Valneva s Lyme vaccine candidate VLA15

Transcription

1 Valneva s Lyme vaccine candidate VLA15 Thomas Lingelbach, President & CEO, Valneva March 30, 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 - WVC March

3 Valneva s unique business model dedicated to Vaccines Marketed products, R&D portfolio and technology platforms Products/Commercial R&D and Technologies Japanese encephalitis vaccine 30.6m sales in Cholera and ETEC Diarrhea Vaccine 21.0m sales in Research & pre-clinical Pseudomonas aeruginosa Clostridium difficile Lyme borreliosis New targets* Cell-based platform EB66 Phase I / II Phase II / III * viral / travel Third Party products Marketing & Distribution 9.9m sales in 2015 IC31 adjuvant / Other laboratory services 1 Net sales revenues to Valneva (differ from in-market sales) 2 from acquired business as of Feb 10 th 2015; Valneva s Lyme vaccine candidate VLA15 - WVC March

4 Valneva s Lyme vaccine candidate (VLA15) A prophylactic vaccine targeting Lyme borreliosis Lyme borreliosis Transmitted by Ixodes ticks 1 Most common vector borne illness in the Northern Hemisphere (~300,000 cases per year in US 3 and ~85,000 cases per year in Europe 2 ) Delayed or inadequate treatment can lead to disabling sequels Valneva s vaccine candidate Only active clinical program, no human vaccine on the market Multivalent, protein-based subunit 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 IND submission initiated Source picture: PHIL Public Health Photo Library; 1 Stanek et al. 2012, The Lancet 379: ; 2 Estimated from available national data. However, this number is largely underestimated as case reporting is highly inconsistent in Europe and many LB infections go undiagnosed, based on WHO Europe Lyme Report; ECDC tick-borne-diseases-meeting-report; 3 CDC PR on Aug 19, 2013, Valneva s Lyme vaccine candidate VLA15 - WVC March

5 Valneva s Lyme vaccine candidate (VLA15) A new hexavalent OspA based Vaccine Candidate Vaccination with OspA has been proven to be efficacious and safe in the past Two OspA based vaccines have proven to be efficacious in the 1990 s: - LYMErix (licensed in 1998, withdrawn from market in 2002): Vaccine efficacy (symptomatic LB): 49% in 1 st year, 76% in 2 nd year) - ImuLyme: Vaccine efficacy (symptomatic LB): 68% in 1 st year, 92% in 2 nd year Postulate that OspA vaccines might induce antibiotic-refractory Lyme arthritis due to molecular mimicry of OspA and human LFA-1* epitopes was disproved for LYMErix - No difference of arthritis incidence seen in vaccinated subjects versus unvaccinated subjects in a post-licensure VAERS study (after 1.4 million distributed doses) and a Phase 4 safety study (2,568 vaccinated subjects vs 7,497 control subjects) - Postulate withdrawn in Mechanism of action of OspA based vaccines well understood * Leucocyte Function.associated Antigen 1 A.C. Steere et al. CID 2011:52 (Suppl 3) S259 Valneva s Lyme vaccine candidate VLA15 - WVC March

6 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 borreliosis 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 , 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 borreliosis, since infection with Borrelia might not confer protective immunity *: to be finally determined during development Valneva s Lyme vaccine candidate VLA15 - WVC March

7 Valneva s Lyme vaccine candidate (VLA15) Target Product Profile Rationales for Schedule and Age Schedule: M LYMErix was licensed with schedule M (VE 49% in 1 st year; 76% in 2 nd year) 1 - ImuLyme was developed through Ph3 with schedule M (VE 68% in 1 st year; 92% in 2 nd year) 2 - Target Schedule M eases combined handling of vaccinations against tick-borne diseases (same vaccination schedule as TBE vaccines) Age Group: individuals aged 5 years of age - Highest incidence of LB cases in children aged 5-9 years 3 and adults aged years - Non-availability of LYMErix in individuals aged < 15 years seen as major limitation of vaccine 1 A.C Steere et al. NEJM (1998), Vol. 339, ; 2 L.H. Sigal et al. NEJM (1998), Vol. 339, Valneva s Lyme vaccine candidate VLA15 - WVC March

8 Valneva s Lyme vaccine candidate (VLA15) Mechanism of action of an OspA based vaccine Expression of OspA - OspA is expressed when spirochetes are located in the mid-gut of an unfed tick - During feeding, the incoming blood elicits the down regulation of OspA expression, allowing the Borreliae to migrate to the salivary glands and into the blood of the new host Function of anti-ospa antibodies - The anti-ospa antibodies in the blood of the host bind to the spirochetes before OspA expression is down regulated - Borreliae are killed in the tick gut in a complement independent manner* - Thus, only antibodies that bind OspA are needed for elimination of spirochetes in the tick * Valenzuela et al., JMB 2000,Rathinavelu et al., Inf. Imm. 2003, Gipson et al., Inf. Imm Valneva s Lyme vaccine candidate VLA15 - WVC March

9 Valneva s Lyme vaccine candidate (VLA15) Several Borrelia species and OspA serotypes cause LB Analysis of 595 European* (16 countries) LB-patient isolates and CDC statistics** - B. afzelii (ST2) is the most common causative agent of LB in Europe - Borrelia belonging to OspA ST1 to ST6 are responsible for almost all European LB cases - In US LB is caused almost exclusively by B. burgdorferi (ST1) - The novel species B. mayonii rarely cause LB in US*** (prevalence to be studied further!) 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 - WVC March

10 Valneva s Lyme vaccine candidate (VLA15) Three engineered proteins with or w/o Alum form product candidate 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 - WVC March

11 VLA15 Current protein manufacturing 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 - WVC March

12 VLA15 Efficacy in mice Layout and readout of two mouse challenge models 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 - WVC March

13 VLA15 Efficacy in mice Challenge of VLA15 immunized mice 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 Tick challenge ST1 / ST2 / ST4 Data are average values from three (tick challenge) or four (needle challenge) experiments Average infection (%) Needle challenge ST5 / ST6 3 µg VLA µg VLA µg VLA µg VLA15 Placebo Significant protection seen down to 0.3 µg or 0.03 µg dose when mice were challenged with Borrelia expressing any of the five different OspA serotypes Valneva s Lyme vaccine candidate VLA15 - WVC March

14 VLA15 Efficacy in mice Passive immunization of mice and challenge with Borrelia infected ticks (ST1) Mice were passively immunized with 200 µl (i.p.) of different percentages of VLA15-immune sera diluted in naïve sera 24 hours later the mice were challenged with B. burgdorferi (ST1; Pra1) infected ticks Average infection (%) 100 VLA15-immune sera % Tick challenge ST1 * * * 70% 40% 10% Placebo Dose dependent protection with VLA15-immune sera observed in two separate experiments Similar data obtained for mice challenged with Borrelia infected ticks (ST2 and ST4) as well as in vitro grown Borrelia (ST5 and ST6) using a needle Only mice with at least two fully fed tick were included in the readout. Infection data are average of two separate tick challenge experiments Valneva s Lyme vaccine candidate VLA15 - WVC March

15 VLA15 Efficacy in mice OspA serotype specific mouse challenge models - Summary Statistical significant protection Active immunization Passive immunization Serotype 1 Challenge route OspA VLA15 VLA15 needle - 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 - WVC March

16 Endpoint titer (GMT) Endpoint titer (GMT) Endpoint titer (GMT) Endpoint titer (GMT) Endpoint titer (GMT) Endpoint titer (GMT) VLA15 Long term immunogenicity and booster immunization 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) Time (week) Time (week) Time (week) M4B-His (Endpoint) M5B-His (Endpoint) M6B-His (Endpoint) 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 - WVC March

17 VLA15 Toxicity study Study initiated 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 expected to support the anticipated clinical plan Valneva s Lyme vaccine candidate VLA15 - WVC March

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

19 VLA Planned Phase I Study Single-blind, partially randomized, dose escalation study 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 - WVC March

20 VLA15 Preliminary Clinical Development Plan* Estimated timelines y0 y2-3 y4-5 y5-6 y8-10 PHASE I Adults» Safety» Immunogenicity» Dose/Formulation» N ~ 180 PHASE II Adults» Confirmation Dose/Formulation» Schedule» Booster (M12)» N ~500 subjects PHASE III Adults» Pivotal efficacy study (ST1)» Placebo-controlled» N ~ PHASE III Adults LICENSURE» Pivotal efficacy study (non-serotype specific)» Placebo-controlled» N ~ PHASE II Pediatric» Safety» Dose finding» Booster (M12)» N ~ 300 PHASE III Pediatric» Immunogenicity ST 1-6» Placebo-controlled» N ~ 3,000 * subject to development progress, regulatory concurrence and company funding Valneva s Lyme vaccine candidate VLA15 - WVC March

21 Thank you.