Post on 11-Apr-2017
Slide 1 Confidential and Proprietary · © 2016 OnkaidoConfidential and Proprietary · © 2016 Onkaido
Improved outcomes after intratumoral administration of immunostimulatory mRNA in a novel cationic lipid4th International mRNA Health ConferenceNovember 1, 2016; Boston, MA Steve Kelsey MD, President, Onkaido, a Moderna venture
Slide 2 Confidential and Proprietary · © 2016 Onkaido
onkaido------------a moderna venture
ONCOLOGY
About Onkaido• Formed 2014• Wholly-owned Moderna Venture• mRNA cancer therapeutics• Fully integrated leverage of
Moderna platform and ecosystem
Slide 3 Confidential and Proprietary · © 2016 Onkaido
Cancer Immunotherapy Coming of Age
Coley’s toxins BCG IL2Checkpoint inhibitors IFNaImmunosurveillance
theoryAllogeneic
BMT
1891 1957 1970s 1986 1995 1998 2010-2015
Cancer vaccines
Slide 4 Confidential and Proprietary · © 2016 Onkaido
Potential for intratumoral injection of mRNA encoding immunostimulatory molecules
• Combining immunostimulatory proteins with checkpoint inhibitors may improve outcomes from cancer therapy
• Direct injection of mRNA encoding immunostimulatory molecules such as OX40L has huge potential in the treatment of amenable tumors
• Immunosuppressive effects of cytokines induced by lipid nanoparticles, or pre-medication, are counterproductive in the context of immunotherapy
Yao et al Nature Rev Drug Discov 2013
Slide 5 Confidential and Proprietary · © 2016 Onkaido
Why messenger RNA for cancer?
Potential advantages over conventional
therapeutics
Potential advantages over gene therapy
• ‘Undruggable’ targets with intra-cellular proteins• Induction of unwanted peptides or proteins• Induction of transmembrane proteins• Repletion of missing proteins• Vaccines
• Transient, regulatable effect• Does not need to enter the nucleus• No risk of genomic integration
• Easily enabled combinations• Rapid research turnaround time
Slide 6 Confidential and Proprietary · © 2016 Onkaido
• Lipid nanoparticles remain the most tractable method of delivering mRNA in vivo
• Cationic lipids such as Dlin-DMA and derivatives (eg. Dlin-MC3-DMA) are associated with toxicity in vivo
• Complement activation and cytokine induction, such as IL6, is observed
• Premedication with corticosteroids is frequently used in the clinic
From: Tabernero et al, Cancer Discovery, 2013
Slide 7 Confidential and Proprietary · © 2016 Onkaido
Moderna has invested heavily in discovery and development of novel LNP components
• 2+ year effort• >30 FTEs• chemistry, formulation, drug product development, pharmacology, bioanalytics
Relative protein expression in tumors after intratumoral injection of LNP-formulated mRNA
mRNA formulated at Onkaido TherapeuticsStudies performed at Medicilon Inc, Shanghai
GFP expression in A20 Tumor2.5 ug/mouse, iTu, 6 hours
PBS
MC3
SM10
0SM
102
SM10
3SM
104
SM10
7SM
113
SM12
2SM
123
SM12
8SM
140
SM15
1SM
157
SM18
0SM
187
SM22
3SM
233
SM23
4M
C3SM
28SM
144
SM17
5SM
191
SM19
2SM
193
SM21
2SM
224
SM24
6SM
247
SM24
8SM
249
SM25
2SM
253
SM25
4M
C3SM
86SM
217
SM22
1SM
225
SM22
6SM
227
SM22
8SM
251
SM25
5SM
259
SM26
2SM
263
SM26
4SM
265
SM26
6SM
267
SM26
8SM
269
MC3
SM86
SM02
7SM
034
SM07
3SM
085
SM09
7SM
143
SM17
4SM
178
SM27
1SM
287
SM28
8SM
289
SM29
0SM
012
SM21
2SM
175
SM22
0M
C3 (D
PBS)
SM86
(tris
)0
2
4
6
8
10
GFP
/tiss
ue(N
orm
aliz
ed to
MC
3)GF
P pe
r gra
m tu
mor
no
rmal
ized
to st
anda
rd
Stan
dard
Stan
dard
Stan
dard
Stan
dard
N1G
L
Slide 8 Confidential and Proprietary · © 2016 Onkaido
N1GL, a novel cationic lipid, has a favorable profile on initial in vivo screening
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
100
50
0
Protein expression
Tumor IL6 levels
Protein to IL6 ratio
N04GL N51GL N22GL N1GL N04GL N51GL N22GL N1GL
Studies performed at Medicilon Inc, Shanghai
Rela
tive
tum
or le
vels
Slide 9 Confidential and Proprietary · © 2016 Onkaido
N1GL has a short plasma and tissue half life
100
1000
1E+04
1E+05
0 5 10 15
Mean vs TimeMC3SM-86
0 4 8 12 16 20 240
100
200
300
400
500
SM-86 liver
Time (h)
ng/g
tiss
ue
Day 1
Day 8
Day 15
Plasma lipid after a single IV infusion NHP
N1GL in liver 24hrs after weekly dosing
Tissue PK in mice
Studies performed at Charles River Labs, and Agilux Labs
N1GL in plasmaAfter single IV dose
Slide 10 Confidential and Proprietary · © 2016 Onkaido
N1GL-based LNPs are well tolerated after local injection to rodents and primates
Toxicology findings
Injection site reactions
Systemic inflammation
Systemic inflammation induced stress
Secondary findings
STD10 (mg RNA/kg) 1
HNSTD (mg RNA/kg) 0.3
Studies performed at Charles River Laboratories
Slide 11 Confidential and Proprietary · © 2016 Onkaido
Intratumoral injection of mRNA in N1GL results in 20-25% of transfected cells, including tumor and myeloid populations
A20 tumor modelAnalyzed by flow cytometry 24hrs after dosingStudies and analysis performed at Onkaido Therapeutics
Control 0.5ug 2.5ug 12.5ug0
5
10
15
20
25
Proportion of Transmembrane Targetexpressed across cell type
% o
f liv
e ce
lls
CD4+ T Cells
CD8+ T Cells
CD11b+ Myeloid CellsNK Cells
A20 Cancer CellsB Cells
Non-cancer/non-immune cells
N1GLMajority of expression in tumor cells and myeloid cells
Slide 12 Confidential and Proprietary · © 2016 Onkaido
Minimal G-CSF induction with N1GL
NT 0.5ug 2.5ug0.0
0.5
1.0
1.5
2.0
Tumor G-CSF
Con
cent
ratio
n (n
g/g
tum
or)
6hr24hr
N1GLNT 0.5ug 2.5ug
0
10
20
30
40
Plasma G-CSF
Con
cent
ratio
n (p
g/m
L)
6hr24hr
N1GL
A20 tumor modelStudies and analysis performed at Onkaido Therapeutics
Slide 13 Confidential and Proprietary · © 2016 Onkaido
mRNA in N1GL associated with minimal increase in tumor myeloid-derived suppressor cells (MDSCs)
PBS 0.5ug 2.5ug 12.5ug0.0
0.5
1.0
1.5
Average Ly6G+ cells (PMN-MDSCs / neutrophils)%
of l
ive
cells
N1GLA20 tumor modelAnalyzed by flow cytometry 24hrs after dosingStudies and analysis performed at Onkaido Therapeutics
Slide 14 Confidential and Proprietary · © 2016 Onkaido
Single agent OX40L formulated in N1GL is efficacious
10 20 30 40 50 60 70 80 90 100 1100
500
1000
1500
2000
SM86 2.5g Transmembrane Target
Days post implant
2 CRs
Individual tumor volumes in MC38 tumor model with weekly intratumoral injection of mRNA encoding murine OX40LStudy performed at Onkaido Therapeutics
N1GL 2.5ug OX40L mRNA
Slide 15 Confidential and Proprietary · © 2016 Onkaido
Overcoming resistance to anti-PD1 therapy THREE PATIENT POPULATIONS:
• Primary failures: 60% progress within 6 months
• Partial responders: 23%, many progress
• Complete responders: 10%
3yr follow-up for Keytruda in melanoma Robert et al, ASCO 2016
Anitei et al, Clin Cancer Res 2014
Slide 16 Confidential and Proprietary · © 2016 Onkaido
Leveraging multiple entry points and combinations to enhance the cancer immunity cycle
Priming“Start Ignition”
Supply co-stimulatory signals“Step on Gas”
Remove inhibitors“Release Brakes”
1
2
3
Co-stimulators
Block co-inhibitors
Chen and Mellman, Immunity, 2013
Slide 17 Confidential and Proprietary · © 2016 Onkaido
Lack of compelling monotherapy efficacy in an ‘immune resistant’ or ‘cold’ strain of the MC38 colon cancer model, MC38’R’
8 12 16 20 24 28 32 36 400
500
1000
1500
2000
Anti-PD1 antibody
Day post implantTu
mor
vol
ume
(mm
3 )10 14 18 22 26 30 34 38 42
0
500
1000
1500
2000OX40L mRNA in N1GL
Days post implant
Tum
or v
olum
e (m
m3 )
5 mg/kg 2x/week IP dosing2.5 g Q7D ITu dosing
Slide 18 Confidential and Proprietary · © 2016 Onkaido
Robust combination efficacy in MC38’R’ model
• 5 g total mRNA, ITu, Q7D
12 16 20 24 28 32 36 400
500
1000
1500
2000
IL23 with miR122(5g)
Day post implant
Tum
or v
olum
e (m
m3 )
0/12 CRs;8 escapers
12 16 20 24 28 32 36 400
500
1000
1500
2000
IL23_miR122 :IL36_miR122(2.5 g each)
Day post implant
Tum
or v
olum
e (m
m3 )
3/12 CRs;6 escapers
12 16 20 24 28 32 36 400
500
1000
1500
2000
IL23_miR122 : IL36_miR122 :OX40L_miR122
(1.7 g each)
Day post implant
Tum
or v
olum
e (m
m3 )
3/12 CRs;4 escapers
Study performed at Onkaido Therapeutics
Cytokine A mRNA only 5ugCytokine A mRNA 2.5ug +Cytokine B mRNA 2.5ug
Non-translated control mRNA and Cytokine B alone all mice progressed by day 26 (data not shown)
Cytokine A mRNA 1.7ug +Cytokine B mRNA 1.7ug +OX40L mRNA 1.7ug
Slide 19 Confidential and Proprietary · © 2016 Onkaido
Summary and Conclusions
• Feasibility and potential of direct intratumoral injection of mRNA encoding immunostimulatory proteins
• Combinations feasible with relative ease
• Significant contribution from lipid to toxicity and tolerability
• Favorable impact of novel, less toxic cationic lipids
• Overcoming resistance to anti-PD1 therapy
Slide 20 Confidential and Proprietary · © 2016 Onkaido
• John Zielenski• Susannah Hewitt• Dyane Bailey• Russell Karp• Kana Ichikawa• Ameya Apte• Ailin Bai• Bo Ying• Josh Frederick
• Maja Sedic• Kerry Benenato• Alex Bulychev• Sarah Peterson• Ellalahewage Kumarasinghe• Staci Sabnis • Tim Salerno
Acknowledgments
And a load of other people probably not mentioned by name here