developing a vaccine against lyme disease...who europe lyme report as case reporting is highly...

Developing a vaccine against Lyme disease Progress update post Phase 1 interim results

World Vaccine Congress

April 4, 2018

Thomas Lingelbach

Chief Executive Officer, Valneva SE

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 statements and 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. Any information in this

presentation is purely indicative and subject to modification at any time. 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.

Certain information and statements included in this presentation are not historical facts but are forward-looking

statements. The forward-looking statements (a) are based on current beliefs, expectations and assumptions, including,

without limitation, assumptions regarding present and future business strategies and the environment in which Valneva

operates, and involve known and unknown risk, uncertainties and other factors, which may cause actual results,

performance or achievements to be materially different from those expressed or implied by these forward-looking

statements, (b) speak only as of the date this presentation is released, and (c) are for illustrative purposes only.

Investors are cautioned that forward-looking information and statements are not guarantees of future performances and

are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of

Valneva.

April 2018 Valneva - World Vaccine Congress 2

About Valneva

Lyme disease (Epidemiology & Clinical manifestations)

Vaccination against Lyme disease

Valneva‘s Lyme disease vaccine candidate VLA15

VLA15 – Pre-clinical data (Summary)

VLA15 – Phase 1 (Design & Key Phase 1 interim results)

VLA15 – First outline of Phase 2/3 clinical development plan

Conclusions

Valneva - World Vaccine Congress 3 April 2018

Developing a vaccine against Lyme disease

Progress update post Phase 1 interim results

Valneva has two main value drivers

March 2018 Valneva - Company Presentation 4

Combination of strong revenues and high value R&D assets

Other

Repeated double digit product sales growth

(15% in 2017)

A valuable R&D pipeline

2017 revenues

IXIARO®/ JESPECT®

€60.0m

Others €17.1m

TPP* €4.0m

DUKORAL® €28.5m

*Third party products

Total revenues

and grants

€109.8m

+12.1%

Direct sales

73.5%

Gross

Margin

58%

Cash

generated

€12.8m

Product sales

€92.6m

About Valneva






VLA15 – First outline of Phase 2/3 clinical development plan

Conclusions




Lyme disease

Tickborne disease (Vector-Ixodes ticks)

Caused by Borrelia burgdorferi spirochete (resides in

gut of tick – migrates to salivary gland – enters host

during feeding)

Early signs and symptoms (3-30 days after tick bite)

include flu-like sympthoms1 and Erythema migrans

rash2

Left untreated, can spread to joints (arthritis), heart

(carditis) and cause neurological problems

Diagnosed by clinical symptoms, exposure to known

endemic area, and lab tests

Treatment: antibiotics (doxycycline, amoxicillin, or

cefuroxime axetil)


(Lyme borreliosis)

1 Fever, chills, headache, fatigue, muscle and joint aches, swollen lymph nodes; 2 Occurs in approx. 70-80% of infected persons

LYME DISEASE

A severe tick-transmitted infection

that is increasingly common

in the US and Europe

Lyme disease

Four stage lifecycle (<2-6 years)

› Eggs, larva, nymph, adult

› Feed only once per stage

› Stage to stage takes several months

Feeding on different reservoirs

› Rodents, birds (mainly)

› Deer is non-reservoir host

(just needed for blood-meal)


A tick-transmitted infection

Stanek et al , Lancet 2012; 379: 461–73

Transmission of Lyme borrelia requires >24 hours of feeding

Transmission to humans through injection of infected tick saliva

Lyme disease in Europe & the US


Stanek et al - Lancet 2012; 379: 461–73

Global Distribution of Vectors for Lyme Borrelia

Main vector in Europe is Ixodes ricinus

Main vector in the Eastern part of the US is Ixodes scapularis, in the West Ixodes

pacificus

Lyme disease – Most common vector-borne illness in

Northern Hemisphere


Medical need steadily increasing as disease footprint widens

1 Centers for Disease Control and Prevention; 2 https://wwwnc.cdc.gov/eid/article/21/9/15-0417_article; 3 Estimated from available national data. Number largely underestimated based on

WHO Europe Lyme Report as case reporting is highly inconsistent in Europe and many LB infections go undiagnosed; ECDC tick-borne-diseases-meeting-report

~ 300,000 cases in US (p.a.)2

~ 200,000 cases in EU (p.a.)3

Disease spread in the United States1

https://wwwnc.cdc.gov/eid/article/21/9/15-0417_article



Lyme disease – Epidemiology


Prevalent Strains in the US & Europe

Lyme disease progression

Stage I (early localized infection)

› 3-30 days after tick bite

› Erythema migrans (EM) (70-80% of patients)

› Non-specific flu-like symptoms

Stage II (early disseminated infection)

› Days or weeks after initial infection

› Borrelia lymphocytom (Europe), rheumatologic and cardiac involvement

› Neuroborreliosis (10-15% of patients)

Stage III (late “persistent” infection)

› After several months or years without treatment or without adequate treatment

› Chronic neurological symptoms (5% of patients)

› Lyme arthritis (USA) (10% of patients)

› Acrodermatitis chronica atrophicans (Europe)


Stages

Plotkin (2016)


Lyme disease – Clinical manifestations

Comparison between US, Sweden and Slovenia

Markowicz (2015)

Lyme disease – Epidemiology (US)

Valneva - World Vaccine Congress 13

Cases by Age

0,1%

3,9%

17,3%

10,2%

12,5%

36,6%

19,3%

1,4%

5,5%

13,2% 12,7%

20,2%

31,8%

15,2%

0%

10%

20%

30%

40%

< 1 y 1-4 y 5-14 y 15-24 y 25-39 y 40-64 y > 65 y

% of Cases % of Population

April 2018

Sources: Adams DA, Thomas KR, Jajosky R, et al. Summary of Notifiable Infectious Diseases and Conditions — United States, 2014. MMWR Morb Mortal Wkly Rep 2016;63:1-152 DOI:

http://dx.doi.org/10.15585/mmwr.mm6354a1; US Census 2017 projection

http://dx.doi.org/10.15585/mmwr.mm6354a1

http://dx.doi.org/10.15585/mmwr.mm6354a1

Lyme disease – Epidemiology (Europe)

Lyme borreliosis cases are

reported throughout the year

with majority of cases during

spring and summer

The distribution in various age

groups shows 2 peaks

› at 5-9 years

› at 50-70 years

In younger age groups, more

cases are seen in males; in

older age groups, more occur in

females


Seasonality & Cases by Age

RKI (2015) – Bavaria 2013/4

About Valneva






VLA15 – First outline for Phase 2/3 clinical development plan

Conclusions





Vaccination with OspA has been proven to work in the past

(Lymerix®, ImuLyme®)

Disproven postulate1, restrictive recommendations and

corporate decisions resulted in there being no Lyme vaccine

available for humans since 2002

Delayed or inadequate treatment can lead to disabling

sequelae

Disease footprint widens2

Direct medical costs in the U.S. estimated up to $1.3 billion3

– indicating an attractive health economical benefit

Other preventive measures have not been shown to work on

a public health scale


Justification for a Lyme vaccine

1 Steere et al. CID 2011: 52 (Suppl3) S259; 2 New Scientist, Lyme disease is set to explode and we still don’t have a vaccine; March 29,

2017 https://www.newscientist.com/article/mg23431195-800-lyme-disease-is-set-to-explode-and-you-cant-protect-yourself/ ; 3 Adrion, E.

et al PLOS ONE Feb 2015

https://www.newscientist.com/article/mg23431195-800-lyme-disease-is-set-to-explode-and-you-cant-protect-yourself/

























History of Lyme disease vaccines

Efficacy of two OspA (ST-1) based vaccines in the 1990s:

› LYMErix (licensed in 1998, withdrawn from market in 2002): Vaccine efficacy

(symptomatic LD) 1: 49% in 1st year, 76% in 2nd year

› ImuLyme: Vaccine efficacy (symptomatic LD) 2 : 68% in 1st year, 92% in 2nd year

Postulate that OspA vaccines might induce antibiotic-refractory Lyme arthritis due to

molecular mimicry of OspA and human LFA-1* epitope was disproven for LYMErix

› Postulate withdrawn in 2011 3

- FDA Panel concluded no evidence for association between vaccine and arthritis

- 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)

- Later, FDA retrospective review of all safety data concluded no safety signal

Mechanism of action of OspA based vaccines well understood


Vaccination with OspA has been proven effective in the past

* Leucocyte Function.associated Antigen ;

1 N Engl J Med. 1998 Jul 23;339(4):209-15; 2 Sigal LH et al N Engl J Med. 1998 Jul 23;339(4):216-22. 3 A.C. Steere et al. CID 2011:52 (Suppl 3) S259 / Lathrop et al, Vaccine 2002

Anti-OspA protective response with Lyme disease vaccines


Mode of Action

Step 1 Step 2 Step 3 Step 4

Vaccine, when

injected, elicits high

levels of anti-OspA

antibodies

Tick attaches

to vaccinated

human and begins

blood meal

(24- to 48-hour

attachment needed

to transmit

B. burgdorferi)

Anti-OspA

antibodies from

vaccinee enter tick

Antibodies kill B.

burgdorferi in

midgut,

preventing

transmission to

human host

A vaccine against Lyme disease


The “Ideal” Target Product Profile …

Prof. Stanley A. Plotkin: Need for a Lyme Disease Vaccine, N. Engl. J Med 375;10, 2016

About Valneva







Conclusions





Multivalent, protein subunit-based vaccine – intended for global reach

Based on Borrelia Outer Surface Protein A (OpsA), expressed by the bacteria when

present in a tick

› Vaccine design allowed elimination of epitope with homology to hLFA-1

Only active clinical Lyme vaccine program to date

FDA Fast Track designation granted1

Positive Phase 1 interim results reported2

Pre-clinical data showed that VLA15 has the potential to provide protection against

the majority of Borrelia species pathogenic for humans3

Phase 2 currently expected to commence in H2/2018

Valneva‘s Lyme vaccine candidate (VLA15)

Summary

1 http://www.valneva.com/download.php?dir=News_2018&file=2018_03_22_Valneva_2017_FY_Results_PR_EN.pdf; 2 http://www.valneva.com/en/investors-media/news;

3 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0113294

http://www.valneva.com/download.php?dir=News_2018&file=2018_03_22_Valneva_2017_FY_Results_PR_EN.pdf

http://www.valneva.com/download.php?dir=News_2018&file=2018_03_22_Valneva_2017_FY_Results_PR_EN.pdf

http://www.valneva.com/en/investors-media/news




http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113294

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0113294

Valneva‘s Lyme disease vaccine candidate (VLA15)


Target Product Profile

Indications Prophylactic active immunization against Lyme disease in individuals ≥ 2

years of age in US and Europe

Dose and

Administration

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 (alternative schedule: Month 0-2), first booster

after 1 year, further booster after 3-5 years (3 years for elderly)

Dosage Form Single dose syringe (2-8°C)

Contraindications Hypersensitivity to any component of the vaccine

Adverse Reactions Comparable to intramuscularly injected Alum adjuvanted vaccines

Target Population/

Target Groups

Individuals at risk who live in endemic areas

People who plan to travel to endemic areas to engage in outdoor activities

(e.g., hiking)

People at risk with prior history of Lyme disease, since infection with Borrelia

may not confer protective immunity

VLA15 – Design


Epitope LA-2 (OspA-ST1) correlates with

protective immunity after vaccination2

Truncated OspA monomers are stabilized

through introduction of disulfide bonds

T-cell epitope mimicking hLFA-1 sequence

replaced by respective region from ST21

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

Focus on C-terminal region of OspA 3 heterodimers targeting major OspA-serotypes1

Product based on three engineered proteins with or w/o Alum

N

C

Full-length OspA

C

N

Truncated stabilized

OspA monomer

Stabilized OspA monomers representing 6

serotypes joined with a linker to 3 heterodimers

C

ST1

ST2

Linker*

ST1-ST2

ST4-ST3

ST5-ST6

1 Comstedt et al. 2014, PLoS One 9:e113294; Comstedt et al. 2015, Vaccine 33:5982-8 2 Golde et al. Inf. Imm 1997

* linked with a 21 amino acid linker derived from two N-terminal

loops of OspA-ST1 (aa 65-74, aa 42-53)

VLA15 – Manufacturing process

Efficient semi-generic production process designed


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

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

+

About Valneva







Conclusions




VLA15 – Pre-clinical data


Summary

Pre-clinical study in mice1 Key results

Challenge after active immunization

- VLA15 induced significant protection at

different dose levels in mice when

challenged with different Borrelia OspA

serotypes2

Challenge after passive immunization

- Sera from VLA15 immunized mice

provided dose dependent, significant

protection when challenged with different

Borrelia OspA serotypes2

VLA15 induced anti-OspA antibodies with

bactericidal activity against ST3 1 Valneva pre-clinical study results published in November 2014 (Comstedt et

al.2014. PLoS ONE 9:e113291); 2 ST1, ST2, ST4, ST5, ST6

Potential to provide protection against the majority of Borrelia species

About Valneva



Valneva‘s Lyme disease Vaccine candidate VLA15




Conclusions





Phase I study conducted in US and EU

6 groups, 3 doses, 2 formulations ▪ Primary objective: Safety and tolerability to Month 3

~180 subjects aged 18-<40 years ▪ Secondary objectives: Safety and tolerability until M12;

Immunogenicity

TREATMENT

Visit 0 1 2 3 4 5 6 7 8

Day (Month) -14 0 7 28(1) 56(2) 84(3) 180(6) 236(8) 365 (12)

VLA15 90 µg w/o Alum

VLA15 90 µg w/ Alum



30 subjects

Estimated

Primary Endpoint

Safety

Interim Analysis



FOLLOW-UP SCREENING

30 subjects

30 subjects

30 subjects

30 subjects

30 subjects

Final Analysis

Phase 1 study design (VLA15-101)

Observer-blind, partially randomized, dose escalation study

Phase 1 study (VLA15-101)

Conducted in 179 subjects in US and EU (www.clinicaltrials.gov, identifier NCT03010228):

Study primary endpoint met

Favorable safety profile

No safety concerns associated with VLA15 in any treatment group1

Encouraging immunogenicity with VLA15

VLA15 immunogenic in all doses and formulations

Good OspA-specific IgG antibody responses against all OspA serotypes 2

Clear dose responses seen between the lowest / higher doses, adjuvanted / non-adjuvanted

groups

Highest, adjuvanted dose group - Seroconversion Rates3 (SCR) from 71.4% to 96.4% for

different OspA serotypes4


Positive Interim Results Reported

1 No differences in the safety profile were observed for the adjuvanted groups compared to the non-adjuvanted treatment groups; 2 IgG levels were substantially higher after three

immunizations (Day 84) compared to after two (Day 56); 3 >= 4-fold rise against baseline against base-line; 4 Preferred for further development / Further dose optimization will be

considered.

http://www.clinicaltrials.gov/

Phase 1 study (VLA15-101) – Safety

No associated safety concerns:

No Serious Adverse Event considered related to VLA15 immunization

No cases of arthritis or rheumatoid arthritis

Very few severe, related AEs:

Total of 8 subjects with severe, related AEs, from different treatment groups

All were solicited AEs (i.e., predefined, volunteer-reported, by default considered

related to vaccination)

Study investigators considered AEs as related in 4 subjects:

› 2 Subjects with severe local pain/tenderness

› Both not medically attended, one treated with a single Paracetamol dose

› 1 Subject with Nausea, not medically attended, no treatment

› 1 Subject with Headache, not medically attended, treated with a single Paracetamol

dose

Severe Arthralgia and Myalgia seen in one subject, considered unrelated to vaccination

by study investigator, following an ultramarathon 100 km walk


Favorable safety profile and no associated safety concerns

Phase 1 study (VLA15-101) – Immunogenicity


*Average = Arithmetic Mean of SCRs against individual Serotypes 1-6 (Rate of

subjects with ≥4-fold increase in OspA-specific IgG)

** Error Bars represent highest / lowest individual Serotype SCR for treatment group

SCR for Highest Adjuvanted Dose Group between 71.4% and 96.4%

0

20

40

60

80

100

12 µg + Alum 12 µg - Alum 48 µg + Alum 48 µg - Alum 90 µg + Alum 90 µg - Alum

Pe

rce

nt

Treatment Group

Average* Seroconversion Rate by Treatment Group,

Day 84

Seroconversion Rates (SCR) Key results

OspA specific IgG antibody responses

induced in all treatment groups and against all

OspA serotypes

Significant difference in response between the

lowest adjuvanted dose group and the two

highest ones

Alum-adjuvanted treatment groups more

immunogenic compared to non-adjuvanted

groups in same dose levels

No significant dose response between 48µg

and 90µg. Day 56 data indicate better kinetics

of immune response at higher dose levels

Highest dose considered for further

development***

*** Further dose optimization will be considered

About Valneva







Conclusions




Lyme vaccine candidate (VLA15)

Phase 2 expected to commence H2/2018 and last approximately 2 years

› Confirmation Dose/Formulation/Schedule

› Booster

› N ~500 subjects

› First Interim Results (3m) after ~1 year

Phase 3 could be initiated 2020/21

› Efficacy study with >10,000 subjects, over two tick seasons if necessary

› A correlate of protection immunogenicity trial combined with a safety data set in

3,000-5,000 subjects might be an option if verified to be predictive for protection in

humans

› Phase 3 should include data in children at point of licensure

› We expect a Phase 3 duration of approximately three years


First Outline for Phase 2/3 Clinical Development Plan*

* subject to development progress, regulatory concurrence and company funding

VLA15 Lyme vaccine candidate

Antibodies against the LA-2 epitope were correlated with a protective response in

humans1. In the LYMErix Phase 3 vaccine trial, the LA-2 equivalent antibody titers were

significantly lower in subjects that were breakthrough cases and developed Lyme disease

A correlate of protection against B. burgdorferi was established based on OspA IgG ELISA

titers2. Titers of 700 to 1,400 ELISA units/mL provided 70% to 95% sensitivity, allowing

differentiation between vaccine failure and success, and are predictive for protection

The ability of OspA antibodies to inhibit Borrelia growth was reported to be predictive for

protection in humans3

› Growth inhibition strongly correlated with OspA ELISA results

Valneva will actively seek ways to collaborate with regulatory authorities in order to

potentially accelerate the path to licensure through a correlate of protection-based pivotal

Phase 3 immunogenicity trial


A Potential for a Correlate of Protection Strategy?

1 Steere et al. NEJM 1998; 339:209-215, 2 Parenti et al. 1998 Abstract in annual meeting of the Infectious Diseases Society of America, 3 Luke et al. JID 2000; 181:1062-8

About Valneva







Conclusions




VLA 15 – A potential vaccine against Lyme disease


Conclusions

There is a strong need for vaccination against Lyme disease both in the US and Europe

LYMErix was a scientific success confirming that Lyme is a vaccine preventable disease,

but a public relations fiasco

VLA 15 is a modern vaccine candidate with encouraging first data in humans, providing

all necessary characteristics for a potential future multivalent OspA-based Lyme vaccine

Thank you

Merci

Danke

Tack

developing a vaccine against lyme disease...who europe lyme report as case reporting is highly...

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