Nivalis Therapeutics, Inc., October 2015 Analyst Breakfast at NACFC We strive to develop innovative solutions that improve and extend the lives of people with cystic fibrosis
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Expertise in Drug Development, Cystic Fibrosis & Inflammation Management Team Jon Congleton President and Chief Executive Officer Janice Troha Chief Operating Officer Mike Carruthers Chief Financial Officer Sherif Gabriel, PhD Vice President Research & Discovery Steven Shoemaker, MD Vice President Clinical R&D / Medical Director Prior Experience Teva Pharmaceuticals; Sanofi (Aventis) Endo Pharmaceuticals; RxKinetix; Cortech; Boehringer Ingelheim Array BioPharma; Ionics; Sievers Instruments; Dover (Waukesha Bearings); Coopers & Lybrand University of North Carolina Cystic Fibrosis Center Nicosof; Cephalon; Anesta 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
AUC (fold change) N91115 Significantly Increases and Prolongs CFTR Activity N91115 stabilizes F508del CFTR in human lung cells (1) 50% increase in net chloride secretion (1) Ussing chamber studies. 50% increase in net chloride secretion with N91115 8
DMSO VX-770 VX-809 VX-809 + VX-770 VX-661 VX-661 + VX-770 PM density (% of DMSO) N91115 Increases Surface Expression of F508del CFTR N91115 Increases Surface Expression of F508del CFTR in CFBe41o- Cells Effects Demonstrated with corrector + potentiator combinations 1200 1000 800 DMSO N91115 * P = 0.05 ** p = 0.01 * * ** ** 600 400 * 200 0 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
Δ ppfev1 (mean ± SD) Mean Absolute Change in ppfev 1 No adverse effect on ppfev 1 during the study 8 Placebo 50 mg 100 mg 200 mg 6 4 2 0-2 -4-6 -8 1 7 14 21 28 Days Per protocol population 16
Effects on ppfev 1 Compared with Placebo 17 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
Mean Change in Sweat Chloride (mmol/l ± 95% CI) Mean Change in Sweat Chloride (95% CI) at 28 days 8 6 4 Placebo 50 mg 100 mg 200 mg Modest trend toward improvement at 28 days on 200 mg BID 2 0-2 Data suggests that 200 mg is a threshold dose for sweat chloride signal -4-6 Placebo difference at 28 days of -5.2 mmol/l -8-10 Day D28 - Baseline -D1 18
Sweat Chloride More Patients in 200 mg Arm Show Improvement Placebo 50 mg 100 mg 200 mg Day 7 - Baseline Day 14 - Baseline Day 21 - Baseline Day 28 - Baseline 19
Change in Sweat Chloride (mmol/l) Difference From Placebo Comparison of Sweat Chloride Treatment Differences to Vertex Compounds 0-1 -2-3 -4-5 -6 200 mg N91115 100 mg VX- 661 + IVA IVA The magnitude of the sweat chloride response on N91115 is similar to VX-661 plus ivacaftor currently being studied in Phase 3 Day 28 Wk 16 (onset at D15) 1. VX-661+IVA: Data extrapolated from Donaldson 2013 NACFC presentation 2. IVA: Flume et al 2012 Chest 142(3): 718-724; Ivacaftor monotherapy D1 to Week 16; 150 mg BID; p=0.04; onset of effect at D15 20
Conclusions There were no dose limiting toxicities N91115 was well-tolerated at all doses for 28 days Sweat chloride response may suggest a threshold dose effect at 200mg Testing a higher dose warranted Phase 2 active arms planned at both 200 and 400 mg 21
N91115 Phase 2 Study Design Janice Troha, COO
Safety Margins Support Higher Dosing in Phase 2 Species & Design Estimated Safety Margins at 200 mg Twice Daily Based on C max Based on AUC last Estimated Safety Margins at 400 mg Twice Daily Based on C max Based on AUC last Dose Limiting Toxicity Rat 90-day NOAEL 150 mg/kg Dog 90-day NOAEL 50 mg/kg Dog CV Safety 13-fold 4-fold 7-fold 2-fold 29-fold 22-fold 15-fold 12-fold 48-fold 34-fold 24-fold 18-fold At 1000 mg/kg: Mild reversible anemia Liver weight increases Kidney weight increases At 500 mg/kg: Mild biliary hyperplasia Mild tubular changes in kidney Anemia 1 dog euthanized At 1000 mg/kg: Increased heart rate and decreased blood pressure Compared with efficacious doses in preclinical in vivo models, these doses provide 4 to 8-fold the exposure (2 to 4-fold based 23 on protein binding differences)
N91115 Phase 2 Study Design N91115 added to Orkambi in adults with CF who are homozygous for F508del Double-blind, randomized, placebo controlled, parallel group study Three arms, 45 patients per arm, total 135 Placebo N91115 at 200 and 400mg BID Primary Endpoint Absolute change from baseline in ppfev 1 at 12 weeks Sample Size Provides > 90% power to detect 5% absolute change in ppfev 1 Study Duration 12 weeks followed by 4-week follow-up period Study Start First Patient First Visit targeted for late 2015 24
N91115 Milestones in Homozygous F508del Patients 2017 2018 Complete Phase 3 program File NDA for treatment of adult CF patients Initiate Phase 3 program (two trials) - show clinically meaningful benefit of triple therapy Complete Phase 2 clinical trial Request Breakthrough 2016 Initiate Phase 2 randomized, controlled clinical trial - demonstrate safety and efficacy of triple therapy Request Orphan/Fast Track Complete Phase 1b clinical trial (dose-finding safety study) 2015 Demonstrate efficacy and safety of N91115 in triple therapy along with lumacaftor/ivacaftor 25