2016 annual general & special meeting of shareholders
TRANSCRIPT
2016 Annual General and Special Meeting of Shareholders
October 13, 2016
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• MEETING CALLED TO ORDER – Mr. John Drake, Chairman
• CHAIRMAN’S OPENING REMARKS
• APPOINTMENT OF THE SECRETARY FOR THE MEETING
• APPOINTMENT OF THE SCRUTINEER & SCRUTINEER’S REPORT
• READING OF THE NOTICE OF THE MEETING
• READING OF THE MINUTES OF THE ANNUAL MEETING OF SHAREHOLDERS OF OCTOBER 15/15
• FINANCIAL STATEMENTS
• FIX THE NUMBER OF DIRECTORS
• ELECTION OF THE DIRECTORS
• APPOINTMENT OF THE AUDITOR AND AUTHORITY TO FIX THEIR REMUNERATION
• APPROVAL OF DISCRETIONARY SHARE CONSOLIDATION
• APPROVAL OF AMENDMENTS TO THE ORGANIZATIONAL BY-LAW
• APPROVAL OF AMENDMENTS TO THE SHAREHOLDER RIGHTS PLAN
• APPROVAL OF AMENDMENTS TO THE STOCK OPTION PLAN
• APPROVAL OF CONTINUATION OF THE STOCK OPTION PLAN AS A ROLLING PLAN
• BUSINESS AND SCIENTIFIC UPDATE PRESENTATION – Dr. W. Danter, CEO; Ms. A. Silva, President
• OTHER BUSINESS
Meeting Agenda
Business and Scientific Update
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When used anywhere in this presentation, whether oral or written, the words expects,believes, anticipates, estimates and similar expressions are intended to identify forward-looking statements. Forward-looking statements may include statements addressingfuture financial and operating results of Critical Outcome Technologies Inc. (COTI).
COTI bases these forward-looking statements on its current expectations about futureevents. Such statements are subject to risks and uncertainties including, but not limitedto, the successful implementation of COTI’s strategic plans, the acceptance of newproducts, the obsolescence of existing products, the resolution of potential patentissues, competition, changes in economic conditions, and other risks described in COTI’spublic documents such as press releases and filings with the Toronto Stock Exchange andthe Ontario Securities Commission.
All forward-looking statements are qualified in their entirety by the cautionarystatements included in this document and such filings. These risks and uncertaintiescould cause actual results to differ materially from results expressed or implied byforward-looking statements contained in this presentation. These forward-lookingstatements speak only as of the date of this presentation.
Disclaimer
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• Clinical stage biotech company focused on the development of novel therapeutics for the treatment of cancer
• Pipeline of internally developed compounds
• CHEMSAS platform – in silico high throughput screening for molecule identification
• ROSALIND technology – genomics profiling for personalized oncology care
• Two offices: London, ON and Boston, MA
TSX-V: COT
OTCQB: COTQF
Company and Pipeline Synopsis
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COTI-2
A Potential Breakthrough Therapy for Many Cancers
• Oral small molecule compound that functions via a novel mechanism of action that reactivates the tumor suppressor function of p53– Mutant p53: single most important cancer causing gene mutation
known• > 50% of all human cancers
• Active against common cancers in multiple preclinical models– High oral bioavailability and effective at low doses in preclinical models– Low toxicity in preclinical development
• Currently in an open label, multi-site Phase I in gynecological malignancies– Opportunity for a novel therapy as a single agent and combination
therapy
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COTI-2 Synopsis
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• The centrality of p53 in human cancer makes it a potentially effective target for cancer therapy development– In response to cellular stress, wild-type p53 induces cell cycle arrest and/or apoptotic
cell death1
– Mutant p53 promotes tumor formation (loss of tumor suppressor function)2
• TP53 is the most frequently mutated gene in human cancer with mutation frequencies ranging from 38% to 96%1
• COTI-2 induces a wild-type-like conformational change in the p53 mutant protein that restores sequence-specific p53 transcription3
1Levin AJ & Oren M (2009). Nature Rev Cancer, 9: 749-758.2Ozaki T & Nakagawara A (2011). J Biomed Biotech, 2011: 603925, 1-13.3Yu X et al (2012) Cancer Cell, 21: 614-625.
mutp53mutp53
Sequence-specific transactivation defective
Conformational change to a more wild-type configuration
Restoration of sequence-specific transcriptional activity
Apoptosis, growth arrest, senescence
mutp53
Drug Drug
COTI-2: Mechanism of Action
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• COTI-2 induces a ‘wild-type-like’ conformational change in mutant p53R175H in TOV-112D ovarian cancer cell line but has no effect on p53WT conformation in H460 NSCLC cell line
• Similar results with multiple p53 mutant proteins in HCT-116 constructs
0
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TOV-112D H460
Me
an F
luo
resc
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ce In
ten
sity
(A
rbit
rary
Un
its)
Cell Line
Mutant p53 Levels in Presence/Absence of COTI-2
Control
COTI-2
0
20
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TOV-112D H460
Me
an F
luo
resc
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ce In
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sity
(A
rbit
rary
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its)
Cell Line
Wild-type p53 Levels in the Presence/Absence of COTI-2
Control
COTI-2
• (*) Significant difference in p53 protein levels between COTI-2 treated and untreated cells (control)
*
*
James Koropatnick, LRCC, London, ON.
Conformational Change Induced in p53 by COTI-2
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• COTI-2 induced no significant resistance through 5 generations, whereas cisplatin and paclitaxel induce significant increases in IC50 after the first generation of selection
• COTI-2 induced no significant cross-resistance in cisplatin- and paclitaxel-resistant SCLC cell lines
0.0
1.0
2.0
3.0
4.0
Parentalcells
Round 1selection
Round 2selection
Round 3selection
Round 4selection
IC5
0R
atio
Acquired Resistance in the DMS-153 SCLC Cell Line
COTI-2
Cisplatin
Paclitaxel
* *
*
* *
* * *
0.0
2.0
4.0
6.0
8.0
10.0
Parentalcells
Round 1selection
Round 2selection
Round 3selection
Round 4selection
IC5
0R
atio
Acquired resistance in the SHP-77 SCLC Cell Line
COTI-2
Cisplatin
Paclitaxel
**
**
* *
*
0
1
2
3
4
A549 - CP Resist DMS153 - CPResist
SHP77 - CP Resist
IC5
0(F
old
Ch
ange
Re
lati
ve
to P
are
nta
l Ce
lls)
Sensitivity to cisplatin-resistant cell lines
COTI-2
Cisplatin
0
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4
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A549 - PACResist
DMS153 - PACResist
SHP77 - PACResistIC
50
(Fo
ld C
han
ge R
ela
tive
to
Par
en
tal C
ells
)
Sensitivity to paclitaxel-resistant cell lines
COTI-2
Paclitaxel
* *
*
*
*
*
James Koropatnick, LRCC, London, ON.
No Significant Resistance or Cross-Resistance
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• COTI-2 administered IV and PO produced a significant tumor growth inhibition as a single agent in an OVCAR-3 ovarian cancer xenograft model
– In fact, COTI-2 caused significant and complete tumor shrinkage when administered IV (p<0.01); treatment of Group 3 animals stopped since tumors were rapidly shrinking
0
50
100
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0 5 9 16 23 30 37 44 51 61
Tum
or
Vo
lum
e (
mm
3)
Study Day
Effect of IV Treatment on OVCAR-3 Tumor Volume
Group 1 = Vehicle IV
Group 2 = COTI-2 20mg/kg IV
Group 3 = COTI-2 40mg/kg IV
0
50
100
150
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0 5 9 16 23 30 37 44 51 61
Tum
or
Vo
lum
e (
mm
3 )
Study Day
Effect of PO Treatment on OVCAR-3 Tumor Volume
Group 4 = Vehicle PO
Group 5 = COTI-2 75mg/kg PO
Group 6 = COTI-2 100mg/kg PO
* * * * * *
* * * * * * * * * * *
*
* * * * *
* * * * * * * * *
James Koropatnick, LRCC, London, ON.
Significant Tumor Growth Inhibition as a Single Agent
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• COTI-2 administered PO caused significant tumor growth inhibition in the HCT-116 p53G245C
colorectal cancer cell line construct
• No effect on tumor growth observed with HCT-116 (GFP) construct without p53 mutation
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100
200
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400
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1 4 7 10 14
Tum
or
Vo
lum
e (
mm
3)
Study Day
Effect of Treatment on HCT-116 (p53 G245C) Tumor Volume
Vehicle Control
COTI-2 (30 mg/kg)
COTI-2 (75 mg/kg)
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1 4 7 10 14 17
Tum
or
Vo
lum
e (
mm
3 )
Study Day
Effect of Treatment on HCT-116 (GFP) Tumor Volume
Vehicle Control
COTI-2 (75 mg/kg)
* *
*
*
Gordon Mills, U of Texas, MDACC, Houston, TX.
p53 Mutant-specific Tumor Growth Inhibition as a Single Agent
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• COTI-2 in combination with cisplatin (CDDP) has a synergistic effect as indicated by a combination index1 (CI) < 1.0 in the PCI13 p53G245D construct
• Similar results were obtained with paclitaxel, carboplatin, erlotinib, and cetuximab
COTI-2 and CDDP Curves
1Chou TC &Talalay P (1983) Trends Pharmacol Sci. 4: 450-454.
Jeffrey Myers, U of Texas, MDACC, Houston, TX.
Effectiveness of Cisplatin Enhanced in p53 Mutant Cells
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• COTI-2 whether as a single agent or in combination with cisplatin produced significant tumor growth inhibition relative to untreated controls in the PCI13 pG245D head and neck cancer xenograft models
• Cisplatin treatment alone did not yield significant tumor growth inhibition
* * * * *
* * * * * * * *
Jeffrey Myers, U of Texas, MDACC, Houston, TX.
Significant Tumor Growth Inhibition in Combination with Cisplatin
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• COTI-2 significantly improves in vitro response to radiation
• The addition of COTI-2 sensitized head and neck cancer cell lines to radiation in a dose-dependent manner irrespective of TP53 status
Dose-Dependent Curves
Jeffrey Myers, U of Texas, MDACC, Houston, TX.
Sensitization of p53 Mutant Cells to Radiation
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No Significant COTI-2 Associated In Vivo Toxicity
• COTI-2 administered IV or PO up to 61 days in an OVCAR-3 ovarian cancer tumor model had no significant effect on mouse weight
• Similar observations in multiple mouse models
15.00
20.00
25.00
0 5 9 16 23 30 40 47 54 61
We
igh
t (g
)
Study Day
Effect of Treatment on Mouse Weight in OVCAR-3 Tumor Model
Vehicle IV
COTI-2 20mg/kg IV
COTI-2 40mg/kg IV
Vehicle PO
COTI-2 75 mg/kg PO
COTI-2 100 mg/kg PO
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COTI Pipeline
Rapidly Advancing Therapeutics to the Clinic
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• COTI-219 inhibits KRAS activation
– Inhibition is time- and concentration-dependent
– This inhibitory effect is also evident in downstream targets
• Lymphoma
Experimental design• Millipore’s Ras Activation ELISA Assay Kit was utilized to detect KRAS
and other relevant proteins in the presence/absence of COTI-219• Cell viability was assessed using the PrestoBlue® assay
HeyA8 Cell Line OVCAR8 Cell Line
CELL LINEDURATION OF COTI-219
EXPOSURE (days)IC50 (nM)
HeyA8
1 10,000
3 72
5 50
7 55
CELL LINEDURATION OF COTI-219
EXPOSURE (days)IC50 (nM)
OVCAR8
1 10,000
3 N/A
5 79
7 47
COTI-219 Inhibits KRAS Activation
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• COTI-219 significantly inhibits tumor growth in colorectal cancer cell lines with a KRAS mutation
– HCT-15 (KRASG13D) and SW620 (KRASG12V) tumor growth was inhibited by COTI-219 at approximately 50% and 25%, respectively
– TGI likely to be much higher in cell lines expressing high levels of KRAS
Experimental design• HCT-15 and SW620 human tumor cells inoculated subcutaneously in right flank of female athymic mice (NCR-nu)• Groups of 10-12 mice each were treated PO with COTI-219 (150 or 75 mg/kg ) or phosphate-citrate buffer vehicle control every other day 3
times per week for roughly 25 days • Tumor weights were graphed as means (±SE) and significant difference between groups was determined using Student’s T-test (p<0.05)
COTI-219 Significantly Inhibits KRAS Mutant Tumor Growth
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• COTI-219 demonstrates single agent efficacy greater than standard chemotherapeutics in SHP-77 (KRASG12V) mouse xenograft model
• COTI-219 significantly inhibits tumor growth in the SHP-77 cells relative to vehicle control
Experimental Design• SHP-77 human tumor cells inoculated
subcutaneously in right flank of female athymic mice (NCR-nu)
• Groups of 10 mice each were treated IP with varying doses of COTI-219 (4 mg/kg every 2 days), taxotere (12.5 mg/kg every 2 days), cisplatin (3.0 mg/kg once per week), and 0.9% saline vehicle
• Mean tumor volumes at day 38 were graphed
Effect of Treatment on Tumor Volume
Tu
mo
r V
olu
me
(m
m3)
Test Compound
TGI~80%
* All animals died
COTI-219 Significantly Inhibits KRAS Mutant Tumor Growth
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COTI2-101 • Clinical Trial Synopsis
• Clinical Trial Timelines
• Competitive Landscape
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Protocol Title A PHASE 1 STUDY OF COTI-2 FOR THE TREATMENT OF ADVANCED OR RECURRENT GYNECOLOGIC MALIGNANCIES
Study Sites MD Anderson Cancer Center, Houston, TX Northwestern University Memorial Hospital, Chicago, IL
Principal Investigators
Dr. Shannon Westin Dr. Wilberto Neives-Niera
Study Phase Phase 1
Objective Primary• To evaluate the safety and tolerability of COTI-2 in patients with advanced or recurrent gynecologic
malignancies.• To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of COTI-2 for the
treatment of patients with advanced or recurrent gynecologic malignancies.
Secondary• To evaluate the pharmacokinetics of COTI-2 at all dose levels in patients with advanced or recurrent gynecologic
malignancies.• To estimate the clinical activity of COTI-2 at all dose levels and the RP2D in patients with advanced or recurrent
gynecologic malignancies by response rate (Response Evaluation Criteria In Solid Tumors [RECIST] v1.1 criteria) and the progression-free survival (PFS) rate at 6 months.
• To estimate the response duration for COTI-2 at all dose levels and the RP2D in patients with advanced or recurrent gynecologic malignancies.
Exploratory• To determine if baseline molecular aberrations, including p53 mutation, correlate with activity of COTI-2 in
advanced or recurrent gynecologic malignancies.• To evaluate pharmacodynamic markers of COTI-2 activity at all dose levels and at the RP2D in patients with
advanced or recurrent gynecologic malignancies.
Patient Population • Females with ovarian, fallopian tube, primary peritoneal, endometrial or cervical cancer that is recurrent, metastatic, or unresectable and for which no effective or curative measures exist
Sample Size • Maximum 46 patients • Dose Escalation Phase: up to 36 patients (up to 6 cohorts)
• Dose Expansion Phase: 10 patients with ovarian cancer (one cohort)
COTI2-101 Study Summary
• Regular updates as each cohort commences dosing with Cohort 3 announced in July 2016
– Announcement of dose escalation is the only “releasable” information during this clinical phase
• February/March 2017 – preliminary results on the safety and clinical activity of COTI-2
• First half of 2017 – additional multi center clinical trial programs:
– Recurrent Head and Neck Squamous Cell cancer (HNSCC)
– Li-Fraumeni Syndrome (LFS)
• Final trial results and conclusions
– Mid 2017 - gynecological phase
– Late 2017 - expansion phase
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Anticipated COTI2-101 Clinical Trial News Flow
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Anticipated COTI2-101 Clinical Timeline
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DRUG COTI-2 Kevetrin APR-246 / PRIMA-1MET
COMPANYCritical Outcome Technologies Inc.
Cellceutix Corp Aprea
MECHANISM OF ACTION
Targets mutant p53 (restoration of wild-type p53 conformation and activity)
Targets wild-type and mutant p53 (MDM2-related mechanism)
Targets mutant p53 (restoration of wild-type p53 conformation and activity)
IN VITRO EFFICACY
Most potent (nanomolar range of activity)
Least potent (activity >100 µM)
Much less potent than COTI-2 (activity in high µM range)
CLINICAL PHASE OF DEVELOPMENT
Phase 1 Phase 1 Phase 1/2
INDICATIONS Gynecologicalmalignancies (first patient in February 2016)
Solid tumors (complete with safety established, but PK under MEC)
Hematological malignancies and prostate cancer (phase1/2 completed)
Competitor Comparison to COTI-2
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Fiscal 2016 & 2017 Corporate Objectives
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Granted FDA orphan drug status for ovarian cancer
Appointed experienced Scientific Advisory Board (SAB)
Received Investigational New Drug Application (IND) approval
Filed for FDA orphan drug status for Li-Fraumeni syndrome
Commenced patient dosing of Phase 1 clinical trial at MDACC
Published first scientific article in Oncotargets
Activated second clinical trial site at NWU
Initiated third patient cohort of Phase 1 clinical trial
Recap of Fiscal 2016 Corporate Objectives
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Opened US office (Boston, MA) in Aug 2016
• Broaden the potential for COTI-2 in multiple additional clinical indications and combination therapies
Designate next preclinical candidate for clinical development
• Establish collaborations/partnerships for COTI-2, pipeline programs and other technologies
• Strengthen the balance sheet to execute on the strategy
• Obtain Li-Fraumeni (or other sarcoma indication) orphan drug status
Fiscal 2017 Corporate Objectives
Pursue Multiple Indications/Combinations with COTI-2
• Additional multi center clinical trial programs– Recurrent Head and Neck Squamous Cell cancer (HNSCC)
SPORE grant submitted with MDACC
• Trial anticipated to commence in early-mid 2017
– Li-Fraumeni Syndrome (LFS)
• Exploring clinical trial design with key opinion leaders (KOLs) and Scientific Advisory Board (SAB)
• Rhabdomyosarcoma
• Adult and pediatric soft tissue sarcoma
• Trial anticipated to commence in mid 2017
– Combination trials
• COTI-2 synergizes with many first line agents including Cisplatin
• COTI-2 sensitizes HNSCC cell lines to radiation therapy
• Combination trials with COTI-2 plus Cisplatin or radiation are being planned
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• Chemistry– Small molecule, easy to synthesize (3 steps)
• MOA– COTI-219 docks in KRAS allosteric pocket at two sites– COTI-219 inhibits the activation of KRAS– COTI-219 sensitivity is correlated with KRAS expression levels
• Efficacy– COTI-219 has IC50’s in the nanomolar range in multiple human cancer cell lines, particularly
in colorectal cancer– No significant acquired or cross resistance with COTI-219– COTI-219 induced significant tumor growth inhibition in the SHP-77 (SCLC), HCT-15
(colorectal cancer) and SW620 (colorectal cancer) tumor models
• ADME-Tox– Good in vitro metabolic stability– Pharmacokinetics suggests once a day dosing
• Intellectual property– Issued composition of matter patents
Next Clinical Candidate - COTI-219
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Next Clinical Candidate - COTI-2192016 Q4 2017 Q1 2017 Q2 2017 Q3 2017 Q4
Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
CHEMISTRY MANUFACTURING CONTROLS
DRUG SUBSTANCE
Manufacturing & Analytical Method
Testing & Characterization
DRUG PRODUCT
Formulation Development
Manufacturing & Analytical Method
NONCLINICAL STUDIES
PHARMACOLOGY
Mechanism of Action
Efficacy
PHARMACOKINETICS
ADME-Tox Studies
Bioanalytical Method Development & Validation
TOXICOLOGY
Dose Formulation Method Development
Acute Toxicity – Rodent & Non-Rodent
Sub-Acute Toxicity – Rodent & Non-Rodent
REGULATORY AFFAIRS
IND Drafting
IND Compilation & Document QC
IND Submission
• Clinical candidate declaration: Oct ‘16• IND filing: Sept ‘17
Business Development Efforts for COTI-2, COTI-219 & ROSALIND32
Pharma partners in discussion for COTI-2 licensing deals in the US
Pharma partners in discussion for COTI-2 development and ex-US licensing deals
Recent Pharma Partners inbound interest in COTI-219 (both in combination with COTI-2 and solo; US and ex-US interest)
Cancer centers for academic collaborations, including institutional or government support for pre-clinical and clinical studies (combination), grant opportunities
ROSALIND: Bioinformatics groups, oncologists directly or via patient request
Strengthen the Balance Sheet to Execute on Strategy
• Current cash position: ~$5MM
• Cash runway: ~April 2017
• Opportunities for funding and possible corporate re-positioning:
– Private placement• Existing shareholder base
• US potential investors
– Institutional investors
– Partnership activities• COTI-2 ex-US
• COTI-219 US or ex-US
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LFS Orphan Drug Application
• Office of Orphan Products Development (OOPD) designates products for the treatment of cancer by tumor type
• If COTI wishes to receive designation for the use of COTI-2 in the treatment of a cancer that is related to the p53 mutation, submit a request for each of these tumor types separately
• Path forward:
– COTI drafted resubmission for rhabdomyosarcoma– Recent KOL meetings have recommended all comers in soft tissue
sarcoma as rhabdo patients typically are successful after receiving first line treatment
– COTI assessing clinical trial design against orphan drug application– Resolution expected in fourth quarter 2016
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Communications and Investor Outreach
• Communications Outreach (previous 6 months at-a-glance):
– Release regular news flow announcing progress and key events (16 press releases)
– Post strategic and informative blog articles (12 blog posts with 34,381 page views/6,048 unique readers)
– Distribute email updates to keep the community informed on company progress (19 reports to 273 subscribers)
– Publish peer reviewed publications (Oncotarget, May '16)
– Enhance visibility and profile with 3rd party coverage (11 articles)
– Increase social media outreach (COTI Twitter 3,181 followers; COTI Facebook 1,379 followers; ROSALIND Twitter 3,200 followers; ROSALIND Facebook 160 followers; SharePitch Twitter 17,500 followers; SlideShare 68,000+ views)
• Investor Visibility:
– Obtain additional analyst coverage (Zack’s)
– Establish routine updates to the investment community (management calls/visits)
– Refine approach to IR (new firm combined with internal management)
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Management Team Directors
Wayne Danter, MD, FRCPC• Co-founder, CEO & CSO • Former Associate Professor of Medicine at
Western University
Alison Silva, MSc• President• Co-founder, former EVP & COO, Synlogic• Co-founder & Principal, The Orphan Group
Gene Kelly• Chief Financial Officer• Former VP Finance, Cuddy Farms
Kowthar Salim, PhD, MBA• Program Director and Senior Scientist
John Drake, LLB, Chairman• Chairman, Whippoorwill Holdings Limited
Wayne Danter, MD, FRCPC, CEO
Alison Silva, MSc, President
Douglas Alexander, CPA, CA• Chairman, Hydrogenics Corporation
Bruno Maruzzo, MASc, MBA• President, TechnoVenture Inc.
Dave Sanderson, LLB• President & CEO, KFL Investment Management
Inc.
John Yoo, MD FRCPC• Professor, Chairman and City-wide Chief of
Otolaryngology – Head and Neck Surgery at Western University
Bharatt Chowrira, PhD, JD• President, Synlogic
Committed Leadership
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Dr. Gordon Mills from the University of Texas MD Anderson Cancer Center, Houston, TX, Chairman
Dr. Douglas Levine from the Memorial Sloan-Kettering Cancer Center, New York City, NY
Dr. David Parkinson from New Enterprise Associates, Menlo Park, CA
Dr. Marshall Strome from the Center for Head and Neck Oncology at Roosevelt St. Luke's Hospital, New York City, NY
Dr. Nancy Chang, President, Apex Enterprises, Inc, and adjunct professor at the Departments of Medicine and Genetics at Baylor College of Medicine, Houston, TX………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………..
Dr. Wayne R. Danter, Chief Scientific Officer, Critical Outcome Technologies Inc, London, ON
Scientific Advisory Board
2016 Annual General and Special Meeting of Shareholders
Thank you