Corporate Presentation

Corporate Presentation
September 2016
Forward Looking Statements
This document does not constitute or form part of any offer or invitation to sell or issue, or any solicitation
of any offer to purchase or subscribe for, any shares in the Company, nor shall any part of it nor the fact of
its distribution form part of or be relied on in connection with any contract or investment decision relating
thereto, nor does it constitute a recommendation regarding the securities of the Company.
This document may contain forward-looking statements and estimates made by the Company, including
with respect to the anticipated future performance of TiGenix and the market in which it operates. They
include all matters that are not historical facts. Such statements, forecasts and estimates are based on
various assumptions and assessments of known and unknown risks, uncertainties and other factors,
which were deemed reasonable when made but may or may not prove to be correct. Actual events are
difficult to predict and may depend upon factors that are beyond the Company's control. Therefore, actual
results, the financial condition, performance or achievements of TiGenix, or industry results, may turn out
to be materially different from any future results, performance or achievements expressed or implied by
such statements, forecasts and estimates. Forward-looking statements, forecasts and estimates only
speak as of the date of this document and no representations are made as to the accuracy or fairness of
such forward-looking statements, forecasts and estimates. TiGenix disclaims any obligation to update any
such forward-looking statement, forecast or estimates to reflect any change in the Company’s
expectations with regard thereto, or any change in events, conditions or circumstances on which any such
statement, forecast or estimate is based.
2
Management Team With Proven Track Record of Success
Managing Director and CEO: Eduardo Bravo, MBA
•
More than 25 years experience in the pharma and biotech industries at Sanofi-Aventis, Recordati,
Cephalon and SmithKline Beecham. With company since: July 2005
CFO: Claudia D’Augusta, PhD
•
More than 15 years experience in equity and debt financing at Aquanima (Santander Group), Apax
Corporate Finance and Deloitte Corporate Finance. With company since: April 2004
CTO: Wilfried Dalemans, PhD
•
More than 25 years experience in the pharma and biotech industries; previous engagements at GSK
Biologicals and Transgène. With company since: April 2007
CMO: Marie Paule Richard, MD
•
More than 25 years experience in the global pharma and biotech industries at Bristol-Myers Squibb,
Sanofi Aventis, GSK, Sanofi Pasteur, Crucell and AiCuris. With company since: September 2014
VP Regulatory Affairs & Corporate Quality: María Pascual, PhD
•
More than 10 years experience in cell therapy companies; specialized in regulatory affairs for
advanced therapies; external adviser to EMA. With company since: July 2003
VP Medical Affairs & New Product Commercialisation: Mary Carmen Diez, MD
•
More than 20 years experience in the biopharmaceutical industry at Meda Pharma, Asta Médica,
Pfizer and Dupont Pharma. With company since: September 2014
3
Key Facts About TiGenix
Headquarters / Operations
Leuven, Belgium / Madrid, Spain
Employees
Approximately 75 employees
Stock Exchange
Euronext Brussels. Ticker: TIG
Market Capitalization
Approx. EUR 190M September 20, 2016
Reference Shareholders
Grifols (~16%); Cormorant Asset Mgmt. (~6%); BNP Paribas (~4%)
Liquidity
~80% free-float, of which ~30% held by institutional investors
Analyst Coverage
5 analysts covering the stock
Cash and Cash Equivalents
EUR 24.1M at June 30, 2016
Last Capital Increase
EUR 23.8M raised from US and EU investors in March 2016
License Agreement
EUR 25M upfront received July 2016
EUR 10M equity investment can be called at any time until June 2017
4
Compelling Investment Case
• Complex perianal fistulas in Crohn’s disease patients in United States & EU is a multi-billion
dollar opportunity
• Pivotal Phase III (local administration of a single dose of allogeneic adipose derived stem cells)
Cx601: Global
Agreement Ex-US
with Takeda
• Primary endpoint met. Cx601 statistically superior to placebo in achieving combined remission
at week 24 (p=0.024)
• Long term efficacy sustained at week 52 on same endpoint (p=0.019)
• MAA submitted to EMA in 1Q16. Decision expected 2017
• GMP process approved for commercial manufacturing by Spanish Agency in 1Q16.Takeda will
co-invest in the expansion of the Madrid facility to secure supply for the initial few years
• Up to €380M agreement with Takeda for the exclusive ex-US rights to Cx601 for the treatment of
complex perianal fistulas in Crohn’s disease patients
• Use of data from positive pivotal Phase III trial in EU to support a BLA in the US
Cx601: Clear
pathway to US
market
• FDA’s agreement on SPA obtained for pivotal phase III trial in the US
• Same primary endpoint as positive EU Phase III trial
• US Phase III to start 1H17
• Fully-owned asset; granted patent valid until 2030
• Lonza selected as contract manufacturing organization for Cx601 in the US
Valuable Pipeline
Opportunities:
AlloCSC-01 and
Cx611
• AlloCSC-01: intra-coronary administered allogeneic cardiac stem cells, being developed for acute
myocardial infarction
• Randomized, double blind, placebo controlled Phase II trial ongoing
• Interim 6 months data confirmed safety. Final one-year follow up data expected 1H17
• Cx611: Intravenously-administered allogeneic adipose derived stem cell product for severe sepsis
• Phase I study completed
• Severe sepsis Phase I/ll trial design has been finalized; expected to enroll first patient in 2H16
1 Advanced
Therapy Medicinal Product
5
Cx601
Local injection of expanded Adipose-derived Stem Cells
(“eASCs) for the treatment of complex perianal fistulas in
Crohn’s disease patients
6
Cx601 Inhibits Pro-inflammatory Cytokines
Mechanism of Action (“MoA”) is IDO1-Mediated
Inhibition of pro-inflammatory cytokines
IFN- (ng/ml)
0 5 10 15 20
TNF- (ng/ml)
0 1 2 3 4 5
Key Characteristics of Cx601
Cx601
PBMCs
Activated PBMCs
PBMCs+Cx601
Actiivated PBMCs+Cx601
*
*
• Cx601 has the ability to balance an inflammatory
milieu, through the reduction of PBMC2 mediated
secretion of pro-inflammatory cytokines among
other immunological processes
* p<0.05 relative to supernatant from activated PBMCs
Inhibition of Immune Cell Proliferation
Inhibits pro-inflammation
• IDO is key to the immunomodulatory properties of
Cx601, as shown here by its effect on PBMC
proliferation
* p<0.05 relative to activated PBMCs
without ASCs
Source: Tigenix
data
IDO Mediated
Activated PBMC + Cx601
2
1 IDO: Indoleamine 2,3-dioxygenase
PBMC: Peripheral Blood Mononuclear Cells
Source: De la Rosa et al. Tissue Engineering 2009
7
GMP Facility in Madrid Approved for Commercial Manufacturing
Takeda1 Will Endeavor to Take Over Manufacturing ex-US
Manufacturing Capabilities
Consistent and Robust Process
• Production facility in Madrid approved for
commercial manufacturing
1 Liposuction
• Current capacity is about 400 patient lots of
finished product per year
• TiGenix will initially supply Cx601 to Takeda
at cost for the EEA2 and Switzerland (CH)
• Takeda will co-fund the expansion of the
Madrid facility to secure supply for the initial
few years
• Takeda will endeavor to take over
manufacturing to leverage on a global
supply network
2,400 Finished Products (Cx601)
• Outside of the EEA and CH, Takeda is
responsible for manufacturing from July
2016
• Takeda will be fully responsible for
distribution and logistics in the whole
Territory
2
1 In July 2016 TiGenix and Takeda entered into an exclusive Ex-US Licensing Agreement for Cx601
EEA stands for European Economic Area, it includes all 28 states currently part of the European Economic
Area as well as the three states Iceland, Lichtenstein and Norway
8
A Common and Severe Complication of Crohn’s Disease
Complex Perianal Fistulas Affect 1 in 12 Adult Crohn’s Disease Patients
120,000 adult patients in Europe and the US alone
•
Complex fistulas are sores or
ulcers that tunnel through the
affected area into surrounding
tissues, and that:
•
•
•
•
Fistula
•
Affect anal sphincters
Present multiple tracts
Are recurrent
Are often associated with
perianal abscess
Complex fistulas cause
compromised Quality of Life
(QoL), pain, depression and risk
of anal epithelial carcinoma
Fistula
9
Treatments Lack Long Term Efficacy and Present Safety Issues
• Optimal management remains challenging
• Little progress due to limited trials and poorly validated endpoints
• Clear gap for a clinically validated treatment with long term efficacy
Treatment options
Benefit
• Improve symptoms and short term
healing
Antibiotics
Immunosuppressants
Shortfall
• High relapse on cessation1
• Safety concern with prolonged use
• Moderate benefit reported
• High relapse on cessation2,3
• Limited clinical trial data
• Risk of infectious complications
• Low remission4,6 and high relapse4,5
Anti-TNFs
Infliximab- Remicade®
Adalimumab - Humira®
• Moderate benefit in clinical trials
• Eliminating risk of recurrence is possible
with radical, mutilating surgery7,8
Surgery
1
2
3
4
5
6
7
8
9
• Safety concern with long term use and
systemic immunosuppression
• Conservative surgery risks recurrence
• Risk of complications (incontinence, non
healing wounds, abscesses)8,9
L.J. Brandt et al. Metronidazole Therapy for Perineal Crohn’s Disease: a Follow-Up Study, 83 GASTROENTEROLOGY 383-7 (1982)
E.S. Goldstein et al., 6 - Mercaptopurine Is Effective in Crohn’s Disease Without Concomitant Steroids, 10 INFLAMM BOWEL DIS 79-84 (2004)
B.I. Korelitz et al., Favorable Effect of 6-Mercaptopurine on Fistulae of Crohn’s Disease, 30 DIGEST DIS SCI 58-64 (1985)
B.E. Sands et al., Infliximab Maintenance Therapy for Fistulizing Crohn’s Disease, 350 N ENGL J MED 876-85 (2004)
E. Domenech et al., Clinical Evolution of Luminal and Perianal Crohn’s Disease after Inducing Remission with Infliximab, 22 ALIMENT PHARMACOL THER 1107-13 (2005)
J.F. Colombel et al., Adalimumab for Maintenance of Clinical Response and Remission in Patients with Crohn’s Disease: The CHARM Trial, 132 GASTROENTEROLOGY
52-65 (2007)
C.B. Geltzeiler et al., Recent Developments in the Surgical Management of Perianal Fistula for Crohn’s Disease, 27 ANN GASTROENTEROL 1-11 (2014)
T. Sonoda et al., Outcomes of Primary Repair of Anorectal and Rectovaginal Fistulas Using the Endorectal Advancement Flap, 45 DIS COLON RECTUM 1622-28 (2002) 10
A. Soltani and A. Kaiser, Endorectal Advancement Flap for Crypto Glandular or Crohn’s Fistula-in-Ano, 53 DIS COLON RECTUM 486-495 (2010)
Cx601: A Completely Different Approach; A Single Dosage
Suspension of Expanded Adipose-derived Stem Cells (“eASC)
Product description
Four (4) vials of 6ml suspension, each with
30 million cells (total dose 120 million cells)
Mode of Administration
• Fistula curettage and closure of internal
opening (sutured)
• Half of Cx601 dose (2 vials) injected into
tissue around internal opening (small blebs)
• Other 2 vials injected along the walls of the
fistula tracts (several small blebs)
a. Fistula internal opening
Injection sites:
b. Fistula tract
Injection sites:
11
Phase III ADMIRE-CD1 Trial
Double-Blind, Placebo-Controlled, Designed to Qualify as a Single Pivotal Study
Trial Summary
Study design
• Randomized, double-blind,
placebo-controlled trial
• All tracts treated. Single
procedure2
Number of
sites
47 active sites in 8 countries
Enrollment
289 patients recruited
Primary
endpoint
Combined Remission3 at week 24
with α<0.025 for all existing
fistulas
Secondary
endpoints at
Weeks 24
and 52
•
•
•
•
Combined Remission at week 52
Clinical Remission4
Response5
Time to Clinical Remission / to
Response
• PDAI6 and other scores
• Safety and tolerability
Patients selected to ensure clear cut-off results
•
Men and women aged 18 years or older
•
Non active or mildly active luminal Crohn’s
disease (CDAI ≤ 220) diagnosed for ≥ 6
months
•
Patients with complex perianal fistulas with
≤ 2 internal openings and ≤ 3 external
openings
•
Fistula draining ≥ 6 weeks prior to inclusion
•
Patients with inadequate response to at
least one of the following: antibiotics,
immunosuppressants or anti-TNFs
•
Medical standard of care was allowed to
continue without modification of treatment
dose or regimen
Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulising Crohn’s Disease
million cells
3 Closure of all treated external openings draining at baseline despite gentle finger compression, and absence of collections > 2cm by MRI (Magnetic Resonance Imaging)
4 Closure of all treated external openings draining at baseline despite gentle finger compression
5 Closure of at least 50% of all treated external openings draining at baseline despite gentle finger compression
6 Perianal Disease Activity Index
1
2 120
12
Clinical and MRI Combined Primary Endpoint at Week 24
Long Term Follow-Up for Persistence (Week 52) and Safety (up to Week 104)
Screening
Preparation
W-5
W-3
Treatment
D0
Primary Endpoint
W6
W12
W18
W24

Follow-Up
W36

W52
W104
week
Randomization
Baseline
MRI
Clinical Assessment
W24
MRI
W52
MRI
MRI: Magnetic Resonance Imaging
13
Cx601 Phase III Patient Populations
Largest Ever Study in Complex Perianal Fistulas
Screened
n=289
• 43 Wrong Inclusion /
Exclusion criteria
Screening
Failures
n=77
• 20 Other3
• 12 Informed Consent
Withdrawn
ITT 1 set
n=212
Randomized
n=212
• 2 (Serious) Adverse
Events
Cx601
n=107
Placebo
n=105
• 1 Informed Consent
Withdrawn
• 1 Reoccurrence of
Crohn’s Disease
Not
Treated
n=4
• 1 Deep Vein
Thrombosis
• 1 Informed Consent
Withdrawn
Treated
n=103
Treated
n=102
Not
treated
n=3
• 1 No Longer Met
Inclusion Criteria
• 1 Did Not Have Postbaseline Efficiency
Evaluation
• 1 Missing Data
Safety Set 2
n=205
1 ITT:
Intention To Treat i.e. patients randomized
Safety Set: patients randomized and treated
procedures for other reasons than fistulas; Fistulas not healing/worsening of fistula symptoms; No tract found or additional blind tract found by the surgeon
during preparation visit; Impossibility to administer 12 ml into the tract or to identify the primary opening; Fistula closed, etc
2
3 Surgical
14
Good Balance Among Groups Except for Topography of Fistulas
Cx601 Group Contained More Difficult to Treat Patients
• Similar demographics and PDAI1 score between arms
• Higher proportion of multiple-tract fistulas in Cx601 group
Cx601
Placebo
n= 107
n= 105
39.0 (13.1)
37.6 (13.1)
Men (%)
60 (56.1)
56 (53.3)
Caucasian (%)
100 (93.5)
96 (91.4)
Weight (kg) mean (SD)
73.9 (15.0)
71.3 (14.9)
6.8 (2.5)
6.6 (2.9)
51.4
44.8
67.7
29.6
Demographics (ITT)
Age (years) mean (SD)
PDAI (ITT)
Mean (SD)
Topography of Internal &
External Openings (%) (ITT) 2
One-tract fistula
Multiple-tract fistula*
* Primary endpoint measured combined remission on all tracts
1 Perianal Disease Activity Index
2 Fistula topography not available in seven (7) patients (4 in Cx601, 3 in Placebo)
15
Primary endpoint met at week 24
Benefit Sustained at Week 52
%
60
40
• Primary endpoint met: Combined remission at W24 was
44.3% higher in treated patients versus placebo (p=0.024)
Combined Remission at W24
(ITT1 Population n= 212)
p = 0.024
49.5%
34.3%
20
0
60
Combined Remission at W52
(ITT1 Population n= 212)
p = 0.012
54.2%
• Benefit maintained at W52: Combined remission was 46%
higher in treated group versus placebo (p=0.012)
40
37.1%
20
0
80
• 75.0% of Cx601 treated patients who achieved combined
remission at week 24 remained in combined remission at
week 52 compared to only 55.9% in the placebo arm
60
Sustained Remission at W52
75.0%
55.9%
40
20
0
Cx601
1 ITT:
Intention To Treat i.e. patients randomized. Efficacy results are consistent across all statistical populations
Placebo
16
Faster Time to Remission
Cx601 Achieves Remission Twice as Fast as Placebo
• Cx601-treated patients achieved Clinical Remission after 6.7 weeks 50% sooner that
placebo-treated patients
• The placebo-treated patients achieved Clinical Remission after 14.6 weeks (HR 1.75, 95%
CI (1.27-2.44))
ITT Population1 n=212
1 ITT:
Intention To Treat i.e. patients randomized
17
Safety Profile Maintained Over the Long Term
Product is Free From Serious Side Effects of Biologic Treatments
Overview of TEAEs up to Week 24 & Week 52 (Safety population n= 205)
Number of Patients with (%)
*TEAEs
Related TEAEs
Withdrawn due to a TEAEs
**TESAEs
Related TESAEs
Withdrawn due to TESAEs
Cx601
Placebo
n= 103
n=102
W24
W52
W24
W52
68 (66.0)
79 (76.7) 66 (64.7)
74 (72.5)
18 (17.5)
21 (20.4) 301 (29.4) 271 (26.5)
5 (4.9)
9 (8.7)
6 (5.9)
9 (8.8)
18 (17.5)
25 (24.3) 14 (13.7)
21 (20.6)
5 (4.9)
7 (6.8)
7 (6.9)
7 (6.9)
4 (3.9)
6 (5.8)
4 (3.9)
7 (6.9)
Note: If a patient has multiple events of the same severity, relationship or outcome, then they are counted only once in that severity,
relationship or outcome. However, patients can be counted more than once overall.
*Most common TEAEs: Anal Abscess; Proctalgia; Nasopharyngitis; Diarrhoea; Abdominal pain; Pyrexia
**TE(S)AE: Treatment-Emergent (Serious) Adverse Events
1 Figures are cumulative; however prior AEs reevaluated at W52 as non-related are not adjusted retroactively.
18
Cx601: Communication of ADMIRE-CD Results
ECCO1 2016 (Amsterdam, 16-19th March 2016)
Oral presentation in Plenary Session by
Dr. Panés (March 17, 2016)
Satellite Symposium chaired by
Dr. Van Assche (March 18, 2016)
1European
Crohn’s and Colitis Organization
19
Cx601: Communication of ADMIRE-CD Results
ECCO 2016 (Amsterdam, 16-19th March 2016)
20
Cx601: Communication of ADMIRE-CD Results
DDW 1 2016 (San Diego, 21-24th May 2016)
ADMIRE-CD results presented at the DDW session dedicated to Controlled Clinical Trials
in Inflammatory Bowel Diseases on May 24, 2016
“Cx601 has proven to be a novel approach to treat complex perianal fistulas, for
which there is still no cure. In the US alone, 30,000 patients are waiting for an
effective treatment for this debilitating disease”
- Dr. William J. Sandborn
Digestive Disease Week, the world’s largest congress gathering physicians and researchers in the fields of gastroenterology, hepatology, endoscopy and
gastrointestinal surgery
1
2
Dr. W. J. Sandborn is Professor of Medicine and Adjunct Professor of Surgery, Chief of Gastroenterology, and Director of the UCSD Inflammatory Bowel Disease
Center, University of California San Diego and UC San Diego Health System, San Diego. Dr. Sandborn, Chairman of TiGenix’s US Scientific Advisory Board
21
Cx601: Communication of ADMIRE-CD Results
The Lancet (published online July 28, 2016)
22
Cx601: A Regulatory De-Risked Asset
MAA1 Already Submitted to EMA2 Aiming for Approval in 2H17
Clear and fast pathway to the market built on a solid regulatory strategy
•
Team with previous experience in obtaining MA3 of cell therapy product
•
5 Scientific Advice Meetings held with EMA (2 pre-clinical, 2 CMC4, 1 clinical)
•
Approved PIP5 with 20 patients to be started not before 2020
•
GMP license for commercial manufacturing granted in 1Q16
•
MAA submitted in 1Q16
•
Assuming industry-average clock stops, final approval expected in 2H17
D1

MAA
Submitted
1Q2016

Start of the
procedure
D80
D120


AR6
LoQ7
1st Clock
Stop
D121
Responses
D150
Joint AR
D180
2nd Clock
Stop
LoOI8
D181
Responses
1
6 AR:
2 EMA:
7 LoQ:
MAA: Marketing Authorization Application
European Medicines Agency
3 MA: Marketing Authorization
4 CMC: Chemistry Manufacturing and Controls
5 PIP: Pediatric Investigational Plan
D210
CHMP9
Opinion
D277
European
Comission
Decision
Assessment Report
List of Questions
8 LoOI: List of Outstanding Issues
9 CHMP: Committee of Human Medicinal Products
(EMA)
23
Cx601’s Approach to the US Market
Leveraging EU Data With Approved Phase III Protocol
• Preparing for US BLA1 Filing with clear pathway to US Market
• Solid regulatory and clinical development strategy
•
•
Type B meeting with FDA2 confirmed:
•
Adequacy of existing non-clinical package to support an IND3 filing
•
Acceptability of using data from the ADMIRE-CD trial to support BLA
SPA4 for US Phase III protocol agreed with FDA:
•
Primary end-point identical to ADMIRE-CD trial
•
p-value < 0.05 (vs. p-value <0.025 in ADMIRE-CD trial)
• US Phase III trial scheduled to start by 1H17
• Lonza selected as contract manufacturing organization for Cx601 in the US,
technology transfer ongoing
1 BLA:
Biological License Application
Food and Drug Administration
3 IND: Investigational New Drug
4 SPA: Special Protocol Assessment
2 FDA:
24
Cx601: Estimated Potential Patient Population (EU & US)
An Attractive Commercial Opportunity
Crohn’s Disease Patients *1-9 = 1.540.710
93% 7,8
Adult Crohn’s Disease Patients = 1,432,860
11% 10-17
Non-Perianal fistulas = 109,529
(41% of fistulas are not perianal 13,14)
Perianal fistulas = 157,615
75%15,18
Complex fistulas
# of cases = 118,211
66%19
Controlled luminal CD
# of cases = 78,019
25%
• A total of 267,144 CD patients experience fistulas
• 34-61% of CD patients with fistulas experience ≥ 2
fistulizing episodes13,14 or 90,829 - 162,958 patients
Simple fistulas
# of cases = 39,404
• 33% of CD patients with perianal fistulas experience
≥ 2 fistulizing episodes13 or 52,013 patients
34%
Non-Controlled luminal CD
# of cases = 40,192
1
2
3
4
5
90%19, 20
Refractory fistulas
# of cases = 70,217
10%
Non-refractory fistulas
# of cases = 7,802
6
7
Stone MA et al. 2013
8 Kappelman MD et al. 2013
Hein R et al. 2014
9 Molodecky NA et al. 2012
Lucendo AJ et al. 2014
10 SEESGCD.19
Dal Pont E et al. 2010
11 Gibson PR et al. 2007
Cottone M et al. 2006
12 Dranga M et al. 2015
Herrinton LJ et al. 2007 13 Schwartz DA et al. 2002
Kappelman MD et al. 200714 Bell SJ et al. 2003
15
Eglinton TW et al. 2012
Gray BK et al. 1965
17 Galandiuk S et al. 2005
18 Molendijk I et al. 2014
19 Sands BE et al. 2004
20 Domènech E et al. 2005
16
(Further details on references provided in Appendix )
* Estimated prevalence in US: 190/100,000
(average from US nationwide studies comprising study periods post year 2000) 6-9
Estimated average prevalence in EU: 180/100,000
(no nationwide studies available; average of regional studies conducted in EU5
comprising study periods post year 2000, weighed by country populations) 1-5, 9
25
Cx601: Pricing Considerations
Lower Prevalence Would Suggest Higher Price
Prevalence per 10,000 patients vs. prices for selected drugs
Soliris
€450
Orphan drugs
Non-orphan drugs
€350
Kalydeco
€400
Zavesca
€300
€250
Samsca
Xyrem
Tysabri
Esbriet
€100
Revolade
€150
Adempas
€200
Kuvan
Ex-manufacture price per year (000) 1
€500
€50
€0
0
1
2
3
4
5
6
7
8
9
10
Ex-manufacturer prices per patient per year, including mandatory published discounts, obtained from CMS, L’Assurance Maladie, G-BA, Gazzetta
Ufficiale, Spanish MoH, British National Formulary. $1 = €0.90. Indications for select products: Kalydeco, G551D-mutation cystic fibrosis; Kuvan,
Phenylketonuria; Adempas, Chronic thromboembolic pulmonary hypertension; Revolade, Low blood platelet count in adults with chronic immune
thrombocytopenic purpura; Esbriet, idiopathic pulmonary fibrosis. Full list of references provided at back.
1
26
Takeda exclusive Ex-US Licensing Agreement for Cx601
Takeda Pharmaceutical Company Limited
A Global Leader in GI
• Global R&D driven pharmaceutical company committed to bringing better health and a
brighter future to patients by translating science into life-changing medicines. Takeda
focuses its research efforts on oncology, gastroenterology and central nervous system
therapeutic areas
• More than 30,000 Takeda employees are committed to improving quality of life for
patients, working with partners in health care in more than 70 countries.
• Takeda currently has a number of promising early stage GI assets in development, and
remains committed to delivering innovative, therapeutic options for patients with
gastrointestinal and liver diseases
• ENTYVIO® (vedolizumab) demonstrates Takeda’s global capabilities and expansion into
the specialty care market in gastroenterology and biologics.
Cx601 ties into Takeda’s GI focus, with clear
synergies with ENTYVIO®
28
Licensing Agreement with Takeda
Summary of Key Terms
• Takeda acquires the exclusive ex-US rights to Cx601 for the treatment of complex perianal
fistulas in Crohn’s disease patients. US market to be estimated at 50% of Cx601 global
market. TiGenix retains the right to develop Cx601 in new indications
• Upfront payment for EUR 25M; EUR 10M equity investment within 12 months, discretionary
on TiGenix
• TiGenix eligible to receive additional regulatory and sales milestones for up to EUR 355M
• Double-digit royalties on net sales, tiered to reimbursement price (increased by 2% if annual
net sales were to be > EUR 500M)
• No compete clause: Takeda can not develop adipose-derived stem cells products nor any
therapy for the treatment of complex perianal fistulas in Crohn’s disease patientes
• Takeda to become Marketing Authorization Holder (MAH) upon obtaining the Marketing
Authorization in the European Economic Area (EEA). Takeda to co-fund the expansion of
the current manufacturing facility to serve initial product supply after launch and Takeda to
become responsible for manufacturing Cx601 thereafter
29
Cell Therapy Product Deals to Date
The Largest “Product” Licensing Deal in Cell Therapy
Deal
Indication/ Phase
TiGenix licenses Ex-US
rights of Cx601 to
Takeda (2016)
Complex Perianal
Worldwide
Fistulas in Crohn’s
Ex-US
disease patients; MAA
submitted to EMA
Mesoblasts acquires
MSC business from
Osiris (2013)
Janssen options rights
to CAP-1002 from
Capricor (2014)
Chugai licenses
Multistem from
Athersys (2015)
United Therapeutics
licenses PLX-PAD
from Pluristem (2011)
Territory
Upfront
€25M
€10M in
equity
Total deal
Comments
Up to
€380M
TiGenix maintains 100% rights
to US market, (≈50% market)
and full rights to develop Cx601
in new indications
> 50% potentially payable in
stock
Prochymal: Acute
GvHD in children
(approved in
Canada and NZ)
Large myocardial
infarction (in Ph. II)
Worldwide
$20M
$100M
Worldwide
$12.5M
Up to
$337.5M
Ischemic stroke (in
Ph. II)
Japan
$10M
Up to
$205M
Pulmonary
hypertension
(in Ph. I)
Worldwide
$7M
$55M
Exclusive right to license CAP1002 at any time until 60 days
post 6-month follow-up data
from Phase II
Agreement ended by UT
December 2015
30
Cx601 a Major Breakthrough
Clear Plan to Secure Even Further Upside
•
Cx601 addresses a severe and common unmet need in Crohn’s Disease
•
Current treatment options lack long term efficacy and present safety concerns
•
European Phase III clinical trial results show clear superiority in efficacy vs. standard of
care with just one single treatment
•
Clinical effect is significantly quicker and efficacy persists at 52 weeks
•
Industry recognition: ECCO, DDW, and publication in The Lancet
•
Product has good safety profile and is easy to administer
•
Approval and launch in Europe expected 2H17
•
Signed up to EUR 380M ex-US licensing agreement with Takeda Phamacutical
•
US Pivotal Phase III trial agreed with FDA (SPA) to start 1H17
31
AlloCSC-01: Phase ll Data
To Be Announced 1H 17
Intracoronary administration of allogeneic cardiac stem cells for the
treatment of acute ischaemic heart disease
32
AlloCSC-01: Preventing Chronic Heart Failure
Myocardial Repair May Be The Only Feasible Alternative
•
1.9M Acute Myocardial Infarctions (US+EU)1 occur annually, mostly treated by PCI2 and stent
implantation
•
Successful treatment of Acute Myocardial Infarctions (“AMI”) has increased short term survival
but contributed to a Chronic Heart Failure (CHF) epidemic (26M patients worldwide3)
•
CHF post-AMI is a terminal disease with an annual mortality rate of ~5% after the first
episode, for which no curative treatment exists with the exception of heart transplantation
Myocardial repair is the only
feasible treatment to
address the post-acute
phase of the disease and
prevent the onset of CHF
1 Datamonitor:
2
3
Stakeholder Insight: Acute coronary syndromes, DMHC2347, 2007
PCI: Percutaneous Coronary Intervention
Ambrosy PA et al., J Am Coll Cardiol. 2014;63:1123-1133.
33
AlloCSC-01: Efficacy Demonstrated in Pig Model
• AlloCSC-01 prevents cardiac remodelling after infarction preserving heart function
• AlloCSC-01 reduces scar size promoting formation of new contractile tissue
• Significant dose effect observed
Efficacy Data from MRI1
CARDIAC FUNCTION
CARDIAC REMODELING
2
Histological Analysis
3
CONTROL
4
*
*
*
AlloCSC-01
* p-value < 0.05
1
MRI: Magnetic Resonance Imaging
EDVi: End-Diastolic Volume Index
ESVi: End-Systolic Volume Index
4 EF: Ejection Fraction
2
3
34
CAREMI Phase I/II Trial Final Results Expected 1H17
Safety and Efficacy of Intracoronary Infusion of Allogeneic Cardiac Stem Cells in
Patients with Acute Myocardial Infarction (“AMI”)
PATIENT SELECTION
Initial clinical pre-screening:
TRIAL SUMMARY
Condition
Acute Myocardial Infarction
Study design
AlloCSC-01 administered 5-7 days after
PCI4
• Phase 1. Open label dose escalation
in 6 patients
• Phase 2: Placebo controlled, 49
patients randomized 2:1 (35M cell
dose in active arm)
Recruitment
• Phase 1: Completed
• Phase 2: Completed recruitment in
4Q15
• Bare-metal stents or second generation drug
eluting stent at PCI
# of centers
8 sites
• The infarct culprit coronary artery is adequate for
treatment administration and the procedure is
technically feasible
Primary endpoint
Mortality and MACE5 from any cause at
30 days
• The patient is stable and in adequate clinical
condition to undergo the procedure
Secondary
endpoints (6 and
12 months)
Safety: Mortality and MACE
Efficacy: evolution of infarct size,
biomechanical parameters by MRI
Clinical parameters: 6m walk test, NYHA6
scale
Completion
1H17 (Interim data announced June 16)
• Males, females ≥18 years and ≤80 years
• Patients who present a STEMI1
• Killip ≤ 2 on admission
• Successful revascularization by PCI (TIMI2 = 3)
within 12h after the onset of symptoms
• EF≤50% by echocardiography (day 2 after infarct
symptoms)
• EF≤45% by MRI on D3-5 post-STEMI
• Infarct size
(1st
MRI) >25% in
1
LV3
STEMI: ST-Segment-Elevation Myocardial Infarction
TIMI: Thrombolysis In Myocardial Infarction
3 LV: Left Ventricle
4 PCI: Percutaneous Coronary Intervention
5 MACE: Major Adverse Cardiac Events
6 NYHA: New York Heart Association
2
35
CAREMI Phase I/II Trial
Positive Preliminary Results from Phase I Presented at ESC
•
In the dose-escalation open-label phase, 6 patients were treated and 5 of them were
followed up for 6 months
•
Patients received a single injection of 11 million (M), 22M or 35M cells of AlloCSC-01 (n=2
each) by intracoronary infusion 5 to 7 days after Percutaneous Coronary Intervention
(PCI)
•
Data presented at the European Society of
Cardiology meeting in London, showed that
AlloCSC-01 has a good safety profile as no
adverse events or Major Adverse Cardiac
Events (MACE) were observed during the 6
month follow-up period
•
Preliminary data from this treated group
showed a reduction in infarct size, and a
LVEF improvement on MRI, over the 6-month
follow-up period (n=54; p<0.05 for both
parameters)
* p-value < 0.1
** p-value < 0.05
1
2
3
1
LVEF (%): Left Ventricular Ejection Fraction % change versus screening MRI
IS (mL): Infarct Size
IS (% of LV): Infarct Size as % of Left Ventricular mass
4 The patient lost to follow-up received the 11 million dose
2
3
36
CAREMI Phase I/II Trial
Interim Results at 6 Months Confirm Safety Profile of AlloCSC-01
•
51 patients were evaluated: 34 patients received AlloCSC-01 (35 M cells) and 17 patients
received placebo
•
Primary endpoint met: No mortality of any cause within one month was recorded for both
placebo and AlloCSC-01 groups
•
No major adverse cardiac event (MACE) was recorded within one month in either group
•
Importantly for the long term safety evaluation, no mortality of any cause nor MACE was
recorded in either group at six months
•
Preliminary secondary efficacy data at six months was limited to infarct size evolution,
defined as a percent of the left ventricular mass measured by magnetic resonance
imaging. The mean absolute change in infarct size from baseline to six months was similar
in both groups
•
The final full set of safety and efficacy study results at twelve months will be reported in
first half of 2017
37
Cx611: Phase lI Ready
Intravenous injection of eASCs for the treatment of severe sepsis
38
Severe Sepsis - A High Unmet Medical Need
Diagnosed cases and mortality of Sepsis vs.
Breast Cancer, Prostate Cancer & AIDS4
•
•
Sepsis is a life-threatening complication of
infection leading to systemic inflammation and
organ failure
Between 15M to 19M sepsis cases occur
worldwide each year1
1.200.000
Diagnosis
1.000.000
600.000
84.000
•
•
Soon to start Phase II trial has received the
support of the Horizon 2020 European
Commission Program and the endorsement of
key opinion leaders in Europe
466.000
0
In the US, sepsis generates USD 20 billion in
hospital-related costs and is the most
expensive condition billed to Medicare3
Cx611’s novel mechanism of action may offer
an innovative alternative to the treatment of
severe sepsis
750.000
200.000
Sepsis
Breast, Prostate Cancer &
AIDS
Trend in U.S. hospital stays with septicemia
2000−20095
1800
Discharges thousands
•
Mortality reaches 50% for severe sepsis raising
to 80% in septic shock2
375.000
800.000
400.000
•
Deaths
1600
1400
1200
8% CAGR
1000
800
600
The Lancet Infectious Diseases; Volume 12; issue 2; page 89; February 2012
2000
2002
2004
2006
2 Martin GS Expert Rev Anti Infect Ther. 2012 June ; 10(6): 701–706.
3 Torio et al. National inpatient hospital costs: the most expensive conditions by payer. AHRQ, Healthcare Cost Brief No. 160 August 2013.
4 Adapted from Lagu, T., et al. Critical Care Medicine, 40(3):754-761; 2012
5 Adapted from: Elixhauser et al. Septicemia in U.S. Hospitals 2009, AHRQ, Healthcare Cost Brief No. 122 October 2011
1
2008
2010
39
Cx611 Reduces Mortality in Animal Models of Sepsis
•
This effect is due to a combination of reducing pro-inflammatory and increasing antiinflammatory mediators, production of anti-microbial effectors, and increased
phagocytosis
CLP2 Model
LPS1 Model
Source: Gonzalez-Rey, 2009
* p < 0.001
1
2
LPS: lipopolysaccharide. LPS model is based on endotoxemia induced by high-dose of endotoxin
CLP: cecal ligation and puncture. This model mimics the clinical situation of patients with colonic leakage following surgical procedures or diffused peritonitis
40
Cx611 Has an Effect at Cytokine and Cellular Level
• ↓ of pro-inflammatory mediators
CLP model
LPS model
* p<0.001
•  of anti-inflammatory mediator
• ↓ of inflammatory cells
Source: Gonzalez-Rey et al. Gut. 2009 Jul;58(7):929-39
41
Cx611: Phase I/II in Severe Sepsis Expected to Start 2H16
CELLULA Phase I trial results
• 250k, 1M, 4M eASC/kg and placebo administered to 32 healthy volunteers (8 per group)
• Favorable safety and tolerability profile of Cx611, consistent with Phase I/IIa in refractory RA1
patients
SEPCELL Phase I/II study in severe sepsis to start 2H16
• Randomized, double blind, parallel groups, placebo controlled, multicenter study
• 180 patients (90 per group) with sCABP2 requiring mechanical ventilation and/or vasopressors,
admitted to the ICU. At least 50 centers in at least 4 countries
• 160M eASC or placebo on days 1 and 3 (320M in total) in addition to standard of care therapy.
90 days follow up
• Primary endpoint: Adverse event and potential immunological host responses against the
administered cells
• Secondary endpoint: Reduction in the duration of mechanical ventilation and/or vasopressors
needed and/or improved survival, and/or clinical cure of the CAPB, and other infection-related
endpoints
• Partially funded with EUR 5.4 million from the European Commission through its Horizon 2020
Program
1 Rheumatoid
2 Severe
Arthritis
community-acquired bacterial pneumonia
42
IP, Key Milestones and
Compelling Investment Case
43
Key Intellectual Property Patent Portfolio in Cell Therapy
• 29 patent families related to cell therapy products
• Pending & granted patents in over 20 jurisdictions including the US; expiry dates
2024 onwards for the products in development
•
Patent covering eASC population and therapeutic uses granted in EU recently
•
Key patent for Cx601 (PCX007) granted in US, AU, RU, MX, IL and NZ
•
Patent protects use of ASCs in treatment of fistula
•
Complementary protection possible through additional patents under review
• Portfolio covers key features of TiGenix’s stem cell and chondrocyte platforms
•
Expanded cell compositions and preparations
•
Use of expanded cells in treatment of broad range of indications
•
Cell preparation methods & delivery systems
• FTO for indications in clinical development reviewed by external counsel
•
US: Morrison & Foerster
•
Europe: Carpmaels & Ransford
44
Key Milestones
Product
Europe
Cx601
(local)
US
AlloCSC-01
(intracoronary)
Cx611
(IV)
2014
4Q14 Phase 3
enrollment
completed
2015

3Q14 CMO
selection 
4Q14 SPA
submission
ChondroCelect


3Q15
positive SPA

4Q14 Phase 1
initiated

1Q15 Phase 2
enrollment initiated

 (1 year follow-up)
 1Q16 EMA filing
 Takeda Deal
2H17 EMA
approval
Transfer MAH
to TDKA
2H16 tech
transfer finalized

4Q15 Phase 2
enrollment completed
2017
1Q16 study results
3Q15 Phase 3 primary
endpoint met (24 weeks)
acute
myocardial
infarction
severe
sepsis
2016

2H16 Phase 2
interim analysis
1H17 start
Phase 3 for
US BLA
1H17 Phase 2
study results

2Q15 Phase 1
2H16 Phase 2
study results enrollment initiated
1Q14 manufacturing
facility sold

Termination of
agreement with
SOBI
2Q14 licensed to
SOBI

Withdrawal of
MAA requested


45
Compelling Investment Case
• Complex perianal fistulas in Crohn’s disease patients in United States & EU is a multi-billion
dollar opportunity
• Pivotal Phase III (local administration of a single dose of allogeneic adipose derived stem cells)
Cx601: Global
Agreement Ex-US
with Takeda
• Primary endpoint met. Cx601 statistically superior to placebo in achieving combined remission
at week 24 (p=0.024)
• Long term efficacy sustained at week 52 on same endpoint (p=0.019)
• MAA submitted to EMA in 1Q16. Decision expected 2017
• GMP process approved for commercial manufacturing by Spanish Agency in 1Q16.Takeda will
co-invest in the expansion of the Madrid facility to secure supply for the initial few years
• Up to €380M agreement with Takeda for the exclusive ex-US rights to Cx601 for the treatment of
complex perianal fistulas in Crohn’s disease patients
• Use of data from positive pivotal Phase III trial in EU to support a BLA in the US
Cx601: Clear
pathway to US
market
• FDA’s agreement on SPA obtained for pivotal phase III trial in the US
• Same primary endpoint as positive EU Phase III trial
• US Phase III to start 1H17
• Fully-owned asset; granted patent valid until 2030
• Lonza selected as contract manufacturing organization for Cx601 in the US
Valuable Pipeline
Opportunities:
AlloCSC-01 and
Cx611
• AlloCSC-01: intra-coronary administered allogeneic cardiac stem cells, being developed for acute
myocardial infarction
• Randomized, double blind, placebo controlled Phase II trial ongoing
• Interim 6 months data confirmed safety. Final one-year follow up data expected 1H17
• Cx611: Intravenously-administered allogeneic adipose derived stem cell product for severe sepsis
• Phase I study completed
• Severe sepsis Phase I/ll trial design has been finalized; expected to enroll first patient in 2H16
1 Advanced
Therapy Medicinal Product
46
References
47
References
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2. Hein R et al. Prevalence of inflammatory bowel disease: estimates for 2010 and trends in Germany from a large insurance-based regional cohort. Scandinavian
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3. Lucendo AJ et al. Epidemiology and temporal trends (2000-2012) of inflammatory bowel disease in adult patients in a central region of Spain. European Journal of
Gastroenterology & Hepatology 2014; 26:1399-1407.
4. Dal Pont E et al. Inflammatory bowel diseases (IBD) incidence and prevalence in a North East limited area of Italy. Digestive Liver Disease 2010; S180.
5. Cottone M et al. Incidence of Crohn’s disease and CARD 15 mutation in a small town in Sicily. European Journal of Epidemiology 2006; 21:887-892.
6. Herrinton LJ et al. Estimation of the period prevalence of inflammatory bowel disease among nine health plans using computerized diagnoses and outpatients
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7. Kappelman MD et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clinical Gastroenterology &
Hepatology 2007; 5:1424-1429.
8. Kappelman MD et al. Recent trends in the prevalence of Crohn’s disease and ulcerative colitis in a commercially insured US population. Digestive Diseases &
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9. Molodecky NA et al. Increasing incidence and prevalence of inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142:4654.
10. Spanish Epidemiological and Economic Study Group on Crohn’s disease. Epidemiological and clinical features of Spanish patients with Crohn’s disease. European
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11. Gibson PR et al. Relationship between disease severity, quality of life and health care resource use in a cross-section of Australian patients with Crohn’s disease.
Journal of Gastroenterology & Hepatology 2007; 22:1306-1312.
12. Dranga M et al. Are there any particularities in Crohn’s disease in North-Eastern Romania? Revista Medico-Chirurgicala a Societatii de Medici si Naturalisti din Iasi
2015; 119:334-339.
13. Schwartz DA et al. The natural history of fistulizing Crohn’s disease in Olmsted county, Minnesota. Gastroenterology 2002; 122:875-880.
14. Bell SJ et al. The clinical course of fistulating Crohn’s disease. Alimentary Pharmacology & Therapeutics 2003; 17:1145-1151.
15. Eglinton TW et al. The spectrum of perianal Crohn’s disease in a population-based cohort. Diseases of the Colon & Rectum 2012; 55: 773-777.
16. Gray BK et al. Crohn’s disease of the anal region. Gut 1965; 6:515-524.
17. Galandiuk S. Perianal Crohn’s disease. Predictors of need for permanent diversion. Annals of Surgery 2005; 241:796-802.
18. Molendijk I et al. Disappointing durable remission rates in complex Crohn’s disease fistula. Inflammatory Bowel Disease 2014; 20:2022-2028.
19. Sands BE et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. The New England Journal of Medicine 2004; 350:876-85.
20. Domènech E et al. Clinical evolution of luminal and perianal Crohn’s disease after inducing remission with infliximab: how long should patients be treated?
Alimentary Pharmacology & Therapeutics 2005; 22:1107-1113.
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Corporate Presentation
September 2016
49