Valneva s Lyme vaccine candidate VLA15

Transcription

1 Valneva s Lyme vaccine candidate VLA15 New York December 12, 2016

2 Disclaimer This presentation does not contain or constitute an offer of, or the solicitation of an offer to buy or subscribe for, Valneva SE shares to any person in the USA or in any jurisdiction to whom or in which such offer or solicitation is unlawful. The Valneva shares may not be offered or sold in the USA. The offer and sale of the Valneva shares has not been and will not be registered under the 1933 US Securities Act, as amended. Valneva is a European company. Information distributed is subject to European disclosure requirements that are different from those of the United States. Financial information may be prepared according to accounting standards which may not be comparable to those used generally by companies in the United States. This presentation includes only summary information and does not purport to be comprehensive. Valneva does not warrant the completeness, accuracy or correctness of the information or opinions contained in this presentation. None of Valneva, or any of their affiliates, directors, officers, advisors and employees shall bear any liability for any loss arising from any use of this presentation. Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

3 Valneva s approach to address vaccination against Lyme disease VLA15 A new hexavalent OspA-based vaccine candidate Overview Valneva has worked on Lyme vaccines since 2004; The Company has investigated alternative antigens for vaccine use but no competitive antigen identified was comparable to OspA Two OspA-based vaccines have proven to be efficacious in the 1990s (Lymerix, Imulyme) Mechanism of action of OspA-based vaccines well understood Safety of OspA vaccine (Lymerix) confirmed; Postulate that OspA vaccines might induce antibiotic-refractory Lyme arthritis (mimicry of OspA to hlfa-1*) disproven 1 Valneva s vaccine candidate has shown outstanding efficacy in established and newly developed animal models *, Leucocyte Function.associated Antigen; 1, A.C. Steere et al. CID 2011:52 (Suppl 3) S259 Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

4 Valneva s Lyme vaccine candidate (VLA15) Successful pre-clinical testing allows progression into clinical Phase I study 1 Valneva s vaccine candidate Addressing a high unmet medical need Market potential above 500m Only active clinical program, no vaccine on the market Multivalent, protein subunit- based vaccine Targets the outer surface protein A (OspA) of Borrelia Current development status VLA15 (Pre-clinical) Pre-clinical testing completed Data showed that the vaccine has the potential to provide protection against the majority of Borrelia species pathogenic for humans 1 Clinical entry in U.S. and EU (Dec.) Clinical sites ready to go IND clearance EMA-clinical trial application approval imminent Source picture: PHIL Public Health Photo Library; 1 Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

5 VLA15 Development principles Addressing all critical design criteria OspA C-terminal fragment stabilized for use as vaccine antigen Three heterodimeric proteins designed to cover 6 OspA serotypes, using E. coli lipidation signal and OspA derived linker sequence Postulated OspA ST1 sequence (mimicry to hlfa-1*) replaced by OspA ST2 sequence Valneva has established several Borrelia animal models, previously not available Valneva owns IP rights to OspA and has filed new patents on proprietary VLA15 design * Leucocyte Function-associated Antigen Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

6 VLA15 drug substances Product based on three engineered proteins with or w/o Alum Full-length OspA Truncated stabilized OspA monomer Stabilized OspA monomers representing 6 serotypes joined with a linker to 3 heterodimers N N ST1 Linker* ST1-ST2 C C C ST2 ST4-ST3 ST5-ST6 * linked with a 21 amino acid linker derived from two N-terminal loops of OspA-ST1 (aa 65-74, aa 42-53) Focus on C-terminal region of OspA 3 heterodimers targeting major OspA-serotypes 1 Epitope LA-2 (OspA-ST1) correlates with protective immunity after vaccination 2 Truncated OspA monomers are stabilized through introduction of disulfide bonds T-cell epitope mimicking hlfa-1 sequence replaced by respective region from ST2 1 3 heterodimers target the most relevant Borrelia OspA serotypes (ST1- ST6) in Europe and US 3 proteins reduce industrialization complexity Lipidation and Alum-adjuvantation increase immunogenicity in mice 1 Comstedt et al. 2014, PLoS One 9:e113294; Comstedt et al. 2015, Vaccine 33: Golde et al. Inf. Imm 1997 Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

7 VLA15 Manufacturing process Efficient semi-generic production process designed Fermentation in E. coli (fed-batch) in defined synthetic medium + 1 High Pressure Homogenisation 2 Extraction, Clarification and Phase separation 3 Q-Sepharose (non-binding mode) 4 Hydroxyapatite 5 DEAE Sepharose (non-binding mode) 6 Ultrafiltration 7 SEC 1 Cell lysis by high pressure homogenization 2 Selective solubilization of lipidated protein 3 Anion exchange chromatography for removal of major impurities (HCP, LPS, DNA, aggregates) 4 Hydroxyapatite (binding/elution mode) for removal of other impurities 5 Anion exchange chromatography for removal of aggregates, LPS, DNA 6 Ultrafiltration / Diafiltration 7 Size-Exclusion Chromatography for removal of final trace impurities +HCP: host cell proteins +LPS: lipopolysaccarides Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

8 Lyme Disease: OspA serotypes Several Borrelia species with different OspA serotypes cause disease Analysis of US CDC statistics** and 595 European* (16 countries) LD-patient isolates - US: LD is caused almost exclusively by B. burgdorferi s.s. (ST1) - The novel species B. mayonii rarely causes LD in US*** (prevalence and incidence to be watched) - Europe: B. afzelii (ST2) is the most common causative agent of LD - Borrelia belonging to OspA ST1 to ST6 are responsible for almost all European LD cases Europe B. afzelii (ST2) B. bavariensis (ST4) B. burgdorferi (ST1) B. garinii (ST6) B. garinii (ST5) B. garinii (ST3) B. spielmanii (snd) B. garinii (ST7) US B. burgdorferi (ST1) B. mayonii (snd) * Data from German National Reference Centre for Borrelia at the Bavarian Health and Food Safety Authority (Germany) and Baxter have been summarized. ** Centers for Disease Control and Prevention. *** Pritt et al., Lancet. Infect. Dis Snd; Serotype not determined Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

9 VLA15 Efficacy in mice Two mouse challenge models mimicking real route of infection MOUSE TICK CHALLENGE MODEL MOUSE NEEDLE CHALLENGE MODEL s.c. immunize C3H/HeN mice collect immune sera collect final sera and organs s.c. immunize C3H/HeN mice collect immune sera collect final sera and organs Application of infected ticks in vitro grown spirochetes Weeks Removal of ticks Serology VlsE ELISA Weeks Serology VlsE ELISA ELISA qpcr Ear ELISA qpcr Ear Mice are challenged with ticks feeding for 3-5 days Mice are sacrificed 6 weeks after tick application Readout based on VlsE ELISA and qpcr Mice are challenged with in vitro grown bacteria Mice are sacrificed 4 weeks after challenge Readout based on VlsE ELISA and qpcr VlsE: Variable major protein [VMP]-like sequence E Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

10 VLA15 Efficacy in mice Significant protection in challenge with Borrelia (ST1, ST2, ST4, ST5 and ST6) Mice were immunized with three immunizations with 3 µg down to 3 ng VLA15 (0.15% Al(OH) 3 ) Mice were either challenged with ticks harboring B. burgdorferi (ST1), B. afzelii (ST2) or B. bavariensis (ST4), if not challenged with in vitro grown B. garinii (ST5 or ST6) using a needle Average infection (%) Tick challenge ST1 / ST2 / ST4 Needle challenge ST5 / ST6 3 µg VLA µg VLA µg VLA µg VLA15 Placebo Data are average values from three (tick challenge) or four (needle challenge) experiments Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

11 VLA15 Efficacy in mice OspA serotype specific mouse challenge models successfully established Statistical significant protection Active immunization Passive immunization Serotype Challenge route OspA VLA15 VLA15 needle - 1 tick 2 tick 3 needle/tick (ongoing) tick 5 needle 6 needle Five of six serotype specific challenge models have been established: 3 serotype specific tick challenge models (ST1, ST2 and ST4) & 3 needle models (ST1, ST5 and ST6) VLA15 showed significant protection in all models evaluated Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

12 VLA15 Long term immunogenicity and booster in mice Three immunizations with 5 µg VLA15 (with Al(OH) 3 ) and booster 10 months after 3rd immunization, Read-out: ELISA for serotype specific IgG against truncated stabilized OspA monomers M1B-His (Endpoint) M2B-His (Endpoint) M3B-His (Endpoint) Endpoint titer (GMT) Endpoint titer (GMT) Endpoint titer (GMT) Time (week) Time (week) Time (week) M4B-His (Endpoint) M5B-His (Endpoint) M6B-His (Endpoint) Endpoint titer (GMT) Endpoint titer (GMT) Endpoint titer (GMT) Time (week) Time (week) Time (week) Serotype specific total IgG antibody titers declined over time (half-life approx. 7 weeks) Booster dose resulted in 4 to 18 fold higher IgG titers as compared to titers after 3 rd immunization Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

13 VLA15 Tox Toxicity study successfully concluded Standard GLP repeat dose toxicity as per guidance Tox proposal/protocol has been agreed with regulators incl. FDA prior to study start Standard repeat dose toxicity study in rabbits - 4 immunizations on Days 1, 15, 29 and 43 - Injection route: Intramuscular - Dose: highest dose planned for clinical testing - Analyses: Systemic and local tolerability; histopathology; recovery The toxicity study is finalized without any findings and supports clinical Phase I entry Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

14 Valneva s Lyme vaccine candidate (VLA15) Target Product Profile Indications Dose and Administration Dosage Form Contraindications Adverse Reactions Target Population/ Target Groups Prophylactic active immunization against Lyme disease in individuals 5 years of age* Route of administration: Intramuscular injection Recommended dose: Best formulation of 3 heterodimers (ST 1/2, 4/3, 5/6) with or without Alum Dosage schedule: Month 0-1-(2)-12, further booster after 3-5 years (3 years for elderly)* Single dose syringe (2-8 C) Hypersensitivity to any component of the vaccine Comparable to intramuscularly injected Alum adjuvanted vaccines Individuals at risk who live in endemic areas People who plan to travel to endemic areas to pursue recreational outdoor activities (e.g., hiking) People at risk with prior history of Lyme disease, since infection with Borrelia might not confer protective immunity *: to be finally determined during development Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

15 VLA15 Development status Ready for clinical testing (first time in man) TODAY Research Pre-clinical development Clinical development Nov 2014 Dec 2016 Constructs Challenge models Assays Process development mabs Scientific advice Industrialization Tox Clinical trial material IND/CTA Phase I IMMINENT Phase II preparation Regulatory advice for acceleration Passive protection / human sera Potential correlate of protection Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

16 VLA Phase I Study Observer-blind, partially randomized, dose escalation study Phase I study to be conducted in US and EU 6 groups, 3 doses, 2 formulations Primary objective: Safety and tolerability to Month subjects aged 18-<40 years Secondary objectives: Safety and tolerability until M12; Immunogenicity Estimated SCREENING TREATMENT FOLLOW-UP VLA15 12 µg w/ Alum VLA15 12 µg w/o Alum VLA15 48 µg w/ Alum VLA15 48 µg w/o Alum VLA15 90 µg w/ Alum VLA15 90 µg w/o Alum 30 subjects 30 subjects 30 subjects 30 subjects 30 subjects 30 subjects Visit Day (Month) (1) 56(2) 84(3) 180(6) 236(8) 365 (12) Primary Endpoint Safety Interim Analysis Final Analysis Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

17 VLA Phase I Study Observer-blind, partially randomized, dose escalation study Study sites Lincoln (NE), Gent (BEL) Safety measures First 24 subjects (i.e. 4 subjects/treatment group) will be enrolled in a staggered dose escalation scheme Pre-definition of study stopping rules Safety laboratory parameters include assessment of markers for inflammation (e.g. CRP, ESR) and Rheumatoid Arthritis (e.g. Rheumatoid Factor (RF) and Anti Citrullinated Protein Antibodies (ACPA) ). Immunogenicity read-out Measurement of IgG antibodies specific against six OspA serotypes (ST1-6) by ELISA (coating antigens: full length lipidated OspA ST1-6) ESR: Erythorcyte Sedimentation Rate; CRP: C-reactive Protein Valneva s Lyme vaccine candidate VLA15 DECEMBER 12,

18 Thank you.