Download NewLink Genetics Corporation

Jefferies 2015 Global Healthcare Conference
NewLink Genetics Corporation
Nasdaq: NLNK
November 19, 2015
Forward-Looking Disclaimer
These slides contain forward-looking statements. The Company’s
actual results may differ materially from those suggested here.
Additional information concerning factors that could cause such a
difference is contained in the Company’s Annual Report on
Form 10-K for the fiscal year ended December 31, 2014 and other
prior and subsequent regulatory filings.
NASDAQ: NLNK
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NewLink Genetics
Building a Leading Immuno-Oncology Company
 Industry-leading advanced pipeline across multiple cancer types with
7 product candidates in clinical development from Phase 1 to Phase 3
 Unique HyperAcute® Cellular Immunotherapies that suggest clinical activity
associated with potent anti-cancer immune responses
 Potential to have the first product with an FDA approval for the adjuvant
treatment of patients with surgically resected pancreatic cancer
 Multiple small molecules targeting the key IDO checkpoint blockade
 Well-positioned to execute on our vision of combining checkpoint blockade
inhibitors and cellular immunotherapies
 Founding scientific and business leadership with proven expertise in drug
discovery, manufacturing, clinical development, and commercialization
 Proven success in substantial strategic collaborations
 ~$200 million in cash with the potential for near-term catalysts
 Opportunity in infectious diseases
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Immuno-Oncology
The Solution
 The emerging scientific and clinical consensus is that
patients in the future will require both approaches:
– Generating a targeted immune response
– Disrupting checkpoint blockade
Generating
a Targeted
Immune
Response
HyperAcute Cellular
Immunotherapy
(NLNK)
and CAR-T cells
Disrupting
Checkpoint
Blockade
Enhanced
Immune
Response
IDO inhibitors
(NLNK), PD-1,
PD-L1, CTLA-4,
OX40 antibodies
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HyperAcute Cellular Immunotherapy
Highly Differentiated From Other Immunotherapies
 Technology derived from serendipitous observation in the clinic
that led to unexpected anti-tumor responses
 HyperAcute mechanism based on potent anti-αGal antibodies
that protect humans from zoonotic infection
 Metabolically active, whole-cell immunotherapy with multiple
antigens
 Does not require tissue from patient (allogeneic)
 Multi-faceted immune response: antibodies, T cells and
eosinophils
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HyperAcute Cellular Immunotherapy
Educating the Immune System to Attack Cancer
1
Pre-Existing “HyperAcute® ”
Anti-α-Gal Antibody Response
1
LEADS
TO…
2
Humoral Immunity:
2
 Anti-Tumor Antibodies
3
3
4
Cellular Immunity:
4
 Tumor-specific T cells
Cellular Infiltration:
 Eosinophilia, Anti-Parasitic-Like
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Leading Pipeline in Immuno-Oncology
HyperAcute Cellular Immunotherapy Clinical Development Program
HyperAcute Cellular Immunotherapy
AGENT
Algenpantucel-L
Tergenpumatucel-L
Dorgenmeltucel-L
HyperAcute
Prostate
HyperAcute Renal
TARGET DISEASE
DESIGN DETAILS
Phase1
Pancreatic cancer (resected)
IMPRESS: algenpantucel-L +
standard of care; randomized
Pancreatic cancer
(borderline resectable or
locally advanced unresectable)
PILLAR: algenpantucel-L +
chemotherapy; randomized
ENROLLING
NSCLC
(advanced or metastatic)
Tergenpumatucel-L vs docetaxel
and controlled for follow-on
chemotherapy;
phase 2b; randomized
ENROLLING
Melanoma (advanced)
Dorgenmeltucel-L + ipilimumab or
PD-1 inhibitors; randomized
ENROLLING
Prostate cancer
(castrate-resistant)
HyperAcute Prostate: single
agent, dose escalation
ENROLLED
Renal cancer (advanced)
HyperAcute Renal; single agent,
dose escalation
ENROLLING
Phase 2
Phase 3
ENROLLMENT COMPLETE
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Algenpantucel-L
Phase 2 Results in Resected Pancreatic Cancer
Anti-CALR Ab
Increased Ab
No Increase
Total
Number Patients
31
33
64
OS (months)
>35
19.2
P < 0.04 (log rank test)
30 month survival
55%
21%
P <0.01 (Fisher’s exact test)
Rossi, G.R. et al, ASCO 2014: Highlights Selected. Poster 3029
Anti-CALR Antibody Elevation Correlates with Improved Overall Survival
8
IMPRESS Trial
Algenpantucel-L Phase 3 Registration Trial
 Randomized two-arm study of immunotherapy added to standard
adjuvant treatment versus standard treatment alone
 722 patients with surgically removed cancers enrolled in 70+ U.S. sites
from May 2010 to September 2013
 Protocol under SPA with FDA, also orphan drug and fast track status
 Statistical method employed is a log rank analysis powered at 80% to
detect approximately a 20% difference in overall survival
 Algenpantucel-L given at high dose used in Phase 2 study (300 million
cells) for a longer treatment period: every two weeks for six months,
then monthly for an additional six months
 Stratified for nodal status, radiotherapy administration and CA19-9
 The characteristics of the patients enrolled in the IMPRESS study are
consistent with patient populations enrolled in previous U.S. multiinstitutional trials in pancreatic cancer
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IMPRESS Trial
Data Analyses
 The study was fully enrolled in September 2013
 The second interim analysis showed an estimated median overall
survival of 28.5 months* from the time of randomization for both
cohorts blended together
 We estimate that overall survival in the control arm, even allowing for
advances in the SOC, should be in the low twenties following surgery
 These initial data from the Phase 3 trial have given us confidence to
proceed with commercialization plans
*Kaplan Meier analysis based estimate
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PILLAR: Second Phase 3 Trial
Locally Advanced Pancreatic Cancer
 Launched October 2012 (FPI, Q113)
 Open label, two-arm, randomized study (n=280)
 FOLFIRINOX or nab-paclitaxel +/- algenpantucel-L
 Algenpantucel-L: 300 million cells Q2 weeks up to 18 doses
 Overall survival is the primary endpoint
 Includes borderline or locally advanced unresectable patients
 Enrollment expected to be completed in 2015
Positive results might more than double the treatable patient population
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NewLink Genetics
About Pancreatic Cancer
 Approximately 48,960 new cases of pancreatic cancer will occur in 2015 in the
U.S.*
 Pancreatic cancer has the lowest survival rate of all cancers**
– 1-year survival rate of all stages combined is 26%
– 5-year survival rate of all stages combined is 6%
 Treatment options vary by stage, but primarily include
– Surgical resection
– Chemotherapy
• Gemcitabine
• Gemcitabine + nab-paclitaxel
• FOLFIRINOX
• Erlotinib
 An estimated 15,000 patients are eligible for resection and an additional
10,000 patients have locally advanced disease***
*American Cancer Society
**National Cancer Institute
***SEER data
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Commercialization Strategy
Algenpantucel-L for Patients with Pancreatic Cancer
 NewLink Genetics plans to execute an independent U.S.
commercial launch
– Establishing experienced oncology commercial team
– Leverage key pancreatic surgical centers as hubs
– Provide strong product support across entire multidisciplinary team
 Key launch components currently being assembled
– Utilizing state-of-the-art cold chain distribution
– Conducting reimbursement analysis and establishing support services
– Corporate and product branding initiatives underway
 Evaluating different options for ex-U.S. commercialization
– Anticipate EMEA submission with IMPRESS results
– Exploring potential partnerships with large global companies
– Assessing options to develop ex-U.S capability
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Indoleamine 2,3-Dioxygenase (IDO) Pathway
A Key Immune Checkpoint Target
Regulates Innate and Adaptive Immune Response
 Is counter-regulatory (induced by inflammation)
 Inhibits effector T cells, activates suppressive Tregs
 Can create peripheral tolerance de novo
Dominant Regulatory Role
 Maternal tolerance; autoimmune disorders; transplant tolerance
 Tumor-induced immunosuppression
Overexpressed in Cancer
 Within tumor cells to directly suppress T cells
 Within antigen-presenting cells resulting in peripheral tolerance to
tumor-associated antigens
IDO is central to immune escape
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Leading Pipeline in Immuno-Oncology
IDO Pathway Inhibitor Clinical Development Program
IDO Pathway Inhibitor Platform
AGENT
Indoximod
TARGET DISEASE
DESIGN DETAILS
Breast cancer (metastatic)
Indoximod + taxane;
randomized
ENROLLING
Prostate cancer
(metastatic, castrate-resistant)
Indoximod following
sipuleucel-T; randomized
ENROLLING
Pancreatic cancer (metastatic)
Indoximod + gemcitabine
and nab-paclitaxel;
phase 1b/2
ENROLLING
Melanoma (advanced)
Indoximod + ipilimumab or PD-1
inhibitors; phase 2
ENROLLING
Glioblastoma multiforme
Indoximod + temozolomide;
phase 2
ENROLLING
Solid tumors
GDC-0919
Solid tumors
GDC-0919 + PD-L1 inhibitor or
anti-OX40
GDC-0919
Phase1
Phase 2
Phase 3
Partnered with Genentech, Inc.
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Indoximod + Docetaxel Combination
Phase 1b Efficacy Results
 18% (4/22) partial response rate (2 breast, 1 lung, 1 thymic)
 41% (9/22) rate of stable disease
Fold Change in Tumor Volume
60%
40%
20%
NSCLC
Esophageal
Laryngeal
0%
Breast
-20%
Thymic type
-40%
Rectal
-60%
Pancreatic
-80%
Ovarian
-100%
Encouraging responses in heavily pre-treated patients
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Indoximod Plus CTLA-4 Blockade
100
0.8
0.6
0.4
* **
0.2
0.0
0
5
10
15
20
25
Days post tumor challenge
untreated
aCTLA4
Indoximod
aCTLA4 + Indoximod
100
80
Survival (%)
1.0
Survival (%)
Average tumor size (cm^3)
Tumor Regression and Survival Improvement
80
60
60
40
*
40
20
*
20
0
00
0
10
10
20
20
30
30
40
40
50
50
60
60
Days
challenge
Dayspost
post tumor
tumor challenge
untreatred
untreatred
aCTLA4
aCTLA4
Indoximod
Indoximod
aCTLA4 ++Indoximod
aCTLA4
Indoximod
Dual checkpoint blockade is more effective than single
Holmgaard et al, JEM 2013
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Phase 1b Trial of IDO (Indoleamine 2,3-Dioxygenase Pathway) Inhibitor
Indoximod Plus Ipilimumab in Unresectable Stage 3/4 Melanoma
Results:
 Favorable Safety profile with no dose-limiting toxicities were observed
 9 patients enrolled: 3/9 (33%) were female
 Median age: 64 years (range: 45-83 years)
 Most adverse events (AEs) were grade 1/2 in severity
 Most common AEs: fatigue (7/9 pts., 78%) pruritus (6/9 pts., 67%), diarrhea and
rash (4 pts. each, 44%), and abdominal pain and headache (3/9 pts. each, 33%;)
 Two Serious Adverse Events (SAEs) reported on study:
One grade 3 diarrhea possibly related and one grade 3 atrial flutter unrelated
 Currently, 7 of 9 patients evaluable for response:
 Two responses (1 complete, 1 partial) reported based on RECSIST criteria
 Five patients had progressive disease & two patients awaiting follow up
 All patients still alive when reported and follow up for response continues
Zakharia, Y et al, Abstract #514, ESMO/ECC Vienna, September 2015
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Phase 1b Trial of IDO (Indoleamine 2,3-Dioxygenase Pathway) Inhibitor
Indoximod Plus Ipilimumab in Unresectable Stage 3/4 Melanoma
Conclusions:
 Combination was well tolerated
 No potentiation of autoimmune AEs
 Promising early clinical activity
 Phase 2 dose for indoximod has been established as the 1200-mg BID dose
– Up to 96 patients currently being enrolled in the Phase 2 study
 Using a revised study design, standard of care immune checkpoint inhibition
consisting of sequential ipilimumab and PD-1 inhibitor (nivolumab or
pembrolizumab) administration will be given in combination with indoximod
 Primary endpoint of progression free survival
 Secondary endpoints of overall survival, safety and subgroup analysis
Zakharia, Y et al, Abstract #514, ESMO/ECC Vienna, September 2015
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Genentech Alliance on GDC-0919 IDO Inhibitor
Validation of NewLink’s Approach
 Exclusive worldwide license agreement for NewLink Genetics IDO and
TDO inhibitors except indoximod, including GDC-0919
 $150 million upfront payment; >$1 billion in potential milestones
 Escalating double-digit royalties, with additional escalation if NewLink
Genetics co-promotes in the United States
 Research collaboration agreement
– Genentech funds FTEs at NewLink Genetics
– Research focuses on discovery of novel TDO inhibitors, dual IDO/TDO inhibitors,
and the use of GDC-0919 in combination with TDO inhibitors and/or other
immune checkpoint inhibitors
– Joint Research Committee oversees research activities
 Clinical development
– Joint Development Committee oversees clinical development activities
– Clinical plans to combine GDC-0919 with atezolizumab (MPDL3280A, anti-PDL1)
and other checkpoint inhibitors
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GDC-0919
Ongoing Clinical Trials
 Phase I study of GDC-0919 results presented in conjunction with Genentech at
ESMO/ECC in September 2015 in Vienna
 A Phase Ib, open-label, dose-escalation study of the safety and pharmacology
of GDC-0919 in combination with atezolizumab (MPDL3280A, Anti-PD-L1) in
patients with advanced solid tumors opened to enrolment, July 2015
 Preclinical poster presented at SITC: “Improved anti-‐tumor immunity and
efficacy upon combination of the IDO1 inhibitor GDC-‐0919 with anti-‐PD‐L1 blockade versus anti-‐PD-‐L1 alone in preclinical tumor models”
 Additional combination study planned with anti-OX40
Combinations of GDC-0919 and other checkpoint inhibitors
entering the clinic
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Phase 1a Study of the Safety, Pharmacokinetics & Pharmacodynamics
of GDC-0919 in Patients with Recurrent/Advanced Solid Tumors
Safety:
 Well tolerated with 19 patients enrolled
– All patients experienced at least one adverse event regardless of attribution
– Grade ≥3 adverse events regardless of attribution reported in 11/19 (58%) of patients
– No adverse events requiring withdrawal of study drug were reported
 MTD not reached
 Grade ≥3 AE related to GDC-0919 in 1 patient with Grade 4 lower GI hemorrhage
 Only one SAE reported as possibly related, Grade 4 lower GI hemorrhage
 SAEs reported in 8/19 (42%) of patients regardless of attribution included:
– Grade 5 progression of neoplasm (3/19, 16%; <30 days of last GDC-0919 dose); 1 patient
each with Grade 4 lower gastrointestinal hemorrhage, Grade 4 hypotension, Grade 3
pneumonia, Grade 3 mental status change and Grade 3 small intestinal obstruction, and
Grade 2 hypoxia
Nayak, A et al, Abstract #346, ESMO/ECC Vienna, September 2015
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Phase 1a Study of the Safety, Pharmacokinetics & Pharmacodynamics
of GDC-0919 in Patients with Recurrent/Advanced Solid Tumors
Conclusions:
 Overall, well tolerated up to 800 mg BID on a 21/28 day cycle
 Best response was limited to stable disease (SD) in 7 of 17 patients
 Higher doses modulate plasma Kyn in a manner consistent with half-life of drug
 Single and multiple dose exposures from 50 to 800 mg increased in approximately
dose-proportional manner
 Evaluation of the PK/PD relationship is ongoing to identify the dose that will achieve
maximal inhibition of IDO
 No immune-related AEs evident, although a possible relationship between study
treatment and elevation of liver enzymes cannot be ruled out at this time
 Study continues to evaluate safety, PK, activity, and PD at a continuous dosing
schedule (BID 28/28 days) to enable greater flexibility in future dosing regimens
 Phase 1b combination of GDC-0919 with atezolizumab (PD-L1 inhibitor) ongoing
Nayak, A et al, Abstract #346, ESMO/ECC Vienna, September 2015
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Improved anti-tumor immunity & efficacy upon combination of the
IDO1 inhibitor GDC- 0919 with α-PD-L1 blockade versus α-PD-L1
alone in preclinical studies
GDC-0919 favorably alters tumor microenvironment
GDC-0919 decreases blood and tumor kynurenine levels in the EMT6 model.
Balb/c mice were injected with EMT6 cells followed by treatment with α-PD-L1 alone (10 mg/kg,
2x/week), GDC-0919 alone (200 mg/kg twice daily), or a combination of the two. At 2 hrs post-lastdose, blood and tumors were assessed for kyn/trp.
Spahn, J et al, SITC Annual Meeting , November 2015
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Improved anti-tumor immunity & efficacy upon combination of the
IDO1 inhibitor GDC- 0919 with α-PD-L1 blockade versus α-PD-L1
alone in preclinical studies
Summary and Conclusions:
 In the clinic, peripheral blood testing of Kyn levels showed transiently decreasing
plasma Kyn beyond 95% CI, in a manner consistent with its PK profile; PK was
approximately dose proportional with a t1/2 ~ 12 hrs (Nayak et al.)
 Preclinically, GDC-0919 decreased plasma and tumor Kyn levels in tumor-bearing
mice in a dose-dependent manner
 A combination treatment of GDC-0919 with αPD-L1 in the EMT6 syngeneic model
resulted in improved anti-tumor activity compared with αPD-L1 alone
 EMT6 treatment of GDC-0919 in combination with αPD-L1 led to increased
CD8+/Treg ratio and increased serum levels of IFNγ consistent with a stronger
adaptive anti-tumor immune response
 GDC-0919 induces activation of intratumoral CD11b+F4/80+ macrophages as well
as CD11b+CD11c+ and CD103+CD11c+ DCs as single agent and in combination
 Phase 1b combination of GDC-0919 with atezolizumab (PD-L1 inhibitor) ongoing
Spahn, J et al, SITC Annual Meeting , November 2015
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Indoximod Plus CTLA-4 Blockade Plus
Cellular Immunotherapy
Survival (%)
100
80
untreated
aCTLA4
aCTLA4 + Indoximod
60
40
*
20
0
Vaccine
+ Indoximod
Gvax
+ Indoximod
Vaccine
+ aCTLA4
Gvax
+ aCTLA4
Gvax
+ aCTLA4
+Indoximod
Vaccine
+ aCTLA4
+
Indoximod
0
20
40
60
80
Days post tumor challenge
untreated
Immune-refractory tumors can respond to cellular
aCTLA4 immunotherapy + checkpoint blockade
aCTLA4 + Indoximod
Holmgaard et al, JEM 2013
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Combination Immunotherapy Trials
The Future of Immuno-Oncology
 Combination therapies will be necessary to build upon initial
successes seen in immuno-oncology
 NLG0304 dorgenmeltucel-L (HyperAcute Melanoma) plus
checkpoint inhibitors ipilimumab, nivolumab, or pembrolizumab
 NLG2103 indoximod in combination with checkpoint inhibitors for
patients with advanced melanoma
 NLG0401 tergenpumatucel-L (HyperAcute Lung) plus indoximod for
patients with advanced NSCLC
Combination therapies of cancer vaccines and checkpoint inhibitors
could significantly expand the effectiveness of immuno-oncology
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Infectious Disease Program
Ebola Vaccine
 Novel recombinant viral vector (vesicular stomatitis virus, rVSV)
developed by the Public Health Agency of Canada
 100% protective after one dose in lethal monkey challenge model
 100% of human subjects develop strong immune response after
just one dose
 Manufactured multiple GMP lots meeting global requirements
 Program being supported by Merck in an agreement signed in
November 2014 - $50 million of milestones through July 2015
 NewLink Genetics has established an experienced infectious disease
clinical development team
 Found to have 100% efficacy in an analysis of interim data from a Phase
3 ring vaccination trial in Guinea published in The Lancet (July 31, 2015)
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Financial Position
(as of September 30, 2015)
Cash and equivalents
$200.4 million
Debt
~$1.0 million
YE 2015 Cash Guidance
>$160 million
Shares Outstanding
28.8 million
Market Capitalization
~$1.1 billion*
Well-funded to develop many opportunities
*As of November 1, 2015
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NewLink Genetics
Near-Term Catalysts, 2015 - 2017
 Algenpantucel-L: results of IMPRESS in 2016, validation of
HyperAcute Cellular Immunotherapy platform and commercial
pathway
 Partnership clinical advancements with Genentech/Roche
(GDC-0919 clinical milestones)
 Validation of IDO pathway inhibitor program (indoximod)
across multiple cancer studies
 New combination trials with multiple checkpoint inhibitors and
HyperAcute Cellular Immunotherapy
Potential for significant catalysts in next 24 months
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