We strive to develop innovative solutions that improve and extend - - PowerPoint PPT Presentation

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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Disclaimer Regarding Forward Looking Statements

This presentation contains forward-looking statements that are based on our management's belief and assumptions and on information currently available to our management. Although we believe that the expectations reflected in these forward-looking statements are reasonable, these statements relate to future events or our future financial performance, and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as "may," "might," "could," "would," "will," "should," "expect," "intend," "plan," "anticipate," "believe," "estimate," "predict," "project," "target," "potential," "continue" or the negative of these terms or other comparable

• terminology. These statements are only predictions. You should not place undue reliance on forward-looking statements because they involve known and

unknown risks, uncertainties and other factors, which are, in some cases, beyond our control and which could materially affect results. These risks, uncertainties and other factors include, among others, the risk that there is a delay in the initiation or completion of our planned clinical trials, that unanticipated costs or expenditures arise in connection with our clinical trials that affect our need for capital and/or that results from clinical trials fail to meet primary or secondary endpoints. Any forward-looking statements made in this presentation are also subject to the risks and uncertainties that are described more fully in our filings with the SEC, including our most recent quarterly report on Form 10-Q and our registration statement on Form S-1, including the prospectus contained therein. If one or more of these risks, uncertainties or other factors occurs, or if our underlying assumptions prove to be incorrect, actual events or results may vary significantly from those implied or projected by the forward-looking statements. The forward-looking statements in this presentation represent our views as of the date of this presentation. We anticipate that subsequent events and developments will cause our views to change but we undertake no obligation to update these forward-looking statements in the future, except to the extent required by applicable law. All trademarks and registered trademarks are the property of their respective owners. Such use should not be construed as an endorsement of our

• business. Certain data in this presentation was obtained from various external sources, and neither we nor our affiliates, advisers or representatives has

verified such data with independent sources. Accordingly, neither we nor any of our affiliates, advisers or representatives makes any representations as to the accuracy or completeness of that data or to update such data after the date of this presentation. Such data is subject to change based on various factors. This presentation shall not constitute an offer to sell or the solicitation of an offer to buy any securities in any jurisdiction in which such offer or solicitation is not permitted under applicable law.

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Management Team Prior Experience

Jon Congleton President and Chief Executive Officer Teva Pharmaceuticals; Sanofi (Aventis) Janice Troha Chief Operating Officer Endo Pharmaceuticals; RxKinetix; Cortech; Boehringer Ingelheim Mike Carruthers Chief Financial Officer Array BioPharma; Ionics; Sievers Instruments; Dover (Waukesha Bearings); Coopers & Lybrand Sherif Gabriel, PhD Vice President — Research & Discovery University of North Carolina Cystic Fibrosis Center Steven Shoemaker, MD Vice President — Clinical R&D / Medical Director Nicosof; Cephalon; Anesta

Expertise in Drug Development, Cystic Fibrosis & Inflammation

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• 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

Michael Knowles, MD University of North Carolina

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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

Preclinical Data Update

Sherif Gabriel, Vice President Research & Discovery

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N91115 Improves CFTR Stability in F508del

Addition of N91115 to potentiator + corrector approach could improve patient outcomes

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N91115 Significantly Increases and Prolongs CFTR Activity

(1) Ussing chamber studies.

N91115 stabilizes F508del CFTR in human lung cells(1)

50% increase in net chloride secretion

50% increase in net chloride secretion with N91115

AUC (fold change)

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N91115 Increases Surface Expression of F508del CFTR in CFBe41o- Cells

Performed by Dr. Guido Veit and Dr. Gergely Lukacs – McGill University

Human Bronchial Cell Line CFBE41o-

N91115 Increases Surface Expression of F508del CFTR

Effects Demonstrated with corrector + potentiator combinations

200 400 600 800 1000 1200

DMSO VX-770 VX-809 VX-809 + VX-770 VX-661 VX-661 + VX-770 PM density (% of DMSO)

DMSO N91115

* * * ** **

* P = 0.05 ** p = 0.01

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N91115 Caused a Significant Increase in Chloride Secretion

(1) Intestinal current measurement studies

N91115 increases F508del CFTR activity in CF mice(1)

Phase 1b N91115 Trial

F508del Homozygous Monotherapy Trial with N91115 to Evaluate Safety and Determine Phase 2 dosing

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• 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

Phase 1b Trial of N91115 in F508del Homozygous Patients

Study was not powered or optimized to show an efficacy signal. For example, there was no upper limit placed on FEV at entry

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Baseline and Demographic Characteristics

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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 1 1 Discontinuation due to adverse event 1 Adverse Event by Preferred Term Cough 5 (42%) 2 (17%) 3 (23%) 6 (43%) Chest discomfort 2 (17%) 2 (14%) Fatigue 1 (8%) 1 (8%) 3 (21%) Pulmonary exacerbation of CF During 28-day treatment period 1 (8%) 1 (8%) 1 (8%) During 14-day withdrawal period 1 (8%) 1 (8%) 3 (21%) hsCRP↑ 1 (8%) 2 (15%) 1 (7%) Dyspnea 1 (8%) 2 (14%) Nasal congestion 1 (8%) 2 (14%) Oropharyngeal pain 1 (8%) 1 (8%) 2 (14%) Weight ↓ 3 (21%) Wheezing 2 (14%)

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• 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

N91115 Safe and Well Tolerated

No dose-limiting toxicities identified by independent DMC

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Mean Absolute Change in ppFEV1

• 8
• 6
• 4
• 2

2 4 6 8

1 7 14 21 28

Δ ppFEV1 (mean ± SD) Days Placebo 50 mg 100 mg 200 mg

No adverse effect on ppFEV1 during the study

Per protocol population

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Effects on ppFEV1 Compared with Placebo

Dose of N91115 BID

Placebo 50 100 200 N = 11 12 12 13 ppFEV1: 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 ppFEV1: 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 ppFEV1: Relative treatment response (versus placebo) at Day 28 Mean

• 2.3
• 1.3

2.8 Median

• 1.1
• 1.8

3.9 ppFEV1: Absolute treatment response (versus placebo) at Day 28 Mean

• 2.4
• 0.4

2.3 Median

• 1.5

3.0

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Mean Change in Sweat Chloride (95% CI) at 28 days

• Modest trend toward

improvement at 28 days

• n 200 mg BID
• Data suggests that 200

mg is a threshold dose for sweat chloride signal

• Placebo difference at 28

days of -5.2 mmol/L

• 10
• 8
• 6
• 4
• 2

2 4 6 8

D28 -D1 Mean Change in Sweat Chloride (mmol/L ± 95% CI) Day 28 - Baseline

Placebo 50 mg 100 mg 200 mg

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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

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Comparison of Sweat Chloride Treatment Differences to Vertex Compounds

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

• 6
• 5
• 4
• 3
• 2
• 1

200 mg N91115 100 mg VX- 661 + IVA IVA

Change in Sweat Chloride (mMol/L) Difference From Placebo

Day 28 Wk 16 (onset at D15)

The magnitude of the sweat chloride response

• n N91115 is similar to

VX-661 plus ivacaftor currently being studied in Phase 3

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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

N91115 Phase 2 Study Design

Janice Troha, COO

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Estimated Safety Margins at 200 mg Twice Daily Estimated Safety Margins at 400 mg Twice Daily Dose Limiting Toxicity Species & Design Based on Cmax Based on AUClast Based on Cmax Based on AUClast

Rat

90-day NOAEL 150 mg/kg 13-fold 4-fold 7-fold 2-fold At 1000 mg/kg: Mild reversible anemia Liver weight increases Kidney weight increases

Dog

90-day NOAEL 50 mg/kg 29-fold 22-fold 15-fold 12-fold At 500 mg/kg: Mild biliary hyperplasia Mild tubular changes in kidney Anemia 1 dog euthanized Dog CV Safety 48-fold 34-fold 24-fold 18-fold At 1000 mg/kg: Increased heart rate and decreased blood pressure

Safety Margins Support Higher Dosing in Phase 2

Compared with efficacious doses in preclinical in vivo models, these doses provide 4 to 8-fold the exposure (2 to 4-fold based on protein binding differences)

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• 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 ppFEV1 at 12 weeks

• Sample Size

– Provides > 90% power to detect 5% absolute change in ppFEV1

• Study Duration

– 12 weeks followed by 4-week follow-up period

• Study Start

– First Patient First Visit targeted for late 2015

N91115 Phase 2 Study Design

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N91115 Milestones in Homozygous F508del Patients

Demonstrate efficacy and safety of N91115 in triple therapy along with lumacaftor/ivacaftor

Complete Phase 1b clinical trial (dose-finding safety study) Initiate Phase 3 program (two trials)

• show clinically meaningful benefit of triple therapy

Complete Phase 3 program Complete Phase 2 clinical trial Initiate Phase 2 randomized, controlled clinical trial

• demonstrate safety and efficacy of triple therapy

2015 2016 2017 2018

File NDA for treatment of adult CF patients

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