Savara, Inc. · NASDAQ:SVRA
Savara — Technical Presentation (October 2019)
25 slides from Savara's technical presentation, Oct 2, 2019
Slide 1: Safety and Efficacy of Inhaled GM-CSF (Molgramostim) in Autoimmune PAP - The IMPALA Trial
Safety and Efficacy of Inhaled GM-CSF (Molgramostim) in Autoimmune Pulmonary Alveolar Proteinosis - The IMPALA Trial - Baseline Data and Blinded Treatment Period Results Bruce C. Trapnell, M.D. Translational Pulmonary Science Center Cincinnati Children’s Hospital Medical Center Professor of Medicine
Slide 2: Disclosures
Disclosures The Impala trial was sponsored by Savara Pharmaceuticals I receive grant funding from the US National Institutes of Health I have consulted for: Boehringer Ingelheim, CSL Behring, Genzyme, Gilead, Grifols, GSK, Kiniksa, Medimmune, Merck, Savara, Sanofi, Takeda
Slide 3: Background: Autoimmune Pulmonary Alveolar Proteinosis (aPAP)
Thick layer of surfactant ‘PAP sediment’ Epithelial basement membrane Alveolar air space Endothelial basement membrane Red cell Fibroblast Normal oxygen uptake Displaced alveolar air Cellular debris Thin film of surfactant Alveolar macrophage Type II cell Interstitium Type I cell Normal Alveolus M-C
Slide 4: Background: Inhaled GM-CSF Therapy of aPAP
Background: Inhaled GM-CSF Therapy of aPAP 1996, Seymour: First patient treated with GM-CSF (SQ) 2000, Kavuru: 4 patients treated (SQ) 2001, Seymour: 14 patients treated (SQ) 2004, Aria: 1 patient treated (Inhaled) 2005, Tazawa: 3 patients treated (Inhaled) 2006, Wylam: 12 patients treated (Inhaled)
Slide 5: Study Design of the IMPALA Trial
Study Design of the IMPALA Trial Screening Randomized, blinded Treatment (6 m) 0 24 Placebo Open-Label Treatment (6 or 12 m) 48 or 72 Time (weeks) Intermittent GM-CSF* Intermittent GM-CSF Continuous GM-CSF Continuous – Daily administration of inhaled GM-CSF (300 µg) (n=46) Intermittent – Daily admin
Slide 6: Study Design: Endpoints
Study Design: Endpoints Safety: Number of adverse events (AE) and serious adverse events (SAE) Efficacy: Change from baseline at 24 weeks in the following endpoints: Disease element Variable Pathology Chest CT ground glass opacification (GGO) score Serum PAP biomarkers Physiology Alveolar-arterial d
Slide 7: Baseline Characteristics: Demographics
Baseline Characteristics: Demographics Characteristic Continuous Intermittent Placebo Age, years 54.0 ± 13.3 49.2 ± 14.0 46.1 ± 14.8 Gender (Male), % 60.9 57.8 53.2 Smoking history, % Never smoker 28.3 35.6 34.0 Ex smoker 58.7 44.4 42.6 Current smoker 13.0 20.0 23.4 Geographic region, % Europe 34.8
Slide 8: Baseline Characteristics: Disease Severity
Baseline Characteristics: Disease Severity Characteristic Continuous Intermittent Placebo A-aDO2*, mm Hg (FAS) 40.5 ± 19.6 40.9 ± 20.2 40.2 ± 14.3 DLCO, % predicted 52.1 ± 18.6 46.1 ± 14.5 49.6 ± 14.3 Disease severity score (DSS), % DSS 1 (Mild) 8.7 11.1 6.4 DSS 2 26.1 31.1 34.0 DSS 3 37.0 28.9 29.8
Slide 9: Baseline Characteristics: Previous Therapies
Baseline Characteristics: Previous Therapies Characteristic Continuous Intermittent Placebo Supplemental oxygen use, % 32.6 26.7 23.4 Whole lung lavage Prior use of WLL (any), % 47.8 68.9 63.8 Total Number of WLLs 3.3 ± 2.2 3.3 ± 3.0 2.8 ± 3.0 Time since last WLL, m 25.0 ± 53.7 19.7 ± 27.4 17.7 ±20.
Slide 10: Safety: AE, SAE, and Respiratory AE Occurring in at least 5% of Patients
Safety: AE, SAE, and Respiratory AE Occurring in at least 5% of Patients No clinically significant changes in laboratory values No evidence of anti-drug antibody development Study completion: Continuous: 97.8%, Intermittent: 97.8%, Placebo: 91.5% AE (all) AE (Poss/prob related) SAE (all) Worsening o
Slide 11: Pathology: GM-CSF Improved Chest CT GGO Score
Pathology: GM-CSF Improved Chest CT GGO Score P=0.0002 P=0.1776 Continuous Intermittent Placebo *Comparison to Placebo * *
Slide 12: Pathology: GM-CSF Improved Serum Biomarkers
Pathology: GM-CSF Improved Serum Biomarkers * Continuous Intermittent Placebo * = P<0.05, ns = P>0.05, comparison to Placebo * * * * ns * * ns ns ns ns SP-D LDH KL-6 SP-A Cyfra21-1 CEA
Slide 13: Physiology: GM-CSF Trended Towards Improvement in the Primary End Point (A-aDO2)
Physiology: GM-CSF Trended Towards Improvement in the Primary End Point (A-aDO2) – Full Analysis Set (FAS) P=0.1688 Continuous Intermittent Placebo P=0.4444 * * *Comparison to Placebo
Slide 14: Correlation of PaO2 and A-aDO2 Identifies Patients Who Received Oxygen Therapy
Correlation of PaO2 and A-aDO2 Identifies Patients Who Received Oxygen Therapy During Blood Collection as Outliers Patients that received supplemental oxygen via nasal canula during ABG specimen collection Patient A Patient B Patient C Patient D
Slide 15: Exclusion of Data for Patients On Oxygen Therapy Influenced the Primary Endpoint
Exclusion of Data for Patients On Oxygen Therapy During Arterial Blood Collection Significantly Influenced the Primary Endpoint (A-aDO2 – Revised) P=0.0249 Continuous Intermittent Placebo P=0.2313 *Comparison to Placebo * *
Slide 16: Physiology: GM-CSF Improved DLCO
Physiology: GM-CSF Improved DLCO P=0.0074 Continuous Intermittent Placebo P=0.3097 *Comparison to Placebo * *
Slide 17: Health Status: GM-CSF Improved SGRQ Total Score
Health Status: GM-CSF Improved SGRQ Total Score P=0.0103 Continuous Intermittent Placebo P=0.0173 + MCID is 4 Points in COPD patients *Comparison to Placebo * *
Slide 18: The Improvement in SGRQ was Robust as Shown by Responder Analysis
The Improvement in SGRQ was Robust as Shown by Responder Analysis ß Favors Placebo | Favors GM-CSF à Odds Ratio 8 points 6 points 4 points Threshold value used as ‘cut off’ for a positive response Placebo versus GM-CSF (Continuous)
Slide 19: A Pattern of Improvement was Seen Across all SGRQ Domains
A Pattern of Improvement was Seen Across all SGRQ Domains Continuous Intermittent Placebo Activity Impact Symptoms P=0.0107 P=0.0223 P=0.4884
Slide 20: Function: GM-CSF Trended Towards Improved 6MWT-Distance
Function: GM-CSF Trended Towards Improved 6MWT-Distance P=0.3159 Continuous Intermittent Placebo P=0.7809 *Comparison to Placebo * *
Slide 21: Rescue Therapy: GM-CSF Trended Towards a Reduction in WLL
Rescue Therapy: GM-CSF Trended Towards a Reduction in WLL WLL Therapy Requirement Group # patients # treatments Rate Ratio vs Placebo Continuous (n=46) 4 9 0.284 Intermediate (n=45) 4 7 0.367 Placebo (n=47) 6 17 - ß Favors Placebo | Favors GM-CSF à Hazards Ratio Placebo versus GM-CSF Time to WLL: In
Slide 22: Systemic Response: GM-CSF Trended Towards Reduced Hemoglobin Levels
Systemic Response: GM-CSF Trended Towards Reduced Hemoglobin Levels P=0.0506 Continuous Intermittent Placebo P=0.5886 *Comparison to Placebo * *
Slide 23: Totality of Outcome Data Favors Continuous GM-CSF over Placebo
Totality of Outcome Data Favors Continuous GM-CSF over Placebo Disease element Endpoint Units Treatment effect P-value Pathology Chest CT – GGO Score -2.4 0.0002 Serum LDH, KL-6, SP-D, CEA, Cyfra 21‑1 IU/L pg/ml All favor GM-CSF <0.05 Physiology A-aDO2* – FAS mm Hg -4.6 0.1688 A-aDO2* – Revised mm H
Slide 24: Conclusions
Conclusions Baseline clinical features of aPAP A large, global cohort of adult aPAP patients was identified and carefully characterized Study groups were well-balanced for demographics and disease severity Clinical trial observations The Placebo group experienced an unexpected degree of improvement
Slide 25: Acknowledgments
Acknowledgments We are grateful to and thank: Our PAP patients whose collaboration made the IMPALA trial possible IMPALA Investigators - PAP care providers and staff – at 30 centers in 18 countries including: Australia Troy S (Sydney); Denmark Bendstrup E (Arhus); France Jouneau S (Rennes); Israel K