4th International mRNA Health Conference – November 2, 2016 Boston, MA Moderna mRNA Vaccines: from Concept to Clinic

1. Moderna mRNA Vaccines:
From Concept to Clinic
4th International mRNA Health Conference
November 2, 2016; Boston, MA
Giuseppe Ciaramella, Ph.D., CSO, Valera, a Moderna Venture
Copyright © 2016 Valera, a Moderna venture

2. Influenza vaccine program against strains with
pandemic potential H10N8 (A/Jiangxi/2013) and H7N9
(A/Anhui/2013)
H10N8
H7N9
• High potential for pandemic
• >600* cases so far in China; mortality rate of approximately 1/3
• Sporadic, non-sustained human-to-human transmission may have
occurred
• Several vaccines in development…Low immunogenicity without
adjuvants.
• Lower potential for Pandemic
• HA preferentially binds avian Sialyglycan receptor (a2,3)
• Mutation in PB2 (E267K) consistent with higher virulence in
human
• 3 cases in China in 2013 with two deaths
• No available vaccine
Copyright © 2016 Valera, a Moderna venture
*WHO/CDC

3. Strong HAI and T cell response against the H10(N8)
Vaccine in mice (Balb/c)
0 2 4 6 8 1 0
1 0
1 0 0
1 0 0 0
1 0 0 0 0
H A I T ite rs a g a in s t H 1 0
D o s e p e r M o u s e (u g )
HAITiters
ID
IM
Copyright © 2016 Valera, a Moderna venture
U
nstimH
10
Peptide
PoolH
1
Peptide
Pool
P+I
0
500
1000
1500
IFNg Elispot
(5 pooled splenocytes)
SFU/10^6splenocytes
Naive
10 ug ID
2 ug ID
0.4 ug ID
0.08 ug ID
U
nstimH
10
Peptide
PoolH
1
Peptide
Pool
P+I
0
500
1000
1500
SFU/10^6splenocytes
Naive
10 ug IM
2 ug IM
0.4 ug IM
0.08 ug IM

4. Very high H10 HAI titers can be achieved in ferrets with
two doses.
Copyright © 2016 Valera, a Moderna venture
50
ug
D
ay
0
O
nly50
ug
D
ay
0,21
50
ug
D
ay
0,21,35
100
ug
D
ay
0
only
100
ug
D
ay
0,21
100
ug
D
ay
0,21,35
10
100
1000
10000
HAITiters
Day 0
Day 7
Day 21
Day 35
Day 49
Geomean +/- 95% CI; n=9

5. High HAI Titers in NHP (Cynomolgus Monkey) after immunization
with the H10 vaccine
Copyright © 2016 Valera, a Moderna venture
0 10 20 30 40 50 60 70
10
100
1000
10000
100000
HAITiters
50 ug
200 ug
400 ug
Days
Immunization

6. A single injection of an H7N9 vaccine achieves rapid and
sustained protection from a lethal challenge in mice
0 5 1 0 1 5
0
2 0
4 0
6 0
8 0
1 0 0
S u rv iv a l o f D a y 2 1
D a y s p .i.
Percentsurvival
1 0 u g
2 u g
0 .4 u g
P B S
1 4 k D a C a p
0 5 1 0 1 5
0
2 0
4 0
6 0
8 0
1 0 0
S u rv iv a l o f D a y 7
D a y s p .i.
Percentsurvival
1 0 u g
2 u g
0 .4 u g
P B S
1 4 k D a C a p
0 5 1 0 1 5
0
2 0
4 0
6 0
8 0
1 0 0
S u rv iv a l o f D a y 8 4
D a y s p .i.
Percentsurvival
1 0 u g
2 u g
0 .4 u g
P B S
1 4 k D a C a p
Copyright © 2016 Valera, a Moderna venture

7. Similar to the H10 vaccine, the H7 vaccine shows
strong immunogenicity in NHP, irrespective of ROA and
gender
Copyright © 2016 Valera, a Moderna venture
D
a
y
1
D
a
y
8
D
a
y
1
5
D
a
y
2
2
D
a
y
2
9
D
a
y
3
6
D
a
y
4
3
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
V A L - 3 3 9 8 5 1 d e l i v e r e d I D
HAItitersagainstH7
G 1 - 0 . 2 m g I D - M a le
G 1 - 0 . 2 m g I D - F e m a le
G 2 - 0 . 4 m g I D - M a le
G 2 - 0 . 4 m g I D - F e m a le
D
a
y
1
D
a
y
8
D
a
y
1
5
D
a
y
2
2
D
a
y
2
9
D
a
y
3
6
D
a
y
4
3
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
V A L - 3 3 9 8 5 1 d e l i v e r e d I M
HAItitersagainstH7
G 3 - 0 . 2 m g I M - M a le
G 3 - 0 . 2 m g I M - F e m a le
G 4 - 0 . 4 m g I M - M a le
G 4 - 0 . 4 m g I M - F e m a le
D
a
y
1
D
a
y
8
D
a
y
1
5
D
a
y
2
2
D
a
y
2
9
D
a
y
3
6
D
a
y
4
3
1
1 0
1 0 0
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
V A L - 5 0 6 4 4 0
HAItitersagainstH10
G 5 - 0 . 4 m g I D - M a le
G 5 - 0 . 4 m g I D - F e m a le
G 6 - 0 . 4 m g I M - M a le
G 6 - 0 . 4 m g I M - F e m a le
1 8 15 22 29 4336Days
H7N9 H10N8

8. VAL-506440 P101 Clinical Dosing Scheme
Copyright © 2016 Valera, a Moderna venture
Low ug Dose
(IM)
40 subjects
Medium ug
Dose (IM)
40 subjects
Low ug Dose
(ID)
40 subjects
Medium ug
Dose (ID)
40 subjects
High ug
Dose (IM)
40 subjects
Part A: Two Doses, 3 dose levels
Part B: Two Doses, 3 dose levels
• Placebo Controlled, double blinded
• Safety and Immunogenicity

9. Part A: Two doses, 3 dose levels
Part B: One dose, 3 dose levels
VAL-339851 P101 Clinical Dosing Scheme
Copyright © 2016 Valera, a Moderna venture
Low µg (IM)
40 subjects
Medium µg
(IM)
40 subjects
Low µg
(IM)
12 subjects
Medium µg
(IM)
12 subjects
High µg
(IM)
12 subjects
High µg
(IM)
40 subjects
• Placebo Controlled, double blinded
• Safety and Immunogenicity

10. Chikungunya – “that which bends up”
Confidential and Proprietary
Copyright © 2015 Valera
• First described in 1952 following
outbreak in Tanzania
• Category C Priority pathogen (NIH)
• No licensed vaccine or therapeutic
Makonde language

11. mRNA candidates evaluated
Copyright © 2016 Valera, a Moderna venture
Weaver et al (2015) NEJM 372(13): 1231-9
Li et al (2010) Nature 468(7324):705-8
DNA encoding structural polyprotein produces VLPs in cells
This VLP vaccine made by NIAID and tested in humans
Akahata et al (2010)
Nature Med 16(3):334-9
CHIKV genome
Processing of structural polyprotein

12. A single 2 µg IM injection of mRNA encoding
structural polyprotein achieves 100% protection
Copyright © 2016 Valera, a Moderna venture
Route,
Dosing regimen
10 µg
Ag 1
2 µg
Ag 1
10 µg
Ag 2
2 µg
Ag 2
10 µg
Ag 3
2 µg
Ag 3
IM, wk 0 100 100 0 0 0 0
IM, wk 0 & 4 100 100 100 80 60 0
ID, wk 0 100 80 0 0 0 0
ID, wk 0 & 4 100 100 100 100 80 0
• Ag 1
• Similar results for IM and ID
Control group: 0% survival
% survival at 10 days post challenge
1st
immunization
Week: 0
2nd immunization
(some mice)
4
104 pfu CHIKV
strain 181/25
ID (footpad)
8
observation for 10
days post challenge:
weight, health,
survival
AG129 mouse model
Interferon α/β &  receptor
KO Lethal challenge with
CHIK 181/ 25

13. Chikv vaccine mRNA induces a robust antibody
response in NHP
Copyright © 2016 Valera, a Moderna venture
D ay -1 D ay 28 D ay 56 D ay 84
10 0
10 1
10 2
10 3
10 4
10 5
CHIKlysateantibodytiter(unit/ml)
1 s t d o s e
2 n d D o s e
3 rd d o s e
D ay -1 D ay 28 D ay 56 D ay 84
10 0
10 1
10 2
10 3
10 4
CHIKVPRNT50%
1 s t d o s e
2 n d D o s e
3 rd d o s e
D ay - 1 D ay 28 D ay 56 D ay 84
0
1
2
3
4
5
T im e p o in ts p o s t im m u n iz a tio n
7 5 u g - V A L -1 8 1 3 8 8 -M T D S 1 5 0 1 9
2 5 u g -V A L -1 8 1 3 8 8 -M T D S 1 5 0 1 9
7 5 u g -N T IX u n sp e c ific
1 s t d o s e
2 n d D o s e
3 r d d o s e
C-E3-E2-6k-E1 mRNA
C-E3-E2-6k-E1 mRNA
Control mRNA
Binding Ab titers against CHIKV lysate Neutralizing titers against 37997 CHIKV
• Response detected after prime, increases with boost, little additional increase after 3rd immunization
• 25 and 75 ug both immunogenic, small dose response
• Neut titers a few fold below those seen in mice, but still quite robust

14. • Timing: December 2016
• Location: US
• Design:
– Healthy adults
– 3 dose levels, 20 subjects each
– Placebo controlled
– 2 immunizations, spaced by 4 weeks
• Endpoints:
– Safety
– Immunogenicity: neutralizing and binding Ab titers
CHIKV vaccine phase 1 study
Copyright © 2016 Valera, a Moderna venture

15. ZIKA Virus Genome
Viral Protease
VA Kostyuchenko et al. Nature 1–4 (2016) doi:10.1038/nature17994
Copyright © 2016 Valera, a Moderna venture

16. mRNA-1325 protects AG129 mice from lethal challenge
• 10μg provided 100% protection, even with a single dose.
• Protection is correlated with lack of body weight loss
• Single dose (day 0) or two doses (days 0, 21)
• Challenged with 100pfu of Malaysian strain at day 42
Copyright © 2016 Valera, a Moderna venture
Julander Lab, Utah State University

17. Copyright © 2016 Valera, a Moderna venture
Protection associated with significant neutralizing titers
and suppression of viral replication
PRNT50s average ~1:4000
• Achieved similar neutralizing titers to those observed in animals naturally infected with zika.
• Viral load is significantly suppressed (below LLQ in the 10ug/2 dose regimen)
Day 5 post-infection
Julander Lab, Utah State University

18. mRNA-1325 protects mice from a Zika Challenge
after anti-IFNr Ab
• Comparison of constructs with different signal peptides
• 2X 10ug dose in immunocompetent mice (B/6)
• Challenged after administration of IFNr antibody
• Similar immunogenicity between both constructs: Average Titers ~1:10,000
• Complete protection from lethal challenge
Vaccine #1 = IgE
Vaccine #2 = IgG
Diamond Lab, Washington University Copyright © 2016 Valera, a Moderna venture

19. Zika Vaccine (mRNA-1325) Phase 1/2
Low Dose μg
Low Dose μg
Medium Dose μg
Medium Dose μg
High Dose μg
High Dose μg
Flavivirus seronegative
Flavivirus seropositive
n=20
n=10
• Projected Start: End 2016
• Location: US, 3 sites (FL, CA, IL)
• Design:
• Healthy adults (18-49)
• 2 dose regimen, 28 day interval
• 3 dose levels, 30 subjects each:
• Naïve X20
• Flavivirus seropositive X10
• Endpoints:
• Safety
• Immunogenicity (neutralizing titers)
Copyright © 2016 Valera, a Moderna venture

20. Development Pipeline
As of October 27, 2016
Development
Candidate (DC)
Lead
Indication /
Target
GLP
Toxicology
IND/CTA
Filed
Ph I Ph 2 Funding
Abbreviations: GLP = good laboratory practice; IND = investigational new drug; VEGF-A = vascular endothelial growth factor A; CV =
cardiovascular.
Viral
Vaccines
mRNA-1440 Moderna undisclosed
mRNA-1851 Moderna undisclosed
mRNA-1388 Moderna undisclosed DARPA
mRNA-1325 Moderna Zika DARPA, BARDA
mRNA-1706 Moderna undisclosed Ongoing
mRNA MRK-1777 Merck undisclosed
mRNA-1647 Moderna undisclosed
Immuno-
Oncology
mRNA-4379
Moderna
Merck
Personalized
Cancer Vaccines
Ongoing
mRNA-2416 Moderna undisclosed Ongoing
mRNA-2905
AstraZeneca
Moderna
undisclosed Ongoing
Rare
Diseases
mRNA ALXN-1540 Alexion
Crigler-Najjar
Type 1
CV mRNA AZD-8601 AstraZeneca VEGF-A
Started:
Dec ‘15
Started:
May ‘16
Copyright © 2016 Valera, a Moderna venture

21. • Orn Almarsson
• Kapil Bahl
• Stephane Bancel
• Luis Brito
• Matthew Brudner
• Sayda Elbashir
• Kimberly Hassett
• Eric Huang
• Shaila Jayaram
• Shinu John
• John Joyal
• Laureen Knowles
• Michael Laska
• Tej Pavoor
• Hari Pujar
• Mick Ribeiro
• Ipsita Roymoulik
• Joe Senn
• Christin Shaw
• Mike Smith
• Christine Swenson
• James Thompson
• Mike Watson
• Jeremy Webber
• Phil White
• Tal Zaks
• IBT Bioservices
• UTMB –Scott Weaver Lab (CHKV)
• Mike Diamond Lab (Zika)
• Justin Julander Lab (Zika)
Acknowledgments
Copyright © 2016 Valera, a Moderna venture
CHKV Funding by:
Zika Funding by: