Post on 05-Jul-2020
New First-in-Kind Oral Chemotherapeutic Targets Hematologic and Solid Tumor Cancers
Pacylex Pharmaceuticals 1
Overview• Recently discovered mechanism of cancer proliferation
exposes new therapeutic target• Pacylex is developing a rationally designed, first-in-kind, oral,
small molecule target inhibitor with high activity in vitro and in vivo• Lead drug PCLX-001 is water soluble and 93% orally
bioavailable
• The biomarker is lost in 19 cancer cell lines at prevalence ranging from 5-82% and at a much higher prevalence in tumor cells taken from patients• a predictive diagnostic test that identifies cancer patients
with key biomarker also in development
• POC in: DLBCL & AML• Proof-of-efficacy in 4 of 4 hematological cancer mouse
xenografts including one PDX
TeamCEO Michael J. Weickert PhDCSO Luc G. Berthiaume PhDCMO John Mackey, MD, FRCPCCOO Ryan Heit, MSc, MBA
Founded: 2012Non-dilutive capital to date ->$7,200,000 CADFounder capital - $590,000 CAD
Project status: Pre-INDCompleted: Animal efficacy, PK/PD, Biomarker monoclonal antibodyNext steps: pre-IND tox studies, Regulatory filings, Phase I/IIa study
Approximately $3 million in funding required to get to first Phase I clinical trials, $20+ million to finish initial Phase II
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ExitPacylex Pharmaceuticals 2
Cancer survival still has a long way to go
Pacylex Pharmaceuticals 3
Age-Standardised Ten-Year
Net Survival, Selected
Cancers, Adults (Aged 15-99),
England and Wales, 2010-
2011Overview
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Key finding: NMT2 low in poorer prognosis tumours
Pacylex Pharmaceuticals 4
IM9
BL2
Ram
os
DOHH2
WSU-D
LCL2
0
5000
10000
15000
********* *** ***N
MT
2 m
RN
A c
op
ies/m
g R
NA
Kaplan-Meier plot of progression-free survival 470 DLBCL* patients with high (red) versus low (blue) NMT2 expression
***, P < 0.0001
Diffuse large B-cell lymphoma (DLBCL)
7X 300X
BL DLBCL
Number of NMT2 mRNA copies in various lymphocytic cell lines compared to an immortalized “normal” B cell line (IM9)
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Exit*Diffuse large B-cell lymphoma (DLBCL)
Myristoylation modifies proteins by adding a 14C-fatty acid myristate at their N-terminus- All human cells have two NMTs (NMT1 / NMT2):
• NMT1 and NMT2 are crucial for cell signaling and survival- Over 200 proteins are myristoylated in cells - Abrogation of myristoylation also abrogates proper targeting and function
Co- or post-translational myristoylation Mediates membrane binding
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NMT2 function: Myristoylation enzyme regulating cell homeostasis
Pacylex Pharmaceuticals 5
TCF/LEF
β-catenin
β-catenin
Frizzled LRP5/6
Dvl
β-catenin
P
P
P
β-TrCP
APC CK1
GSK3
Axin
P
P
P
P
Nkd1CDK1cMycMmp-7…
Nkd1
cMyc CDK1
Mmp-7
Mmp-7
Wnt
Nkd1
Nkd1
NMT2
Wnt On
NMT2 (+) cells
β-catenin
P
P
NMT2 myristoylates Nkd1
Nkd1 localizes to membrane
Nkd1 inhibits Wnt signaling through Dvl and β-catenin
Wnt signaling controlled = Cell homeostasis maintained
Pacylex Pharmaceuticals 6
Nkd1 is an obligate and universal Wnt-induced negative feedback regulator of the Wnt signaling pathway
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Key finding: NMT2 acts as a tumor suppressor and myristoylates Nkd1 which then can inhibit Wnt signaling
Pacylex Pharmaceuticals 7
Epigenetic silencing NMT2
No myristoylation of Nkd1
Nkd1 localizes to cytosol not membrane
Wnt signaling up-regulated
Cell proliferation and metastasis
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Proposed Mechanism
Key finding: Loss of NMT2 through epigenetic silencing increases Wnt signaling output
N-myristoyltransferase (NMT) activity is essential for cell viabilityNMT2 deficient cancer cells should be more vulnerable to NMT inhibition
Our strategy: NMT2 silencing makes cancer cells vulnerable
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Normal cell Cancer cell
No treatment
NMT inhibitorTherapy
Normal cell survives NMT2 deficient cancer cell dies
Pacylex Pharmaceuticals 8
Completely inhibiting
myristoylationselectively induces
apoptosis
PCLX-001 selectively kills cancer cells deficient in NMT2 by disabling myristoylation at a drug concentration to which normal cells are insensitive which initiates apoptosis
PCLX-001 (µM)
Cell viability Apoptosis*
NMT2 Normal Cells NMT2 Deficient Cells
Lead NMT inhibitor PCLX-001:Selectively kills cancer cells deficient in NMT2
Normal cell linesCancer cell lines
*indicated by cleaved PARP-1 and caspase-3
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Exit PCLX-001 has a large therapeutic windowPacylex Pharmaceuticals
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Breath of efficacy (BOE) study* of activity against various cancer cell lines including solid tumor lines: breast, non small cell lung cancer (NSCLC), small cell lung cancer (SCLC)
(*BOE study independently performed by large pharmaceutical company)
Efficacy
Breast AML NSCLC SCLC DLB
CL
Man
tle
Cel
l
PCLX-001 effect on 131 cell lines screened; 94% of cell lines tested are sensitive to PCLX-001(Cell Titer Blue Assay)
PCLX-001 Breadth of Efficacy Study*: Day 6
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PCLX-001 works against multiple cancers in vitro
Pacylex Pharmaceuticals
PCLX-001 dose-response curves for murine subcutaneous xenografts derived
from cell line BL2
PCLX-001 causes complete tumor regression in B cell lymphoma xenografts
0 5 10 150
500
1000
1500
2000
Vehicle
20mg/kg/day
50mg/kg/day
60mg/kg/day
**
***
Day of study
BL
2 t
um
or
vo
lum
e (
mm
3)
Vehic
le
20m
g/kg/d
ay
50m
g/kg/d
ay
60m
g/kg/d
ay0
5
10
15
20
NM
T s
pecif
ic a
cti
vit
y (
fmo
l/m
in/m
g p
rote
in)
*
Total NMT specific activity in BL2 tumor samples
Pacylex Pharmaceuticals 11
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PCLX-001 dose-response curves for murine xenograft derived from patient
DLBCL3
PCLX-001 causes complete regression of drug resistant* xenograft tumors from DLBCL Patient
Identification of NMT2-deficiency
Pacylex Pharmaceuticals 12
0 5 10 15 200
500
1000
1500
2000
20mg/kg/day
50mg/kg/day******
***
Day of study
DL
BC
L3 t
um
or
vo
lum
e (
mm
3)
Vehicle
Diffuse large B-cell lymphoma (DLBCL)
(NMT2+control)
***(P<0.001)
*DLBCL cancer refractory to multiple lines of chemotherapy including CHOP, RICE, and DHAP
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xenograft
Initial Orphan Disease Candidates
North American market AML BL & DLBCLIncidence 20,000 65,000
Average treatment cost $100,000 $30,000
5 year relapse rate ~80% ~60%
Palliative costs per patient $500,000 $500,000
Primary treatment costs ~$2 B ~$3 B
Secondary and Palliative treatment costs ~$8 B ~$20 B
Pacylex Pharmaceuticals 13
May also be eligible for Fast Track Designation
✓ Animal POC complete
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Pacylex Pharmaceuticals 14
Tumor type% Cell lines NMT2 null
Burkitt’s lymphoma 82%Diffuse large B-cell Lymphoma 70%Acute myeloid leukaemia 41%Myeloma 36%Ovarian clear-cell carcinoma 29%Transitional cell carcinoma (ureter and bladder cancer) 21%Chronic myelogenous leukaemia 20%Chronic lymphocytic leukaemia 20%Small-cell lung carcinoma 13%Breast carcinoma 12%Colorectal adenocarcinoma 12%Pancreatic adenocarcinoma 9%Ovarian carcinoma 9%Non-small-cell lung carcinoma 8%Osteosarcoma 8%Melanoma 7%Gastric adenocarcinoma 5%Endometrial adenocarcinoma 5%Esophageal squamous carcinoma 5%
IHC based NMT2 Diagnostic test using proprietary monoclonal anti-NMT antibodies is in later phase of development and available if needed.
Frequency of NMT2 deficiency in tumors is higher than that seen in cancer cell lines.
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Frequency of NMT2 Deficiency is ≥ 5% in Cell Lines Originating from 19 Different Cancer Types
Clinical strategy: 3 Phase I/II Studies Planned
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Phase I/IIA oral monotherapy safety and dose escalationPopulation: Pre-treated advanced cancers, esp. DLBC LymphomaDesign: Standard 3+3 dose escalation
Phase IB/IIA oral monotherapy basket trialPopulation: Pre-treated advanced cancers, incl. DLBC Lymphoma, AML, myeloma, small cell lung and colon cancerDesign: RP2D in NMT2lo / sensitive histologies
Phase IB/IIA dose escalation combination basket trialPopulation: Pre-treated advanced cancers, combinations with gemcitabine, doxorubicin or carboplatinDesign: 3+3 PCLX escalation starting 50% RP2D standard dose partners with preclinical synergy
Pacylex Pharmaceuticals
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Phase I/II Part 1
Phase I/II
Part 2
Phase I/II
Part 3Phase III
NDA Prep
FDA Review
IND
3-mo tox
Orphan drug designation
Fast Track designation
NDA submission
NDA approval
EOP2 meeting
Pre-NDA meeting
**Clinical costs do not include CMC/manufacturing, regulatory costs or operating costs
Clinical costs**
$3M $12M $60M
Pacylex Pharmaceuticals 16
Clinical Development Overview: – Timeline and Clinical Costs
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Year 1 Year 2 Year 3
Based on development and registration of Tagrisso for NSCLC
Additional Advisors:Mark Vickers, LLC: IP CounselJacques Roberge: Chemistry and Manufacturing ControlsJohn Simon: Regulatory Planning
Experienced Team and Knowledgeable Advisors
Luc Berthiaume, PhD – CSO World leader in protein fatty acylation; Founder of Eusera and Pacylex; global distribution experience; 3 patents; commercialized antibody design and production
John Mackey, MD, FRCP – CMO Director of clinical trials at the CCI; Director of TRIO (International clinical trial organization, 200 people); founder of 3 companies including Pacylex; Extensive links to pharma
Ryan Heit, MSc, MBA – COO Technology and business development expert; 20+ companies assisted in early-stage commercialization; founder/co-founder of 4 companies; leads deal screening for VA Angels
Jason Ding – Licensing and TransactionsExpert and experience in Mergers & acquisitions, biotechnology & pharmaceutical partnering, licensing & alliances, corporate finance, valuations & accounting & audits
David Jenish – Drug Development30+ years experience in research and process development for therapeutics
Vanessa Grant - Counsel Counsel with expertise in mergers and acquisitions, corporate governance, and private equity and venture capital Recognized as Chambers Canada: 2017: Life Sciences
Team Advisors
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Michael Weickert, PhD – CEO CEO Sonescence and SEA Medical Systems, CBO, Corium, Stratagent Life Sciences, Therashock, VP Development Auspex, Senior Program Executive, Nektar, Ligand, NCI/NIH
Pacylex Pharmaceuticals
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Established IP with Growing Portfolio
18Pacylex Pharmaceuticals
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• N-myristoyl transferase inhibitors - WO 2010026365 A1 (in-license)• Issued: EP 2323987 A1 and US 9,156,811 B2
• Filing date 2009/08/29
• Issued: US 9828346 B2 • Filing date 2015/08/31
• Synthetic lethality and the treatment of cancer - WO 2013013302 A1 (inventor)• USPTO application 14/234,312, PCT/CA2012/000696• National filing phase, AU & NZ, BR, CN, IL, JP, KR, MX,
RU, SG, ZA, EP, US, and CA• Filing date 2012/07/23
• Synthetic lethality and the treatment of cancer -WO2014067002 (inventor) A1• PCT/CA2013/050821
• Filing date 2013/10/30
• Epigenetic silencing of NMT2 – WO2017/011907 (inventor)• PCT/CA2016/050846
• Filing date 2017/01/26
Most Likely Exit Through M & A
• Four of top ten pharmaceutical firms already engaged in discussions• Scientific diligence successful at replicating and confirming Pacylex results
19Pacylex Pharmaceuticals
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Oncology is THE hot spot
BioPharma Dealmakers, Jun 09, 2017
Investor Summary
• First-in-class, oral, small molecule chemotherapeutic• New mechanism – publication underway• Potentially effective against many cancer types
• Companion diagnostic in development if needed• Pharmaceutical interest and validation – hottest M&A space• Ready for pre-IND tox• First-in-man in ~1 year• Initial investment $1.5M note with matching $1.5M non-
dilutive funds available• Follow with $25M Series A later this year
20Pacylex Pharmaceuticals
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Thank you
Contact InfoMichael Weickert, PhDCEOMichael.weickert@pacylex.com650-218-1840
Ryan Heit, MSc, MBACOOryan.heit@pacylex.com780-264-4295
21Pacylex Pharmaceuticals