Challenging Current Control Strategies of Livestock

Diseases

Nesya Goris Sr Director Antivirals; Vice President Discovery Research

Robert VranckenDirector Discovery Research

FESASS Assemblée Générale, March 20 2015, Brussels

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Special Note Regarding Forward-Looking StatementsThis presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this presentation that do not relate to matters of historical fact should be considered forward-looking statements, including statements regarding our expectations regarding the approval of products; the sufficiency of financial resources; expected future cash balance and liquidity; expectations regarding development programs, trials, studies and approvals; expectations regarding in-license initiatives, divestitures and partnerships; and expectations regarding the Company’s plans and opportunities.

These forward-looking statements are based on management’s current expectations. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: our limited operating history and expectations of losses for the foreseeable future; our lack of commercial sales; our failure to obtain any necessary additional financing; our substantial dependence on the success of certain of our lead product candidates, AT-001, AT-002, AT-003, AT-004 and AT-005; our inability to identify, license, develop and commercialize additional product candidates; our inability to obtain regulatory approval for our existing or future product candidates; the lack of commercial success of our current or future product candidates; uncertainties regarding the outcomes of studies regarding our products; our inability to realize all of the anticipated benefits of our acquisitions of Vet Therapeutics and Okapi Sciences; effects of competition; our failure to attract and keep senior management and key scientific personnel; our complete reliance on third-party manufacturers and third parties to conduct all our target animal studies and certain other development efforts; our lack of a sales organization; our significant costs of operating as a public company; changes in distribution channels for pet therapeutics; consolidation of our customers; impacts of generic products; unanticipated safety or efficacy concerns; our limited patents and patent rights; our failure to comply with our intellectual property license obligations; our infringement of third party patents and challenges to our patents or rights; our failure to comply with regulatory requirements; our failure to report adverse medical events related to our products; legislative or regulatory changes; the volatility of our stock price; our status as an “emerging growth company,” as defined in the JOBS Act; the potential for dilution if we sell shares of our common stock in future financings; the significant control over our business by our principal stockholders and management; effects of anti-takeover provisions in our charter documents and under Delaware law; and our intention not to pay dividends. These and other important factors discussed under the caption "Risk Factors" in the Company’s prospectus included as part of the Registration Statement on Form S-1 filed with the Securities and Exchange Commission, or SEC, on January 13, 2014, along with our other reports filed with the SEC, could cause actual results to differ materially from those indicated by the forward-looking statements made in this presentation. Any such forward-looking statements represent management's estimates as of the date of this presentation. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this presentation.

Safe Harbor Statement

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Antivirals = Proven concept in human medicine

In vitrodiscovery

Pre-clinical

Phase I Phase II Phase III

Drug development in human medicine

Animal models

No antivirals for animals?

HIV / AIDS Hepatitis B/C

Herpes: HSV/VZV/CMV

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Why antivirals for livestock?

Prevent spread of the virus– Rapid response

Rapid response stockpile: no stability issues

– Ease of application Mix in feed

– Rapid containment Acts directly on the virus: freeze, reduce and prevent infection

Minimise impact on export– Not depending on immune system

Differentiation with infected animals

– Residues Optimise compound for short withdrawal time

Epidemiological and cost-effective strategy

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FMD control measures

Prophylactic vaccination (conventional vaccines) 1990

• Ban on prophylactic vaccination• Pre-emptive culling• Emergency vaccination (DIVA)

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Summary of 2001 FMD outbreak in the UK

• Total cost £8 billion

• First case 19 Feb 2001

• Last case 30 Sep 2001

• Total # cases 2030

• Last cull 01 Jan 2002

• 80,000 – 93,000 culls/week

• 6 million culls for disease control– 1.3 million on infected premises

– 1.5 million on dangerous contacts

– 1.2 million on neighbouring premises

– 2.0 million welfare culls

• 4 million extra culls “at foot” of young animals

• 10 million animals were culled

• £2.5 billion in compensations

■ 100–893 outbreaks■ 50–100 outbreaks■ 10–50 outbreaks■ 1–10 outbreaks

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FMDV hit screening – Unique collaboration

70,000 compounds

[Willems et al., 2011]

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Hit compound

From hit to lead compound

Combination compoundCompound profile

Active against 7 FMDV serotypes

Active in low nM range

Stable and soluble compound

Easy synthesis

only Eurasian

4.5 µM

±

√

√

45 nM

√

√

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What a difference a factor 100(0) makes...

Economic viability of FMD antiviral containment approach will be key

Hit Initial optimisation Lead Aim4.5 µM 0.9 µM 45 nM 4.5 nM

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Proof-of-concept with antivirals and FMDV

• SCID mice FMDV A22 Iraq 24/64 inoculation i.p.

• 2’-CMC administration s.c.– 5 consecutive days from day 0 → day 4 p.i.

– 2 x 50 mg/kg per day

SCID mice have crippled immune system (lacking T-cell and B-cell responses)

13 of 15 mice completely protected by 2’-CMC

Protection is solely due to 2’-CMC

Mortality 100% 0%

Mean day of death p.i. 4.0 ± 1.3 >14

Weight loss >20% healthy

Respiratory distress severe healthy

Viraemia serum 2 d.p.i. 100% 2000-fold decrease

Viraemia serum 14 d.p.i. † negative (13/15)

[Lefebvre et al., 2010; 2013]

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Classical swine fever

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CSF control measures

Prophylactic vaccination (conventional vaccines) 1990

• Ban on prophylactic vaccination• Pre-emptive culling• Emergency vaccination (DIVA)

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Classical Swine Fever Benelux 1997-1998

12,000,000 Pigs killed

Damage above €3 billion

United Kingdom 2000

75,000 Pigs killed

Compensation £4.4 million

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Proof-of-concept with antivirals and CSFV

Experimental efficacy studies in pigs– BPIP treatment of CSFV-infected piglets reduces

• Viral load by 1000-fold

• Viraemic period by 74%

• Transmission rate to untreated sentinels by 85%

→ Input parameters used in epidemiological disease modelling studies

BPIP = early hit compound; not optimised; not highly potent

Hit = BPIP

EC50 ≈ 1.2 µM

RdRp inhibitor

+

15 days

Vrancken et al., 2008; 2009a; 2009b.

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CSF outbreak in De Peel, a DPLA in the Netherlands with intensive pig reeringSource farm and 10 others farms infected before detection of CSFV

Dense pig population in The Netherlands

Backer et al., Antiviral Res. 2013;99(3):245-50.

Control strategies (selection)

o 1 km pre-emptive culling (all animals)

o 2 km vaccination (except sows)

o 2 km antiviral treatment (all animals)

o 2 km vaccination (except sows) + 2 km

antiviral treatment (sows)

Starting situation(e.g. simulation 74 of 1000)

Model impact of different CSF control measures

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Model impact of different CSF control measures

EU preferred method for densely populated pig areas

Application of pre-emptive culling in 1-km radius around detected farms

83 detected herds

Backer et al., Antiviral Res. 2013;99(3):245-50.

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Dutch CSF contingency plan preferred method for densely populated pig areasSows are left unvaccinated

Application of E2-subunit emergency vaccination in 2-km radius around detected farms

Model impact of different CSF control measures

46 detected herds

Backer et al., Antiviral Res. 2013;99(3):245-50.

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Application of antiviral treatment in 2-km radius around detected farms

Model impact of different CSF control measures

56 detected herds

Backer et al., Antiviral Res. 2013;99(3):245-50.

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Application of antiviral treatment combined with E2-subunit emergency vaccination in 2-km radius around detected farms

37 detected herds

Model impact of different CSF control measures

Backer et al., Antiviral Res. 2013;99(3):245-50.

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EU minimal measures

1 km pre-emptive culling

2 km vaccination2 km treatment2 km vaccination + treatment

Backer et al., Antiviral Res. 2013;99(3):245-50.

Model impact of different CSF control measures

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• Costs of ripple effects

• Costs of spill-over effects

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• Costs of trade restrictions

• Costs of ripple effects

• Costs of spill-over effectsOnly this small fraction of total costs were considered in model

Dense pig population in The Netherlands

Simulating CSF outbreaks in The Netherlands

Economic aspects

Direct costs of CSF outbreak Indirect costs of CSF outbreak

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Simulating CSF outbreaks in The Netherlands

Economic aspects

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* Cost of antiviral drug not included

Benchmark:

Pre-emptive culling (1km)Difference: 132 M€Doses: 13 millionPrice tolerance: 10 €/dose

Emergency vaccination (2km)Difference: 7 M€Doses: 1 millionPrice tolerance: 7 €/dose

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Concluding remarks

• Antiviral drugs are a viable alternative for conventional control measures

• Innovative and conventional methods not mutually exclusive

• Additional weapon in disease control arsenal

CSFV FMDV ASFV

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Relevant Literature

• General concept – Containment of livestock diseases using antiviral drugs– Goris N, Vandenbussche F, De Clercq K. Potential of antiviral therapy and prophylaxis for controlling RNA viral infections of livestock.

Antiviral Res. 2008;78(1):170-8.

• FMD and antiviral drugs– Goris N, De Palma A, Toussaint JF, Musch I, Neyts J, De Clercq K. 2'-C-methylcytidine as a potent and selective inhibitor of the replication

of foot-and-mouth disease virus. Antiviral Res. 2007;73(3):161-8.

– Lefebvre DJ, Neyts J, De Clercq K. Development of a foot-and-mouth disease infection model in severe combined immunodeficient mice for the preliminary evaluation of antiviral drugs. Transbound Emerg Dis. 2010;57(6):430-3.

– Lefebvre DJ, De Vleeschauwer AR, Goris N, Kollanur D, Billiet A, Murao L, Neyts J, De Clercq K. Proof of Concept for the Inhibition of Foot-and-Mouth Disease Virus Replication by the Anti-Viral Drug 2'-C-Methylcytidine in Severe Combined Immunodeficient Mice. Transbound Emerg Dis. 2013 [Epub ahead of print].

– Willems T, Lefebvre DJ, Neyts J, De Clercq K. Diagnostic performance and application of two commercial cell viability assays in foot-and-mouth disease research. J Virol Methods. 2011;173(1):108-14.

• CSF and antiviral drugs– Backer JA, Vrancken R, Neyts J, Goris N. Antiviral agents to control Classical Swine Fever epidemics. Antiviral Res. 2013 [conditionally

accepted].

– Haegeman A, Vrancken R, Neyts J, Koenen F. Intra-host variation structure of classical swine fever virus NS5B in relation to antiviral therapy. Antiviral Res. 2013;98(2):266-72.

– Ribbens S, Goris N, Neyts J, Dewulf J. Classical swine fever outbreak containment using antiviral supplementation: a potential alternative to emergency vaccination and stamping-out. Prev Vet Med. 2012;106(1):34-41.

– Vrancken R, Paeshuyse J, Haegeman A, Puerstinger G, Froeyen M, Herdewijn P, Kerkhofs P, Neyts J, Koenen F. Imidazo[4,5-c]pyridines inhibit the in vitro replication of the classical swine fever virus and target the viral polymerase. Antiviral Res. 2008 Feb;77(2):114-9.

– Vrancken R, Haegeman A, Paeshuyse J, Puerstinger G, Rozenski J, Wright M, Tignon M, Le Potier MF, Neyts J, Koenen F. Proof of concept for the reduction of classical swine fever infection in pigs by a novel viral polymerase inhibitor. J Gen Virol. 2009 Jun;90(Pt 6):1335-42.

– Vrancken R, Haegeman A, Dewulf J, Paeshuyse J, Puerstinger G, Tignon M, Le Potier MF, Neyts J, Koenen F. The reduction of CSFV transmission to untreated pigs by the pestivirus inhibitor BPIP: a proof of concept. Vet Microbiol. 2009;139(3-4):365-8.