Slide 1: Etripamil Nasal Spray For Acute Termination Of Spontaneous Episodes Of PSVT
Etripamil Nasal Spray For Acute Termination Of Spontaneous Episodes Of Paroxysmal Supraventricular Tachycardia. NODE-301 Trial Bruce S. Stambler, MD, FHRS; Francis Plat, MD; Philip T. Sager, MD; Jose M. Dizon, MD; Silvia Shardonofsky, MD; A. John Camm, MD, FHRS on behalf of the NODE-301 Investigator
Slide 2: Disclosures
Disclosures • B Stambler: Honoraria, Consulting Fees, Contracted Grants for PIs - Milestone. • The NODE-301 trial and these analyses were funded by Milestone Pharmaceuticals. • The trial was conducted and coordinated by Medpace.
Slide 3: Etripamil
Etripamil • Novel, L-type calcium channel blocker • Administered as a nasal spray • Being developed as a self-administered therapy to terminate AV nodal-dependent PSVT outside of the emergency room or hospital.
Slide 4: PR Interval Prolongation
NODE-102 Etripamil Nasal Spray Pharmacological Study Effective pharmacologic activity of etripamil occurs between 5 and 45 minutes Change from Baseline (%, with 95% CI) 20 15 Etripamil 70mg PR Interval Prolongation 10% PR 10 Prolongation Threshold 5 0 Placebo -5 -10 0 10 20 30 40 50 Time (min)
Slide 5: Induced PSVT Conversion Rate within 15 minutes
Induced PSVT Conversion Rate within 15 minutes * 100 * 95 90 87 80 * 75 70 65 60 % 50 35 40 30 20 10 0 Placebo Etripamil Etripamil Etripamil Etripamil 35 mg 70 mg 105 mg 140 mg *p<0.05 vs placebo Stambler BS, et al. HRS 2017 Late Breaking Clinical Trials Stambler BS, et al. JACC 2018;72:489
Slide 6: Multi-center, randomized, double-blinded, placebo-controlled efficacy and safety study
MULTI-CENTER, RANDOMIZED, DOUBLE-BLINDED, PLACEBO-CONTROLLED, EFFICACY AND SAFETY STUDY OF ETRIPAMIL NASAL SPRAY 70 MG FOR TERMINATION OF SPONTANEOUS EPISODES OF PSVT ClinicalTrials.gov ID: 0346401
Slide 7: Eligibility Criteria
ELIGIBILITY CRITERIA Subjects who met all of the following inclusion criteria were eligible to participate: • ECG-documented history of sustained episodes of PSVT (lasting ≥20 min); • Male or female, aged ≥18 years; • Signed written informed consent. 77 sites in US and Canada
Slide 8: Key Exclusion Criteria
Key Exclusion Criteria • History of a non-AV nodal dependent tachycardia • Atrial tachycardia, flutter, or fibrillation • Ventricular tachycardia or fibrillation, torsades de pointes • History of severe symptomatic hypotension or syncope during PSVT • Systolic blood pressure < 90 mm Hg at screening
Slide 9: Etripamil Test Dose in Sinus Rhythm
Etripamil Test Dose in Sinus Rhythm • Failure of the medically supervised, self-administered test dose of etripamil: • Any symptoms consistent with clinically severe hypotension (pre-syncope, lightheadedness, syncope, nausea, vomiting) • Decrease in SBP ≥40 or SBP <75-80 mm Hg after test dose • 3rd
Slide 10: Study Design
Study Design Objective: Superiority of etripamil over placebo in terminating PSVT events in the outpatient setting Randomized Patient dosed for suspected episode Etripamil:Placebo (2:1) Safety Dataset (N=419, 97%) (N=198, Etripamil=138, Placebo=60) Positively-Adjudicated PSVT events Test Dose Active
Slide 11: Consort Flow Diagram
Consort Flow Diagram Screened subjects N=518 Overall safety population n=431 Test dose Screening In screening at N=431 failure N=81 time of lock N=6 Safety population N=197* Efficacy population N=156 Passed test Failed test dose dose N=421 N=10 (2.3%) ITT population N=198 Test Dose only Not Randomiz
Slide 12: Demographics
Demographics Efficacy Population Overall Safety Etripamil Placebo Population (N=107) (N=49) (N=431) Age, years 56.9 54.3 55.2 Gender Male, n (%) 34 (31.8) 16 (32.7) 158 (36.7) Female, n (%) 73 (68.2) 33 (67.3) 273 (63.3) PSVT Duration, yrs 1.5 1.3 1.4 # PSVT in past yr 7.4 11.3 7.8 Lifetime ED visit
Slide 13: NODE-301 Primary Endpoint – Time to Conversion
NODE-301 Primary Endpoint – Time to Conversion Kaplan-Meier analysis of time to conversion of positively-adjudicated PSVT episodes over 5 hours 100% 90% % Patients Converted to SR 80% 70% Etripamil 70mg 60% 50% 40% Placebo 30% HR (95% CI) 1.086 (0.726, 1.623) p=0.1212 20% 10% 0% 0 30 60 90 120 150 1
Slide 14: NODE-301 Efficacy – Time to Conversion over 45 Minutes
NODE-301 Efficacy – Time to Conversion over 45 Minutes 70% HR (95% CI) 1.668 (1.026, 2.712) p=0.02 60% 50% % Converted to SR 40% Etripamil 70mg 30% 20% Placebo 10% 0% 0 5 10 15 20 25 30 35 40 45 Time to Conversion (minutes) • Median time to conversion: 25 vs. 50 minutes (Etripamil vs. Placebo)
Slide 15: Time to Conversion of an Adjudicated PSVT Episode up to Hour 5
Time to Conversion of an Adjudicated PSVT Episode up to Hour 5 HR (95% CI) 1.086 (0.726, 1.623) p<0.1212 peto-peto
Slide 16: NODE-301 Safety Analysis
NODE-301 Safety Analysis Treatment Emergent Adverse Events Etripamil (N=138) Placebo (N=60) 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) Headache 4 (2.9) 0 (0.0) Sneezing 3 (2.2) 0 (0.0) At
Slide 17: Summary
Summary • Etripamil nasal spray (70 mg dose) did not meet the primary endpoint of conversion of PSVT over 5 hours. • During the first 45 minutes, etripamil had a clinically meaningful treatment effect, consistent with the drug’s pharmacology. • Etripamil had an acceptable safety profile when self- a