Medicago overview
Update on
plant-made VLPs
Focus
Vaccines & Protein-based pharmaceuticals
Manufacturing technology
Transient expression in tobacco
Vaccine technology
Virus-like particles
Employees
240
Quebec City, CANADA
Headquarters, laboratories
Research Triangle Park, NC, USA
& cGMP facilities
Genopole d’Evry, FRANCE
Corporate structure
Nathalie Landry
Vice President Product
Development
[email protected]
WHO meeting
May 6th 2014
Public company from 2006- Sept 2013
Private company since Sept 2013
Mitsubishi Tanabe Pharma Corporation
(majority shareholder)
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Transient expression in N. benthamiana
2
Influenza virus-like particle production in plants
 Influenza hemagglutinins accumulate at the plasma membrane
forcing curvature of the membrane and budding of virus-like particles
DNA sequence + plants
Infiltration
Incubation
No need for NA:
No sialic acid in plants
Extraction
Purification
VLP
Flu virus
From D’Aoust et al., Plant Biotechnology Journal, Volume 8: 607-619 (2010)
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3
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1
Clinical development overview and status update
Rotavirus-like particle production in plants
Clinical trials – Pandemic vaccine
 Rotavirus particle assembly
 Phase I H5 VLP + Alhydrogel completed in 2009
– 48 healthy adults (18-60 years of age)
– Multi-step process initiated in the cytosol and completed in the ER
– Requires 4 structural antigens: VP2, VP6, VP7, VP4
 Phase II H5 VLP + Alhydrogel completed in 2010
– 255 healthy adults (18-60 years of age)
Plant-produced rotavirus-like particles
 Phase I H5 VLP + GLA completed in 2013 (IDRI’s trial)
– 100 healthy adults (18-49 years of age)
– First trial evaluating an adjuvant with intradermal administration
– H5 VLP + Alhydrogel compared well with all other formulations
– GLA-AF increased cross-reactivity of antibodies
 Phase II H5 VLP + GLA or Alhydrogel initiated in 2013
– 390 healthy adults (18-60 years of age)
– All subjects received 2 doses, no SAEs
– Analysis of immune response ongoing
© Medicago Inc.
From
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ed
5
Trask et al., Nature Reviews Microbiology, Volume 10: 165-177 (2012)
 Phase I H7 VLP + Alhydrogel initiated at beginning of 2014
– 100 healthy adults (18-60 years of age)
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Findings from preclinical studies
Clinical development overview and status update
Cross-protection
Clinical trials – Seasonal vaccine
From preclinical trials (one dose (10 µg), no
adjuvant):
 Phase I H1 VLP completed in 2011 (non-adjuvanted)
– 100 healthy adults (18-49 years of age)
– The 5 microgram dose met the CHMP criteria
– Good antibody response against human viruses
– 100% protection in mice and ferrets against H5N1 Indonesia
– Independent NIAID heterologous challenge:
• 100% protection against H5N1 Vietnam
• 70% protection against H2N2 Japan
• Rec-HA failed to protect
 Phase I/II with seasonal quadrivalent launched in Oct. 2013
– 120 healthy adults (18-49 years of age)
Challenge against heterologous
H5N1 Vietnam
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Completed
Ongoing
Completed
Ongoing
7
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Challenge against heterolsubtypic
H2N2 Japan
8
2
Efficacy of H7 VLP after 1st dose in mice
H5 VLP clinical results
100% protection against lethal challenge with H7N9
Trial NCT01657929
**
**
*
*
#
GMT: 135
(16/16)
GMT: 27 (16/16)
H5N1 split
(A/Vietnam)
H5 VLP
(A/Indonesia)
Medicago
GMT: 15
(12/16)
20 µg + 2.5µg
GLA-AF (ID)
20 µg + 2.5µg
GLA-AF (IM)
20 µg (ID)
20 µg + 0.5mg
Alhydrogel(IM)
90 µg (IM)
Seroconversion rate
(4-fold increase) D42
Target of 40%
65.0%
80.0%
52.6%
83.3%
43.8%
Seroprotection rate
(%  1:32) D42
Target of 70%
70.0%
85.0%
52.6%
88.9%
50.0%
10.3
8.7
4.9
11.4
4.5
GMI D42/D0
Target of 2.5
*** significantly different from matched-placebo, p < 0.005
# significantly different from Placebo Alhydrogel, p < 0.05
Note: H7 VLP is not significantly different from adjuvanted
groups
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•
•
•
•
100% protection of mice immunized with one dose of 3 µg adj. H7 VLP
62.5% protection of mice immunized with one dose of 3 µg non-adj. H7 VLP
100% protection of mice immunized with 2 non-adj. doses of 3 µg (not shown)
Phase I ongoing
 H5 VLP with GLA-AF IM or ID or with alum IM meet the 3 CHMP criteria for
licensure of pandemic vaccines
9
TREATMENT
GROUP
NO. OF
SUBJECTS
DOSE LEVEL
10
Safety profile
Phase I/II trial with seasonal quadrivalent VLP vaccine
TEST MATERIAL
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Phase I/II with seasonal quadrivalent VLP vaccine (trial NCT01991587)
ADMINISTERED ON
DAY
Solicited local reactions, during the first 7 days after
immunization
100%
90%
Seasonal quadrivalent VLP
Influenza vaccine
Treatment Grp 1
(low dose)
30
3 µg per
strain\ total of
12 µg HA
0
9 µg per
strain\ total of
36 µg HA
0
80%
Severe
Moderate
70%
Mild
Seasonal quadrivalent VLP
Influenza vaccine
Treatment Grp 2
(medium dose)
30
Seasonal quadrivalent VLP
Influenza vaccine
Treatment Grp 3
(high dose)
30
15 µg per
strain\ total of
60 µg HA
0
100mM phosphate buffer + 150
mM NaCl + 0.01% Tween 80
Treatment Grp 4
(placebo)
30
None
0
60%
50%
40%
30%
20%
10%
ERYTHEMA
9 µg VLP Vaccine (n=30)
Placebo (N=30)
3 µg VLP Vaccine (n=30)
9 µg VLP Vaccine (n=30)
Placebo (N=30)
3 µg VLP Vaccine (n=30)
9 µg VLP Vaccine (n=30)
PAIN
15 µg VLP Vaccine (n=30)
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15 µg VLP Vaccine (n=30)
11
15 µg VLP Vaccine (n=30)
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3 µg VLP Vaccine (n=30)
Placebo (N=30)
0%
SWELLING
3
Safety profile
Phase I/II with Quadrivalent VLP vaccine
Phase I/II with seasonal quadrivalent VLP vaccine (trial NCT01991587)
Hemagglutination-Inhibition Antibody Titers 21 days post-dose (trial NCT01991587)
Solicited systemic reactions, during the first 7 days after
immunization
50%
Strain
Criteria
Groups
3 µg/strain
9 µg/strain
15 µg/strain
≥ 4-fold (%)
41.4
50.0
40.7
0
≥ 1:40 (%)
79.3
73.3
81.5
33.3
1.1
45%
Severe
40%
Moderate
Mild
35%
H1N1
OT over 38C
Placebo
30%
GMI ≥ 2.5 (%)
3.6
4.5
3.7
25%
≥ 4-fold (%)
48.3
60.0
44.4
0
≥ 1:40 (%)
79.3
90.0
81.5
23.3
1.0
20%
H3N2
15%
GMI ≥ 2.5 (%)
10%
5%
B/Brisbane
FATIGUE
HEADACHE
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MUSCLES
ACHES
JOINT ACHES
CHILLS
FEVER
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
Placebo (N=30)
9 µg VLP Vaccine (n=30)
3 µg VLP Vaccine (n=30)
15 µg VLP Vaccine (n=30)
0%
4.7
7.6
5.0
≥ 4-fold (%)
13.8
43.3
48.1
3.3
≥ 1:40 (%)
65.5
70.0
85.6
30.0
GMI ≥ 2.5 (%)
B/Wisconsin
2.0
3.9
3.8
1.1
≥ 4-fold (%)
24.1
53.3
51.9
10.0
≥ 1:40 (%)
72.4
73.3
96.3
43.3
2.3
6.3
4.9
GMI ≥ 2.5 (%)
GENERAL
SWELLING IN SWELLING IN SWELLING IN
DISCOMFORT THE AXILLA
THE GROIN
THE NECK
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Phase I/II with Quadrivalent VLP vaccine
1.3
14
Meets CHMP criteria
A single dose of H1 VLP vaccine induced polyfunctional T cell
response
Micro-Neutralisation antibody titers 21 days post-dose (trial NCT01991587)
PBMCS collected 6-month post-vaccination, trial NCT01302990
Peptide pool stimulation H1
3 µg/strain
9 µg/strain
15 µg/strain
Placebo
GMT
93.4
103.1
153.9
16.2
≥ 4-fold (%)
44.8
46.7
55.6
0
436.6
544.4
570.2
62.0
≥ 4-fold (%)
48.3
70.0
63.0
0
GMT
24.5
31.0
57.3
13.0
≥ 4-fold (%)
20.7
26.7
40.7
0
GMT
69.3
71.3
107.5
23.0
≥ 4-fold (%)
34.5
53.3
44.4
0
GMT
H3N2
B/Brisbane
B/Wisconsin
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H1 VLP stimulation
Groups
Responsive CD4+ to H1 pept.
pool per 106 CD4+ T cells
H1N1
Criterium
Responsive CD4+ to H1 pept.
pool per 106 CD4+ T cells
Strain
Placebo
IFN-g
IL-2
TNF-a
B/Mass
GMT
27.9
30.6
62.6
12.7
(Yamagata strain
for 2014-2015
season)
≥ 4-fold (%)
13.8
26.7
33.3
0
Placebo
+
+
+
+
+
H1 VLP
+
+
Fluzone
H1 VLP
+
+
-
+
-
Placebo
Fluzone
Pie
Arc Chart
legendArc LegendPie Category
IFN-g +
15
H1 VLP
Fluzone
+
-
Test Results
Placebo
H1 VLP
Fluzone
Placebo
IL-2 +
H1 VLP
0.0042
TNF-a +
Fluzone
0.8281
0.0276
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H1 VLP induces cross-reactive T cells to H5N1
Polyfunctional CD4+ T Cell response to H5
PBMCs collected 6 months after vaccination, trial NCT01302990
Homotypic response after vaccination with H5 VLP (21 days post-boost, trial
NCT01991561)
Responsive CD4+ cells
to H5 peptides per 106 CD4+ cells
*
*
*
10 µg H5 VLP + Alhy
15 µg H5 VLP + Alhy
20 µg H5 VLP + Alhy
*
Placebo
*
Statistically
significant
compared
to placebo
Cross-reactive responses of CD4+ (left panel) and CD8+ (right panel) T cell responses from the H1 VLPvaccinated patients ex vivo stimulated with H5 VLP. The symbol * indicates statistically significant
differences between two-groups analyzed by the Mann-Whitney test (P≤0.05).
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• More CD4 & CD8 T cells cross-reactive for H5N1 compared to
egg-based and placebo
• Cross-protective effects similar to those reported for H5N1
vaccines administered with oil-in-water adjuvants
+
+
+
IL-2
IFN-g
TNF-a
17
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+
+
-
+
+
+
-
+
+
+
-
+
Cytokines expressing profile in CD4+ cells after ex vivo stimulation with H5 peptides pool
Cross-reactive CD4+ T Cell response to HA of H7N9
Heterotypic (group 1) response after vaccination with H5 VLP (trial
NCT01991561)
NCT01991561)
IL-2
IFN-g
TNF-a
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Heterotypic (group 2) response after vaccination with H5 VLP (trial
10 µg H5 VLP + Alhy
*
*
15 µg H5 VLP + Alhy
*
20 µg H5 VLP + Alhy
Placebo
*
+
+
+
+
+
-
+
+
+
-
+
+
+
-
+
Cytokines expressing profile in CD4+ cells after ex vivo stimulation with H2 VLP
Statistically
significant
compared
to placebo
One non-adj
H5 VLP dose:
70% protection
against H2N2
in mice
IL-2
IFN-g
TNF-a
19
*
Responsive CD4+ cells
to H7 VLP per 106 CD4+ cells
Responsive CD4+ cells
to H2 VLP per 106 CD4+ cells
Cross-reactive CD4+ T Cell response to HA of H2N2
18
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10 µg H5 VLP + Alhy
15 µg H5 VLP + Alhy
*
20 µg H5 VLP + Alhy
Placebo
*
+
+
+
+
+
-
+
+
+
-
+
+
+
-
Statistically
significant
compared
to placebo
+
Cytokines expressing profile in CD4+ cells after ex vivo stimulation with H7 VLP
20
5
Conclusion
Conclusion
 H5 VLP pandemic vaccine
 Animal challenge studies and CMI results during clinical trials with
plant-based VLP vaccines show potential for cross-protection
 When formulated with alum, induce HI antibody titers that meet surrogate
correlates of protection based on HI antibody titers
 Induce polyfunctional T cell response
– H5 vs. H1, H2 & H7 demonstrated to date
 CMI important for seasonal flu vaccine in terms of cross-protection
 H7 VLP pandemic vaccine
– 2009 H1N1 pandemic: elderly protected by memory CD4 response from previous
H1N1 infections (Hsu et al. 2012 Int J Infect Dis)
– Shown to protect humans in the absence of antibodies (Wilkinson 2012)
– Characterization ongoing in current Phase I/II with seasonal VLP vaccine
 Induced a comparable or superior antibody response to H5 VLP in 2 animal
models
 Currently evaluated in humans formulated with alum
 Seasonal Quadrivalent vaccine
 Plant-based VLPs
– Good safety profile
– Dosages of 9 and 15 µg per strain meets the CHMP criteria for licensure of
seasonal vaccines
– Induced a good MN antibody response cross-reactive towards other strain (B
Yamagata)
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–
–
–
–
–
21
Numerous manufacturing advantages
Good safety and immunogenicity results in ~1,000 subjects
Good antibody response
Cross-protective effects possibly related to strong T cell response
Good compromise to natural infection
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22
Future plans
Merci!
Thank you!
Arigatō!
 To evaluate the alum-adjuvanted pandemic vaccine in a pivotal
phase 3 trial
 To increase the safety database
 Will include a lot-to-lot consistency trial
 To continue the clinical evaluation of the seasonal quadrivalent VLP
vaccine
 Larger group size to evaluate CBER criteria for licensure
 In healthy adults
 In the elderly population
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6