Medicago overview. Update on plant-made VLPs. Influenza virus-like particle production in plants. Transient expression in N.

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1 Medicago overview Focus Vaccines & Proteinbased pharmaceuticals Update on plantmade VLPs Manufacturing technology Transient expression in tobacco Vaccine technology Viruslike particles Employees 240 Headquarters, laboratories & cgmp facilities Quebec City, CANADA Research Triangle Park, NC, USA Genopole d Evry, FRANCE Nathalie Landry Vice President Product Development landryn@medicago.com Corporate structure Public company from 2006 Sept 2013 Private company since Sept 2013 Mitsubishi Tanabe Pharma Corporation (majority shareholder) WHO meeting May 6 th Transient expression in N. benthamiana Influenza viruslike particle production in plants Influenza hemagglutinins accumulate at the plasma membrane forcing curvature of the membrane and budding of viruslike 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: (2010) 3 4 1

2 Rotaviruslike particle production in plants Rotavirus particle assembly Multistep process initiated in the cytosol and completed in the ER Requires 4 structural antigens: VP2, VP6, VP7, VP4 Plantproduced rotaviruslike particles Clinical development overview and status update Clinical trials Pandemic vaccine Phase I H5 VLP Alhydrogel completed in healthy adults (1860 years of age) Phase II H5 VLP Alhydrogel completed in healthy adults (1860 years of age) Phase I H5 VLP GLA completed in 2013 (IDRI s trial) 100 healthy adults (1849 years of age) First trial evaluating an adjuvant with intradermal administration H5 VLP Alhydrogel compared well with all other formulations GLAAF increased crossreactivity of antibodies Phase II H5 VLP GLA or Alhydrogel initiated in healthy adults (1860 years of age) All subjects received 2 doses, no SAEs Analysis of immune response ongoing All rights reserv From ed Trask et al., Nature Reviews Microbiology, Volume 10: (2012) 5 Phase I H7 VLP Alhydrogel initiated at beginning of healthy adults (1860 years of age) Completed Ongoing 6 Clinical development overview and status update Clinical trials Seasonal vaccine Phase I H1 VLP completed in 2011 (nonadjuvanted) 100 healthy adults (1849 years of age) The 5 microgram dose met the CHMP criteria Good antibody response against human viruses Phase I/II with seasonal quadrivalent launched in Oct healthy adults (1849 years of age) Findings from preclinical studies Crossprotection From preclinical trials (one dose (10 µg), no adjuvant): 100% protection in mice and ferrets against H5N1 Indonesia Independent NIAID heterologous challenge: 100% protection against H5N1 Vietnam 70% protection against H2N2 Japan RecHA failed to protect Challenge against heterologous H5N1 Vietnam Challenge against heterolsubtypic H2N2 Japan Completed Ongoing 7 8 2

3 Efficacy of H7 VLP after 1 st dose in mice 100% protection against lethal challenge with H7N9 H5 VLP clinical results Trial NCT # GMT: 135 (16/16) GMT: 27 (16/16) GMT: 15 (12/16) significantly different from matchedplacebo, p < # significantly different from Alhydrogel, p < 0.05 Note: H7 VLP is not significantly different from adjuvanted groups 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 nonadj. H7 VLP 100% protection of mice immunized with 2 nonadj. doses of 3 µg (not shown) Phase I ongoing 9 Seroconversion rate (4fold increase) D42 Target of 40% Seroprotection rate (% 1:32) D42 Target of 70% 20 µg 2.5µg GLAAF (ID) 20 µg 2.5µg GLAAF (IM) H5 VLP (A/Indonesia) Medicago 20 µg (ID) 20 µg 0.5mg Alhydrogel(IM) H5N1 split (A/Vietnam) 90 µg (IM) 65.0% 80.0% 52.6% 83.3% 43.8% 70.0% 85.0% 52.6% 88.9% 50.0% GMI D42/D0 Target of H5 VLP with GLAAF IM or ID or with alum IM meet the 3 CHMP criteria for licensure of pandemic vaccines 10 Phase I/II trial with seasonal quadrivalent VLP vaccine Safety profile Phase I/II with seasonal quadrivalent VLP vaccine (trial NCT ) TEST MATERIAL Seasonal quadrivalent VLP Influenza vaccine Seasonal quadrivalent VLP Influenza vaccine TREATMENT GROUP Treatment Grp 1 (low dose) Treatment Grp 2 (medium dose) NO. OF SUBJECTS DOSE LEVEL 3 µg per strain\ total of 12 µg HA 9 µg per strain\ total of 36 µg HA ADMINISTERED ON DAY % 90% 80% 70% 60% 50% Solicited local reactions, during the first 7 days after immunization Severe Moderate Mild Seasonal quadrivalent VLP Influenza vaccine Treatment Grp 3 (high dose) µg per strain\ total of 60 µg HA 0 40% 30% 20% 100mM phosphate buffer 150 mm NaCl 0.01% Tween 80 Treatment Grp 4 (placebo) 30 None 0 10% 0% 11 PAIN ERYTHEMA SWELLING 3

4 Responsive CD4 to H1 pept. pool per 10 6 CD4 T cells Responsive CD4 to H1 pept. pool per 10 6 CD4 T cells Safety profile Phase I/II with seasonal quadrivalent VLP vaccine (trial NCT ) 50% 45% Solicited systemic reactions, during the first 7 days after immunization Phase I/II with Quadrivalent VLP vaccine HemagglutinationInhibition Antibody Titers 21 days postdose (trial NCT ) Strain Criteria Groups 3 µg/strain 9 µg/strain 15 µg/strain 40% Severe Moderate 4fold (%) % 30% Mild OT over 38C H1N1 1:40 (%) GMI 2.5 (%) % 4fold (%) % 15% H3N2 1:40 (%) GMI 2.5 (%) % 4fold (%) % 0% B/Brisbane 1:40 (%) GMI 2.5 (%) fold (%) B/Wisconsin 1:40 (%) GMI 2.5 (%) FATIGUE HEADACHE MUSCLES ACHES JOINT ACHES CHILLS FEVER GENERAL SWELLING IN SWELLING IN SWELLING IN DISCOMFORT THE AXILLA THE GROIN THE NECK Meets CHMP criteria 14 Phase I/II with Quadrivalent VLP vaccine MicroNeutralisation antibody titers 21 days postdose (trial NCT ) Strain Criterium Groups 3 µg/strain 9 µg/strain 15 µg/strain A single dose of H1 VLP vaccine induced polyfunctional T cell response PBMCS collected 6month postvaccination, trial NCT Peptide pool stimulation H1 H1 VLP stimulation H1N1 H3N2 GMT fold (%) GMT fold (%) GMT B/Brisbane 4fold (%) B/Wisconsin GMT fold (%) B/Mass GMT (Yamagata strain for season) 4fold (%) IFNg IL2 TNFa H1 VLP Fluzone H1 VLP Fluzone H1 VLP Fluzone Pie Arc Chart legend Arc Legend Pie Category H1 VLP Fluzone Test Results IFNg IL2 H1 VLP TNFa Fluzone

5 Responsive CD4 cells to H2 VLP per 10 6 CD4 cells Responsive CD4 cells to H7 VLP per 10 6 CD4 cells Responsive CD4 cells to H5 peptides per 10 6 CD4 cells H1 VLP induces crossreactive T cells to H5N1 PBMCs collected 6 months after vaccination, trial NCT Polyfunctional CD4 T Cell response to H5 Homotypic response after vaccination with H5 VLP (21 days postboost, trial NCT ) 10 µg H5 VLP Alhy 15 µg H5 VLP Alhy 20 µg H5 VLP Alhy Crossreactive 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 twogroups analyzed by the MannWhitney test (P 0.05). More CD4 & CD8 T cells crossreactive for H5N1 compared to eggbased and placebo Crossprotective effects similar to those reported for H5N1 vaccines administered with oilinwater adjuvants 17 IL2 IFNg TNFa Cytokines expressing profile in CD4 cells after ex vivo stimulation with H5 peptides pool 18 Statistically significant compared to placebo Crossreactive CD4 T Cell response to HA of H2N2 Heterotypic (group 1) response after vaccination with H5 VLP (trial NCT ) Crossreactive CD4 T Cell response to HA of H7N9 Heterotypic (group 2) response after vaccination with H5 VLP (trial NCT ) 10 µg H5 VLP Alhy 10 µg H5 VLP Alhy 15 µg H5 VLP Alhy 20 µg H5 VLP Alhy 15 µg H5 VLP Alhy 20 µg H5 VLP Alhy Statistically significant compared to placebo Statistically significant compared to placebo IL2 IFNg TNFa One nonadj H5 VLP dose: 70% protection against H2N2 in mice IL2 IFNg TNFa Cytokines expressing profile in CD4 cells after ex vivo stimulation with H2 VLP 19 Cytokines expressing profile in CD4 cells after ex vivo stimulation with H7 VLP 20 5

6 Conclusion Conclusion H5 VLP pandemic vaccine When formulated with alum, induce HI antibody titers that meet surrogate correlates of protection based on HI antibody titers Induce polyfunctional T cell response H7 VLP pandemic 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 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 crossreactive towards other strain (B Yamagata) Animal challenge studies and CMI results during clinical trials with plantbased VLP vaccines show potential for crossprotection H5 vs. H1, H2 & H7 demonstrated to date CMI important for seasonal flu vaccine in terms of crossprotection 2009 H1N1 pandemic: elderly protected by memory CD4 response from previous H1N1 infections (Hsu et al 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 Plantbased VLPs Numerous manufacturing advantages Good safety and immunogenicity results in ~1,000 subjects Good antibody response Crossprotective effects possibly related to strong T cell response Good compromise to natural infection Future plans To evaluate the alumadjuvanted pandemic vaccine in a pivotal phase 3 trial To increase the safety database Will include a lottolot consistency trial Merci! Thank you! Arigatō! 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 23 6