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|Item 2.02.||Results of Operations and Financial Condition.|
On November 12, 2021, Milestone Pharmaceuticals, Inc. (the "Company") issued a press release announcing its financial results for the third quarter ended September 30, 2021, which also provided a clinical and corporate update. A copy of the press release is attached as Exhibit 99.1 hereto and is incorporated herein by reference.
|Item 8.01.||Other Events.|
In addition, on November 12, 2021, the Company updated its corporate presentation that it intends to use in connection with presentations at conferences and meetings. The full text of the Company’s corporate presentation is filed as Exhibit 99.2 hereto and incorporated herein by reference.
|Item 9.01.||Financial Statements and Exhibits.|
|99.1||Press Release dated November 12, 2021|
|99.2||Corporate Presentation dated November 12, 2021.|
|Cover Page Interactive Data File––the cover page XBRL tags are embedded within the Inline XBRL document|
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
|MILESTONE PHARMACEUTICALS INC.|
|By:||/s/ Amit Hasija|
|Chief Financial Officer|
Dated: November 12, 2021
Milestone Pharmaceuticals Reports Third Quarter 2021 Financial Results and Provides Clinical and Corporate Update
Montreal and Charlotte, N.C., Nov. 12, 2021 -- Milestone Pharmaceuticals Inc. (Nasdaq: MIST), a biopharmaceutical company focused on the development and commercialization of innovative cardiovascular medicines, today reported financial results for the third quarter ended September 30, 2021 and provided a clinical and corporate update.
“We continue to make meaningful progress across our etripamil PSVT program. We’ve advanced our Phase 3 efficacy and safety studies and completed important patient research which enables a deeper understanding and characterization of the burden experienced by patients,” said Joseph Oliveto, President and Chief Executive Officer of Milestone Pharmaceuticals. “Additionally, we look forward to presenting data from an analysis of heart rate in patients treated in the NODE-301 trial at the upcoming AHA Scientific Sessions 2021 meeting. We believe these data underscore the potential of etripamil to serve as an important intervention for patients with episodic cardiovascular conditions.”
|·||Milestone Remains on Track to Report Topline Data from Pivotal Phase 3 RAPID Trial in the Second Half of 2022. As previously announced, enrollment continues in the ongoing pivotal Phase 3 RAPID trial of etripamil nasal spray in patients with paroxysmal supraventricular tachycardia (PSVT). Milestone is working closely with study investigators to support patient enrollment and continues to activate new centers. The Company remains on track to report topline data in the second half of 2022.|
The RAPID trial, which is targeting a total of 180 adjudicated PSVT events, is expected to randomize approximately 500 patients 1:1 to receive either etripamil or placebo. To maximize the potential treatment effect of etripamil, patients will be directed to administer a repeat dose of study drug if they do not experience symptom relief within 10 minutes of the first study drug administration. The primary efficacy analysis for both the RAPID trial and the completed NODE-301 trial will be time to conversion of supraventricular tachycardia (SVT) over the first 30 minutes following initial study drug administration, with a target p-value of less than 0.05 for each trial. The RAPID and NODE-301 trials could potentially serve to fulfill the efficacy requirement for a future New Drug Application (NDA) for etripamil in patients with PSVT.
|·||Heart Rate Data from NODE-301 Study to be Presented at the American Heart Association (AHA) Scientific Sessions 2021. New analyses on the impact of etripamil on heart rate in patients with PSVT, from the NODE-301 Study, will be presented at the upcoming AHA Scientific Sessions 2021 meeting. The presentation, titled “Etripamil Nasal Spray Reduces Heart Rate in Patients with Paroxysmal Supraventricular Tachycardia Prior to Conversion to Sinus Rhythm”, will be featured during an ePoster session on November 14, 2021 at 11:00 a.m. ET.|
|·||Analysis of Large Longitudinal Patient Reported Outcome Market Research Study Establishes Disease Burden in PSVT and Market Opportunity for Etripamil. In the third quarter, Milestone completed an important patient reported outcomes (PRO) market research study in PSVT. The 247 patients who participated in the longitudinal portion of the study represent the broader PSVT population in terms of age, sex, medical history and time since diagnosis. Patients on average participated for 8.5 months and completed a survey every 12 days. In total, over 5,000 episodes were reported and characterized. Of these episodes, approximately 60% lasted longer than 10 minutes and 35% longer than 30 minutes.|
Patients who participated in the study demonstrated a wide range of annual SVT episode frequency (0 to >50), with a median frequency of 12-15 episodes per year. Based on internal analysis, Milestone estimates approximately 60% of patients experience multiple 10+ minute episodes each year characterized as moderate or severe in intensity. In addition, approximately 30% of patients experiencing episodes sought medical care for the episode, the majority of which were treated in the emergency department.
|·||ReVeRA Phase 2 Proof-of-Concept Trial Continues Recruitment in Patients Experiencing Atrial Fibrillation with Rapid Ventricular Rate (AFib-RVR). Recruitment is ongoing in ReVeRA, Milestone’s Phase 2 proof-of-concept study of etripamil nasal spray in patients experiencing AFib-RVR. Patients are being randomized 1:1 to receive either 70 mg of etripamil or placebo. The Phase 2 double blind, placebo controlled, proof-of-concept in-patient study is designed to assess the safety and efficacy of etripamil nasal spray to reduce the ventricular rate in patients with AFib-RVR. The trial is being conducted in Canada in collaboration with the Montreal Heart Institute and other research centers. The primary endpoint will assess reduction in ventricular rate, with key secondary endpoints including the time to achieve the maximum reduction in rate and duration of the effect.|
Third Quarter 2021 Financial Results
|·||As of September 30, 2021, Milestone had cash, cash equivalents, and short-term investments of $126.4 million and 29.9 million common shares issued and outstanding and 12.3 million common shares issuable upon exercise of pre-funded warrants outstanding.|
|·||Research and development expense for the third quarter of 2021 was $9.7 million compared with $8.2 million for the prior year period. The increase reflects higher clinical consulting fees and contract research organization (CRO) costs due to advancing RAPID Phase 3 efficacy and safety trials in etripamil for the treatment of PSVT along with an increase in clinical personnel related costs. For the nine months ended September 30, 2021, research and development expense was $27.8 million compared with $28.7 million for the prior year period. The decrease was due to a reduction in clinical trial expenses of $2.3 million which was partially offset by an increase of $1.3 million in clinical personnel related costs which included a non-cash share-based compensation expense.|
|·||General and administrative expenses for the third quarter of 2021 and 2020 were $3.0 million. For both of the nine month periods ended September 30, 2021 and 2020, respectively, general and administrative expense was $8.6 million.|
|·||Commercial expense for the third quarter of 2021 was $1.6 million compared with $0.9 million for the prior year period. The increase is attributable to investment in commercial activities during the three months ended September 30, 2021 in contrast to the three months ended September 30, 2020, a period during which Milestone reduced commercial spending in order to focus efforts on an optimized clinical development pathway for etripamil after issuing topline results of the first part of the NODE-301 in March 2020. For the nine months ended September 30, 2021, commercial expense was $4.8 million compared with $4.6 million for the prior year period. This change was due to an increased investment in commercialization activities.|
|·||For the third quarter of 2021, operating loss was $14.3 million compared to $12.1 million in 2020. For the nine months ended September 30, 2021, Milestone’s operating loss was $26.2 million compared to $41.9 million in the prior year period.|
About Paroxysmal Supraventricular Tachycardia
Paroxysmal supraventricular tachycardia (PSVT) is a condition characterized by intermittent episodes of rapid heart beat that starts and stops suddenly and without warning that affects approximately two million Americans. Episodes of supraventricular tachycardia (SVT) are often associated with palpitations, sweating, chest pressure or pain, shortness of breath, sudden onset of fatigue, lightheadedness or dizziness, fainting, and anxiety. Adenosine and certain calcium channel blockers have long been approved for the treatment of PSVT. However, these medications must be administered intravenously under medical supervision, usually in an emergency department or other acute care setting.
About Atrial Fibrillation with Rapid Ventricular Rate
Atrial fibrillation (AFib) is a common arrhythmia marked by an irregular and often rapid heartbeat. AFib is estimated to affect five million patients in the United States, a prevalence projected by the Centers for Disease Control to increase to twelve million patients within the next 10 years. Atrial fibrillation with rapid ventricular rate (AFib-RVR) is a condition in which patients with AFib experience episodes of abnormally high heart rate, often with symptoms such as palpitations, shortness of breath, dizziness, and weakness. Oral calcium channel blockers and/or beta blockers are commonly used to manage the heart rate in this condition. When episodes do occur, the corresponding symptoms often cause patients to seek care in the acute care setting such as the emergency department, where standard of care procedures include intravenous administration of calcium channel blockers or beta blockers under medical supervision. Milestone’s initial qualitative market research indicates that approximately 40% of patients with AFib experience one or more symptomatic episodes of RVR per year that require treatment, suggesting a target addressable market for etripamil in patients with AFib of approximately two million patients.
Etripamil, Milestone's lead investigational product, is a novel calcium channel blocker designed to be a rapid-response therapy for episodic cardiovascular conditions. As a nasal spray that is self-administered by the patient, etripamil has the potential to shift the current treatment experience for many patients from the emergency department to the at-home setting. Milestone is conducting a comprehensive development program for etripamil, with Phase 3 trials ongoing in paroxysmal supraventricular tachycardia (PSVT) and now a Phase 2 proof-of-concept trial underway in patients with atrial fibrillation and rapid ventricular rate (AFib-RVR).
About Milestone Pharmaceuticals
Milestone Pharmaceuticals Inc. (Nasdaq: MIST), is a biopharmaceutical company focused on the development and commercialization of innovative cardiovascular medicines. Milestone's lead product candidate etripamil is currently in a Phase 3 clinical-stage program for the treatment of paroxysmal supraventricular tachycardia (PSVT) and in a Phase 2 proof-of-concept trial for the treatment of patients with atrial fibrillation and rapid ventricular rate (AFib-RVR). Milestone Pharmaceuticals operates in Canada and the United States. For more information, visit www.milestonepharma.com and follow the Company on Twitter at @MilestonePharma.
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as "believe," "will," "expect," "continue," "estimate," “potential,” “progress” and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Milestone's expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this press release include statements regarding the potential of etripamil to serve as a promising therapy for PSVT patients, the design, progress, timing, scope and results of the RAPID and ReVeRA trials; Milestone’s ability to execute on the remainder of the PSVT program, Milestone’s ongoing plans to study etripamil in atrial fibrillation patients, the sufficiency of Milestone’s current cash resources to support its operations, and estimates about the addressable market and commercial potential for treatments of atrial fibrillation with rapid ventricular rate. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, but are not limited to, the risks inherent in biopharmaceutical product development and clinical trials, including the lengthy and uncertain regulatory approval process, uncertainties related to the timing of initiation, enrollment, completion and evaluation of clinical trials, and whether the clinical trials will validate the safety and efficacy of etripamil for PSVT or other indications, among others, as well as risks related to pandemics and public health emergencies, including those related to the ongoing COVID-19 pandemic, and risks related the sufficiency of Milestone’s capital resources and its ability to raise additional capital. These and other risks are set forth in Milestone's filings with the U.S. Securities and Exchange Commission, including in its annual report on Form 10-K for the year ended December 31, 2020, under the caption "Risk Factors." Except as required by law, Milestone assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available.
INTERIM CONDENSED CONSOLIDATED STATEMENTS OF LOSS AND COMPREHENSIVE LOSS
(Unaudited, in thousands of US dollars, except share and per share data)
|Three months ended|
|Nine months ended|
|Research and development, net of tax credits||9,733||8,228||27,755||28,722|
|General and administrative||2,961||2,952||8,612||8,611|
|Loss from operations||(14,273||)||(12,085||)||(26,155||)||(41,948||)|
|Interest income, net||48||89||186||630|
|Loss before income taxes||(14,225||)||(11,996||)||(25,969||)||(41,318||)|
|Income tax benefit||—||17||—||17|
|Weighted average number of shares and pre-funded warrants outstanding, basic & diluted||42,182,887||29,774,065||41,707,563||26,329,581|
|Net loss per share, basic and diluted||$||(0.34||)||$||(0.40||)||$||(0.62||)||$||(1.57||)|
INTERIM CONDENSED CONSOLIDATED BALANCE SHEETS
(Unaudited, in thousands of US dollars, except share data)
|September 30, 2021||December 31, 2020|
|Cash and cash equivalents||$||111,426||$||72,310|
|Research and development tax credits receivable||275||725|
|Total current assets||132,758||148,686|
|Operating lease assets||780||980|
|Property and equipment||238||308|
|Liabilities, and Shareholders' Equity|
|Accounts payable and accrued liabilities||$||5,593||$||5,914|
|Operating lease liabilities||254||245|
|Total current liabilities||5,847||6,159|
|Operating lease liabilities (net of current portion)||512||696|
|Common shares, no par value, unlimited shares authorized 29,869,785 shares issued and outstanding as of September 30, 2021, 29,827,997 shares issued and outstanding as of December 31, 2020||251,766||251,682|
|Pre-funded warrants - 12,327,780 issued and outstanding as of September 30, 2021 and 11,417,034 as of December 31, 2020||52,927||48,007|
|Additional paid-in capital||13,793||8,530|
|Cumulative translation adjustment||(1,634||)||(1,634||)|
|Total shareholders’ equity||127,417||143,119|
|Total liabilities and shareholders’ equity||$||133,776||$||149,974|
Joseph Oliveto President & CEO Corporate Overview November 2021
Disclaimers The Presentation contains forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, as amended. Words such as ‘‘aim,’’ ‘‘anticipate,’’ ‘‘assume,’’ ‘‘believe,’’ ‘‘contemplate,’’ ‘‘continue,’’ ‘‘could,’’ ‘‘design,’’ ‘‘due,’’ ‘‘estimate,’’ ‘‘expect,’’ ‘‘goal,’’ ‘‘intend,’’ ‘‘may,’’ ‘‘objective,’’ ‘‘plan,’’ ‘‘predict,’’ ‘‘positioned,’’ ‘‘potential,’’ ‘‘project,’’ ‘‘seek,’’ ‘‘should,’’ ‘‘target,’’ ‘‘will,’’ ‘‘would’’ (as well as other words or expressions referencing future events, conditions or circumstances) are intended to identify forward-looking statements. These forward- looking statements are based on Milestone's expectations and assumptions as of the date of this Presentation. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this Presentation include statements regarding (i) the design, progress, timing, scope and results of the etripamil clinical trials in PSVT and AFib-RVR, (ii) the possibility that data will support FDA approval, (iii) the potential market size and the rate and degree of market acceptance of etripamil and any future product candidates and the implementation of Milestone's business model and strategic plans for its business, etripamil and any future product candidates, and (iv) the sufficiency of Milestone's capital resources. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, but are not limited to, the risks inherent in biopharmaceutical product development and clinical trials, including the lengthy and uncertain regulatory approval process, uncertainties related to the timing of initiation, enrollment, completion and evaluation of clinical trials, including the RAPID and ReVeRA trials, and whether the clinical trials will validate the safety and efficacy of etripamil for PSVT, AFib-RVR, or other indications, among others, as well as risks related to pandemics and public health emergencies, including those related to COVID-19, and risks related the sufficiency of our capital resources and our ability to raise additional capital. These and other risks are set forth in Milestone's filings with the U.S. Securities and Exchange Commission, including in its annual report on Form 10-K for the year ended December 31, 2020, under the caption "Risk Factors." Except as required by law, Milestone assumes no obligation to update any forward- looking statements contained herein to reflect any change in expectations, even as new information becomes available. This Presentation contains trademarks, trade names and service marks of other companies, which are the property of their respective owners. Certain information contained in this Presentation and statements made orally during this Presentation relate to or is based on studies, publications, surveys and other data obtained from third-party sources and Milestone's own internal estimates and research. While Milestone believes these third-party studies, publications, surveys and other data to be reliable as of the date of the Presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, no independent sources has evaluated the reasonableness or accuracy of Milestone's internal estimates or research and no reliance should be made on any information or statements made in this Presentation relating to or based on such internal estimates and research. 2 Milestone Corporate Overview
3 Milestone Corporate Overview Phase 3 Cardiovascular Company Etripamil: novel calcium channel blocker (IP protection until 2036) Shift from the ED to patient self-management Targeting Large Areas of Unmet Need PSVT AFib-RVR Additional pipeline opportunities First Phase 3 study findings and FDA guidance in PSVT Next Pivotal Phase 3 efficacy result in PSVT expected by 2H 2022 Financial runway expected through mid-2023 Milestone (Nasdaq: MIST) - Corporate Highlights PSVT = Paroxysmal Supraventricular Tachycardia; AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate; ED = Emergency Department Paradigm-Changing Approach Recent Events Position for Future Success
PSVT Atrial Fibrillation 2.6 Million3 10 Million1 145 Thousand 785 Thousand 1.0-1.6 Million5 ~3-4 Million4 Source(s): 1. Colilla et al., Am. J. Cardiol. 2013, 112(8), 1142-1147; Miyasaka et al., Circulation, 2006, 114, 119-125. American Heart Association 2. HCUP ED & Admissions Data (2016), accessed January 2021. 3. Rehorn et al. Journal of Cardiovascular Electrophysiology. 2021 Aug; 32(8): 2199-2206. doi: 10.1111/jce.15109. Epub 2021 Jun 14. 2018 prevalence of 2M anticipated to grow at a CAGR of ~2% 4. 30%-40% of AF patients have >1 symptomatic episode per year of AF with RVR requiring treatment, Triangle Insights Group Market Research, N=25, January 2021. 5. Estimate of TAM (~40%-60% of prevalence) based on internal PSVT patient market research (BluePrint Research Group, n=247) and longitudinal analysis of claims data. 4 Milestone Corporate Overview PSVT & Atrial Fibrillation Populations in the US Total Patients (2030) Discharged ED Visits & Hospital Admissions (2016)2 Target Market Addressable (2030) (Patient Population)
Atrial Arrhythmias with a Common Patient Burden Sources: adapted from https://en.ecgpedia.org/index.php?title=Supraventricular_Rhythms, accessed 2/2021 5 Milestone Corporate Overview PSVT (AVNRT and AVRT) AFib-RVR (a subset of AFib) Regular rapid heart rate Irregular rapid heart rate Typically 150 - 250 bpm Typically 100 - 175 bpm Episode frequency and duration is highly variable AV Node SA Node Atrial Fibrillation (multiple atrial wavelets) AV Reentrant Tachycardia (AVRT) AV Nodal Reentrant Tachycardia (AVNRT) Patients with PSVT and AFib-RVR report feeling a loss of control PSVT = Paroxysmal Supraventricular Tachycardia; AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate Common Symptoms Include Heart palpitations Chest pressure or pain Shortness of breath Fatigue Light-headedness Anxiety
Role of L-Type Calcium Channel Blockers 6 Milestone Corporate Overview for PSVT for AFib-RVR Sino-Atrial Node Atrio- Ventricular (AV) Node IV CCBs like verapamil or diltiazem slow conduction over the AV node… …to reduce the ventricular rate while still in AFib …to break the tachycardia and return the heart to sinus rhythm CCBs = Calcium Channel Blockers; PSVT = Paroxysmal Supraventricular Tachycardia; AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate; IV = Intravenous
Potential Paradigm-Changing Treatment to Empower Patient Control of their Condition • Time consuming • Anxiety provoking • Costly 7 Milestone Corporate Overview Drawbacks with the current standard of care in the Emergency Department (ED) • Often results in a hospital admission • Experienced by patients as a loss of control Intervention used by the patient whenever & wherever an episode occurs [placeholder for device image] [placeholder for device image] • Reduces ED visits / hospital admissions • Less need for chronic medications • Alternative or bridge to ablation procedure
Etripamil Nasal Spray is Designed to be Fast, Convenient, and Empowering 8 Milestone Corporate Overview Etripamil Class Novel CCB Potency (IC50) 11 nM Metabolism Rapid: Esterase-mediated • Clinically-validated mechanism − Calcium channel blockers (CCBs) prolong refractoriness and slow conduction over the AV node • Rapid onset of action • Convenient patient self-administered nasal spray • Short duration of action 0 20 40 60 80 100 120 140 160 180 200 220 240 0 20 40 60 Minutes after Dose Etripamil Plasma Levels (ng/ml) • Rapid onset (Tmax < 5 min) • Transient plasma levels Error bars indicate standard error of the mean 14 mg 60 mg 140 mg Prospectively designed to treat common tachycardias outside the Emergency Department (ED) AV = Atrio-ventricular; nM = nanomolar
Clinical Program Overview for Etripamil 9 Milestone Corporate Overview NODE-1 PSVT ReVeRA AFib-RVR NODE-301 PSVT RAPID PSVT NODE-303/302 PSVT Phase 2 Phase 2 Phase 3 Phase 3 Phase 3 Efficacy Efficacy POC Efficacy Efficacy Safety Published Enrolling Complete Enrolling Enrolling/ Complete Electrophysiology Lab Emergency Department At home At Home At Home N= 104 1:1 randomized N=50 1:1 randomized N=419 2:1 randomized N~500 1:1 randomized N ~1000 Open label Clinical development programs designed to support NDA filing in PSVT while concurrently building safety database and running Phase 2 ReVeRA to support AFib-RVR program POC = Proof of Concept; AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate; PSVT = Paroxysmal Supraventricular Tachycardia
Development Plan for Etripamil 10 Milestone Corporate Overview AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate; POC = Proof of Concept NODE-301: Efficacy & Safety RAPID NODE-302: Open-Label Extension NODE-303: Open-Label Safety 2019 2020 2021 Data ReVeRA: AFib – RVR Efficacy POC 2022 Expanded Access Program RAPID Phase 3 PSVT Program Pipeline Expansion (Phase 2) Data
NODE-301 Study Design 11 Milestone Corporate Overview NODE-301 patients taking etripamil had no serious adverse events Test Dose Randomization Event Primary Efficacy Analysis 70 mg dose of etripamil Administer in office while in sinus rhythm for safety evaluation (N=431) Randomized 2:1 70 mg etripamil: placebo (N=419) 1. Patient recognizes symptoms 2. Applies cardiac monitor (ECG) 3. Attempts vagal maneuver 4. Administers study drug (N=198) • ECG of event is adjudicated for PSVT; only PSVT events count towards primary efficacy • Primary Endpoint: PSVT conversion to SR Kaplan Meier analysis over 5 hours • Powering: 90%, alpha <0.01; delta = 40% • Study concluded when 150 confirmed PSVT events reached (N = 156) 1 2 3 SR = Sinus Rhythm; ECG = Electrocardiogram; PSVT = Paroxysmal Supraventricular Tachycardia 4
Primary Endpoint - over 5 hours Hazard Ratio = 1.09; p<0.12 NODE-301 Kaplan-Meier Plot of Conversion to Sinus Rhythm 12 Milestone Corporate Overview Post hoc analysis: over 30 minutes Etripamil 54% vs. Placebo 35% HR = 1.87; p<0.02 Primary analysis: over 5 hours HR = 1.086; p<0.12 Source: Data on File, Milestone Pharmaceuticals Inc.
Randomized Treatment Emergent Adverse Events (RTEAE) Etripamil N=138 (%) Placebo N=60 (%) Subjects with any RTEAE 53 (38.4) 12 (20.0) Maximum severity of RTEAE Mild 45 (32.6) 10 (16.7) Moderate 8 (5.8) 3 (3.3) Severe 0 (0.0) 0 (0.0) Most Common Adverse Events (>5%) Nasal discomfort 27 (19.6) 4 (6.7) Nasal congestion 11 (8.0) 2 (3.3) Epistaxis 9 (6.5) 0 (0.0) Rhinorrhea 8 (5.8) 1 (1.7) Throat irritation 7 (5.1) 1 (1.7) NODE-301 Safety Analysis Source: Data on File, Milestone Pharmaceuticals Inc. 13 Milestone Corporate Overview RTEAE timing: up to 24 hours following double-blind study drug administration
PK of Etripamil 30 mg Repeat Administration at T=10 min (Study MSP-2017-1096) 14 0 10 20 30 40 50 60 70 80 90 100 0 10 20 30 40 50 60 Plasma Concentration (ng/ml) Time (minutes) 30mg 30mg Milestone Corporate Overview Repeat administration increases both Cmax and AUC N=7, Error bars are standard error Source: Data on File, Milestone Pharmaceuticals Inc.
RAPID Study Design 1 includes ~30 events expected to be treated with the single dose double-blind study drug administration from NODE-301 patients who experienced an event prior to the RAPID study being available 15 Milestone Corporate Overview Test Dose Randomization Event Primary Efficacy Analysis 70 mg etripamil repeat dose regimen given as 2 doses 10 minutes apart Administered in office while in sinus rhythm for safety evaluation 1:1 randomization of 70 mg etripamil x2: Placebo x2 (N~500) 1. Patient recognizes symptoms 2. Applies cardiac monitor (ECG) 3. Attempts vagal maneuver 4. Administers study drug 5. If symptoms persist for 10 minutes, dose study drug again • ECG of event is adjudicated for PSVT; only PSVT events count to primary efficacy • Primary Endpoint = PSVT conversion to SR Kaplan Meier analysis over 30 min • Powering: 90%, alpha < 0.05; delta = 19% • Study concluded when 180 confirmed PSVT events1 1 2 3 4 4
ReVeRA – Proof of Concept for AFib with Rapid Ventricular Rate 16 Milestone Corporate Overview NODE-1 PSVT ReVeRA AFib-RVR NODE-301 PSVT RAPID PSVT NODE-303/302 PSVT Phase 2 Phase 2 Phase 3 Phase 3 Phase 3 Efficacy Efficacy POC Efficacy Efficacy Safety Published Enrolling Complete Enrolling Enrolling/ Complete Electrophysiology Lab Emergency Department At home At Home At Home N= 104 1:1 randomized N=50 1:1 randomized N=419 2:1 randomized N~500 1:1 randomized N ~1000 Open label Clinical development programs designed to support NDA filing in PSVT, while concurrently building safety database and running Phase 2 ReVeRA to support AFib-RVR program SR = Sinus Rhythm; ECG = Electrocardiogram; PSVT = Paroxysmal Supraventricular Tachycardia; AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate; POC = Proof of Concept
The ReVeRA Trial 17 Milestone Corporate Overview Reduction of Ventricular Rate in Patients with Atrial Fibrillation CHADs 0 = No Heart Failure/No Hypertension/Age < 65/No Diabetes/No History of Stroke or TIA/No Coronary ischemic disease; OAC = Oral Anti-coagulant; AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate; TSQM-9, Treatment Satisfaction Questionnaire for Medication; ED = Emergency Department Patient presents to ED with episode of AFib-RVR 1 Dosing & Assessment 2 Efficacy Analysis Inclusion: • Atrial Fibrillation ≥ 1 hour • Ventricular Rate ≥ 110 bpm Select Exclusions: • Treated with antiarrhythmic drugs • Hemodynamically unstable • Heart failure 1. Baseline ECG for ≥ 10 min 2. Administer study drug 70 mg etripamil : Placebo (1:1) 3. Monitor in-patient for 1 hour 4. Discharge if appropriate 5. Six-hour remote cardiac monitor 6. Complete safety 24 hours post dose • Primary: Maximum reduction in ventricular rate within 60 min ― N=50: 90% powered to detect 20 bpm difference in max reduction, α=0.05; • Time from drug administration to lowest ventricular rate • Time to and duration of ventricular rate reductions ― <100 bpm, ≥ 10% reduction, ≥ 20% reduction • Patient satisfaction with treatment (TSQM-9) 4
Commercial Opportunity 18
Etripamil – Addressing Market Needs in PSVT and AFib-RVR Sources: Internal market research 19 Milestone Corporate Overview Future with Etripamil – a Potentially Better Treatment Option Potential for high receptivity to etripamil across stakeholders Patients Physicians (Cards, EPs, PCPs) Payers • Self-management of acute episodes • Reduces ED visits/hospital admissions • Better risk/benefit profile • Expected to have significant adoption in unablated patients • Reduction in ED/hospital admissions • Improvement in patient satisfaction Cards = Cardiologists, EPs = Electrophysiologists, PCPs = Primary Care Providers, PSVT = Paroxysmal Supraventricular Tachycardia, ED = Emergency Department
New Data Enhances Understanding of Burden of PSVT Analysis of Prospective Patient Reported Outcomes Longitudinal Data • Phase 1: Baseline Survey (medical and SVT episode history) • Phase 2: Longitudinal Weekly Surveys (episode survey if experienced an episode, QoL survey if not) 5,277 surveys completed 257 days Average days on study (Avg. 37 weeks/8 months per patient) Longitudinal Surveys Episode Surveys 2,518 surveys Avg. of 10 per patient 5,035 SVT episodes QoL Surveys 2,759 Avg. of 11 per patient 247 US & UK patients Milestone Corporate Overview 20 Source(s): PSVT patient market research, 2019 (BluePrint Research Group, n=247, n=198 US & n=49 UK)
Peak US Market Opportunity for Etripamil in PSVT *Patient stated severity of SVT episode (mild, moderate, or severe) Sources: Internal estimates based on market and outcomes research, Milestone Pharmaceuticals. 1. Rehorn et al. Journal of Cardiovascular Electrophysiology. 2021 Aug; 32(8): 2199-2206. doi: 10.1111/jce.15109. Epub 2021 Jun 14. 2. 2019 market research with patients conducted by BluePrint Research Group (n=247) . 3. 2020 market research with HCPs conducted by Triangle Insights Group, 2020 (n=250). Patients with PSVT 21 Milestone Corporate Overview ~ 2.6 million patients1 US Prevalence (2030) ~1.0-1.6 million patients Addressable Market (2030) ~500-800K patients Peak Share ~4-6 / year Episodes Treated/Pt ~2.5 to 4.0 million episodes/yr Episodes/Yr Peak Net Sales • ~40-60%2 • 50%3 • Avg of 5 / yr 12-15 ~60% 60% 35% ~45% with multiple 10+ minute moderate/severe* episodes per year Experience an average duration ≥30 min / episode median annual episode frequency last at least 10 minutes last at least 30 minutes Episodes of PSVT
AFib-RVR = Atrial Fibrillation with Rapid Ventricular Rate *Reflects the midpoint of published estimates (~8M to ~12M by 2025 or 2030) 1. Colilla et al., Am. J. Cardiol. 2013, 112(8), 1142-1147; Miyasaka et al., Circulation, 2006, 114, 119-125; Colilla et al., Am. J. Cardiol. 2013, 112(8), 1142-1147 ; American Heart Association 2. HCUP ED & Admissions Data (2016), accessed January 2021. 2. Quantitative Survey conducted by Triangle Insights, May 2021, N=250 Clinical Cardiologists, Interventional Cardiologists, and Electrophysiologists Peak US Market Opportunity for Etripamil in AFib-RVR 22 Milestone Corporate Overview Prevalent AFib Patients1† (~10M) Lone Episode (1M) Permanent (3M) ~40% (1.2M) Symptomatic AFib with RVR ~3.3M (~33% of prevalence) Persistent (3M) ~40% (1.2M) ~40%2 ~30%2 ~30%2 ~30% (0.9M) Patient Segments Share Experiencing >1 Symptomatic AFib with RVR Episode Requiring Treatment* per Year2 Target Addressable Market *Treatment was defined as either seeking treatment at the emergency department or outpatient clinic or via self-administration of treatments at home or other unsupervised setting Market research suggests a target addressable market of ~3-4 million patients for AFib-RVR by 2030 Paroxysmal (4M) ~25%2 ~30-40% ~10 million patients* US Prevalence (2030) ~3-4 million patients Addressable Market Peak Share Episodes/Pt Episodes/Yr Peak Net Sales
Peak US Market Opportunity for Etripamil in PSVT and AFib-RVR 23 Milestone Corporate Overview ~2.6 million patients US Prevalence (2030) ~40-60% ~1.0-1.6 million patients ~500k-800k patients 4-6/year Addressable Market Peak Share Episodes/Pt Episodes/Yr ~50% 2030 Peak Net Sales ~10 million patients ~30-40% ~3-4 million patients ~2.5 -4.0 million episodes/year PSVT AFib-RVR Market research suggests a TAM of 4+ million patients across both PSVT and AFib-RVR indications AF – RVR = Atrial Fibrillation with Rapid Ventricular Rate; TAM = Target Addressable Market; Internal estimates based on market and outcomes research, Milestone Pharmaceuticals Sources: Internal estimates based on market research, Milestone Pharmaceuticals Inc. Avg of 5 / yr
Finances – as of September 30, 2021 Cash, cash equivalents and short-term investments of $126.4M Cash funds operations past guidance for top-line data and into mid-2023 24 Milestone Corporate Overview Equity - 42.2Min shares and pre-funded warrants outstanding • 29.9M common shares • 12.3M pre-funded warrants
Etripamil Phase 1 Pharmacology PR Prolongation Used to Select Doses for Phase 2 Error bars indicate standard error of the mean 26 20 40 60 80 100 120 140 placebo 8 4 6 2 10 12 14 16 18 20 0 Target PR threshold PR Interval Prolongation (%) Etripamil Dose (mg) Milestone Corporate Overview
Etripamil Nasal Spray Pharmacological Results (NODE-102) 27 Milestone Corporate Overview Anticipated therapeutic effect within 45 minutes; peak within 10 minutes -10% 0% 10% 20% 0 20 40 60 80 100 120 140 160 0 10 20 30 40 50 60 70 80 90 100 PR Interval – Mean change from baseline (%) Mean Etripamil Plasma Concentration (ng/ml) Time (minutes) Comparison of PK and PD Profile of Etripamil 70mg Mean Etripamil Plasma Concentration (ng/ml) Mean Percentage Change from Baseline PR Interval Target Threshold for PR Prolongation N=24; Error bars indicate standard error of the mean
Placebo n=20 Objectives: Demonstrate superiority of etripamil over placebo in terminating SVT and dose ranging trend analysis Etripamil 140mg n=21 15 min Etripamil 105mg n=20 0 min -5 min Phase 2a/b Study Design EP = electrophysiology, SVT = supraventricular tachycardia, PSVT = Paroxysmal Supraventricular Tachycardia 28 Etripamil 70mg n=23 Etripamil 35mg n=20 Endpoint: conversion to sinus rhythm within 15 minutes >80% power to show a 50% absolute difference vs. placebo SVT Induced PSVT patients with scheduled cardiac ablation (EP lab) Milestone Corporate Overview
Phase 2 Primary Endpoint Source: Stambler, B.S. et al.; Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm; J Am Coll Cardiol. 2018;72(5):489–97 29 Etripamil three highest doses demonstrated 75-95% conversion rates which are statistically significant compared to placebo # patients converted at 15 min 7/20 13/20 20/23 15/20 20/21 p-value 0.1128 0.0006 0.0248 <.0001 % patients successfully converted at T=15min 35% 65% 87% 75% 95% 0% 20% 40% 60% 80% 100% Placebo 35mg 70mg 105mg 140mg Milestone Corporate Overview
Phase 2 Time to Conversion Source: Stambler, B.S. et al.; Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm; J Am Coll Cardiol. 2018;72(5):489–97 30 Milestone Corporate Overview 70mg etripamil dose showed rapid time to conversion (median < 3 min) Kaplan Meier plot showing time to conversion 0 5 10 15 0 20 40 60 80 Time Since Study Drug Administration (min) Etripamil 70mg vs. placebo p=0.0003* Placebo Etripamil 70 mg Etripamil 140 mg Etripamil 35 mg Etripamil 105 mg 100 Cumulative Conversion Rate (%) *Hazard Ratio and 95% Confidence Intervals etripamil 70mg vs. placebo; 4.99 (2.09, 11.93) Etripamil 70mg Placebo
Phase 2 Mean Systolic Blood Pressure Effects Source: Stambler, B.S. et al.; Etripamil Nasal Spray for Rapid Conversion of Supraventricular Tachycardia to Sinus Rhythm; J Am Coll Cardiol. 2018;72(5):489–97 31 Milestone Corporate Overview 1 2 1 Baseline is defined as the average of the 20-min and 10-min pre-dose measurements. 2 Time 0 is defined as the average of the measurements during supraventricular tachycardia between 5 and 0 min before study drug administration. *p < 0.05 versus baseline. * * * * * * * * * 70 mg of etripamil showed no decrease in blood pressure; higher doses transient decreases
NODE-301 Efficacy– Time to Conversion over 45 Minutes 32 0% 10% 20% 30% 40% 50% 60% 70% 0 5 10 15 20 25 30 35 40 45 % Converted to SR Time to Conversion (minutes) Placebo Etripamil 70mg 32% 14% 54% 35% Milestone Corporate Overview New Primary Endpoint Second Dose Option for RAPID HR 1.87, p=0.02 (post-hoc)
NODE-301 Conversion up to Hour 5 with Medical Intervention Patients Analyzed as Treatment Failures at 5 hours (post-hoc) 33 Milestone Corporate Overview Etripamil 70mg Placebo Subjects who convert following medical assistance are censored at 5 hours. Subjects who present missing data from time t to the end are censored at the time of last available data. Subjects who do not convert or are not censored before 5 hours are censored at 5 hours Hazard Ratio = 1.27, p=0.06 (post-hoc)
PRO Analyses Provide A Clearer Picture of Burden of PSVT than Market Research Alone 34 Milestone Corporate Overview Sources: Internal estimates based on market and outcomes research, Milestone Pharmaceuticals. 1. PSVT patient market research conducted by Triangle Insights Group, 2018 (n=250). 2. PSVT patient market research conducted by BluePrint Research Group, 2019 (n=247). Weekly tracking shows that patients are experiencing more episodes than previously thought – but that they tend to recall the moderate/severe episodes of longer duration (e.g., 5+ minutes) Episode Freq. for Patients not Receiving Catheter Ablation Market Research1 (annual recall, n=250) PRO Longitudinal Data2 (weekly tracking, n=247) Annual Episode Freq 4-7 episodes / year 15 episodes/year* % of patients with multiple 10+ min episodes / year 40% 68% Annual Freq of Moderate-Severe 5+ min episodes N/A 5-6 episodes / year* *Patients on study at least 6 months were used to project annual episode frequency. Sample projections were weighted by stated episode frequency from an intake survey Unablated patients experience 5-6 episodes per year relevant for etripamil use
• Prevalence ~2M diagnosed PSVT patients • ~300K newly diagnosed per year • ~600K patients treated per year • >150K ED/hospital visits per year • ~80K ablations per year No Rx ~25% Chronic Therapy ~65% Ablation ~10% Current US PSVT Market Source: Sacks, N.C. et al; Prevalence of Paroxysmal Supraventricular Tachycardia (PSVT) in the US in Patients Under 65 Years of Age; Abstract and Oral Presentation at the International Academy of Cardiology Annual Scientific Sessions 2018, 23rd World Congress on Heart Disease; Precision Xtract, Boston, MA, USA; and data-on-file from IBM Marketscan® Commercial Research Database (<65y) and the Medicare Limited Dataset (≥65y), with demographic, enrollment and claims data for commercially insured (Truven) and Medicare covered patients using PSVT code 427.0 or I47.1 for up to a 9-year interval between 2008 and 2016 inclusive. 35 Current Management Total annual US healthcare expenditures of ~$3B Milestone Corporate Overview
Core PSVT Market is Addressable Now, with Potential for Expansion Source: 1) assumes annual incidence rate for PSVT of ~300k from longitudinal claims analysis and the average time to diagnosis (currently 2-3 years) can be reduced to <6 months 2) Calculated as the difference between PSVT prevalence of 2M and annual treatment rate of ~600k from Truven MarketScan data, 2008-2016 analyzed by Precision Xtract, 2019 3) Estimated number of unique patients with annual claims for PSVT from Truven MarketScan data, 2008-2016 analyzed by Precision Xtract, 2019. 36 Milestone Corporate Overview Diagnosed, Annually Treated PSVT Patients Core Market Diagnosed, Untreated PSVT Patients Expanded Market Undiagnosed PSVT Patients Target PSVT Market Strategy to Address • Increase speed and rates of diagnosis through wearable technology • Re-engage in healthcare system through DTC promotion • MIST specialty sales force • Partner majority of PCP promotion ~600k/year3 ~1.4 Million2 ~600-900k1
PSVT Patient Management and Call Point Targeting • Targeted sales force to reach majority of available opportunity • Significant overlap with most common CV portfolio call points Source: Internal market research 37 Clinical Cardiologists Primary Care Physicians Electro- physiologists % of PSVT patients managed ~60% ~30% ~10% Long-term Use Add to or Replace Chronic Medications Medium-term Use Defer Ablation Short-term Use Bridge to Ablation Primary Target Secondary Target Majority of PSVT patients managed by CV specialists, leading to commercial efficiencies Milestone Corporate Overview
Estimating Prevalence, Incidence, and Annually Treated Patients Using Longitudinal Claims Data Source: Data on file from IBM Marketscan® Commercial Research Database (<65y) and the Medicare Limited Dataset (≥65y), with demographic, enrollment and claims data for commercially insured (Truven) and Medicare covered patients using PSVT code 427.0 or I47.1 for up to a 9-year interval between 2008 and 2016 inclusive. Age Group Year 1 Year 2 Year 3 Year 4 Year 5 Total Age < 65 271,024 196,653 169,988 155,966 145,485 939,116 Age 65+ 377,493 220,596 209,358 188,925 166,286 1,162,658 All Ages 648,518 417,249 379,346 344,891 311,771 2,101,775 Annually Treated PSVT Patients Incident PSVT Patients Prevalent PSVT Patients • Analyzed commercial and Medicare claims data over a 9-year period, where patients were required to have 5 years of continuous enrollment 1+ PSVT code required in the ED or inpatient setting (unique patients managed acutely) 2+ PSVT codes required in the outpatient setting (additional unique patients managed chronically) Milestone Corporate Overview 38
Published Disease Data Likely Under-Reports Burden of PSVT Strengths • Provides important demographic and clinical characteristic data on patients with PSVT • Positive Predictive Values from PREEMPT useful • Less than 40% of incident cases in MESA would have been detected by PSVT ICD-9 Code 427.0 Source: Orejarena LA, Vidaillet H Jr, DeStefano F, Nordstrom DL, Vierkant RA, Smith, PN, Hayes JJ. Paroxysmal supraventricular tachycardia in the general population. J Am Coll Cardiol. 1998;31:150– 157. Alan S. Go, MD; Mark A. Hlatky, MD; Taylor I. Liu, MD, PhD; Dongjie Fan, MSPH; Elisha A. Garcia, BS; Sue Hee Sung, MPH; Matthew D. Solomon, MD, PhD. Contemporary Burden and Correlates of Symptomatic Paroxysmal Supraventricular Tachycardia. J Am Heart Assoc. 2018;7:e008759. DOI: 10.1161/JAHA.118.008759. Weaknesses • Data only from patients presenting to healthcare settings acutely, with the episode confirmed on ECG during the encounter • PSVT episodes were only adjudicated during the first healthcare encounter with a PSVT or PSVT- related code in PREEMPT • Non-representative, small, and non-contemporary population (MESA) 39 Milestone Corporate Overview MESA Study PREEMPT Study