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
2
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
3
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
4
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
5
FMD control measures
Prophylactic vaccination (conventional vaccines) 1990
• Ban on prophylactic vaccination• Pre-emptive culling• Emergency vaccination (DIVA)
6
7
8
9
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
10
FMDV hit screening – Unique collaboration
70,000 compounds
[Willems et al., 2011]
11
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
√
√
12
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
13
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]
14
Classical swine fever
15
CSF control measures
Prophylactic vaccination (conventional vaccines) 1990
• Ban on prophylactic vaccination• Pre-emptive culling• Emergency vaccination (DIVA)
16
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
17
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.
18
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
19
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.
20
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.
21
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.
22
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.
23
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
24
Co
stto
auth
ori
ties
(no
tre
imb
urs
edb
yEU
Vet
erin
ary
Fun
d)
Co
sts
tofa
rmer
sC
ost
sto
auth
ori
ties
(rei
mu
brs
edb
yEU
Vet
erin
ary
Fun
d)
• Costs of trade restrictions
• Costs of ripple effects
• Costs of spill-over effects
Co
sts
toau
tho
riti
es(r
eim
ub
rsed
by
EU V
eter
inar
yFu
nd
)C
ost
toau
tho
riti
es(n
ot
reim
bu
rsed
by
EU V
eter
inar
yFu
nd
)
Co
sts
tofa
rmer
s
• 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
25
Simulating CSF outbreaks in The Netherlands
Economic aspects
0
200
400
600
800
1000
692
185
53 6558
Dir
ect
Co
sts
(M€
)
* 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
26
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
27
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.