Download Apexian Pharmaceuticals 2017 Presentation

Moving mountains to serve cancer patients
Steve Carchedi – CEO
[email protected]
908-720-1786
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Company Overview
•
Apexian is a clinical stage biotech company with first-in-class therapy targeting the
APE1 protein
•
Our lead compound, APX3330 an oral anticancer agent has shown preclinical efficacy
against a variety of APE1-expressing tumors
•
APX3330 safety has been confirmed in 10 Phase I/II human studies of non-cancer
indications with over 422 patients
•
The phase I oncology study of APX3330 is ready for execution. IND approved by FDA,
first site has IRB approval and clinical supplies are ready to ship
•
Pipeline of oral anticancer agents APX2009, APX2014. Additional oncology and nononcology indications could lead to broad clinical utility
•
Key value inflection points in the near term (2017-18)
•
Robust IP estate and plan seeking Orphan Drug Designation, Fast Track and Priority
Review at the appropriate time
•
Experienced management team in discovery, development and commercialization of
oncology products
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Synergy between both company’s portfolios – Prostate, Lung, Inflammatory Programs
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Leadership Team

Steve Carchedi - Chief Executive Officer
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
Mark Kelley, Ph.D. - Chief Scientific Officer
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
Former CMO of ProNAi Therapeutics, with a 25+ years of clinical and pre-clinical drug-development experience
in industry (Endocyte, Eli Lilly), government (NCI, NIH) and academia (University of Michigan, Michigan State
University).
Roger Miller – Chief Operating Officer
•

Professor at Indiana University School of Medicine (IUSM); Betty and Earl Herr Chair of Pediatric Oncology
Research; Professor in Departments of Pediatrics, Biochemistry & Molecular Biology and Pharmacology &
Toxicology, Associate Director, IU Simon Cancer Center. Devoted more than 25 years exploring APE1/Ref-1
and its role in redox signaling, DNA repair, cancer and other diseases.
Rich Messmann, M.D., M.H.S., M.Sc. - Chief Medical Officer
•

Former President and CEO of Cornerstone Pharma. 25+ years of specialty pharmaceutical executive
experience in Fortune 500 companies (BMS, Eli Lilly, J&J and GE) as well as biotech firms (Endo and Sunesis).
More than 40 years of experience at Eli Lilly, Targanta, BioCriteria, Beta Cat and Salarius leading development,
manufacturing, quality and clinical trial operations.
Bill Current, Ph.D. – Vice President, Regulatory Affairs
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More than 30 years of experience at Eli Lilly, Targanta, BioCriteria and other companies leading regulatory
affairs for multiple therapeutic areas.
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Board Members and Scientific Advisors
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John Barnard – chairman, BOD
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David Broecker – member BOD and SAB
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Professor at Indiana University School of Medicine (IUSM); Betty and Earl Herr Chair of Pediatric Oncology Research; Professor in
Departments of Pediatrics, Biochemistry & Molecular Biology and Pharmacology & Toxicology, Associate Director, IU Simon Cancer
Center. Devoted more than 25 years exploring APE1/Ref-1 and its role in redox signaling, DNA repair, cancer and other diseases.
Martin Haslanger, Ph.D. – CEO Emeritus, member BOD and SAB
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
Named CEO of Apexian in 2016. Former CEO of Cornerstone Pharmaceuticals, with 25+ years of specialty pharmaceutical executive experience
in several Fortune 500 companies, BMS, Lillly J & J, GE, Endo, as well as biotech firms.
Mark Kelley, Ph.D. – Chief Scientific Officer
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
35-year veteran of the pharmaceutical industry and former CEO and served as chairmen of the board for Bristol Myers Squibb.
Prior to BMS, Mr. Cornelius served as chairman emeritus of the Guidant Board of Directors and member of the Board of Directors of
Eli Lilly, a member of its Executive Committee and chief financial officer
Steve Carchedi – CEO, member BOD and SAB
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
CEO of APEX from 2014 to 2016. Former CEO of Alkermes and has served in executive leadership positions at Eli Lilly and Company and
several biotech firms. Currently he is CEO of Indiana Bioscience Research Institute
Jim Cornelius – Investor, Advisor and member of SAB
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
Founder of Barnard Associates and Pearl Street Venture Funds. Former financial executive at Eli Lilly and Company. Has assisted
in the formation of many successful new companies.
CEO of APEX from founding until 2014. Former discovery and development executive at Eli Lilly and Company, Squibb and
Schering-Plough.
Homer Pearce, Ph.D. – member BOD and chairman, SAB
•
.
Former Vice President, Cancer Research and Clinical Investigation and Distinguished Research Fellow at Eli Lilly & Company. Led
discovery and development of Gemzar™ and Alimta™
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APE1/Ref-1 Overview
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APE1 (apurinic/apyrimidinic endonuclease),
also called Ref-1 (redox effector factor 1), is
a multifunctional cellular protein with two
distinct and separate functions:
• APE1 Redox Function: Redox regulation
of transcription factors (TFs) effecting
critical aspects of cancer cell survival and
growth including HIF-1, STAT3, NF-KB, and
others.

We can target multiple signaling
pathways relevant to various cancers
with one protein— as APE1 regulates
transcription factors (TFs) HIF1a,
STAT3, NFkB and others.

APX3330 inhibits only the APE1
redox signaling activity.
• DNA Repair Function: DNA base repair
caused by oxidative stress, alkylating
agents, and ionizing radiation
•
Various cancers, including treatment resistant
tumors, have shown elevated expression of
APE1 suggesting adaptation and unique
survival mechanisms through this pathway.
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APE1/Ref-1 Overview (Cont.)
• The drug has a direct and selective interaction with APE1 as
demonstrated by chemical foot-printing, mass spectrometry, and
other biochemical data.
• Although multiple pathways may be modulated, unacceptable
toxicity following APE1 inhibition has not been observed in animal
or human studies.
• Preclinical data supports the use of the drug as a single agent;
future directions indicate partnering APX3330 with various
clinical agents such as JAK2 inhibitors (Ruxolitinib, LY3009104.
etc), STAT3 inhibitors, gemcitabine and Abraxane (nab-paclitaxel).
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APE1/Ref-1 protein has demonstrated relevance in
the following cancers:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Non-small cell lung cancer
Colorectal cancer
Breast cancer
Prostate cancer
Gynecologic cancers (ovarian, cervical)
Pancreatic cancer
Glioblastoma multiforme, meduloblastoma
Renal cancer
Gastric cancer
Germ cell tumors
Head-and-neck cancers
Multiple myeloma (hematologic cancer)
Osteosarcoma and Rhabdomyosarcoma (pediatric)
Green = Mark Kelley’s Laboratory
Black = APE1 expression validated independently in multiple labs references available in Diligence Files
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Why is APE1 Important?
APE1 Protein is a node that controls the downstream signaling multiple transcription factors
APX3330
(reduced
APE1)
C65
C93
Redox
active site
X
HIF-1a
NFkB
STAT3
AP-1
NRF2
(oxidized APE1)
X
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TF
X
(oxidized APE1)
TF
(oxidized TF)
(reduced TF)
(reduced TF binds to target
DNA)
Target gene expression:
Growth
Inflammation
Angiogenesis
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APX3330 Inhibits APE1 Redox Function and
Downstream Transcription Factors
APX3330
DNA
Stat3
APX3330 uM
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APX3330 uM
APX3330 uM
Luciferase
APX3330 uM
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APX3330 Reduces Tumor Growth and Metastasis in a Variety
of Tumor Types
PaCa-2
Human PDAC
Metastasis
Number of lymph
node metastases
# of Lymph Node Metastases
18
16
Individual Mice
Average
14
12
10
8
*
6
4
2
* p<0.01
0
Vehicle
E3330
APX3330
Preclinical Results and Conclusions:
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3+ fold reduction in PaCa-2 or Panc254 tumors
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Significantly less PDAC metastasis
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Multiple models, consistent results
SOURCE: Fishel ML, et al Kelley MR. (2011). Impact of APE1/Ref-1 Redox Inhibition on Pancreatic Tumor Growth. Molecular Cancer Therapeutics.
Sep;10(9):1698-708 and Lou et al Aberrant expression of redox protein Ape1 in colon cancer stem cells.Oncol. Letters 2014 Apr;7(4):1078-1082. Epub
2014 Feb 10.
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Ratio to Actin
APE1 Redox Inhibition with APX3330 Reduces Pro-survival
Downstream Target Proteins in Prostate Cancer Cell Lines
APX3330
APX3330
*
*
*
*
* *
APX3330
PC3
C4-2
E7
• PC3, C4-2, and noncancerous E7 cells were treated with the redox-function
inhibitor APX3330.
• Further, APX3330 preferentially inhibited the expression of survival proteins
in prostate cancer lines relative to benign lines.
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APX3330 Provides Synergistic Anti-tumor Effect
When Added to a JAK2 Inhibitor
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APX3330 Provides Synergistic Anti-tumor Effect
When Added to a JAK2 Inhibitor
Patient-derived Pa03C (pancreatic cancer) and patient-derived cancer
associated fibroblasts (CAF) cells in 3D spheroid model:
2500000 Tumor area –
Tumor area –
Co-culture
Tumor alone
Rux only
uM^2
2000000
Rux+APX
1500000
1000000
CAF area –
Co-culture
500000
0
Ruxolitinib (uM)
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Prior Development of APX3330
Eisai conclusion:
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•
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No significant acute toxicity on neurologic, cardiovascular, or pulmonary
function in patients administered APX3330
Improvements in transaminase levels in patients with hepatitis B and C
Eisai ended APX3330 development after in-licensing Revovir® (clevudine)
for the treatment of hepatitis B and Humira (adalimumab) for treatment of
rheumatoid arthritis, IBD and other indications.
Note: Eisai detected human serum concentrations of APX3330 at 147µM; a level
well above that required for anti-tumor effect in our xenograft models of pancreatic
cancer.
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Apexian Clinical Plans for APX3330
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Apexian will complete a two-part phase I oncology study:
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Increasing doses in patients with treatment-refractory solid tumors
20-40 patients
Phase 1 expansion strategy
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Evidence of anti-tumor effect; indications for which therapy is synergistic/additive with APX3330;
indications that require neurotoxic chemotherapy; biomarker evidence of APX3330 effect
Study details:
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•
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Identify the RP2 dose of APX3330
POC within 12 months
Based upon
•
•
•
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IND accepted by the FDA:
•
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tolerability of the agent
evidence of anti-tumor effect
pharmacokinetic and pharmacodynamic
Contracts pending completion of the funding round
Sites include START (Tolcher and Lakhani) & IU (O’Neil)
*
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Involves Big 10 Consortium
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External Validation of APE1 as a Cancer Target
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Ovarian
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Osteosarcoma
Hepatocellular Carcinoma (HCC)
Glioblastoma
Bladder
Triple Negative BC
Breast cancer
Head and Neck
Endothelial Cell Tumor
Pancreatic
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•
•
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Colorectal
Retinoblastoma
Multiple Myeloma
Non-small cell lung (NSCLC)
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•
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Locally advanced rectal cancer
Pediatric Ependymona
Prostate
Cervical
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Wen et al 2016, Kong et al 2016; Londero et al 2014;
Zhang et al 2009; Tanner et al 2004
Jiang et al 2015; Wang et al 2007
DiMaso et al 2015; Yang et al 2014; Avellini et al 2010
Montaldi et al 2015
Shin et al 2015
Lee et al 2015
Woo et al 2014; Puglisi et al 2002
Koukourakis et al 2001
Biswas 2015
Jiang et al, 2015; Chen 2013; Zou et al 2008; Ziong et al
2010; Zou et al 2009; Jiang et al 2015
Lou et al 2014; Noike et al 2008
Sudhakar et al 2014
Xie et al 2010; Yang et al 2007
Kang et al 2012; Wang et al 2009; Yoo et al 2008;
Kakolyris et al 2000
Kim et al 2012
Bobola et al 2011
Gray et al 2005
Hedley et al 2004; Herring et al 1998
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APX3330 Combination Studies
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Biomarker Strategy: Goal to Identify Patients Most
Likely to Benefit from Treatment
• APE1 Protein levels are measurable in blood and tissue
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Anti-APE1 antibody already developed and commercially available
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Tissue and radiographic imaging techniques are options
• Strategy:
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Pretreatment Tissue samples being collected
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Pre and Post Treatment Blood samples being collected
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Circulating tumor cells to be collected
APE1 levels and downstream effects on transcription factors and
other biomarkers will be analyzed for evidence of anti-tumor
effect and potential selection criteria for future studies.
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APX3330 Manufacturing and Supply Chain
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APX3330 Drug Substance
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Robust 4-step synthesis (replicated from Eisai)
Scaled up at Strides Shasun under cGMP to > 3 Kg scale
Ongoing 36 month ICH stability
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•
APX3330
MW 378.47
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APX3330 Drug Product
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Common excipients (replicated from Eisai)
o Lactose, Microcrystalline Cellulose, Starch, Sodium Carboxymethylcellulose
60 mg
120 mg
and Magnesium Stearate
•
•
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Manufactured, packaged and labeled 60 mg and 120 mg
coated tablets at Catalent Pharma Solutions under cGMP
to supply phase 1 study
Ongoing 36 month ICH stability
APX3330 Clinical Supply Chain
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•
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Packaged inventory stored a controlled room temperature at Catalent
Catalent providing distribution to the clinical sites
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APX3330:
Robust Global IP Portfolio, Orphan Drug Designation & Near Term Approval
US Patent No.
9,040,505
US Patent No.
9,089,605
“Use of APX3330
in treatment of
cancer and
angiogenesis”
“Composition of
matter for
quinone
derivatives”
Expiration Date:
2030
Expiration Date:
2029
US Patent No.
9,193,700
“Composition of
matter for
quinone
compounds for
treating APE1
diseases”
Expiration Date:
2032
US Patent No.
9,315,481
“Methods and
compounds for
ref-1 inhibition in
leukemia”
Expiration Date:
2033
Application No.
PCT
US2016/0309045
“Use of APX3330
in treatment of
ChemotherapyInduced
Peripheral
Neuropathy”
Earliest
Projected
Expiration Date:
2036
Portfolio Patent Estate
Over 70+ issued or filed patents worldwide
 APX3330 is IP protected until 2030 and beyond across US, Australia, EU, Japan,
China, Brazil and other key countries
 Seeking orphan drug designation by the US FDA for the treatment of relapsed and
refractory solid tumors
 APX3330 near term approvals within 2019 – 2020
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Sustainable Horizons for Growth
APX3330
Targeting Large Unmet Need in Terms of Patient Pool
Step 3
Business Plan
Phase 3
Program
Step 2
Phase 2 Program
Step 1
Phase I Program
R/R Solid Tumors
(Accelerated Path to Approval)
Phase 1B
Phase 1A Safety
Study
20-30 Patients
2017
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(APE1
Expressing
Targeted
Indications)
10 patients
Pilot Single
Agent &
Combination
Studies
Proof of
Concept
Studies
Registration
Studies
Pursue Other
High Unmet Need
Tumors
2018-19
2020
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Apexian Company Summary
Company
Our Lead Compound
Privately held, Indiana based, clinical stage, biotech company with first-in-class therapy
targeting the APE1 protein
APX3330 an novel oral anticancer agent has shown preclinical efficacy against a variety
of APE1-expressing tumors
Near to market opportunity
Phase I oncology study of APX3330 is ready for execution. IND approved by FDA and
IRB approval by 1st clinical site
Clinical Plan
Robust manufacturing process with clinical supplies available
APX3330 safety has been confirmed in 10 Phase I/II human studies of non-cancer
indications with over 422 patients
Strong Portfolio
Robust IP
Our Management
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Pipeline of oral anticancer agents (APX2009, APX2014). Additional oncology and nononcology indications could lead to broad clinical utility
Robust IP estate and plan seeking Orphan Drug Designation
Extensive experience in discovery, development and commercialization of oncology
products
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“Moving mountains to serve cancer patients”
www.ApexianPharma.com
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