-207: A Phase 2 Trial of to Assess Safety, Efficacy and Tolerability in Patients with Idiopathic Pulmonary Fibrosis (IPF) K. F. Gibson 1, F. Averill 2, T.E. Albertson 3, D. M. Baratz 4, S. Chaudhary 5, S. M. Humphries 6, D. A. Lynch 6, S. Mobin 7, T. O'Brien 8, M.B. Scholand 9, T.P.M. Whelan 10, M. Poyurovsky 11, O. Schueller 11, J. Ryan 11 1 University of Pittsburgh Medical Center, Pittsburgh, PA; 2 St. Francis Medical Center, Clearwater, FL; 3 University of California, Davis, Sacramento, CA; 4 Pulmonary Associates, PA, Phoenix, AZ; 5 University of Arizona CATS Research Center, Tucson, AZ; 6 National Jewish Health, Denver, CO; 7 Central Florida Pulmonary Group, Orlando, FL; 8 Pulmonary Disease Specialists, Kissimmee, FL; 9 University of Utah Pulmonary Clinical Research, Salt Lake City, UT; 10 Medical University of South Carolina, Charleston, SC; 11 Kadmon Corporation, LLC, New York, NY Kadmon Holdings, Inc. 1
ROCK is the Common Pathway of Initiating Factors in IPF ROCK Regulates Multiple Pro-Fibrotic Processes, Including Myofibroblast Activation Rho-associated coiled-coil kinase (ROCK) is downstream of major pro-fibrotic mediators, including: Transforming growth factor beta (TGF-β) CTGF Myofibroblast Cell Stress fiber formation Connective tissue growth factor (CTGF) Lysophosphatidic acid (LPA) ROCK ROCK regulates fibroblast differentiation to myofibroblasts, a defining feature of pathologic fibrosis ROCK MKL1 Pro-fibrotic genes ROCK mediates stress fiber formation ROCK regulates transcription of pro-fibrotic genes, including CTGF and alpha-smooth muscle actin (α-sma) MKL1 MKL1 CTGF Am J Pathol. 2015 Apr;185(4):909-12. 2
ROCK Inhibitor Reduced Lung Fibrosis in Bleomycin Model Reduced Fibrosis in Multiple Preclinical Models, Including Bleomycin and cgvhd Mouse Models Intratracheal Bleomycin treatment administered when fibrosis is already established (orally, 50, 100 or 150 mg/kg QD) Tissue Harvest Day: 0 8 21 Normal Lung Pre-Treatment Lung Intratracheal Bleomycin Day 0 Vehicle or Day 8 Treatment: Day 21 Control 50 mg/kg QD 100 mg/kg QD 150 mg/kg QD 3
-207: Design and Key Endpoints Key Eligibility Criteria: IPF diagnosis within 5 years by HRCT/ lung biopsy Previously received pirfenidone and/or nintedanib or had been offered both 18 years of age FVC 50% predicted DL CO 30% predicted FEV 1 / FVC ratio 0.70 2:1 400 mg QD (n=24) * (n=12) Option to extend Crossover allowed at investigator s discretion Primary Endpoints: Safety and tolerability Change in FVC from baseline to 24 weeks Key Secondary Endpoints: Percentage of patients with a decline in FVC of 5% at 24 weeks Diffusion capacity (DL CO ) 6-Minute Walk Test (6MWT) Pulmonary Function Test (PFT) High-Resolution Computed Tomography (HRCT) 1 J Manag Care Spec Pharm. 2017 Mar;23(3-b Suppl):S17-S24. 24 weeks 48 weeks Lung fibrosis as measured by quantitative HRCT *Best Supportive Care, as determined by investigator. may include pulmonary rehabilitation, supplemental oxygen therapy, and/or other symptomatic treatments 1 ; excludes pirfenidone/nintedanib Protocol amended to increase total enrollment to ~81 and to allow crossover from to at Week 24 only 4
Analysis Populations Safety Population All patients who were randomized and received at least one dose of or completed Visit 1 on Modified ITT (mitt) Population* All patients from the safety population who have evaluable baseline and at least one evaluable post-baseline FVC measure Per Protocol (PP) Population All patients from the safety population who have both evaluable baseline and W24 FVC measures *Two approaches to handle missing data if W24 FVC not available: 1. Linear Extrapolation 2. Last Observation Carried Forward (LOCF) All data presented in medians 5
Demographics and Baseline Characteristics (N=26) (N=14) Age, years 71.4 ± 6.6 74.4 ± 6.8 Male, n (%) 18 (69.2%) 11 (78.6%) Time since IPF diagnosis, years 2.4 ± 1.8 2.6 ± 2.2 Former smokers, n (%) 18 (69.2%) 10 (71.4%) Prior treatment: Pirfenidone or nintedanib, n (%) 13 (50.0%) 4 (28.6%) Lung function: FVC, % of predicted value 66.9 ± 21.9 69.9 ± 18.2 FVC (L) 2.49 ± 0.84 2.60 ± 0.87 DL CO, % of predicted 45.2 ± 12.1 47.6 ± 10.8 FEV 1 /FVC ratio 0.84 ± 0.07 0.83 ± 0.07 Data are presented as means ± SD, unless otherwise specified Data cutoff date: March 13, 2018 6
Patient Disposition Not yet reached W12 4 Due to AE 1 4 Pt/PI decision 1 Death 1 PFT not evaluable 1 Due to AE 2 1 Lost to follow-up 1 Pt/PI decision 1 Not reached W24 1 Patients Randomized 2:1 (n=40) Crossover to before W24 (n=5) Randomized to (n=26) Crossover to at W24 (n=4) (n=24) mitt W24 (n=20) PP Safety Randomized to (n=14) (n=11) (n=9) 1 Related: Elevated LFTs Not Related: CHF / pneumonia, acute respiratory failure, hypotension 2 Not Related: SCC Crossover to 3 (IPF exacerbation, worsening dyspnoea, Increased SoB) Crossover to 2 (Decrease in FVC, disease progression) 7
Slows FVC Decline at W24 (mitt, Linear Extrapolation) Median Change in FVC (ml) Absolute FVC difference was 125 ml at Week 24 Decline in FVC % predicted was 1% with, compared to 5% with Change in FVC (ml) at W24 0-50 -100-150 -200-250 -50 ml (n=24) -175 ml (n=11) FVC % Predicted Decline 5% 29% of patients experienced FVC decline 5%, compared to 55% of patients at Week 24 % Patients with 5% FVC Decline 60% 50% 40% 30% 20% 10% 0% 29% (n=24) 55% (n=11) 8
PP Analysis Consistent with mitt Median Change in FVC (% predicted) in FVC (ml) (n) (n) (n) (n) Modified ITT (mitt) Linear extrapolation -1% (24) -5% (11) -50 ml (24) -175 ml (11) LOCF -1% (24) -3% (11) -50 ml (24) -175 ml (11) Per Protocol (PP) -1% (20) -2% (9) -48 ml (20) -175 ml (9) 9
Additional Analyses Demonstrate Benefit of (mitt) Showed Benefit in Annualized FVC Decline Compared to 1 Year Prior to Randomization Patients randomized to for whom prior-year data were available (n=18): Annualized FVC decline of 113 ml one year prior to randomization, compared to an annualized FVC decline of 70 ml at 24 weeks of Patients with Prior Pirfenidone/Nintedanib Treatment Responded Better to Previously treated patients (n=10) showed an FVC decline of 2 ml at 24 weeks Previously treated patients (n=2) showed an FVC decline of 273 ml at 24 weeks 10
was Well Tolerated, with No Drug-Related SAEs 18/20 (90%) of Patients Evaluable at W24 Elected to Continue Beyond W24 1 (N=35) (N=14) Mean duration of exposure (weeks) 2 33.3 20.1 Patient-years of exposure 22.4 5.4 All-grade adverse events 30 (86%) 11 (79%) Grade 3+ adverse events 10 (29%) 2 (14%) SAEs in 2 Patients Cardiac failure congestive 3 (9%) 0 Coronary artery disease 2 (6%) 1 (7%) Acute respiratory failure 2 (6%) 0 Dyspnoea 2 (6%) 0 Pneumonia 2 (6%) 0 Troponin increased 2 (6%) 0 1 All patients who received at least one dose of (includes 9 crossovers) 2 arm could receive treatment beyond 24 weeks; arm received maximum 24 weeks of follow-up 11
Treatment-Emergent AEs Non-Respiratory TEAEs Reported in 10% Patients in Either Arm (N=35) 1 (N=14) 2 Liver enzymes increased [HLT] 3 7 (20%) 2 (14%) Fatigue 6 (17%) 1 ( 7%) Nausea 5 (14%) 2 (14%) Diarrhoea 5 (14%) 0 Dizziness 4 (11%) 1 ( 7%) Muscle spasms 4 (11%) 0 Non-cardiac chest pain 1 ( 3%) 2 (14%) Respiratory TEAEs Reported in 10% Patients in Either Arm 1 All patients treated with (includes crossovers) 2 arm received max 24 weeks of treatment; arm could receive treatment beyond 24 weeks 3 All preferred terms except liver enzymes, which is high-level term [HLT] (N=35) 1 (N=14) 2 Cough 5 (15%) 4 (29%) Dyspnoea 4 (11%) 3 (21%) Bronchitis 2 ( 6%) 3 (21%) Upper respiratory tract infection 2 ( 6%) 2 (14%) Productive cough 1 ( 3%) 2 (14%) 12
Conclusions Demonstrated Clinical Activity of in IPF 1 slowed the decline in lung function in IPF patients over 24 weeks of treatment: Absolute change in FVC of -50 ml in patients, compared to -175 ml with patients demonstrated 1.0% FVC decline, compared to 5.0% with 29% of patients experienced an FVC % predicted decline 5%, compared to 55% with was well tolerated, with no drug-related SAEs 90% of patients on elected to continue on treatment beyond 24 weeks Findings support continued development of in IPF 1 Conclusions based on mitt (linear extrapolation) 13
Efficacy Compares Favorably to Approved IPF Therapies Patients who Continue on to Week 48 Maintain Slowed Rate of FVC Decline (mitt Population) Change in FVC (ml) 0-50 -100-150 -200-250 -300-350 -50 ml (n=20) -175 ml (n=9) -120 ml (n=12) 3 Range of ΔFVC in treatment arms of Phase 3 studies of approved IPF therapies nintedanib and pirfenidone 1,2 Range of ΔFVC in placebo arms of Phase 3 studies of approved IPF therapies 1,2-400 0 12 24 36 48 Time (Weeks) 1 Supplement to: N Engl J Med 2014;370:2071-82. Page 18, Table S5: Secondary lung function endpoints in INPULSIS -1 and INPULSIS -2 at week 52 (pooled data). 2 N Engl J Med 2014;370:2083-92. DOI: 10.1056/NEJMoa1402582. Page 2088, Fig 2B (ASCEND). 3 N=12 reflects patients with week 48 FVC, with no imputation 14
Acknowledgements Trial patients and their caregivers All investigators and clinical research staff from participating centers: University of Pittsburgh Medical Center, Pittsburgh, PA St. Francis Medical Center, Clearwater, FL University of California, Davis, Sacramento, CA Pulmonary Associates, PA, Phoenix, AZ University of Arizona CATS Research Center, Tucson, AZ Central Florida Pulmonary Group, Orlando, FL Pulmonary Disease Specialists, Kissimmee, FL University of Utah Pulmonary Clinical Research, Salt Lake City, UT Medical University of South Carolina, Charleston, SC National Jewish Health, Denver, CO 15