Savara, Inc. · NASDAQ:SVRA
Savara — Mast Therapeutics — Investor Presentation (September 2015)
59 slides from Savara's investor presentation, Sep 15, 2015
Slide 1: Corporate Overview
NYSE MKT: MSTX Corporate Overview September 15, 2015 Exhibit 99.1
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation includes forward-looking statements about our business prospects, financial position, and development of vepoloxamer and AIR001 for therapeutic use in humans. Any statement that is not a statement of historical fact should be considered a forward-looking
Slide 3: Corporate Overview
Publicly-traded biopharmaceutical company based in San Diego Developing vepoloxamer (MST-188) for: Sickle cell disease Chronic heart failure Ischemic stroke Developing AIR001 for: Heart failure with preserved ejection fraction (HFpEF) Corporate Overview
Slide 4: Product Pipeline
Preclinical Phase 1 2a 2b Phase 3 Heart Failure (“HFpEF”) Product Pipeline Preclinical Phase 1 Phase 2 Phase 3 Sickle Cell Disease (orphan) Chronic Heart Failure Ischemic Stroke Initiation planned for Sep 2015 Planned for 2016 >75% Enrolled Vepoloxamer AIR001 Data expected Fall 2015 Data expected 20
Slide 5: Lead Program Vepoloxamer
Lead Program Vepoloxamer
Slide 6: Vepoloxamer: A Biophysical Agent
Poiseuille’s Law describes Newtonian flow with = flow (volume/time) = length of the capillary = viscosity of the media = pressure drop over the length = radius of the capillary Vepoloxamer: A Biophysical Agent Want lower viscosity? Reduce friction by lowering adhesion and improving the deformability
Slide 7: Vepoloxamer Overview
API Structure: CMC: Large, synthesized polymer (8500 Da) Composition of matter claims pending Administration: IV infusion (up to 48h) ADME: Rapidly and predominantly cleared by kidneys (4-8h) Ether linkages cannot be cleaved; no drug metabolites Vepoloxamer Overview HO – (CH2CH2O)79– (CH2CHO)30– (CH
Slide 8: Vepoloxamer Mechanism of Action
No Affinity for Healthy Cell Membranes… But Adheres to Damaged Cell Membranes Core of molecule adheres to hydrophobic domains on a cell surface, such as damaged membranes and adhesive proteins. Vepoloxamer Mechanism of Action
Slide 9: Vepoloxamer Pharmacodynamics
Vepoloxamer Pharmacodynamics Vepoloxamer adheres to hydrophobic domains on cells and lowers surface tensions Viscosity is reduced Lowers adhesion Improves flow Membranes are sealed Cell integrity maintained Ca2+ influx reduced Shear Rate (1/sec) 2.5 5 10 20 40 80
Slide 10: Vepoloxamer Pharmacodynamics
Vepoloxamer Pharmacodynamics Vepoloxamer adheres to hydrophobic domains on cells and lowers surface tensions Viscosity is reduced Lowers adhesion Improves flow Membranes are sealed Cell integrity maintained Ca2+ influx reduced Sickle Cell Disease: Less cell adhesion, reduced hemolysis Heart Failure:
Slide 11: Sickle Cell Disease
Sickle Cell Disease Objective Improve blood flow and shorten the duration of crisis
Slide 12: Overview of Sickle Cell Disease
A chronic, genetic disorder and rare (orphan) disease Affects 90,000 to 100,000 people in the U.S. Characterized by severe deformation (i.e., “sickling”) of red blood cells Hallmark of disease is a “vaso-occlusive crisis” Exceedingly painful condition Leading cause of hospitalization Significant unm
Slide 13: SCD Pathophysiology
SCD Pathophysiology (multiple points of intervention) sRBC Adherence to Endothelium VASO-OCCLUSION ORGAN DAMAGE/FAILURE ANEMIA PAIN INTRAVASCULAR Hemolysis NITRIC OXIDE DEPLETION VASOCONSTRICTION INFLAMMATION ACTIVATION OF COAGULATION TISSUE ISCHEMIA LOCAL HYPOXIA STRESS LARGE VESSEL DAMAGE Microvas
Slide 14: Vepoloxamer Effect on Sickle Cells
Vepoloxamer Effect on Sickle Cells Before vepoloxamer Lower surface tension improves flow and deformability (video) After vepoloxamer
Slide 15: Role of Vepoloxamer in Sickle Cell Disease
Role of Vepoloxamer in Sickle Cell Disease Vaso-Occlusive Crisis: Adhesion of poorly-deformable, “sticky” cells to endothelium and to each other leads to vessel obstruction Occluded RBC’s cannot deliver oxygen, leading to ischemia, pain, organ damage Vepoloxamer: Lowers viscosity, reduces adhesion o
Slide 16: Vepoloxamer Lowers Pathologic Blood Viscosity
Vepoloxamer Lowers Pathologic Blood Viscosity Under Low Shear Rates *Vepoloxamer is purified poloxamer 188 Shear Rate (1/sec) 2.5 5 10 20 40 80
Slide 17: Vepoloxamer Reduces RBC Aggregation (normal volunteers)
Vepoloxamer Reduces RBC Aggregation (normal volunteers) The effect of five concentrations of poloxamer 188* on RBC aggregation was determined using a Myrenne aggregometer. Results represent the mean of samples from 20 healthy volunteers relative to PBS controls. (Meiselman, et. al.) *Vepoloxamer is
Slide 18: Vepoloxamer Reduces RBC Aggregation (sickle cell patients)
Vepoloxamer Reduces RBC Aggregation (sickle cell patients) Dose-dependent effect on sickle cell red blood cell aggregation Poloxamer 188* (mg/mL) Aggregate extent Aggregate strength *Vepoloxamer is purified poloxamer 188 The effect of poloxamer 188 on sickle cell RBC aggregation determined by a Myre
Slide 19: Vepoloxamer Decreases Blood Viscosity Under Low Shear Rates
Vepoloxamer Decreases Blood Viscosity Under Low Shear Rates Poloxamer 188 added to whole blood (40% hematocrit) and viscosity measured using a Contraves viscometer at 3 shear rates. Results represent the mean of samples from 11 SCD patients relative to PBS controls. (Meiselman, et al.) *Vepoloxamer
Slide 20: Vepoloxamer Reduced Organ Pathology in Transgenic Sickle Mice
Lung pathology was compared in transgenic mice pretreated with either vepoloxamer (400 mg/kg) or saline and subject to hypoxia (5% O2). (Asakura, et al.) Vepoloxamer Reduced Organ Pathology in Transgenic Sickle Mice Vepoloxamer Control
Slide 21: Vepoloxamer Increased Survival in Transgenic Sickle Mice
Transgenic mice pretreated with either vepoloxamer (400 mg/kg) or saline, subject to hypoxia (5% O2), and monitored for survival. (Asakura, et al.) Vepoloxamer Increased Survival in Transgenic Sickle Mice Vepoloxamer Control
Slide 22: Vepoloxamer Improves Blood Flow
Vepoloxamer Placebo Before Infusion (Crisis Baseline) Velocity (mm/sec) 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2-Hours After Loading 7-Hours After Loading Source: J. Investig. Med. 2004;52(6):402-6 (p = 0.00003) Vepoloxamer improved microvascular blood flow in SCD patients during vaso-occlusive c
Slide 23: Phase 2 Study in Vaso-Occlusive Crisis
Phase 2 Study Source: Blood, September 1, 1997 – Vol 90, No. 5 Subjects Who Received Full Dose± Poloxamer 188* (n=18) Placebo (n=13) p value±± Duration of Crisis 44 hours 80 hours 0.025 Duration of Hospitalization 5 days 7 days 0.111 Total Analgesic Use 34mg 145mg 0.045 Parenteral Analgesic Use 27mg
Slide 24: Acute Chest Syndrome Clinical Study
Acute Chest Syndrome Clinical Study Vepoloxamerⱡ Hi Dose (100-120mg/kg/hr) (n=7) Vepoloxamerⱡ Lo Dose (40-80mg/kg/hr) (n=20) NEJM 2000* Standard of care (n=409) Vepoloxamerⱡ Hi Dose (100-120 mg/kg/hr) (n=4) Vepoloxamerⱡ Lo Dose (40-80 mg/kg/hr) (n=10) NEJM 2000* Standard of care (n=128) Children (≤1
Slide 25: Prior Sponsor's Phase 3 Study
Flawed endpoint selection and premature termination led to loss of power Proportional analysis positive: All ages: 52% vs. 37% (n=249, p=0.02) Under 16y*: 60% vs. 28% (n=73, p=0.009) Lessons learned for Mast’s Phase 3 study: Vepoloxamer has activity in SCD Incorporate FDA, physician, and patient inp
Slide 26: Current Phase 3 Study EPIC
Largest Interventional SCD Trial Ever Conducted 388 patients, randomized 1:1 (standard of care +/- vepoloxamer) Double-blind, placebo-controlled, international (2/3rd U.S. sites) Primary Endpoint: Duration of crisis Assessed from randomization to last dose of parenteral opioid Clinically relevant (n
Slide 27: EPIC Success Factors
Enrollment on-track Enrollment >75% complete Top-line data anticipated Q1 2016 Most Advanced New Drug in SCD Potential to be 1st drug ever approved to treat on-going vaso-occlusive crisis Substantial head start versus other drugs in development Considerations for Regulatory Decision-Making Significa
Slide 28: SCD Market Opportunity
SCD Market Opportunity United States Approximately 100,000 hospitalizations annually ~50% of events occur in just 16 metropolitan areas Effective coverage with small, targeted field force Europe Approximately 40,000 patients ~50% of patients reside in 2 cities: Paris and London
Slide 29: Vepoloxamer Market Opportunity
Addressable market for vepoloxamer is substantially larger than for current gene corrective approaches (e.g. not limited to just “severe” patients) Vepoloxamer Market Opportunity Approximately 100,000 Hospitalizations Annually for Crisis (U.S.) * Estimated research analyst consensus (range 5-25%)
Slide 30: Vepoloxamer Positioned for Success in SCD
Vepoloxamer Positioned for Success in SCD Novel Therapy for Rare Disease with High Unmet Need Unique mechanism Orphan Drug Designation (U.S. and EU) New composition of matter patent application pending No approved therapies available for crisis intervention First-To-Market Advantage Clinical develop
Slide 31: Heart Failure (Chronic and Acute)
Heart Failure (Chronic and Acute) Objective Preserve heart cells and improve cardiac function
Slide 32: Overview of Heart Failure
Overview of Heart Failure Chronic condition characterized by decreasing heart function Heart cannot pump enough blood to meet the body’s needs Primary clinical symptom is difficulty breathing (fluid in lungs – “congestive”) Significant Unmet Medical Need Leading healthcare cost in U.S. and Europe Su
Slide 33: Background: Membrane Injury and Repair in Cardiomyocytes
Membrane injury and repair is a constitutive event in healthy cells, especially those subjected to increased wall tensions from mechanical stress, such as cardiomyocytes. In healthy rat hearts, adrenergic stimulation increases myocyte wounding 3-fold. Frozen sections of normal rat heart were immunos
Slide 34: Development Rationale in Heart Failure
Elevated wall tension in a stressed heart impairs membrane repair, leading to calcium influx and cardiac troponin leak. Vepoloxamer seals membranes and reduces surface tension, reducing calcium damage and preserving cells. Vepoloxamer led to statistically significant improvements in hemodynamic para
Slide 35: Chronic Heart Failure Model Study 1: Single-administration
The primary objective of this study was to examine the effects of acute intravenous administration of vepoloxamer on left ventricular (LV) systolic and diastolic function in dogs with advanced heart failure produced by intracoronary microembolizations Chronic Heart Failure Model Study 1: Single-admi
Slide 36: Study 1 – Single Administration Protocol
21 Heart Failure Dogs (LV EF ~30%) Randomized Placebo – Control 2 hours infusion of normal saline (n=7) Low Dose 2 hours infusion vepoloxamer (225 mg/kg) (n=7) High Dose 2 hours infusion vepoloxamer (450 mg/kg) (n=7) Follow-Up All Groups 24 hours 1 Week 2 Weeks Study 1 – Single Administration Protoc
Slide 37: Study 1 – Single Administration Results
2 Hours Post 24 Hours Post 1 Week Post 2 Weeks Post * p < 0.05 vs. Control * * * * * * * * * * * * * * * * * * Study 1 – Single Administration Results
Slide 38: Study 1: Single Administration Conclusions
Intravenous vepoloxamer elicits improvements in LV systolic and diastolic function that last for at least one week after end of drug infusion The functional improvement is supported by significant reductions of NT-proBNP for up to 2 weeks The decline in plasma troponin-I level suggest that vepoloxam
Slide 39: Chronic Heart Failure Model Study 2: Repeat-administration
The primary objective of this study was to examine the effects of acute intravenous administration of multiple doses of vepoloxamer on left ventricular (LV) systolic and diastolic function in dogs with advanced heart failure produced by intracoronary microembolizations Chronic Heart Failure Model St
Slide 40: Study 2 – Repeat Administration Protocol
14 Heart Failure Dogs (LV EF ~30%) Randomized High Dose 2 hours infusion vepoloxamer (450 mg/kg) on week 0 and week 3 (n=7) Total Follow-Up All Groups 6 Weeks Placebo – Control 2 hours infusion of normal saline on week 0 and week 3 (n=7) Study 2 – Repeat Administration Protocol
Slide 41: Study 2 – Repeat Administration Results
*Preliminary data. Arrows indicate dose events. Placebo Control Vepoloxamer Study 2 – Repeat Administration Results
Slide 42: Repeat Administration Focus On Left Ventricle Ejection Fraction
Dose-1 Dose-2 TIME Study 2 – Repeat Administration Focus On Left Ventricle Ejection Fraction Placebo Control Vepoloxamer
Slide 43: Study 2 – Repeat Administration Conclusions
Reproduced Study 1 findings In addition, intravenous vepoloxamer pulsed once every 3 weeks elicits improvements in LV systolic and diastolic function that can be sustained for at least 6 weeks. Study 2 – Repeat Administration Conclusions
Slide 44: Study 2 – Repeat Administration Supplemental Findings
Protocol: Isolated cardiomyocytes were treated with vepoloxamer at room temperature for 2 hours Cells were then washed and treated with 10 uM Fura-2 AM dye for 1 hour Excess dye was then washed out and cells were resuspended in EDTA (calcium chelator) or 0.5 mM calcium chloride and flourescence inte
Slide 45: Vepoloxamer Seals Cardiomyocyte Membranes
LD = 1.5 mg/mL vepoloxamer HD = 4.5 mg/mL vepoloxamer Vepoloxamer Seals Cardiomyocyte Membranes Cardiomyocytes Isolated from Animals with Advanced Heart Failure Exhibit Reduced Intracellular Calcium n=4 10µM Ca2+ n=4 1.0mM Ca2+
Slide 46: Vepoloxamer Repairs Disrupted Membranes
Vepoloxamer Repairs Disrupted Membranes Seals skeletal muscle cells against carboxyfluorescein dye loss following electroporation (Lee et. al., 1992, PNAS 89 4524 – 4528) Restores action potentials and prevents Ca++ mediated axonal degeneration following crush injury in neurons (Borgens et. al., J N
Slide 47: Ischemic Stroke
Ischemic Stroke Objective Accelerate time to thrombolysis and restore tissue perfusion
Slide 48: Vepoloxamer is Antithrombotic
Vepoloxamer is Antithrombotic Juvenile pigs subjected to balloon angioplasty using pressure and a wire stent Animals randomized to either heparin plus poloxamer 188* (50 mg/kg bolus followed by a 25 mg/kg/hr infusion) or comparable volume of heparin in normal saline p < 0.01 control vs poloxamer 188
Slide 49: Accelerated tPA Activity
Accelerated tPA Activity Animals subjected to femoral thrombotic occlusion randomized to tPA or tPA + poloxamer 188* (n=10), then monitored for blood flow Control (tPA) Poloxamer 188 *Vepoloxamer is purified poloxamer 188 Source: Data on file
Slide 50: Effect on Reperfusion Injury
Cardiac Output (% of normal) Effect on Reperfusion Injury Rat hearts perfused with human packed red cells and heparin subjected to 90% ischemia followed by 10 min reperfusion. Poloxamer 188* protected against no-reflow and reperfusion injury *Vepoloxamer is purified poloxamer 188
Slide 51: Vepoloxamer in Stroke Model
Vepoloxamer in Stroke Model Vepoloxamer alone or in combination with tPA improved neurological outcomes Vepoloxamer alone or in combination with tPA reduced neurological functional deficits following middle cerebral artery occlusion (MCAO) compared with animals treated with saline or tPA alone Note:
Slide 52: Vepoloxamer in Stroke Model
Vepoloxamer in Stroke Model Vepoloxamer alone or in combination with tPA reduced lesion volume Panels are H&E stained coronal sections obtained from representative rats treated with saline, vepoloxamer alone, tPA alone, and the combination of vepoloxamer and tPA following MCAO. Bar graph shows that
Slide 53: Synergy with Thrombolytics in Heart Attack Clinical Trial
Parameter Poloxamer 188* Control Difference p Value N=114 Myocardial Infarct Size (median) 16% 26% 38% reduction 0.031 Myocardial Salvage (median) 13% 4% 125% increase 0.033 Ejection Fraction (median) 52% 46% 13% improvement 0.020 Incidence of Reinfarction 1% 13% 92% reduction 0.016 Synergy with Thr
Slide 54: AIR001 (sodium nitrite) inhalation solution
AIR001 (sodium nitrite) inhalation solution Objective Improve hemodynamics and exercise tolerance of patients with heart failure
Slide 55: AIR001 Overview
Nitrite for intermittent inhalation (via nebulizer) Different molecule and activity than organonitrates or nitric oxide Beneficial effects include dilation of blood vessels and reduced inflammation Hemodynamic benefits include reductions in pulmonary vascular resistance pulmonary capillary wedge pre
Slide 56: AIR001 Clinical Data
Three Phase 1 studies: Established MTD and safe dose level Acute improvements in hypoxia-induced pulmonary hypertension No drug-drug interaction with sildenafil One Phase 2 study: Well-tolerated; no treatment-related serious adverse events Showed improvement in median pulmonary vascular resistance (
Slide 57: AIR001 Clinical Development Plan
AIR001 for Heart Failure with Preserved Ejection Fraction (HFpEF) Responsible for ~50% of heart failure hospitalizations 80% develop pulmonary hypertension No approved medications Supporting two institutional-sponsored Phase 2a studies to: Evaluate the acute hemodynamic effects Evaluate the acute ef
Slide 58: MSTX Financial Overview
Cash/investments at 6/30/15: $43.4 million Market capitalization: ~$74 million* Shares outstanding: ~164 million* Average daily volume (3 mo): ~700,000* * As of September 10, 2015 MSTX Financial Overview
Slide 59: Mast Therapeutics Summary
An Emerging Cardiovascular Company Sickle Cell Disease Most clinically-advanced new drug in development Heart Failure Two distinct programs with novel mechanisms Ischemic Stroke Encouraging nonclinical data; Phase 2 planned for 2016 Mast Therapeutics is committed to: Bringing the first new SCD thera
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