Transforming The Approach to Vaccines and Protein- Based Therapeutics. Alain Doucet, Ph.D. Manager, Process Development, Medicago

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1 Transforming The Approach to Vaccines and Protein- Based Therapeutics Alain Doucet, Ph.D. Manager, Process Development, Medicago

2 1 Medicago Overview 2 Novel Technologies 3 Robust Pipeline 2

3 Medicago Overview Success story Focus Manufacturing technology Development technology Canadian biopharmaceutical company with game-changing technologies that offer potential advantages over current flu vaccines (efficacy, cross-protection) and pandemic response capabilities Vaccines & therapeutic proteins Transient expression in plants Virus-like particles (VLPs) Employees 300+ (expected to grow to 500+ by 2019) Operations Quebec City, Canada (HQ) Research Triangle Park, Durham, North Carolina 3

4 Global Activities Canada Head office in Quebec City 275+ employees R&D laboratory Pilot facility USA Research Triangle Park, Durham, NC 110+ employees Commercial cgmp facility France Research Lab South Africa Research Lab 4

5 New Proposed Facility in Quebec City Commercial production of Influenza vaccines 44,000 m 2 facility on 90,000 m 2 site Projected capacity of million doses Will consolidate corporate management, R&D, testing labs, pilot facility 5

6 1 Medicago Overview 2 Novel Technologies 3 Robust Pipeline 6

7 Transient Plant-Based Expression System Starting material Gene(s) of interest Plants Infiltration Getting the vector into the leaf tissue Incubation (6-8 days) Infiltrated plant cells producing & accumulating recombinant products Vaccines in 5-6 weeks Clinical-grade influenza vaccines ready in 5-6 weeks after strain identification VLP-based vaccines Extraction Releasing the recombinant products into solution Purification Getting highly pure product Monoclonal antibodies Versatility Plants are highly efficient at expressing proteins of varying complexity at high yields. 7

8 Versatile Plant-Based Production Platform Vaccines Potential anti-viral vaccines for 20+ targets Virus-like particles (VLP) Non-infectious Non-enveloped viruses o Rotavirus (3 concentric layers + spike) o Norovirus (1 layer) Antigen presentation similar to natural virus Enveloped viruses o Influenza Influenza Norovirus Rotavirus Therapeutic proteins Monoclonal antibodies against Ebola virus, collaboration with USA Biomedical Advanced Research and Development Agency Ebola virus, collaboration with the Public Health Agency of Canada Other targets 8

9 VLPs: A Novel Approach to Influenza Virus Vaccines 1960s Split (Inactivated) 1980s 1990s (Ph3) Subunit Vaccine Live Attenuated Recombinant Vaccine Virus-Like Particules (VLPs) Less reactogenic than whole virus vaccines Good antibody response No cell-mediated immune response Long production process Fluzone (Sanofi Pasteur), Fluarix, Flulaval (GSK), Afluria (Seqirus) Safe: lacking core genetic material Long production process Fluad, Fluvirin, Flucelvax (Seqirus) Mimics natural infection Shown to be effective in children only Risk: can revert towards virulent form Difficult to produce in scalable setting Flumist (AZ) Safe: lacking core genetic material Good antibody response No cell-mediated immune response documented Flublok (Protein Sciences, acquired by Sanofi Pasteur) Similar to a wild-type virus; match sequence Lacking core genetic material (noninfectious) Highly efficient way to present antigens to immune system Good antibody and cellmediated immune responses Medicago s vaccine candidate *Egg-based vaccines *Cell-based vaccines *Plant- based vaccines 9

10 Influenza VLP Production in Plants Influenza hemagglutinin proteins accumulate at the plasma membrane, forcing curvature of the membrane and budding of virus-like particles containing host cell lipids and Influenza HA proteins Intact VLPs are extracted and purified to produce Influenza VLP candidate vaccines In-planta expression and VLP assembly Drug product Bioprocessing No need for NA: No sialic acid in plants From D Aoust et al., Plant Biotechnology Journal, Volume 8: (2010) 10

11 Competitive Advantages of the Plant-Based Platform RAPID Clinical grade material in 5-6 weeks Rapid monovalent manufacturing 10 million doses in one month (with DARPA in 2012) ACCURATE Ability to accurately match circulating strain No risk of mutation in plants SCALABLE VERSATILE No risk at scale-up vs. fermenters: one plant or 10,000 plants require the same growth conditions Capacity adjustable to market needs High yields Co-expression of different proteins or subunits, from vaccines to antibodies Transient expression, no use of stable transgenic plant lines 11

12 Number of flu cases worldwide First Responder Capability During a Pandemic (H1N1) Vaccine supply gap Avril April May Mai June Juin Juillet July August Août September Septembre October Octobre November Novembre December Décembre 12 Identification of strain A/H1N1 First wave begins Second wave begins

13 1 Medicago Overview 2 Novel Technologies 3 Robust Pipeline 13

14 Our Quadrivalent VLP Flu Vaccine Candidate Phase II Results 5 trials safely completed in 2,820 subjects (ages & 65 and above) 30 µg per strain is the optimal dose that:» Meets licensure criteria in healthy adults» Offer the optimal antibody and cell-mediated responses The antibody response compares to that of licensed vaccines Cell-mediated responses are higher than a standard dose comparator vaccine VLP vaccine induces broader immune responses than licensed vaccines that can offer cross-protection in case of vaccine mismatch End of Phase II meeting with FDA: support Phase III trials in both adults and elderly (ages 65+) 14

15 Phase 3 Efficacy Study in Healthy Adults Pivotal Phase III in 10,000 healthy adults in seven countries (18-64 years old) was recently completed, data analysis is on-going Phase 3 study in elderly (65+ years old, dose of 30 µg per strain) and in pediatric population (7+ years old) planned 15

16 Antibodies Vaccines Current Pipeline Research Preclinical Phase I Phase II Phase III Seasonal Flu Pandemic Emergency use Rotavirus Norovirus Antibody 1 Antibody 2 16

17 Conclusions Medicago plant-based system Production of virus-like particles for new vaccine development Non-infectious product Antigen presentation similar to natural viruses to maximize antibody and cell-based immune response Match sequence of natural viruses with potentially better efficacy Fast response by using transient expression system Expression and purification of high quality therapeutic proteins such as monoclonal antibodies High versatility for protein expression 17

18 Thank you to all Medicago s employees and collaborators over the years! 18