Transcript Diapositive 1 - Moodle Lille 2

Margaux DUBOIS
Dan HAVET
Océane VAMOUR
17 february 2011
1
This is an independent study performed by students from
the Faculté des Sciences Pharmaceutiques of Lille.
The opinions expressed are our own and not necessarily
those of Celgene Corp®.
2
Summary
I
Celgene today
II
At the beginning…
III
Celgene strategy
IV
Thinking ahead
V
Celgene: still a biotech ?
VI
Conclusion
3
I
Celgene Today
4
I/ Celgene Today
Celgene's Corporate Headquarters
NEW
JERSEY
5
Dr. Barer
I/ Celgene Today
4e Biotech USA
2813 employees
CA: 3,4 billions $
Stock is traded on the since 1987 under the
symbol « CELG »
6
I/ Celgene Today
Celgene in the world
7
I/ Celgene Today
Therapeutic areas
Cancers
Immune and inflammatory diseases
8
II
At the beginning…
9
II/ At the beginning…
1986
1986 : Its specialty was single isomer drugs
which are mirror-image forms of existing
medications, but with fewer side effects
10
II/ At the beginning…
1991
 Celgene got an assignment to make a single-isomer drug for
tuberculosis
 They went to discuss with the expert on the disease : Gilla Kaplan
 "You know," Kaplan said, this is all very interesting, but I think I have a
better project for you”
“By the way, I’ve discovered that Thalidomide seems to be
very interesting”
11
II/ At the beginning…
LEPROSY
Leprosy is a chronic infectious disease caused by a bacterium,
Mycobacterium leprae. It is a disease which attacks the skin,
nerves and mucous membranes.
Multiple lesions accompanied by sensory loss in the affected
areas characterize leprosy.
Erythema nodosum lepra (ENL) may involve many parts of the
body but almost always affects the skin. The reaction develops
rapidly and over the course of a few hours painful
erythematous papules develop on the skin.
Erythema nodosum lepra is chronically debilitating.
12
II/ At the beginning…
Thalidomide decrease
expression of TNF - α
TNF-α is a pro inflammatory cytokine :
role in immune and inflammatory response
implicated in pathophysiology of infections and autoimmune diseases
Elevated TNF- α levels are associated with ENL
16
Présentation M,Tartar « Thalidomide_2010 »
II/ At the beginning…
Lot of hurdles to
develop thalidomid…..
14
II/ At the beginning…
Thalidomide
•1953 : Thalidomide
first synthese in West
Germany by Chemie
Grünenthal
II/ At the beginning…
The Damage
Lancet (1961) 2, 1358
Présentation M,Tartar « Thalidomide_2010 »
II/ At the beginning…
The Damage
• 46 affected countries
• More than :
• 10.000 in Germany
• 1000 in Japan
• 400 in GB
• No cases in US
1961 : Thalidomide withdrawn from the market place
II/ At the beginning…
With Celgene the story goes on !
From thalidomide
to THALOMID®
II/ At the beginning…
19
II/ At the beginning…
TM
S.T.E.P.S.
Physician visit
Registered with
S.T.E.P.S.TM
Receive an authorization #
for prescription
Physician phone survey
• Consent signed
• Mandatory contraceptive
counseling
• Pregnancy testing
• Educational video
Prescription provided to a
pharmacist registered with
S.T.E.P.S.TM
Celgene Interactive Voice Response
System
Patient phone survey
Pharmacist phones Celgene gives
authorization #, receives dispensing
authorization
Patient receives
Thalidomid®
Présentation M,Tartar « Thalidomide_2010 »
II/ At the beginning…
With Celgene the story goes on !
From thalidomide
to THALOMID®
18/7/ 1998
Thalomid® FDA approval Celgene for treatment of ENL
II/ At the beginning…
Enantiomers hypothesis
O
R
S
H
H
O
N
O
O
O
Sédatif
N
H
O
N
N
H
O
O
Tératogène
1995 : A fast interconversion of 2 enantiomers in
physiological conditions has been demonstrated
22
II/ At the beginning…
Expansion to new area…
23
II/ At the beginning…
Thalidomide and Multiple Myeloma
1999
24
II/ At the beginning…
 Celgene recorded 2002 sales of US $119 million for
Thalomid
 92% of which came from off-label use of the drug in
treating cancer, primarily multiple myeloma
 Sales reached US $224 million in 2003
25
Multiple Myeloma
Physiopathology
Multiple myeloma (MM) is characterized by
the neoplastic proliferation of a single clone
of plasma cells producing a monoclonal
immunoglobulin known as Bence Jones
protein
Signs and symptoms
Calcium (hypercalcemia)
Renal failure
Anemia
Bone pain with lytic lesions
Second most prevalent blood cancer (10%) after LNH
It represents approximately 1% of all cancers
26
II/ At the beginning…
15/11/ 2005
Celgene Receive FDA Approval for THALOMID in
Treatment of Newly Diagnosed Multiple Myeloma
based on results from a large Phase III randomized Eastern Cooperative
Oncology Group (ECOG) study comparing thalidomide plus
dexamethasone to dexamethasone alone in previously untreated multiple
myeloma patients
27
III Celgene strategy
28
III/ Celgene strategy
A Global Leader in Hematology
29
III/ Celgene strategy
Celgene’s Clinical vision:
Make cancer a Chronic Disease
30
III/ Celgene strategy
A Global Leader in Hematology
4 steps:
- Revlimid®
- Vidaza®
- Istodax®
- Abraxane®
31
III/ Celgene’s strategy
1st step: Revlimid®
 More potent analog of thalidomide
Less toxicity (neuropathies)
Indications:
Myelodysplastic syndromes (2005)
Multiple myeloma (2006)
32
III/ Celgene’s strategy
Lenalidomide
Thalidomide
O
N
O
O
O
H
N
N
O
O
H
N
O
NH2
Imids Compunds
33
III/ Celgene’s strategy
IMID technology
cytotoxicity
Anti-adhesive
Immunomodulation
T-cells and NK cells activation
Angiogenesis
34
III/ Celgene’s strategy
35
III/ Celgene’s strategy
A better Thalomid®?
Products sales
In thousands $
3000
2500
2000
1500
Revlimid
1000
Thalomid
500
Vidaza
0
2005
2007
2008
2009
2010
years
 Thalomid decrease due to Celgene politic
36
III/ Celgene’s strategy
2nd step: Vidaza®
The Pharmion Deal
2008
$2.9 Billion in Cash and Stock
37
III/ Celgene’s strategy

Vidaza® is a pyrimidine nucleoside analog of cytidine

Mechanism of action: - Antimitotic agent
- Hypomethylation of DNA
- Direct cytoxicity on abnormal hematopoietic
cells in the bone marrow
Vidaza is approved in the US and Europe for myelodysplastic syndromes (2008)

With Pharmion, Celgene aquires a new product in the
hematology/oncology drug sphere!
38
III/ Celgene’s strategy
3rd step: Istodax®
The Gloucester Deal
2009
640M $
39
III/ Celgene’s strategy
cutaneous T-cell lymphoma (CTCL)
40
III/ Celgene’s strategy
4th step: Abraxane®
The Abraxis Deal
2010
41
III/ Celgene’s strategy
Abraxis deal
 Complete acquisition of Abraxis bioscience : 15/10/2010
 Total cost = 2,9 Billion $ split in 3 parts:
- buyout of common stock
-receives small parts of celgene common stock
-contingent value right (CVR)
 Only one approved compound: ABRAXANE®
42
III/ Celgene’s strategy
• Paclitaxel protein-bound particles for injectable suspension
• Breast cancer after failure:
combination chemotherapy for metastatic disease
• Approved on January 2005
43
III/ Celgene’s strategy
 Celgene paid approximately ten
times of the revenue
 NSCLC first line FDA submission 2011
 Pancreatic tumor Phase III trial
 Multiple trial underway in major
tumor types
44
III/ Celgene’s strategy
45
nab™ technology
46
III/ Celgene’s strategy
Abraxis deal
New branch in Solid tumors
A valuable technology platform
Six Phase I and one Phase II using nab technology
ABRAXANE®
47
IV
Thinking ahead
48
IV/ Thinking ahead
R&D
Expenses 2010
Cost of goods sold
R&D
Selling, general
administrative
Others
49
IV/ Thinking ahead
R&D
Employees repartition - 2009R&D activities
Sales and
Commercialization
Executive and
general and
administrative
activities
50
IV/ Thinking ahead
R&D
15
Strong
pipeline
Discovery
>25
Phase III
> 10
High skilled
researchers
Clinical
development
51
IV/ Thinking ahead
Hematology
52
IV/ Thinking ahead
Pomalidomide
IMIDS
Pomalidomide
 Highest single agent response rate in R/R MM
 Evaluating Phase II Multiple myeloma data
 Initiating Phase III trial in Relapsed/Refractory multiple myeloma
 Phase III trial in myelofibrosis ongoing
53
IV/ Thinking ahead
Oncology
54
IV/ Thinking ahead
Inflammation/Immunology
55
IV/ Thinking ahead
Pipeline
Apremilast
56
IV/ Thinking ahead
Apremilast
Blockbuster Potential
 Six Phase III trials underway in Psoriatic Arthritis and
Moderate to Severe Psoriasis
 Strong efficacity and manageable side effect profile
observed in phase II
 Phase II trial in Rheumatoid arthritis
 $ 2-3B opportunity in Psoriasis
57
V
Celgene:
Still a biotech?
58
V/ Celgene: Still a biotech?
 Forecast raise of 31% up to 1,2 Billion $ in 2011
59
V/ Celgene : still a biotech?
Multiple myeloma market
60
V/ Celgene : still a biotech?
Partnerships
• Royalties from Novartis  Sales of Ritalin ® family drugs (Focalin)
used to treat Attention Deficit Hyperactivity Disorder
Celgene: agreed to distribute and promote Alkeran®(Melphalan) in USA
61
V/ Celgene : still a biotech?
Revenue
Net product sales
Collaborative
agreements
Royalties revenue
= Total revenue
62
V/ Celgene : still a biotech?
Financial data
IPO: Market capitalization= 12 650 000 $
02/2011: 24,47 Billion $
Major shareholders:
12/2010
63
V/ Celgene : still a biotech?
Financial data
Stock exchange
Revlimid
approval
Thalomid
approval
64
V/ Celgene : still a biotech?
Financial data
Stock exchange
65
V/ Celgene : still a biotech?
Financial data
Total revenues
66
V/ Celgene : still a biotech?
Financial data
A steady progression
 Cash flow: 2,6 Billion $
67
V/ Celgene : still a biotech?
Independence
Independence ratio = Long term debts / stockholders’ equity
= 0,0048
Standard and Poor’s Rate
Issuer Credit Rating
Ratings
Celgene
Corp
Sanofi
Aventis
Genzyme
BBB+
AA-
A-
Rating Date
04-Oct-2010
22-Mar-2005
04-Dec-2008
Regulatory
Identifiers
Review Date/
Type
--
04-Oct-2010
Outlook
Stable
--
07-Sep-2010
CreditWatch
Neg
--
28-Dec-2010
Outlook
Stable
68
V/ Celgene : still a biotech?
Revlimid ® Lenalidomide
A better Thalomid®?
Revlimid: 70% of total
revenues
Good forecasts for 2011
Revlimid price up to
85,000 $
69
V/ Celgene : still a biotech?
Outcomes
Still a biotech ?
Biotech
Celgene
Corp
Pharmaceuticals
Cap Size
Small
24,47 billionBig
$
Balance Sheet
/Cash Flow
2,6Cash
billion $ Strong Cash inflow
Burn
Cost
R&D ++
R&D, Manufacturing.
R&D
Marketing
Manufact./Marketing
Net Income
Negative
Positive
Positive
Pipeline
Strong
Strong
Moderate/Weak
Dividend
None
None
Moderate - Strong
Moderate
Investment Risk Very
High
Moderate
70
VI
Conclusion
71
VI/ Conclusion
SWOT
Strengths:
Steps and RevAssist programs
Blockbuster: Revlimid
Weaknesses:
Reliance on revlimid for majority
company growth
Smart life cycle management
Apremilast: potential blockbuster
72
VI/ Conclusion
SWOT
Opportunities:
Threats:
Development of international market
Vidaza generics expected in US
market in 2011
Healthcare reform benefactor
Revlimid increasing growth
Revlimid and Thalomid face
competition from Velcade
Celgene buyout
73
Thank you for your attention!
Any question?
74
Conclusion
Will we work at Celgene?
75
BACkup
76
Conclusion
• Business development
• AQ?*
• Regulatory affairs: Steps program
77
78
Keep in mind
MM Treatment Options
• Conventional chemotherapy:
o Melphalan
o Doxorubicin
o Cyclophosphamide
• Steroid therapy:
– Dexamethasone
– Prednisone
• Novel therapeutics:
– Thalidomide
– Lenalidomide
– Bortezomib
• Stem cell transplantation:
– Autologous
– Allogenic
• Radiation therapy
79
II/ At the beginning…
80
Peptides Precursors
H2N
O
H2N
NH2
HO
O
O
O
N
HO
O
O
Secondary reaction
H2N
O
O
O
O
N
HO
O
O
N
N
H
O
O
Secondary reaction
H2N
O
O
O
O
N
HO
O
O
N
N
H
O
O
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Celgene was initially founded as a unit of the Celanese Corporation in 1980. However, following the 1986 merger of
Celanese Corporation with American Hoechst Corporation, Celgene was spun off as an independent
biopharmaceutical company.
In July 1998, the company received approval from the FDA to market THALOMID® (thalidomide) for the acute treatment
of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). THALOMID® is not indicated
as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. THALOMID® is also indicated as
maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence. In May 2006,
Celgene received approval for THALOMID® in combination with dexamethasone for the treatment of patients with
newly diagnosed multiple myeloma.
In April 2000, an agreement was reached with Novartis Pharma AG to license d-MPH our chirally pure version of RITALIN®
CII. The FDA subsequently granted approval to market d-MPH or FOCALIN XR® CII in November 2001.
On August 31, 2000, with products on the market, Celgene completed a merger with Signal Pharmaceuticals, Inc., a
privately held biopharmaceutical company focusing on the discovery and development of drugs that regulate genes
associated with disease.
On December 31, 2002, we acquired Anthrogenesis Corporation, a privately held New Jersey based biotherapeutics
company and cord blood banking business, which has also pioneered the recovery of stem cells from human placental
tissue following the completion of a full-term, successful pregnancy. Anthrogenesis now operates as Celgene Cellular
Therapeutics ("CCT"), a wholly owned subsidiary. To learn more about cord blood banking, please visit
www.LifebankUSA.com.
In December 2005, Celgene received approval from the FDA to market REVLIMID® (lenalidomide) for the treatment of
patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk MDS associated with a deletion 5q
cytogenetic abnormality with or without additional cytogenetic abnormalities. In June 2006, the FDA approved
REVLIMID® in combination with dexamethasone for the treatment of multiple myeloma patients who have received at
least one prior therapy. EMEA approval for the REVLIMID® multiple myeloma indication (in combination with
dexamethasone) was received in June, 2007.
Additional history milestone points:
2008 – Celgene acquires Pharmion, bringing VIDAZA to its portfolio
2008 – EMEA grants approval of Thalidomide Pharmion
2008 – Celgene Cellular Therapeutics announces the first clinical transplant of placenta-derived stem cells
2008 – EMEA grants VIDAZA approval in the EU
2010 – Celgene acquires Gloucester Pharmaceuticals bringing ISTODAX into its portfolio of hematologic cancer
therapies
2010 – REVLIMID granted approval for multiple myeloma and deletion-5q MDS in Japan
Celgene is now an integrated biopharmaceutical company focused on discovering, developing and commercializing
innovative therapies to treat cancer and inflammation through gene and protein regulation.
84
85
86
Committed to
improving the
lives of patients
worldwide
Margaud DUBOIS
Dan HAVET
Océane VAMOUR
17 february 2011
8787
88
Quels sont les traitements classiques du myélomes?
-Les corticoïdes
-Les chimiothérapies
Type alkylant: melphalan (alkeran), le cyclophosphamide (endoxan)
Les anthracyclines
89
CONCLUSION
Thalidomide
• Efficacité reconnue en rechute, particulièrement en
association avec la dexaméthasone
• Efficacité consacrée en association avec MP chez
sujet âgé: nouveau standard
• Efficacité potentielle en consolidation post greffe
• Pb toxicité neurologique
• Pas d’indication officielle : ATU cohorte en rechute
SLIDE 90
CONCLUSION
Bortezomib
• Efficacité prouvée, AMM en première rechute
• Potentiel avenir en première ligne en induction
pregreffe voire avec conditionnement
• Efficacité en association au MP en cours de
validation
• Intérêt majeur en association
• PB administration IV, préparation hospitalière, durée
de réponse ?
SLIDE 91
CONCLUSION
Lenalidomide
• Analogue du Thalidomide potentiellement supérieur
avec une toxicité différente (hématologique)
• ATU nominative actuelle, AMM très prochaine en
première rechute
• EN pleine expansion première ligne, entretien…
• Pb toxicité hématologique pour association aux
alkylants
SLIDE 92
CONCLUSION
• Prise en charge du Myélome Multiple totalement
modifiée par l’arrivée de ces nouvelles drogues
• Multiples associations possibles pour aller vers des
taux de réponses majeurs permettant d’espérer
dans un premier temps à un passage à une
maladie chronique avant quelques cas de guérison
• Applicables à tous les patients pas de barrière
d’âge
SLIDE 93
Principaux effets secondaires des nouvelles thérapies du MM
Thalidomide:
Neurotoxicité périphérique sensitive irréversible
Thrombose
Velcade:
Neurotoxicité périphérique sensitive
Thrombopénie
Zona
Revlimid
Myélotoxicité, Thrombose
94
IV/ CELGENE’S STRATEGY
PRODUCTS.
Abraxane
Istodax
Revlimid
Thalomid
Vidaza
Products
newly diagnosed multiple
myeloma
 cutaneous manifestations of
moderate to severe erythema
nodosum leprosum
 cutaneous T-cell lymphoma
95
Lenalidomide: Main
toxicities
•
•
•
•
•
•
•
Neutropenia - 30-40%
Thrombocytopenia - 10-20%
Anaemia - 10%
Thrombo-embolism - 10-15%
Fatigue
Constipation
Neuropathy
IMiDs: Thalidomide, Lenalidomide and Pomalidomide
O O
O
O
N
N
N
O
NH2
Thalidomide
Omg/d
100-200
Lenalidomide
15-25 mg/d
Neuropathy
Constipation
Sedation
DVT
Myelosuppression
Skin rash
DVT
H
N
O
O
O
H
N
N
NH2
O
Pomalidomide
1-4 mg/d
Structurally similar, but functionally different, both qualitatively and quantitatively
O
Autologous Hematopoietic Stem Cell Transplant
[AHSC]
www.makna.org.my/images/autoglass.gif
99
100
Revilimid
101
Vidaza
102
SWOT
Celgene Corporation SWOT Analysis, Sep2010, p1-8, 8p, 2 Charts Chart; found on p5
103
VII/ CONCLUSION
Futur…
Excellent performance on all commercial metrics
– Geographic expansion highlighted by approval in Japan
– Market share and duration gains
– Market access through approvals and reimbursements
• Building for the future
– Multiple regulatory filings in Hematology
– Established solid tumor franchise with Abraxis acquisition
– Initiated multiple Apremilast Phase III trials in I&I
Overall 6
– Overall, advancing >25 Phase III and pivotal trials and >17
early stage trials
104
nab™ technology
105
Multiple Myeloma
Multiple myeloma is the second most frequent type of blood cancer
after non-Hodgkin’s
lymphoma. The disease affects the bone marrow with uncontrolled
growth of particular
types of blood cells called plasma cells. This interrupts development of
normal red cells,
white cells and stem cells, and can lead to damage in the bone
structure itself.
Abnormal plasma cells also produce large amounts of a protein also
known as M
component. This allows physicians to detect multiple myeloma and to
track its treatment.
Multiple myeloma occurs on average around the age of 60 – 70.
Because of the
progressive aging of the population, the incidence of this disease is
sharply increasing,
with 5 cases per 100,000 inhabitants among males and 4.2 among
106
What Is Multiple
Myeloma?
• Cancer of plasma cells.
• Healthy plasma cells produce antibodies or
immunoglobulins.
– Part of our humoral immunity, they are released in response to foreign body
invasion.
• Myeloma cells produce abnormal immunoglobulin.
–
–
–
–
Overproduce monoclonal protein or paraprotein.
Ineffective immunoglobulins.
Leads to decreased bone marrow function.
Destruction of bone tissue.
San Miguel JF, et al. Pathogenesis of Multiple Myeloma: Rationale for New and Novel Therapies. Clinical Care Options:
http://clinicaloptions.com/Oncology/Treatment%20Updates/Myeloma/Modules/Pathophysiology/Pages/Page%203.aspx.
107
Financial data
108
Strategies drug sales
2009/2014
109
OLD S.T.E.P.S.
Physician Visit
1
Consent Signed
2
Prescription
Provided,
Pharmacist to
dispense
3
Survey
Provided
Drug Dispensed
to patient
BU
After therapy
initiation
Actio
n
110
NEW S.T.E.P.S.
Physician Visit
Physician calls IVR
1
Consent Signed
Patient calls IVR
Celgene Voice Response System
A
2
Prescription
Provided,
Pharmacist to
dispense
3
Blinded
Patient List
Sent to BU
(ALL patients)
not
implemented
Envelope supplied to
yet, etc
mail back to BU should
Celgene mails
initial survey with
unique identifier
not implemented
yet
Pharmacist calls IVR
Drug Dispensed to
patient
the patient agree to
participate
BU
B
111
Thalidomide Multiple Myeloma
112
Thalidomide Multiple Myeloma
113
Thalidomide Multiple Myeloma
114
IV/ CELGENE’S STRATEGY
THERAPEUTIC AREAS
115
thousands $
Human
pharmaceutical
clinical programs
Other
pharmaceutical
programs
Biopharmaceutical
discovery and
development
Placental stem cell
and biomaterials
116
117
118
119
120
121
R & D : drug by stage of
development
122
R&D: Investigational drug by therapeutic
categories
123
•
•
Celgene a annoncé le dépôt d’une soumission réglementaire
auprès de l’Agence européenne des médicaments (EMA) pour
ses capsules de REVLIMID® (lénalidomide) destinées au
traitement du myélome multiple nouvellement diagnostiqué et à
la thérapie d’entretien. Une demande d’autorisation de mise sur
le marché de l’ISTODAX ® (romidepsine) en injection, indiqué
dans le traitement du lymphome à cellule T périphérique déjà
traité préalablement, a par ailleurs été déposée auprès de la
FDA américaine en décembre dernier.
La société a introduit une demande d’autorisation de mise sur le
marché (AMM) pour le REVLIMID (lénalidomide) destiné au
traitement d’entretien des patients atteints de myélome multiple
nouvellement diagnostiqué, dont l’état de santé ne s’est pas
amélioré après un traitement initial au melphalan, prednisone et
REVLIMID, ou après une transplantation de cellules souches
autologues. Cette demande a été déposée le 31 décembre
2010 auprès de l’Agence européenne des médicaments (EMA).
124
125
Thalidomide and Multiple Myeloma
126
127
128
129
130
131
MM Treatment Options
• Conventional chemotherapy:
o Melphalan
o Doxorubicin
o Cyclophosphamide
• Steroid therapy:
– Dexamethasone
– Prednisone
• Novel therapeutics:
– Thalidomide
– Lenalidomide
– Bortezomib
• Stem cell transplantation:
– Autologous
– Allogenic
• Radiation therapy
132
V/ Celgene environnement
ASSOCIATED/ SUBSIDIARY COMPANIES
Abraxis BioScience Inc
Cabrellis Pharmaceuticals Corp
Celgene International Sarl
Gloucester Pharmaceuticals Inc
Pharmion Corp
American BioScience Inc
Celgene Cellular Therapeutics
Cenomed BioSciences LLC
Pharmaceutical Partners of Canada Inc
Platco Technologies Ltd
Shimoda Biotech (Pty) Ltd
133
II/ At the beginning…
134
IV/ Thinking forge ahead
Pipeline
135
II/ At the beginning…
136