Anti-inflammatory Therapy Targets Orphan Lung Disease-June 17

Transcription

1 Anti-inflammatory Therapy Targets Orphan Lung Disease-June 17 Disease Modification in Cystic Fibrosis (CF) Targeted Approach in Pulmonary Hypertension (PH)

2 Experienced Management Team Greg Duncan President/CEO Sanjeev Ahuja, MD, MBA, FACP Chief Medical Officer Eric Springman, PhD Chief Scientific Officer Angela Walsh, CPA VP Financial Operations Launch Experience 2

3 Corporate Summary Leukotriene B4 modulation platform reduces inflammation Lead investigational candidate Acebilustat is a first in-class, once-daily, oral medicine Portfolio of anti-inflammatory candidates suitable for oral, inhaled, topical formulations Focused on rare/ orphan diseases Acebilustat granted orphan designation in Cystic Fibrosis (CF) in US and EU Phase 2B CF Lung Preservation Trial Enrolled Reduce lung clogging and damaging neutrophil elastase in CF patients Targets all patients, complement to background therapies Prepared to Execute PH Trial in Second Orphan Lung Disease Preclinical data support Acebilustat treatment of orphan designated form of PH PH resulting from interstitial lung disease, with associated connective tissue disorder Advancing private capital scaling to execute PH in Q

4 Lung Inflammation Drives CF Morbidity & Mortality Persistent inflammation leads to: airway obstruction pulmonary exacerbation permanently impaired lung function Respiratory failure & premature death at years of age No approved treatment for CF lung inflammation 4

5 Excessive Migration of Neutrophils into Lungs Drives Chronic CF Lung Inflammation Clear Healthy Lung Inflamed CF Lung Neutrophil Thickened mucus layer Clear, thin mucus layer Excess Neutrophils & DNA 5

6 Neutrophil Elastase: Key to CF Pathology Elastase disables defense against bacteria Elastase Elastase inactivates CFTR Elastase destroys the collagen matrix 6

7 Acebilustat Tunes Down Over Active Inflammation LTA4 LTB4 LTA4H 12-LO LXA4 ACEBILUSTAT Neutrophil Overactivation: Damaging Inflammation Neutrophil Underactivation: Uncontrolled Infection HOMEOSTASIS 7

8 Acebilustat Immediately Modulates LTB4 and Sustains This Effect with Continued Administration Acebilustat s dose dependent LTB4 inhibition up to 200mg Source: Elborn (2016) Clin Transl Sci PMID: Acebilustat s dose dependent inhibition of LTB4 ranges from 50% to 90% 8

9 Strong Evidential Foundation Underpins Acebilustat PoC Phase 2B Lung Function Preservation Trial High Dose Ibuprofen Slows Lung Fx Decline, Improves Mortality ACEBILUSTAT Phase 2B Targets CF Population Most at Risk for Lung Fx Decline Acebilustat Positively Impacts Key Biomarkers in CF Patients 9

10 High Dose Ibuprofen Sets Precedent for Anti-inflammatory Therapy Slowing CF Lung Function Decline, Improving Survival High Dose Ibuprofen (HDI) (Up to 3200 mg/day) Slows Lung Function Decline HDI Reduces CF Patient Mortality at 7 Years ppfev1 Annual Decline, % ppfev1 Annual Decline, % High Dose Ibuprofen Standard Care All Pts Young Pts 59% p< % p<0.05 Mortality 7 7 years, % % Standard Care (SC) 32 % p< SC + High Dose Ibuprofen Source: Konstan, et al., NEJM 1995; 332, , Vandevanter Ped Pulm Suppl (2012) 35:354 While effective, HDI s safety and tolerability profile limit utilization to less than 1% of the CF population 10

11 HDI Effect Driven by LTB4 Reduction, Acebilustat Demonstrates Rapid & More Sustained Inhibition of Inflammatory LTB4 High Dose Ibuprofen: Inhibits LTB4 production 100 mg/day Acebilustat: Improved Inhibition of LTB4 Production Acebilustat: Sustained Therapeutic Coverage PERCENT BASELINE % LTB4 Reduction: CF Therapeutic Benefit LTB4 PGE IBUPROFEN CONCENTRATION (µg/ml) LTB$, % BASELINE % Immediate & Sustained Reduction 0->24 hr 0->24 hr 0->24 hr Day 1 Day 7 Day 14 LTB4 0 0 Time, hr 24 Source: Konstan, et al., Am Rev Respir Dis : 186 While effective, HDI s safety and tolerability profile limit utilization to less than 1% of the CF population 11

12 Acebilustat Reduces Inflammatory Biomarkers in CF Patients After Only Two Weeks of Therapy Reduced Sputum Neutrophils Reduced Sputum Elastase (NE) Reduced Serum CRP Sputum Neutrophils 300 Change Change from from Baseline, Baseline, % % Placebo Placebo Acebilustat Acebilustat Elastase, % Baseline Placebo mean 40% v Placebo, p<0.05 (one sided t-test) mean 15% v Baseline 8 of 12 v Baseline 4 of 12 50% or m ore Acebilustat Placebo Placebo Acebilustat Source: Elborn (2016) Clin Transl Sci PMID: Elastase and CRP are well documented predictors of lung function decline and future pulmonary exacerbations, respectively 12

13 Highly Correlated Biomarker Changes for Acebilustat Treated CF Patients Supports of Proof of Mechanism 50 mg 100 mg Elastase vs LTB4 Elastase vs WBC DNA vs Elastase 13

14 Importantly, elastase correlates with clinically important measures in CF patients FEV1 decline (Meyer-Hamblett 2007, Sagel 2013) Exacerbation (Cantin 2012) Pseudomonas infection (Pukhalsky 1999) Source: Meyer-Hamblett (2007) AJRCCM 175:822 14

15 200 Patients Enrolled in CF Phase 2 Lung Function Preservation Trial: Top Line Results Mid 2018 Aims to demonstrate disease modification by stemming decline in lung function Primary endpoint: Change from baseline in FEV1pp vs placebo Secondary endpoint: Impact on pulmonary exacerbations (PEx) vs placebo Open to all patients, no gene specific restrictions Patients age years in US, EU Canada Baseline FEV1 percent predicted (pp) 50%, 1 exacerbation in past year Steven M. Rowe, MD, MSPH (North American PI) Prof. J. Stuart Elborn, MD, FRCP (EU PI) 48 week treatment on top of background therapy 4 WK *Source: CF Patient Registry Follow-Up 15

16 Orphan Inflammatory Disease Targets Cystic Fibrosis Pulmonary Hypertension Orphan Inflammatory Disease Lung is Target Organ Focused Commercial Footprint Pricing Complementarity Actively Pursuing Prepared to Execute 16

17 Elevated LTB4 Drives Pathogenesis of Pulmonary Hypertension (PH) Associated with Inflammatory Vascular Remodeling LTB4 Endothelial Cell Death Fibrosis Smooth Muscle Proliferation Tabata - Japanese J Thoracic Dis 35(2):160 (1997) Tian - Sci Transl Med 5, 200ra117 (2013) El Kasmi - J Immunol 193: 597 (2014) Qian - Hypertension 66:1227 (2015) Ee - Am J Physiol 311(2):L292 (2016) Hypertrophy Right Ventricle Strain & Dysfunction 17

18 Unacceptably High Levels of Mortality in Pulmonary Hypertension Catalyzed by Inflammatory Remodeling There 32,000 patients with PH-ILD and comorbid CTD in US/EU ILD is characterized by inflammation, fibrosis, stiffening and thickening of the lung tissues Average Life Expectancy for PH Driven by ILD is only years from Diagnosis LTB4 Inhibition Reverses Pulmonary Hypertension in Rodent Models No approved therapies for PH- ILD patients Elevated LTB4 in about 50% of PH-ILD/CTD Patients Andersen Respir Med (2012) 106: Tian W, et al Sci Transl Med, (2013), 5(200):200ra117. IPAH=Idiopathic Pulmonary Arterial Hypertension, APAH=Associated Pulmonary Arterial Hypertension, CTD=Connective Tissue Disorder, ILD=Interstitial Lung Disease 18

19 Acebilustat Exhibits Reductions in PA Pressure & RV Hypertrophy Comparable to Ubenimex & Sildenafil in Semaxinib-Induced Model 19

20 Acebilustat Exhibited Dose-Dependent Efficacy in Bleomycin Induced Pulmonary Hypertension Sham Induced Acebilustat Dose, mg/kg/day Acebilustat Dose, mg/kg/day Acebilustat 10 mg/kg 20

21 Celtaxsys Orphan Lung Disease Forward Research Plan CF CF P2B Trial CF Fast Track Designation CF P3 Prep PH PH IND/ Fast track PH P2 21