufacturers to report information on the pricing of certain drugs, and state and local laws that require certain regulatory licenses to manufacture or distribute our products commercially and/or the registration of pharmaceutical sales representatives.
+Added: Because of the breadth of these laws, it is possible that some of our business activities could be subject to challenge under one or more of such laws.
+Added: There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution.
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.
2 unchanged sentences
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.
−Removed: Third-party payors generally decide which products they will pay for
−Removed: and establish reimbursement levels for those products.
+Added: Third-party payors generally decide which products they will pay for and establish reimbursement levels for those products.
In particular, in the United States, no uniform policy for coverage and reimbursement exists.
4 unchanged sentences
These pressures can arise from rules and practices of managed care groups, judicial decisions and laws and regulations related to Medicare, Medicaid and healthcare reform, pharmaceutical coverage and reimbursement policies and pricing in general.
+Added: Further, the U.S.
+Added: Department of Health and Human Services, or “HHS,” imposes rebates on many Medicare Part B and Medicare Part D products to penalize price increases that outpace inflation on an annual basis.
+Added: HHS has also been empowered to negotiate the price of certain single-source drugs that have been on the market for at least seven (7) years covered under Medicare as part of the Medicare Drug Price Negotiation Program.
+Added: Each year up to twenty (20) products will be selected by HHS for the Medicare Drug Price Negotiation Program.
+Added: Products subject to the Medicare Drug Price Negotiation Program are expected to experience a significant reduction in reimbursement from the Medicare program on a per unit basis.
Third-party payors are increasingly imposing additional requirements and restrictions on coverage and limiting reimbursement levels for products.
15 unchanged sentences
There have been several U.S.
−Removed: government initiatives over the past few years to fund and incentivize certain comparative effectiveness research, including creation of the Patient-Centered Outcomes Research Institute under the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the PPACA.
−Removed: It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s product could adversely affect the sales of our product candidates.
−Removed: The PPACA became law in March 2010 and substantially changed the way healthcare is financed by both third-party payors.
−Removed: 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;
−Removed: a new Medicare
−Removed: Part D coverage gap discount program;
−Removed: and a new formula that increases the rebates a manufacturer must pay under the Medicaid Drug Rebate Program.
−Removed: 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.
−Removed: There have been amendments to, and executive, judicial and Congressional challenges to certain aspects of the PPACA.
−Removed: For example, on August 16, 2022, the Inflation Reduction Act of 2022, or “IRA”, was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in PPACA marketplaces through plan year 2025.
−Removed: 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.
−Removed: It is possible that the PPACA will be subject to judicial or Congressional challenges in the future.
−Removed: It is unclear how additional healthcare reform measures of the second Trump administration will impact the PPACA.
+Added: government initiatives over the past few years to fund and incentivize certain comparative effectiveness research, including creation of the Patient-Centered Outcomes Research Institute under the Patient Protection and Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the “PPACA.” It is also possible that comparative effectiveness research demonstrating benefits in a competitor’s product could adversely affect the sales of our product candidates.
+Added: There have been amendments to, and executive, judicial and Congressional challenges to certain aspects of the Patient Protection and Affordable Care Act, or the “PPACA.” For example, on July 4, 2025, the One Big Beautiful Bill Act, or the “OBBBA,” was signed into law, which narrowed access to PPACA marketplace exchange enrollment and declined to extend the PPACA enhanced advanced premium tax credits that expired at the end of 2025, which, among other provisions in the law, are anticipated to reduce the number of Americans with health insurance.
+Added: The OBBBA also is expected to reduce Medicaid spending and enrollment by implementing work requirements for some beneficiaries, capping state-directed payments, reducing federal funding, and limiting provider taxes used to fund the program.
+Added: Congress is considering proposed legislation intended to further reduce healthcare costs with alternatives to replace the expired PPACA subsidies.
In addition, other legislative changes have been proposed and adopted since the PPACA was enacted.
−Removed: 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.
−Removed: Additionally, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminated the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024
−Removed: Further, there has been increasing legislative and enforcement interest in the United States with respect to drug pricing practices.
−Removed: Specifically, there have been several recent U.S.
−Removed: 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.
−Removed: For example, the IRA, among other things (i) directs the U.S.
−Removed: Department of Health and Human Services, or “HHS” to negotiate the price of certain high expenditure, single-source drugs that have been on the market for at least 7 years covered under Medicare, or the “Medicare Drug Price Negotiation Program,” and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.
−Removed: These provisions began to take effect progressively in fiscal year 2023.
−Removed: On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations, although the Medicare Drug Price Negotiation program is currently subject to legal challenges.
−Removed: On January 17, 2025, HHS selected fifteen additional products covered under Part D for price negotiation in 2025.
−Removed: Each year thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.
−Removed: 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.
−Removed: While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.
−Removed: 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.
−Removed: 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.
−Removed: 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.
−Removed: Other states have also submitted SIP proposals that are pending review by the FDA.
−Removed: Any such approved importation plans, when implemented, may result in lower drug prices for products covered by those programs.
−Removed: Additional health reform measures may continue and affect our business in unknown ways, particularly given the recent changes in administration.
−Removed: The current Trump administration is pursuing policies to reduce regulations and expenditures across government including at HHS, the FDA, CMS and related agencies.
+Added: These changes include aggregate reductions to Medicare payments to providers of 2% per fiscal year, which began in 2013 and will remain in effect until 2032 unless additional Congressional action is taken.
+Added: The current administration is pursuing policies to reduce regulations and expenditures across government agencies including at HHS, the FDA, CMS and related agencies.
These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business.
−Removed: These actions may include, for example, directives to reduce agency workforce, rescinding a Biden administration executive order tasking the Center for Medicare and Medicaid Innovation to consider new payment and healthcare models to limit drug spending and eliminating the Biden administration’s executive order that directed HHS to establishing an AI task force and developing a strategic plan.
−Removed: Additionally, in its June 2024 decision in Loper
−Removed: Bright Enterprises v.
−Removed: Raimondo, or “Loper Bright”, the U.S.
−Removed: Supreme Court overturned the longstanding Chevron doctrine, under which courts were required to give deference to regulatory agencies’ reasonable interpretations of ambiguous federal statutes.
−Removed: The Loper Bright decision could result in additional legal challenges to current regulations and guidance issued by federal agencies applicable to our operations, including those issued by the FDA.
−Removed: Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program created under the IRA.
+Added: For example, the current administration has announced agreements with several pharmaceutical companies that require the drug manufacturers to offer, through a direct to consumer platform, or “TrumpRx”, U.S.
+Added: and Medicaid programs prescription drug Most-Favored Nation pricing equal to or lower than those paid in other developed nations, with additional mandates for direct-to-patient discounts and repatriation of foreign revenues.
+Added: Other recent actions, for example, include (1) directing agencies to reduce agency workforce and cut programs;
+Added: (2) directing HHS and other agencies to lower prescription drug costs through a variety of initiatives;
+Added: (3) imposing tariffs on imported pharmaceutical products;
+Added: and (4) as part of the Make America Healthy Again, or “MAHA”, Commission’s Strategy Report released in September 2025, working across government agencies to increase enforcement on direct-to-consumer pharmaceutical advertising.
+Added: Additionally, the current administration recently called on Congress to enact "The Great Healthcare Plan," to codify and expand Most-Favored Nation pricing, lower government subsidies to private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase, and enact restrictions on pharmacy benefit manager, or “PBM”, payment methodologies, among other things.
+Added: These actions and policies may significantly reduce U.S.
+Added: drug prices, potentially impacting manufacturers’ global pricing strategies and profitability, while increasing their operational costs and compliance risks.
+Added: In June 2024, the U.S.
+Added: Supreme Court’s Loper Bright decision greatly reduced judicial deference to regulatory agencies, which could increase successful legal challenges to federal regulations affecting our operations.
+Added: Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program.
+Added: Individual states in the United States have also become increasingly active in passing legislation and implementing 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.
+Added: Legally mandated price controls on payment amounts by third-party payors or other restrictions could materially and adversely affect our business, financial condition, results of operations and prospects.
+Added: In addition, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other healthcare programs.
+Added: This could reduce the ultimate demand for our product candidates or put pressure on our product pricing.
Foreign Regulation
38 unchanged sentences
Corporate Information
+Added: Milestone Pharmaceuticals Inc.
+Added: was incorporated under the laws of the province of Québec in July 2003.
Our principal executive offices are located at 1111 Dr.
16 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.