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1
This is an independent study
performed by students from the
Faculté des Sciences
Pharmaceutiques de Lille
The opinions expressed are our own
and not necessarily those of Ablynx
2
Summary
Ablynx’s presentation
Partie I
Ablynx’s Technology:
Nanobodies®
Partie II
Ablynx’s business strategy
Partie IV
Ablynx’s pipeline and drug
candidate
Partie III
Financial analysis
Partie V
3
Summary
Ablynx presentation
Partie I
Ablynx’s Technology:
Nanobodies®
Partie II
Ablynx’s business strategy
Partie IV
Ablynx’s pipeline and drug
candidate
Partie III
Financial analysis
Partie V
4
Ablynx presentation…
•Headquartered in Ghent, Belgium, Ablynx is a spin-off of the Flanders Interuniversity Institute for Biotechnology (VIB) and the Vrije Universiteit Brussel (VUB).
•Ablynx is based on the research of Prof. Dr. R. Hamers, S. Muyldermans and was co-founded and seed-financed (€ 2M) by GIMV* and Biotech Fund Flanders in 2001.
5 GIMV*: Gewestelijke Investerings Maastschappij Vlaanderen
Ablynx story begins more than 20 years ago…
•Ablynx is a biopharmaceutical company engaged in the discovery and development of Nanobodies®, a novel class of therapeutic proteins based on single domain antibody fragments, for a range of serious life-threatening humain disease
Corporate Overview
5 nanobody products now in the clinic – 3 phase II and 2 phase I
•Strong IP position > 550 patents (The « Hamers patents ») • > 250 staff •Listed on Euronext Brussels since November 2007
Market capitalization ~ €350M Cash at 30thSeptember 2010 -€109.5M
8 potential clinical “proof-of-concepts” in the next 3 years
•4 partnerships with leading pharmaceutical companies: Novartis, Pfizer, Boehringer Ingelheim and Merck Serono
Partie I
• >25 programmes in the R&D pipeline
7
Executive Management
Experienced and international management team
Chairman and Chief Executive
Officer
Chief Financial Officer
Chief Business Officer
Chief Medical Officer
Chief Scientific
Officer
8
Summary
Ablynx presentation
Partie I
Ablynx’s Technology:
Nanobodies®
Partie II
Ablynx’s business strategy
Partie IV
Ablynx’s pipeline and drug
candidate
Partie III
Financial analysis
Partie V
9
Ablynx’s Technology: Nanobodies®
Nanobodies ® are antibody-derived therapeutic proteins that contain the unique structural and functional properties of naturally-occurring heavy-chain antibodies.
The Nanobody technology was originally developed following the discovery that camelidae (camels and llamas) possess fully functional antibodies that lack light chains.
Conventional Antibody Heavy-Chain Antibody Heavy and light chains Both chains required for antigen binding and stability
Only heavy chains Full antigen binding capacity and very stable
10
Nanobodies – beyond antibodies and small molecules
11
Nanobodies combine the advantages of conventional antibodies with some features of small-molecule drugs.
The Nanobody platform has broad applicability…
•Growth factors & receptors •Transporters •Chemokines •Cytokines & receptors •Protease •Integrins •Immunoglobulins •Micro-organisms •Ephrin receptors •Enzyme targets •Fc receptor…
•Nanobodies have been raised against >190 different targets across multiple target classes and disease indications.
•Nanobodies have been tested in 28 different in vivo disease models for proof-of-concept studies.
12
Nanobodies can recognize less accessible epitopes than conventional Antibodies…
Stijlemans et al. JBC, 2004
heavy-chain Ab’s Nanobodies
Conventional Ab’s
•recognize variable epitopes
And •recognised conserved epitopes inacessible to conventional Ab’s
•only bind to variable epitope
13
Nanobodies – beyond antibodies and small molecules
14
Powerful Nanobody formatting features…
•Formatting is the linking together of two or more Nanobodies which:
Provides flexibility in creating novel new drugs
bind to same epitopes on single target
bind to different epitopes on target
bind to different target
15
Customized Half-life...
~2 hrs
~ 1-2
days
~ 2-3
days
~ 5-6
days
~ 5-11
days
Pegylation Nanobody targeting serum protein
Peptides targeting serum albumin
For chronic indications, molecule should remain in circulation for days, ideally customized according to the needs
Nexpedite technology
Direct albumin binding
16
Ablynx’s proprietary NExpedite™ technology
Small peptide specific for Human Serum Albumin (HAS)
•< 3KDa (limited loss of benefit of Nanobodies)
•simple genetic fusion
•multiple fragments can be fused to a Nanobody if needed •depending on the fragment used, the serum circulation time
of the Nanobody it is fused to can be tailored.
~2 hrs ~hours ~days
17
Nanobodies – beyond antibodies and small molecules
18
Potential for multiple routes of administration…
Nanobodies can be administered via injection, needle-free device (lyophilized), pulmonary,
intranasal, oral and should be administered via transdermal and ocular
Antibodies can only be administered via injection or SC
19
Nanobodies – beyond antibodies and small molecules
20
Production of Nanobodies®
To reduce the risk of immunogenicity Ablynx humanizes its Nanobodies
4. Extract mRNA, RT-PCR
5. Generate library of ~ 107
transformants
6. Select specific VHHs by panning
21
1. Immunize camel/llama with immunogenes
2. Collect blood
3. Isolate lymphocytes
Nanobody manufacturing short development timelines
Manufacturing costs are ~1/3 of typical production costs for mAb 22
Ablynx’s technology: Nanobodies®: Conclusion
The Nanobody platform
A next generation biologics To the clinic
Monoclonal antibodies Expensive to manufacture, half-life fixed
Roche/Genentech, Biogen, Amgen, Pfizer/Wyeth, Novartis, Merck, Boehringer-Ingelheim
Antibodies fragments Reducing size/cost of manufacturing, tailoring half-life & delivery
ESBAtech/Alcon, Trubion, Dyax, GSK/Domantis, Medimmune/CAT, Genmab, Wyeth/Haptogen, Affimed, Macrogenics
Alternative scaffolds Developing new platforms with Advantages over antibodies via stability, ease of manufacturing, broad target applicability
Dyax, BMS/Adnexus, Amgen/Avidia, Molecular Partners, Pieris, Anaphore
23
Ablynx presentation
Partie I
Ablynx’s Technology:
Nanobodies®
Partie II
Ablynx’s business strategy
Partie IV
Ablynx’s pipeline and drug
candidate
Partie III
Financial analysis
Partie V
Ablynx’s pipeline and drug
candidate
Partie III
Ablynx’s pipeline
A
Ablynx’s cardiovascular program
B
Ablynx’s immunology
program
C
Ablynx’s pipeline and drug
candidate
Partie III
Ablynx’s pipeline
A
Ablynx’s cardiovascular program
B
Ablynx’s immunology
program
C
Pipeline
24 Molecules in development
5 nanobodies in the clinic, 3 more expected during 2011 Therapeutic targets well known
Ablynx’s pipeline and drug
candidate
Partie III
Ablynx’s pipeline
A
Ablynx’s cardiovascular program
B
Ablynx’s immunology
program
C
Acute coronary syndrome (ACS) : ALX-081
Antithrombotic Strategies in Non-ST Elevation Acute Coronary Syndromes: Acute Coronary Syndromes: Definition, Prevalence & Patients at Risk
• Includes: Unstable angina, Myocardial infarction
• 2M coronary angioplasty carried out in the 7 major pharmaceutical markets* each year
• More than 1M hospital admissions in the USA annually
• Major public health concern
Acute Coronary Syndrom
• Anti-Von Willebrand Factor
• Bivalent
• Small size : 28 kDa
• Intravenous administration
• Manufactured in E. coli
• Phase II trials : Potential PoCs in
2011
Product characteristics
*USA, Japan, Germany, France, UK, Italy and Spain
ALX-0081
• Potentialy 1st in class GpIb • Act in first mover in cascade of thrombosis • Could prevent unwanted blood clot formation
Mechanism
Clinical trials in “high risk” patients with ACS undergoing a coronary angioplasty Compare with Reo-pro : GPIIb/IIIa inhibitors
First results
• Successful ALX-0081 Phase I study
Indicating the complete inhibition of vWF
Mediated effect on platelet aggregation and clotting in coronary arteries
• Excellent efficacy and safety profile in this patient study
• Phase II : started in sept 2009 Primary goal : show superiority in safety and equivalence in efficacy compared with ReoPro® primary endpoint bleeding data expected H2 2011
ACS market opportunity
Competitive with main approved drugs : • Glycoprotein IIb/IIIa receptor antagonist (Reo-Pro) had sales of >$500M in 2009
• Inhibitor of receptor P2Y12 (Plavix) in combination with aspirin.
• Coronary angioplasty treatment (Lovenox)
Heavy intracranial bleeding and abdominal bleeding associated with high doses of these anti coagulants significant area of unmet need for a new entrant.
Through 2018, the patent expiries of Merck/GlaxoSmithKline’s Integrilin, Merck/Medicure’s Aggrastat and Sanofi-Aventis’s Lovenox/Clexane
Potential partners for Ablynx
ADP : Adenosine Diphosphate
TTP Thrombotic thrombocytopenic purpura
• Idiopathic
• Secondary : associated with pregnancy, infections, autoimmune disease, malignancies and the use of drugs such as ticlopidine and clopidogrel
Acquired TPP ~90% of total
Congenital TPP ~10% of total
• Genetic mutation and ADAMTS13 gene
• Rare disorder of the blood-coagulation system
• Causing extensive microscopic thromboses
• Inhibition of the enzyme ADAMTS13 a metalloprotease cleaving multimers of von Willebrand factor into smaller units : decreasing their activity
• Plasma exchange is the most important component of treatment for TTP : normalization of platelets • Not painful but patients require frequent and lengthly hospital stay
• Mortality remains high (8-30%)
TTP Treatment / ALX-0681
• Anti-Von Willebrand Factor
• Bivalent
• Small size : 28 kDa
• Subcutaneous administration
• Manufactured in E. coli
• Phase II trials : Potential PoCs in
2013 Study started: September 2010
• Orphan drug designation from
the FDA and EMEA
ALX-0681 TTP Treatment
TTP
• Orphan Drug Designation
• Large unmet medical need
• Could provide first drug approved for use in TTP
• May significantly reduce hospitalization frequency
• May reduce number of transfusions
• Could significantly improve quality of life by an ease administration
ALX-0681 Potential
reduce cost
Clinical trials
Significant potentiel
Phase I : Complete in 2009
Phase II : Started in september 2010, Potential PoC in 2013 Endpoint : Time to recovery of blood markers (normalization of platelets)
Conclusion : Cardiovascular Program
• 2 pathologies : rare disorder and Major public health concern
• Phase I achieved
• Unmet medical need
• ALX-0081 : Potential PoCs in 2011
• ALX-0681 : Potential PoCs in 2013
• TTP : orphan drug designation
• 2 administration forms : - IV : safety and equivalence of efficacity
- SC : easy administration
Ablynx’s pipeline and drug
candidate
Partie III
Ablynx’s pipeline
A
Ablynx’s cardiovascular program
B
Ablynx’s immunology
program
C
Immunology : Rheumatoid Arthritis
• Chronic and progressive inflammatory disorder of the joints and
surrounding tissues Life long treatment
• Frequency : 0.5 -1.0% of adults in developed countries
• 5 % in women over age 55
RA Market Opportunity
• $ 23 billion in 2015 = World market for RA biologic therapeutics expected
Global Arthritis Market Review 2008 (World Top Ten RA Drugs)
11%
29%
51%
9%COXIB
NSAID + others
anti-TNF
DMARDs
Global market Arthritis 2008 = $35Bn
Anti-TNFα “Gold standard”
=> Sales in all indications in 2009 of > $19Bn
Anti-TNFα Market
In 2009, $6.5Bn sales in the Key Geographic Markets
Main Competitor :
Market leader, followed by Remicade® and then by Humira®
Global Arthritis Market Review 2008 (World Top Ten RA Drugs)
0
2
4
6
8
10
12
14
16
18
20
$Bn
TNFalpha
market
2006 2007 2008 2009
Nanobody vs competitor
• Small Size 28 kDa • Bivalent • Subcutaneous administration Potentialy Every 4 or 8 weeks • Potentially patients would not develop anti-drug antibodies • Relatively low cost of goods
ATN-103
• Size 150 kDa
• Bivalent
• Subcutaneous administration
Twice weekly or weekly
• Nearly 30% of patients develop anti-drug antibodies
• Produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system
Licensing Patent expiries
in 2012
Pre-clinical => Data showed more efficacity than enbrel®
ATN-103 : First results
Phase II started in September 2009 :
=> Trials in the US and Japan were initiated and enrolment completed in September 2010
If Pfizer proceed straight to Phase III, 2014 marketing authorization feasible
=> Royalty agreement means that this could be a very important revenue stream for Ablynx
Conclusion Pipeline
• Until now: No clinical failures and attrition
• Distinction by administration (PK) and safety
• Target well known no potential risk
• Uncertainty with the immunogenicity of the Nanobodies
• 3 molecule in phase II, never phase III for the moment
• 5 molecules in clinic and 3 more in 2011
• Success of Pre-clinical/Phase I programmes
Ablynx presentation
Partie I
Ablynx’s Technology:
Nanobodies®
Partie II
Ablynx’s business strategy
Partie IV
Ablynx’s pipeline and drug
candidate
Partie III
Financial analysis
Partie V
key elements
Leverage the advantages of the Nanobody technology broadly across a range of
therapeutic areas
Rapid target selection
Advance programmes internally to the optimal value creation point
Partner
Key element
Partie IV
Ablynx’s key partnerships
2007 2010 2006 2008 2009 2005
Jan
Dec
Sept Dec
Feb
Jul
Oct
May
Nov
Multi-target collaboration across several indications
options to license two of these programmes
TNFa research and licensing collaboration - $212.5 million plus royalties
selected a second Nanobody targeting TNFα that entered a Phase I clinical development.
Research and licensing collaboration on Alzheimer’s disease target - €206 million in milestones plus royalties
Strategic alliance worth up to €1.3 billion: 10 programmes with potential milestone payments up to €1.25 billion, plus royalties and co-promotion options in certain EU countries. In addition, up to €75 million including research-based payments, research milestones,
2 target 50/50 co discovery/ co-development collaboration (oncology & immunology). €10 million upfront fee and profit share on any products
BI selected a Nanobody lead candidate for further development for the treatment of Alzheimer’s disease.
agreed to collaborate to co-discover and co-develop Nanobodies against an inflammatory disease target.
POTENTIAL DEAL VALUE €2.2 billion in milestones and royalties
Ablynx’s platform is validated by partnerships with leading pharma compagnies
WHY Ablynx's balanced business model of internally
funded programs and partner supported programs allows the company to manage the
risks associated with such programs.
More than €117M in cash already received
Ablynx’s goal build a unique proprietary pipeline
Partnerships, fair’s fair…
•Upfront payments •Milestone payments •Royalties And •Annual licence payment
•Licenses rights •Provides scientific support, ressources and expertise
key elements
Leverage the advantages of the Nanobody technology broadly across a range of
therapeutic areas
Rapidly demonstrate proof-of-concept in the clinic
Advance programmes internally to the optimal value creation point
Partner
Key element
Partie IV
Balanced value creation
Ablynx Partners
70% R&D staff
dedicated to ablynx’s in-house programme
Only 30% of Ablynx’s
R&D staff dedicated to partnerships
98% of accessible
targets available for in-house pipeline
< 2% of accessible
targets partnered to date
Significant value creation
for the Ablynx pipeline
Potential value increased through partnered programmes
Ablynx presentation
Partie I
Ablynx’s Technology:
Nanobodies®
Partie II
Ablynx’s business strategy
Partie IV
Ablynx’s pipeline and drug
candidate
Partie III
Financial analysis
Partie V
Financial analysis
Partie V
Ablynx on the stock exchange
A
Ablynx’s revenues and expenses
B
How long will it last ?
C
Financial analysis
Partie V
Summary
Ablynx on the stock exchange
A
Ablynx’s revenues and expenses
B
How long will it last ?
C
Ablynx at the begining
From 2002 to 2006
Sofinnova Partners SAS (Fr) Gilde (Pays-Bas)
Alta (USA) Abingworth (RU)
Existant Shareholder
KBC et SR One (USA) Existant Shareholder
From 2007
IPO
Jan 2002
Ap 2004
Au 2006
€ 3M
€ 25M
€ 40M
TOTAL =
€ 68 M
Nov 2007
€ 86M
Shareholder at the end of 2009
18,77%
16,07%
11,12%
8,50%
Majority Shareholder
= 54,46%
Stock exchange prices
IPO Fund raising €85.2 million
Shares issued ≈ 10.7 M Aggregate number ≈ 34.7 M
€ 7.3 /share
Decrease and increase of the share value with the BEL20 Loss per share at the end of 2010 of € 0.58
€ 8.1 /share
SPO Fund raising €50 M
Shares issued ≈ 6.7 M Aggregate number ≈ 43.6 M
Financial analysis
Partie V
Summary
Ablynx on the stock exchange
A
Ablynx’s revenues and expenses
B
How long will it last ?
C
0
5
10
15
20
25
30
35
Mil
lion
s €
Grants
R & D
Revenues
R & D revenues from partnerships Upfront payment Milestones payment
29.683
1.09
16.755
9.920
3.969
0.844
31.432
0
10
20
30
40
50
60
Mil
lio
ns
€
General and administrative
R & D
Expenses
R & D expenses : ↗ €5.7 million in 2010 Personnel costs (224 employees in 2010 vs. 195 in 2009) External development (↗ €3.8 million due to clinical trials)
General and administrative : stabilised at €8.9 million
17.664
24.232
37.336
51.844
Preclinical
Phase I
Phase II
2006
ALX-0081
2007
ALX-0681 ATN-103
ALX-0081
2008
ALX-0061 ALX-0141
ALX-0081 ALX-0681 ATN-103
2009
ALX-0061 ALX-0171 ALX-0651
ALX-0681 ALX-0141
ATN-103 ALX-0081
2010
ALX-0651 ALX-0171 + 1
ALX-0141 ALX-0061 PF-
05230905
ALX-0081/ALX-0681 (TTP) ATN-
103
57.394
Loss for the year
Loss for the year balanced with the € 50 million from SPO
0
20
40
60
80
100
120
140
3,3 18,2 11,7
25,8
126,5113,6
92,3
115,9
Mill
ions
€
Cash
Cash
Cash
IPO € 85.2 million
In 2010 : € 85.500 in short term investments
SPO € 50 million
Financial analysis
Partie V
Summary
Ablynx on the stock exchange
A
Ablynx’s revenues and expenses
B
How long will it last ?
C
Ablynx at the end of 2010
Low non-current liabilities (€ 1.134 million in 2010 vs. € 0 in 2009)
Considerable cash (€ 115.9 million in 2010 vs. € 92.3 million in 2009)
Revenues €31.4 million
3 more deals in 2010
Reasonable loss for the year (excluding the SPO)
5 nanobody-based products in clinical trials (3 in phase II, 2 in phase I)
With €115.9 million in cash and with expenses growing from €50 million / year to €70 million, Ablynx could continue its activities
during approximately 2 years
63
SWOT Strengths
Opportunities
Weaknesses
Threats
Strengths
•Diverse and broad pipeline with 5 drugs in clinical trials •Potent technology platform that combines benefits of conventional monoclonal antibodies and small molecule drugs •Strong IP position > 550 patents •Partnerships with several major pharmaceutical companies to provide specialist expertise and finance for drug development and reduce risks •Lower cost manufacturing •Strong management with broad experience
Weaknesses
•Dependency on milestone payments to fund research activities •No track record in large clinical trial
64
SWOT Strengths
Opportunities
Weaknesses
Threats
Opportunities •Nanobodies can be administered through alternative delivery route •Nanobodies can recognize less accessible epitopes than conventional Antibodies •Innovative product •Strong growth in antibodies-based therapeutics market
Threats •Market for some therapeutic programmes highly competitive •Immunogenicity
65
ANY QUESTIONS? 66
67
Back-up
68
Competitors
Aug 2005 The Opposition Division of the European Patent Office upheld the key composition of matter claims for Nanobodies contained within EP 0 656 946, one of the Hamers Patents, following opposition proceedings initiated by Domantis.
Founded in 2000 Buy by GSK in 2006 treat many diseases including rheumatoid arthritis Anti-TNF
Oct 2009 Ablynx reached a settlement with Domantis
Feb 2010 Ablynx successfully opposed a half-life extension patent which had been granted to Domantis and that this patent had been revoked in full.
In 2006 : 13 proprietary therapeutic programs 9 partnered therapeutic programs (Bristol Myers Squibb,Abbott)
69
contract manufacturer for protein, antibody and immunodiagnostic solutions
Competitors
designed to support research and development
utilizes a multi-tiered protein expression platform which consists of bacterial, yeast and mammalian expression systems v
antibody production
Shark Antibody
70
Needle-Free
•It works by forcing liquid medication at high speed through a tiny orifice that is held against the skin.
•This creates an ultra-fine stream of high-pressure fluid that penetrates the skin without using a needle.
•Injections can be IM, SC or ID
IM SC ID How does it works
Device advantages
•Better patient compliance – no needle-phobia •Superior safety by removing the potential of a needlestick injury •Speed of Injection •Easy transport…
71
Nanobodies – beyond antibodies and small molecules
Nanobodies may have the potential to be given to patients as an inhaled drug, as a skin patch or as a pill.
Nanobodies have been raised against >190 different targets.
Nanobodies can be made quickly and cost effectively, because they are simple and stable molecules.
Nanobodies are small, 1/10 of the size of a conventional antibody, and so can penetrate tumours and other diseased tissue better.
Nanobodies can be linked together to generate tailor-made therapeutics for acute and chronic diseases..
72
Production of Nanobodies®
To reduce the risk of immunogenicity Ablynx humanizes its Nanobodies
4. Extract mRNA, RT-PCR
5. Generate library of ~ 107
transformants
6. Select specific VHHs by panning
73
1. Immunize camel/llama with immunogenes
2. Collect blood
3. Isolate lymphocytes