Nivalis Therapeutics, Inc. Investor Presentation March 2016

We strive to develop innovative solutions
that improve and extend the lives of
people with cystic fibrosis
Nivalis Therapeutics, Inc., June 2016
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 patient
enrollment for ongoing or future clinical trials will take longer than expected, 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
annual report on Form 10K and quarterly report on Form 10-Q. 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
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is not permitted under applicable law.
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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 studies to explore N91115 in triple therapy along with lumacaftor/ivacaftor
and double therapy along with ivacaftor
• N91115 complementary and agnostic to other CFTR modulators
– Effective across multiple mutations and in all age groups
• Strong proprietary portfolio of GSNOR inhibitors
– Orphan and Fast Track Designations received early 2016
– N91115 composition of matter patent protection until at least 2031
(1)Decision Resources Report, 2014; European Registry Report, 2010
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CF Disease Overview
CF is a rare, life-shortening genetic disease
• There is no known cure for CF and predicted
median age of survival in the US is ~41 years(1)
• Approximately 70,000 CF patients globally
– Approximately 65,000 located in the U.S. and Europe
• CF is caused by mutations in the gene that
encodes CFTR(1)
– CFTR is a chloride channel that regulates the movement of
salt and water into and out of cells
– Defective CFTR decreases chloride secretion leading to
buildup of thick mucus in lungs and other vital organs
• > 90% of all CF patients die of respiratory failure(2)
~86% of patients in US & EU have
F508del complex mutation.
(1)http://www.cff.org
(2)http://www.clevelandclinicmeded.com
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Current Disease Modifying Approaches in CF
Complex F508del mutation likely requires multiple therapies with distinct mechanisms of action
Mechanism
Company
Nivalis
Vertex
PTC Therapeutics
Bayer
Novartis
Concert
Flatley Discovery Labs
Galapagos
ProQR
Proteostasis
Genzyme
Pfizer
Reata
Shire
Drug
Phase
N91115
2
ivacaftor
lumacaftor/ivacaftor
VX-661/ivacaftor
VX-440 or VX-152
VX-371
ataluren
riociguat
QBW251
Deuterated ivacaftor
FDL 169
FDL 176
GLPG1837
GLPG2222
GLPG 2665/2737
QR-010
PTI 428
Undisclosed
Undisclosed
Undisclosed
mRNA
Marketed
Stabilizer Corrector Potentiator
Other
N91115 Potentially
Complementary?
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Marketed
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Preclinical
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Preclinical
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Preclinical
Preclinical
Preclinical
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N91115 could be complementary to many of these other CFTR modulators
Note: Based on Decision Resources Report 2014
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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
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
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N91115 Increases Surface Expression of F508del CFTR
N91115 Increases Surface Expression of F508del CFTR in CFBe41o- Cells
Effects demonstrated with corrector + potentiator combinations
Human Bronchial Cell Line CFBE41oPerformed by Dr. Guido Veit and Dr. Gergely Lukacs – McGill University
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GSNOR Inhibition Leads to Reduced Airway Damage
GSNOR inhibition significantly decreased the progression of elastase-induced
alveolar wall damage in mice
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N91115 Clinical Development Status and Plan
N91115 Development History – Completed Clinical Studies
Clinical data support advancing N91115 development
•
Phase 1a in healthy volunteers – multiple ascending dose study
–
•
Phase 1b (PK) in CF patients homozygous for F508del
–
•
No dosing adjustments required for CF patients (n = 6)
Phase 1a Drug:Drug Interaction Study in Healthy Subjects
–
•
No severe or serious adverse events detected (n = 36)
Rifampin used as surrogate for lumacaftor/ivacaftor, no dose adjustments (n = 15)
Phase 1b Dose finding safety study in CF patients homozygous for F508del
–
–
No dose limiting toxicities, N91115 safe and well tolerated (n = 51)
Significant within group reduction of sweat chloride at highest dose
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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, and sputum microbiology
Study was not powered or optimized to show an efficacy signal. For example,
there was no upper limit placed on FEV1 at entry
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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 adverse effects on sputum bacterial count
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Mean Absolute Change in ppFEV1
No adverse effect on ppFEV1 during the study
Placebo
5.
50 mg
100 mg
200 mg
Δ ppFEV1 (mean ± SD)
4.
3.
2.
1.
0.
-1.
-2.
-3.
-4.
-5.
1
7
14
Study Days
Per protocol population
14
21
28
Sweat Chloride
More Patients in 200 mg Arm Show Improvement
Placebo
50 mg
100 mg
200 mg
Day 7 - Baseline
Day 14 - Baseline
15
Day 21 - Baseline
Day 28 - Baseline
Comparison of Sweat Chloride Treatment Differences to Vertex
Compounds
0
Change in Sweat
Chloride (mMol/L)
Difference From Placebo
-1
-2
-3
-4
-5
-6
200 mg N91115
100 mg VX- 661 +
IVA
Day 28
1.
2.
IVA
The magnitude of the
sweat chloride response
on N91115 is similar to
VX-661 plus ivacaftor
currently being studied in
Phase 3
Wk 16
(onset at D15)
VX-661+IVA: Data extrapolated from Donaldson 2013 NACFC presentation
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
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Phase 1b Conclusions
• There were no dose limiting toxicities
• N91115 was well-tolerated at all doses for 28 days
• Sweat chloride response at 200 mg suggests a
“threshold dose effect”
• Testing a higher dose warranted in Phase 2
– Phase 2 trials include 200 and 400 mg twice daily
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N91115 Phase 2 Study Design in F508del Homozygotes
• N91115 added to Orkambi in CF adults 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 ppFEV1
•
Study Duration
– 12 weeks followed by 4-week follow-up period
•
Study Timing
– Started late 2015 – 50% enrolled early April
– TLR fourth quarter 2016
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N91115 Phase 2 Study Design in F508del Heterozygotes
• N91115 added to Kalydeco in CF adults who have F508del/Gating mutations
• Double-blind, randomized, placebo controlled, parallel group study
• 20 patients, approximately 16 on N91115 400 mg twice daily and 4 on placebo
– Placebo arm added to maintain blind
•
Primary Endpoint
– Absolute change from baseline in ppFEV 1 at 8 weeks within the N91115 dose group
•
Sample Size
– Provides > 90% power to detect a 5% within group absolute change in ppFEV1
•
Study Duration
– 8 weeks followed by 4-week follow-up period
•
Study Timing
– Dosed first patient in May 2016
– TLR mid-2017
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N91115 Milestones in Homozygous F508del Patients
Demonstrate efficacy and safety of N91115 in triple therapy along with lumacaftor/ivacaftor
2018
2017
File NDA for treatment of adult
CF patients
Complete Phase 3 program
Initiate Phase 3 program
- show clinically meaningful benefit of triple and double therapy
Complete Phase 2 in F508del homozygotes
2016
Initiate 2nd Phase 2 in F508del heterozygotes
- demonstrate safety and efficacy of double therapy
Initiate Phase 2 in F508del homozygotes
- demonstrate safety and efficacy of triple therapy
Complete Phase 1b clinical trial (dose-finding safety study)
2015
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Request
Breakthrough
Received
Orphan/Fast Track
Financial Summary
2015 Year End
12/31/2015
2016 Q1
3/31/2016
Cash and Cash Equivalents
$87.3
$80.2
R&D Expenses
$16.1
$5.6
G&A Expenses
$6.8
$2.4
$(22.8)
$(7.8)
$19.2
$7.0
($ in millions)
Loss from Operations
Cash used in Operations
IPO Priced June 16, 2015
$88.6M Gross Proceeds
15.5M Shares Outstanding
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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 studies to explore N91115 in triple therapy along with lumacaftor/ivacaftor
and double therapy along with ivacaftor
• N91115 complementary and agnostic to other CFTR modulators
– Effective across multiple mutations and in all age groups
• Strong proprietary portfolio of GSNOR inhibitors
– Orphan and Fast Track Designations received early 2016
– N91115 composition of matter patent protection until at least 2031
(1)Decision Resources Report, 2014; European Registry Report, 2010
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