Full Press Release Details
Respiratory Diseases January 2024
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corporate milestones; the potential market size, commercial opportunity, and competitive landscape for our product; Savara's disease awareness campaign and GM-CSF autoantibody testing, and the potential impact of those programs; and the
sufficiency of our resources to fund the advancement of our development program and potential sources of additional capital. Savara may not actually achieve any of its plans or product development goals in a timely manner, if at all, or otherwise
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which they were made, except as may be required by law. Third-party information included herein has been obtained from sources believed to be reliable, but the accuracy or completeness of such information is not guaranteed by, and should not be
construed as a representation by, the Company. The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. 2 Savara Inc.
Executive Leadership Team Matthew Pauls, J.D., M.B.A. Chair & Chief
Executive Officer Ray Pratt, M.D. FACP Anne Erickson Dave Lowrance Rob Lutz, M.B.A. Chief Medical Officer Chief Business Officer Chief Financial & Administrative Officer Chief Operating Officer Scott Wilhoit Yasmine Wasfi, M.D., Ph.D. EVP,
Single Phase 3 program with high probability of success Investment
Thesis - Top line data expected end of 2Q24: Molgramostim nebulizer solution (molgramostim) in autoimmune pulmonary alveolar proteinosis (aPAP) Favorable efficacy and safety data generated from the first IMPALA trial
Pivotal Phase 3 trial underway Builds on key learnings from IMPALA Strong global commercial opportunity Significant unmet need - potential to be first and only approved treatment for aPAP globally Chronic dosing
expected Market expansion opportunities As a novel inhaled biologic, molgramostim has: 12-year biologic exclusivity in U.S. Potential for a long-term, durable revenue stream with biosimilar competition unlikely 4
Molgramostim Key Highlights 2012 2022 2020 Molgramostim granted Orphan
Drug UK's Medicines and Healthcare Products Designation IMPALA results published in New Regulatory Agency (MHRA) awarded England Journal of Medicine molgramostim Innovation Passport and Promising Innovative Medicine Designations 2019
Molgramostim granted Fast Track Designation for aPAP 2021 2023 IMPALA-2 first patient dosed IMPALA-2 prespecified DMC* #2: Positive review Molgramostim granted IMPALA-2 Breakthrough Therapy prespecified DMC* Designation for aPAP #1: Positive review
IMPALA top IMPALA-2 line results enrollment completed (n=164, target was 160) Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 *The Data Monitoring Committee (DMC) conducted two pre-planned evaluations of IMPALA-2 to assess safety and
sample size. In both cases the DMC recommended that the study continue unmodified. 5
Molgramostim Molgramostim for Autoimmune Pulmonary Alveolar Proteinosis
aPAP: An Autoimmune Disease of Alveolar Macrophage Dysfunction GM-CSF
Autoantibodies GM-CSF Normal Alveolus Alveolus in PAP NORMAL LUNG aPAP FUNCTION Thin surfactant layer Thick surfactant layer Rare lung disease caused by GM-CSF Alveoli need surfactant to keep autoantibodies which block from collapsing Alveolar
epithelial cells GM-CSF signaling and GM-CSF reduce surfactant clearance. GM-CSF GM-CSF is critical for alveolar GM-CSF This results in: autoantibodies macrophage function and allows for alveolar surfactant homeostasis, Surfactant accumulation that
structure, function, and host defense Foamy blocks movement of oxygen from alveolar the alveoli into the blood Normal macrophage alveolar (lipid filled) macrophage Normal Reduced blood oxygenation that Reduced oxygen delivery makes it hard to breath
Molgramostim Has the Potential to Improve Lung Function Molgramostim may
improve lung function by stimulating alveolar macrophages to clear surfactant from the lungs Following molgramostim treatment, a White lines, called "crazy paving," reduction in "crazy paving" was observed are a hallmark
aPAP is a Rare, Long-Term, Chronic Disease Progressive Shortness of
Breath Fatigue, Decreased Exercise Tolerance Fatigue and significantly reduced exercise capacity can Gas exchange in the lungs is impaired and dramatically impact the simplest of daily activities, e.g., patients may experience
shortness of breath getting winded walking up a flight of stairs At first it occurs upon exertion, but as disease progresses, it can occur even when a person is at rest Cough and Episodes of Fever Fibrosis and Lung Transplant Cough,
sputum production, and episodes of fever, In the long-term, the disease can lead to serious especially if secondary lung infection develops complications, including fibrosis, and may lead to the need for lung transplantation There are no
Unmet Need: aPAP Patients Have Significantly Higher Rates of 1
Healthcare Utilization and Comorbidities Charlson Outpatient visits Comorbidity Index +66% 3.5x (~17 per year) (CCI)* Vs. Vs. matched matched controls controls PAP: 1.84 2.48 PAP: 17.30 13.77 Age and Gender Matched Controls: 0.55
1.44 Age and Gender Matched Controls: 10.40 11.38 P value: <0.0001 P value: <0.01 *Developed to classify comorbid conditions which may influence mortality risk. Most widely used comorbidity index used to determine survival rates
in patients with multiple comorbidities. Longer hospital stays Emergency Room Visits +38% 3.0x (~16 days per year) (~1.5 per year) Vs. Vs. matched matched controls controls PAP: 1.49 1.17 PAP: 15.96 20.71 Age and Gender Matched
Whole lung lavage physically removes excess surfactant from the
lungs and requires hospitalization Whole Lung Lavage is an Invasive Procedure Performed under general anesthesia Performed in a Tertiary Unavailable at many medical institutions Center and is Not Standardized Requires insertion of
double- Treated lung is repeatedly filled Patient is percussed to Saline is drained by gravity and lumen endobronchial tube for with up to 15-50L of saline and emulsify the surfactant continued until lavage fluid lung separation then drained by
gravity sediment becomes clear Sources: 1: Campo, Assessment and Management of PAP in a Reference Center, Orphanet Jour. of Rare Dis., 2013; 2: Campo, Nat. History of PAP Data from Italian Nat. Reference Center, ERJ, 2019.; Seymour, J. J. Pulmonary
alveolar proteinosis: Progress in the First 44 Years, Am. J. Respir Crit. Care Med, 2002. 3: Udwadia, Jain. NEJM (2007) 357:19, 4 McCarthy, Autoimmune Pulmonary 11 Alveolar Proteinosis, Amer. Journal of Respiratory and Critical Care Med., 2022.
Complications and Short-Comings of Whole Lung Lavage Short Comings
Potential Complications Rib fracture Treatment fails to address underlying cause of the disease Hypoxia Patients continue to experience Pneumothorax (collapsed lung) symptomatic deterioration between procedures
- and can require more Hydrothorax (fluid in pleural cavity) than one whole lung lavage Superimposed infection Rollercoaster ride of improvement Acute Respiratory Distress and decline Syndrome (ARDS) The
Historically, Without a Broadly Available Diagnostic for aPAP, the
Journey to Diagnosis Can Be Long and Misdiagnosis Common 1 3-36 months : Range for aPAP time-to- diagnosis 4 U.S. National PAP Registry indicates many patients 2 18 months : Average delay caused by with PAP are diagnosed via an
invasive misdiagnosis (e.g., pneumonia or asthma) transbronchial biopsy, surgical lung biopsy, or 3 both Diagnostic workup frequently involves multiple tests and invasive procedures, including Transbronchial Pulmonary function tests
Surgical Biopsy Biopsy 30% 29% Arterial blood gas analysis Chest radiographs CT scans Surgical plus Bronchoalveolar lavage (BAL) cytology and/or lung Transbronchial No Biopsy 3 Biopsy histopathology 18% 23%
Transbronchial biopsy, surgical lung biopsy, or both Sources: 1: Campo Orphanet J Rare Dis 2013; 2: Trapnell Nat Rev Dis Primers 2019; 3: McCarthy Chest 2019; 4: Trapnell PAP Registry http://clinicaltrials.gov/ct2/show/ 13 Savara Inc. All
Savara Investigational Drug-Device Treatment for aPAP Molgramostim
nebulization time = 3-5 minutes Once daily 300 g inhaled molgramostim Proprietary Pari eFlow Nebulizer System Optimized for molgramostim administration Well-established manufacturer of devices used for
IMPALA Clinical Trial Design Period 1: Double-blind Period 2:
Open-label n=46 molgramostim 300 g daily dosing n=45 Screening molgramostim 300 g intermittent dosing* molgramostim 300 g intermittent dosing* n=47 W48 placebo = Primary efficacy analyses BL W16 W24 W8 Primary Endpoint Key
Secondary Endpoints Change from baseline in A-aDO ** 6-minute walk distance 2 SGRQ*** Time to whole lung lavage/requirement for whole lung lavage Primary analysis was continuous dose vs. placebo Secondary endpoints
were analyzed in parallel and corrected for multiplicity *One week on, one week off **A-aDO2: Gas exchange measure used to calculate difference between oxygen concentration in the alveoli and arterial system ***St. George's Respiratory
IMPALA Trial Did Not Meet the Primary Endpoint Continuous Once Daily
(QD) Dosing Regimen 1 Full Analysis Set (FAS)* Estimated treatment difference of -4.6 mmHg (p=0.17) Revised FAS** Estimated treatment difference of -6.5 mmHG (p=0.025) *Protocol specified analysis (ITT). **Revised analysis excluded 4 patients using
IMPALA: DLCO and SGRQ Showed Robust Improvement with Continuous Once
Daily (QD) Dosing Regimen Change in St. George's Respiratory Questionnaire Change in Diffusion Capacity for Carbon Monoxide 1 1 (SGRQ) From Baseline Over 24-weeks (FAS) (DLCO) From Baseline Over 24-weeks (FAS) 1 20 0 16 -4 12 -8 8 -12 4 0 -16
0 4 8 12 16 20 24 0 4 12 24 Week Week QD estimated treatment difference of QD estimated treatment difference of 7.9% predicted (p=0.007) 7.6 points (p=0.01) Became Primary Endpoint in IMPALA-2 Became Key Secondary Endpoint in IMPALA-2 17 1:
IMPALA Open-Label Data Showed Sustained Effect, or Continued
Improvement, after Longer-Term Drug Exposure Mean Change in DLCO Mean Change in SGRQ Total Score Use of Whole Lung Lavage During 1 1 1 Over Time Over Time the Blinded Treatment Period Blinded Period Open-Label Period 24 Hazard ratio for All patients
received All patients received Time to First Whole molgramostim intermittent molgramostim intermittent Lung Lavage vs 20 dosing dosing Placebo 16 12 Rate ratio for Frequency of Whole Lung Lavage 8 vs Placebo 4 0.01 0.1 1 10 100 0 0 8 16 24 36 48 60
72 Molgramostim Placebo n=44 n=43 n=40 n=19 Week Better Better n=46 n=42 n=41 n=18 Continuous molgramostim Placebo Intermittent molgramostim Dosing schedules for blinded and open-label periods were different. 18 1: Trapnell, Inhaled Molgramostim
IMPALA Safety Overview % PATIENTS WITH ADVERSE EVENTS (AEs) DURING
DOUBLE-BLIND TREATMENT PERIOD* Category Continuous molgramostim Placebo (Patients with AEs >5% in double-blind treatment period) (n=46) (n=47) Any adverse event 84.8% 87.2% Most common adverse events Cough 32.6% 23.4% Chest pain 21.7% 2.1%
Nasopharyngitis 15.2% 12.8% Headache 13.0% 14.9% Dyspnea 10.9% 8.5% Productive cough 8.7% 6.4% Adverse events possibly or probably related to the intervention 32.6% 29.8% Adverse events leading to discontinuation of the intervention 4.3% 2.1%
Phase 3 IMPALA-2 Trial Design Leverages IMPALA Key Learnings Top Line
Data Expected End of 2Q24 Period 1: Double-blind Period 2: Open-label 6-Week Screening n=80 DLCO 70% predicted molgramostim 300 g daily dosing at first screening and baseline molgramostim 300 g daily dosing Change
in % predicted n=80 <15% points to ensure W144 stably impaired patients placebo BL = Primary efficacy analyses W24 W48 = Durability of efficacy / safety Primary Endpoint Secondary Endpoints Change from baseline in DLCO SGRQ Total
Score 90% powered to detect 5.7% predicted SGRQ Activity Score difference with standard deviation of 11* Exercise capacity using treadmill test *Based on patient level data from IMPALA that best matches expected population
IMPALA-2 Study Design Leveraged Lessons from IMPALA IMPALA IMPALA-2
Period 1: Double-blind Period 2: Open-label Period 2: Open-label Period 1: Double-blind n=46 n=80 molgramostim 300 g daily dosing molgramostim 300 g daily dosing n=45 Screening molgramostim 300 g daily dosing molgramostim 300
g molgramostim 300 g Screening n=80 intermittent dosing intermittent dosing W144 n=47 placebo W48 placebo =Primary efficacy analyses BL W24 W48 =Durability of efficacy / safety =Primary efficacy analyses BL W8 W16 W24 Primary Endpoint
(Gas Exchange: surrogate measure): A-aDO2 Primary Endpoint (Gas Exchange: surrogate measure): DLCO Requires subject arterial blood draw Requires subject to blow into a tube Not repeatable Repeatable Supplemental
Oxygen and Primary Endpoint: Supplemental oxygen not allowed Supplemental Oxygen and Primary Endpoint: Not physically feasible to be on during measurement of A-aDO2 supplemental oxygen during measurement of DLCO DLCO Screening Criteria: DLCO <70%
predicted, <15-point % predicted change DLCO Screening Criteria: Vital capacity not improved by more than 5% and/or DLCO during screening not improved by more than 10% as assessed by medical records DLCO Variability Management: Device
standardized across sites, real-time overread DLCO Variability Management: No standardization across sites Key Secondary Endpoints: Key Secondary Endpoints: SGRQ Total SGRQ Total SGRQ Activity 6-minute walk distance
Exercise Treadmill Test Time-to/requirement for whole lung lavage Patients Per Arm On Continuous Molgramostim: ~82 Patients Per Arm On Continuous Molgramostim: ~46 Double Blind Period: 48 weeks (Primary/key secondaries measured at
IMPALA-2 PROTOCOL DLCO: Lung FOR DLCO ASSESSMENT Function Test
Conducted in accordance with ATS/ERS* guidelines Diffusing capacity of the lungs for carbon monoxide Supplemental oxygen EasyOne Pro device used at all IMPALA-2 sites (CO) discontinued 15 minutes before assessment Measures
how well oxygen O saturation must be stable passes from the air sacs of 2 before assessment ( 2% points the lungs into the blood over 5 min.) Can indicate the efficiency Up to 5 assessments allowed to of lung gas
transfer and the obtain at least 2 presence of respiratory acceptable/repeatable problems measurements Cloud-based, real-time overreads at the time of assessment ensure reliability and accuracy of the result *American Thoracic Society (ATS),
MOLGRAMOSTIM IN aPAP REGULATORY DESIGNATIONS Orphan Drug
Designation, Europe (eligible for 10 years exclusivity) Orphan Drug Designation, U.S. (eligible for 7 years exclusivity) Molgramostim Fast Track Designation, U.S. Breakthrough Therapy Designation, U.S. Regulatory
Innovation Passport Designation, U.K. Landscape Promising Innovative Medicine Designation, U.K. IMPALA-2 Trial design endorsed by regulatory authorities in the U.S., Canada, Japan, South Korea, Australia, U.K., and countries in
aPAP Diagnosed Prevalence Before and After Broad Availability of GM-CSF
Autoantibody Testing Published aPAP Epidemiology Studies DIAGNOSED IMPLIED IMPLIED IMPLIED TOTAL INCIDENCE Current REFERENCE METHODOLOGY PREVALENCE US EU JAPAN IMPLIED PER MILLION Diagnosed PER MILLION PATIENTS PATIENTS PATIENTS PATIENTS Prevalence
DIAGNOSED PREVALENCE Before Broad GM-CSF Registry based in 0.48 6.2 Inoue 2008 ~2,058 ~2,325 ~775 ~5,158 Autoantibody Niigata, Japan (0.23-1.00) (3.8-10.3) Testing US insurance claims 6.3 McCarthy 2018 Not reported ~2,092 ~2,363 ~788 ~5,243 data,
2008-2012 (5.2-7.6) DIAGNOSED IMPLIED IMPLIED TOTAL INCIDENCE IMPLIED EU Diagnosed REFERENCE METHODOLOGY PREVALENCE US JAPAN IMPLIED PER MILLION PATIENTS Prevalence After PER MILLION PATIENTS PATIENTS PATIENTS Broad GM-CSF DIAGNOSED PREVALENCE
Re-analysis of Claims Dataset Estimates There Are ~5,000 aPAP Patients
in the U.S. ANALYSIS OF COMPREHENSIVE CLAIMS DATASET Real-World Claims Dataset: ~3,600* 300M+ unique, active patients U.S. patients with at least 1 89-99% providers/sites of care PAP ICD9/10 diagnosis code in claims history