We strive to develop innovative solutions that improve and extend the lives of people with cystic fibrosis Nivalis Therapeutics, Inc., October 2015 – Analyst Breakfast at NACFC
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Expertise in Drug Development, Cystic Fibrosis & Inflammation Management Team Prior Experience Jon Congleton Teva Pharmaceuticals; Sanofi (Aventis) President and Chief Executive Officer Janice Troha Endo Pharmaceuticals; RxKinetix; Cortech; Chief Operating Officer Boehringer Ingelheim Mike Carruthers Array BioPharma; Ionics; Sievers Instruments; Dover Chief Financial Officer (Waukesha Bearings); Coopers & Lybrand Sherif Gabriel, PhD University of North Carolina Cystic Fibrosis Center Vice President — Research & Discovery Steven Shoemaker, MD Nicosof; Cephalon; Anesta Vice President — Clinical R&D / Medical Director 3
Michael Knowles, MD University of North Carolina • Professor of Pulmonary and Critical Care medicine at UNC • Over 3 decades of research and clinical development • Currently head of two large multicenter studies: – Genetic Modifiers of disease phenotype (severity) in cystic fibrosis lung and liver disease – Consortium with 8 sites to study rare genetic disorders of mucociliary clearance 4
Summary Highlights • First-in-class CFTR stabilizer to treat cystic fibrosis (CF) – N91115 significantly increases and prolongs CFTR activity through GSNOR inhibition • N91115 initially targets the most common mutation in CF – F508del mutation present in ~86% of CF patients (1) • Positioned to become a new standard of care in CF – Phase 2 to explore N91115 in triple therapy along with lumacaftor/ivacaftor • N91115 complementary and agnostic to other CFTR modulators – Effective across multiple mutations and in all age groups • Strong proprietary portfolio of GSNOR inhibitors – N91115 composition of matter patent protection until at least 2031 (1) Decision Resources Report, 2014; European Registry Report, 2010 5
Preclinical Data Update Sherif Gabriel, Vice President Research & Discovery
N91115 Improves CFTR Stability in F508del Addition of N91115 to potentiator + corrector approach could improve patient outcomes 7
N91115 Significantly Increases and Prolongs CFTR Activity N91115 stabilizes F508del CFTR in human lung cells (1) 50% increase in net AUC (fold change) chloride secretion ( 1) Ussing chamber studies. 50% increase in net chloride secretion with N91115 8
N91115 Increases Surface Expression of F508del CFTR N91115 Increases Surface Expression of F508del CFTR in CFBe41o- Cells Effects Demonstrated with corrector + potentiator combinations * * ** ** 1200 DMSO N91115 1000 PM density (% of DMSO) * P = 0.05 ** p = 0.01 800 600 * 400 200 0 VX-809 + VX-661 + DMSO VX-809 VX-661 VX-770 VX-770 VX-770 Human Bronchial Cell Line CFBE41o- Performed by Dr. Guido Veit and Dr. Gergely Lukacs – McGill University 9
N91115 Caused a Significant Increase in Chloride Secretion N91115 increases F508del CFTR activity in CF mice (1) (1 ) Intestinal current measurement studies 10
Phase 1b N91115 Trial F508del Homozygous Monotherapy Trial with N91115 to Evaluate Safety and Determine Phase 2 dosing
Phase 1b Trial of N91115 in F508del Homozygous Patients • Double-blind, randomized, placebo-controlled, parallel group • 51 total patients recruited at 19 TDN clinical sites • 12-14 patients each arm – placebo, 50, 100, and 200 mg twice daily • 28 days followed by 2 week withdrawal and follow-up period • Primary endpoints – safety, PK and determine Phase 2 study doses • Exploratory endpoints included – pulmonary function, sweat chloride, inflammatory biomarkers Study was not powered or optimized to show an efficacy signal. For example, there was no upper limit placed on FEV at entry 12
Baseline and Demographic Characteristics 13
Adverse Event Summary N91115 mg BID Placebo 50 100 200 N= 12 12 13 14 Patients with any adverse event, n (%) 11 (92%) 11(92%) 12 (92%) 12 (86%) Patients with any serious adverse event, n 1 0 1 1 Discontinuation due to adverse event 1 0 0 0 Adverse Event by Preferred Term Cough 5 (42%) 2 (17%) 3 (23%) 6 (43%) Chest discomfort 0 2 (17%) 0 2 (14%) Fatigue 1 (8%) 1 (8%) 0 3 (21%) Pulmonary exacerbation of CF During 28-day treatment period 1 (8%) 1 (8%) 1 (8%) 0 During 14-day withdrawal period 1 (8%) 0 1 (8%) 3 (21%) hsCRP ↑ 0 1 (8%) 2 (15%) 1 (7%) Dyspnea 0 1 (8%) 0 2 (14%) Nasal congestion 1 (8%) 0 0 2 (14%) Oropharyngeal pain 1 (8%) 0 1 (8%) 2 (14%) Weight ↓ 0 0 0 3 (21%) Wheezing 0 0 0 2 (14%) 14
N91115 Safe and Well Tolerated No dose-limiting toxicities identified by independent DMC • No adverse effects on pulmonary function • No cardiac toxicity • No liver toxicity • No adverse effect on body weight • No immunosuppressive effects – No effects on white blood cell and absolute neutrophil counts – No effects on CRP – No effects on sputum bacterial count 15
Mean Absolute Change in ppFEV 1 No adverse effect on ppFEV 1 during the study Placebo 50 mg 100 mg 200 mg 8 6 4 Δ ppFEV1 (mean ± SD) 2 0 -2 -4 -6 -8 1 7 14 21 28 Days Per protocol population 16
Effects on ppFEV 1 Compared with Placebo Dose of N91115 BID Placebo 50 100 200 N = 11 12 12 13 ppFEV 1 : Relative Change from Baseline at Day 28 Mean (SD) -2.2 (4.4) 0.1 (6.1) -3.5 (4.7) 0.6 (5.9) Median -1.7 -0.6 -3.5 2.2 ppFEV 1 : Absolute Change from Baseline at Day 28 Mean (SD) -2.1 (3.5) 0.3 (4.3) -2.5 (3.6) 0.2 (4.1) Median -2.0 -0.5 -2.0 1.0 ppFEV 1 : Relative treatment response (versus placebo) at Day 28 Mean - 2.3 -1.3 2.8 Median - 1.1 -1.8 3.9 ppFEV 1 : Absolute treatment response (versus placebo) at Day 28 Mean - 2.4 -0.4 2.3 Median - 1.5 0 3.0 17
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