Transcript moodle.univ

MARCH 2013
Corporation PLC
Léna Castelain
Clément Haeck
Hélène Kaplon
Violette Launoy
1
This is an independent study performed by
students from the Faculté des Sciences
pharmaceutiques et biologiques of Lille .
The opinions expressed are our own and not
necessarily those of Elan Corporation PLC.
2
3
Modern era since
2004
Donald Panoz
Building Elan in
the 1969
1970s
Creation of Elan
Corp began in the
1960s
By the end of the 1960s,
Panoz had become
convinced of the
potential for developing
new drug delivery
technologies
lower tax rates and less restrictive bureaucracy
4
improving the delivery of the
tetracycline
TETRABID
1972
(success for
Organon) 1978 R&D Center
the early 1980s, Elan had
contracts for 25
Headquarter in Dublin, 2012
pharmaceuticals from 16
different companies
Building
Elan in the
1970s
1981 Elan Pharmaceutical
Research Corporation
5

sustained-release oral tetracycline (Tetrabid-Organon)
6
Drug delivery company
with the Tetrabid technology
BIONEUROLOGY
EDT
Oral Controlled
Release
Multiple Sclerosis
Tysabri®
Parkinson’s Disease
Biotechnology company
+ Bipolar Disorder
NanoCrystal
specializing in
Technology
Alzheimer’s
neuroscience, pain &
Disease
immunology
7
8
Nanomedicine: Nanotechnology, Biology and Medicine,Volume 2, Issue 2, June 2006, Pages 127–136
Avinza, Cardizem,
Focalin, Ritalin,
Verelan, Luvox,
Zanaflex
Naprelan
Verelan
Afeditab
9
AIP
EDT
EDT
BioNeurology
Prothena
corp
PD + BD
Tysabri®
AD
subsidiary10
Chairman : Robert A. Ingram
Executive Director & CEO : Kelly Martin
20 years in Merill Lynch : an investment bank
11
Development
PART I :
THE RISE
PART II :
THE DECLINE
12
time
13
2011 the pivotal year
New product in pipeline
Collaboration AIP with Janssen in sept
2009
Collaboration Biogen Idec-Elan corp: Tysabri withdrawal launch and
reapproval
Acquisitions period
Biotech: the first company
by market capitalization in
Ireland
14
tps
2011 the pivotal year
Acquisitions period
Biotech: the first company
by market capitalization in
Ireland
15
tps
Suisse
1993
Israël 1995
Modern era
since 2004
1996 Athena
Neurosciences
South San
Francisco
1998 Neurex Corp
Menlo Park, California
2000 infectious
diseases and
respiratory
ailments
San Diego
2001 Elan's market
value had climbed
past $22 billion-making it Ireland's
largest corporation
16
2011 the pivotal year
Collaboration Biogen Idec-Elan corp: Tysabri withdrawal launch and
reapproval
Acquisitions period
Biotech: the first
company by market
capitalization in Ireland
17
tps
current 50:50 business collaboration
Tysabri was developed and is now being
marketed in collaboration with Biogen Idec.
Biogen Idec is responsible for manufacturing
the product. In the United States, we purchase
Tysabri from Biogen Idec and are responsible for
distribution.
18
Natalizumab : Tysabri®
-> Humanized recombinant MAb targeting alpha4-integrin.
-> Alpha-integrin = transmenbrane receptor on the surface of
lymphocytes and leukocytes.
Function in leukocyte recruitment from the peripheral circulation to
sites of inflammation within tissue.
-> It is designed to hamper movement of potentially damaging
immune cells from the bloodstream, across the blood-brain barrier
and across the intestinal barrier.
19
Tysabri & Multiple Sclerosis
20
- Autoimmune chronic inflammatory disease of the CNS characterized by ongoing
inflammation, which results in neuronal demyelination and multifocal lesions.
Destruction de la gaine de
myéline (altération de la
conduction électrique dans
l’axone
Formation de
« plaques » =
démyélinisation
localisée
inflammatoires
21
There are 3 forms of this disease:
- RRMS (relapsing-remitting) 80%
- SPMS (secondary progressive) 50%
- PPMS (primary progressive) 13%
Expanded Disability
Status Scale
22
- Poor quality of life
- A disease that is triggered on average around 20-40 years,
more often in women
- 1st cause of non-traumatic disability in young patients
acquired severe
- Chronic requiring multidisciplinary
23
for acute relapses : corticosteroids (SMD)
VCAM-1
disease-modifying agents (DMAs) : IFN B 1b, 1a and
Mitoxanthrone (RRMS et SPMS), gatiramer acetate
α4β1integrin
efficacy is evaluated by MRI (inflammation
and lesion formation) & clinical relapse
rate and progression of disability as
measured by the EDSS.
But many patients continue to
experience relapses and disability
progression despite treatment with
these agents
New drugs: Natalizumab
Fingolimod (EMA 2011, FDA 2010)
24
the first in a new class of
adhesion molecule inhibitors
for the treatment of MS
nov 2004 : as a monotherapy the
treatment of RRMS, for patients who
have had an inadequate response to, or
are unable to tolerate, an alternative
MS therapy
2006 : for highly active RRMS
in adult patients who have
failed to respond to beta
interferon or have rapidly
evolving, severe RRMS
25
26
25, fev 2005
27 $
Elan
4, march 2005
5,71 $
25, fev 2005
67 $
Biogen Idec
4, march 2005
38 $
27
http://www.google.com/finance
2009 Committee for Medicinal Products for Human Use
has reassessed the benefits and risks of Tysabri after 23
cases of PML in the world.
=> The benefits outweigh, but we must make changes in
the RCP:
- Duration of treatment / PML
- Patient's consent to treatment initiation and at 2 years
- Risk / benefit re-evaluated after 2 years of treatment
- IRIS information must be added
28
Recombinant humanized
mAb IgG4 anti 4ß1 and
4ß7 integrins expressed
on the surface of
leukocytes (except
neutrophils)
Receptor modulator to sphingosine 1phosphate
Anthracyclines and
related
IV
VO
IV
Biogen / Elan
Novartis
Wyeth
LEMP
opportunistic
infections
increased transaminases
bradycardia and arrhythmia
carcinogenic potential
neutropenia,
leukemia
LVEF
29
1923€ / month
+ Tysabri
indication for
Crohn's disease
21 000
37 000
48 800
56 600
64 400
69 100
30
En juin 2012
Tysabri® & Crohn’s disease
31
Crohn’s disease
• IBD : Inflammatory Bowel Disease.
• Multifactorial disease.
• Most common location : ileocecal
region .
• Non curable disease characterized by
chronic recurring periods of flare-ups
and remission.
https://ufandshands.org/crohns-disease
•Misregulation of the mucosal immune
response against elements of the
intestinal flora.
Symptoms : abdominal and rectal pain, diarrhea (with blood, glair or not), anal
fissure, fistulas, weight loss, abces around the anal area.
32
Crohn’s disease
• Mechanism :
Chronic gut inflammation caused by an abnormal immune response against
normal intestinal bacteria (loss of tolerance).
Characterized by persistent recruitment of leukocytes into gut tissue.
Α-4-integrin = transmenbranary protein.
Expressed on leukocytes, participating in adhesion and extravascular leakage of
leukocytes.
33
Cell 138, August 7, 2009 ©2009 Elsevier Inc.
Tysabri®
•
Humanized monoclonal antibody against α4-integrin
=> Natalizumab blocks leukocyte migration from the blood vessels to
sites of inflammation.
•
Generally reserved for patients with moderate to severe Crohn’s disease
that is refractory to other forms of medical therapy.
•
Approved in the USA but not in Europe, prescription and deliverance are
taking part of the TOUCH® program.
34
August 2010 ■ Volume 41 Number 8 ■ LABMEDICINE
Tysabri® : adverse effects
o
Progressive Multifocal Leukoencephalopathy
o
Hypersensitivity reactions
o
Immunosuppression – Infections
o
Hepatotoxicity
o
Most common AEs : headache, fatigue, arthralgia, urinary tract
infection, lower respiratory tract infection, gastroenteritis, vaginitis,
depression, pain in extremity, abdominal discomfort, diarrhea, and
rash.
35
Crohn’s disease treatments

Salicylic derivatives: Pentasa®, Rowasa® , Fivasa®.
Active substance = 5-ASA (acide 5 aminosalicylique)
Local action.

Corticoids: Cortancyl®, Solupred®, Solu-Médrol®, Entocort®.
Induction therapy of remission of advanced moderate to severe Crohn's disease outbreaks.

Immunosuppressive therapy.: Azathioprine (Imurel®), 6-mercaptopurine (Purinethol®).

Anti-TNF: Infliximab (Rémicade®) , Adalimumab (Humira®).
Reduction of surgery, reduction of hospitalizations number, corticoids weaning, endoscopic
mucosal healing, improvment of quality of patient’s life.
Persistent remission in approximately one third of patients after one year of treatment.
36
“Sales of our only marketed product
Tysabri represented approximately 80%
of our total revenues”
“ January 2012, the U.S.
FDA approved a product
label change for Tysabri that
identifies anti-JCV antibody
status as a risk
factor for PML. »
help physicians and people with
MS have more confidence in their
treatment decisions when
considering TYSABR
regulatory restrictions on the use of
Tysabri efforts at stratifying patients into
groups with lower or higher risk for
developing PML and the commercial
availability of the JCV antibody assay
may have an adverse impact on
prescribing behaviour and reduce sales
of Tysabri
37
TOUCH (TYSABRI Outreach Unified
Commitment to Health)
Objective: To determine the incidence of PML
opportunistic infections and deaths in Tysabri
patients
2 observational studies and TYGRIS
STRATA& Risk minimization program
(doc and education and information
intended for healthcare professionals
and patients)
+ Program of education and information issued by the
laboratory (prescription guide for neurologists + patient
card)
+ National Referent Group Tysabri (group of experts may
be requested by prescribers question if MS or suspected
PML)
+ "Focusing on the use of Tysabri"
38
39
2011 the pivotal year
Collaboration AIP with Janssen in sept 2009
Collaboration Biogen Idec-Elan corp: Tysabri withdrawal launch and
reapproval
Momentum acquisition
Biotech : 1ère compagnie
par capitalisation
bourisière en Irlande
40
tps

In September 2009, JANSSEN Alzheimer Immunotherapy, a subsidiary of J&J,
acquired substantially all of the assets and rights of Elan related to its
Alzheimer's Immunotherapy Program (AIP), including bapineuzumab.
50.1 %
49.9 %
AIP
AIP = Alzheimer’s immunotherapy programm
-Bapineuzumab
-AAB-003
-ACC-001
41
= progressive, degenerative disorder that attacks the brain's
nerve cells, or neurons

Most common cause of dementia (60-80% of cases)

Dementia = a “Public Health priority” (WHO)

no way to prevent,
cure or even slow its progression
www.alzfdn.org; WHO 2012 report

It worsens as it progresses before
leading to death

Mainly affects older people (>65)
although there is a growing
number of cases starting before
the age of 65
Alzheimers Dement. 2012;8(2):131-68.
Dr Aloïs Alzheimer
(1864 – 1915)
42

Progressive loss of neurons due to
neurodegenerescence

2 types of damage in the neocortex:

neurofibrillary tangles NFTs (intraneuronal): accumulation of
hyperphosphorylated Tau proteins

senile plaques (extra-cellular): deposition
of Beta Amyloid peptide (Aß), generated
from AAP (Amyloid Precursor Protein)
43
Ther Adv Neurol Disord. 2013 January; 6(1): 19–33.

ONLY symptomatic treatments exist today
⇒ to counterbalance the NeuroTransmitter disturbance

3 Cholinesterase inhibitors (CIs) for mild to moderate AD
In France:
“SMR faible,
ASMR V”
+ 1 NMDA receptor antagonist for moderate to severe AD

Their aims: decrease symptoms, improve quality of life,
hold dignity, autonomy and social bounding
+ antipsychotic and antidepressants for the behavioural
symptoms
VIDAL Recos 2013.
Ther Adv Neurol Disord. 2013 January; 6(1): 19–33.
44
AN-1792 synthetic
peptid
Bapineuzumab has been
shown to recognise the45
extreme N-terminal 5
residues of Aβ peptide
2011 the pivotal year
New product in pipeline
Collaboration AIP avec Janssen sept 2009
Collaboration Biogen Idec-Elan corp: Tysabri withdrawal launch and
reapproval
Momentum acquisition
Biotech: the first
company by market
capitalization in Ireland
46
tps

Inositol : a simple polyol precursor in a 2nd messenger
system important in the brain
Scyllo-insitol ⇒ stereoisomere of inositol
 decreased in depression
= a beta amyloid (βA) anti-aggregation agent
It disaggregates βA in vitro and in mice

ELND005 licensed from Transition Therapeutics Inc.
⇒ royalties + milestones
ELNDOO5 : Phase 2 Safety and Efficacy Study of Oral
ELND005 as an Adjunctive Maintenance Treatment in
Patients With Bipolar Disorder / study in AD failed:
Co-primary endpoints (ADCS-ADL and NTB) not met.
Trial arms testing 1,000mg and 2,000mg doses were
discontinued
47
MANIA
DEPRESSION
periods
of an excessively
elevated
or
periods
of deep,
prolonged,
manic-depressive
psychosis
→ maniac-depressive
disorder
→ bipolar
disorderand
irritable
profound depression


Prevalence : 1 – 2% in the general population
-
Age
of onset mood
: variable
an
elevated
or euphoria,
-
Probable cause:
overactivity
alcohol…)
- constantly feeling sad or worthless
Multigenic ⇒ predisposing
genetic too much or too little
- sleeping
Multifactorial ⇒ environmental factors (tabacco, cannabis,
- a lack of need for sleep
- feeling tired and having little energy
Characteristic : occurrence of repeated depressive, manic, hypomanic or
mixed
episodes
separated by periods in which
patientsand
appear
to show
no
- an
increased
optimism
- appetite
weight
changes
major psychic dysfunction.

- nonstop talking
- problems focusing
- increased self confidence
- thoughts of suicide

Effects on social, family and professional life ⇨ minimal with a preventive
treatment (prevent recurrent episodes)
48
http://www.orpha.net/

Treatment
Mania
Depression
• Antipsychotics
• Atypical Antipsychotics
• Anticonvulsants
• Electroconvulsive Therapy
• Antidepressants + mood stabilizers
ELND005 still under treatment for bipolar disorder since
August 2012
November 2012 ELND005 Phase 2 clinical treatment of
agitation and aggression in Alzheimer's patients
Phase 3 ready in AD cognition
Eur Neuropsychopharmacol. 1997 May;7(2):147-55. Controlled trials of inositol in psychiatry. Levine J
49
Multiple
Sclerosis
Crohn
Tysabri
Tysabri
Alzheimer
ACC-001 Immuno-conjugate
AAB-001 Bapineuzumab
50
ELND005 (+BP)
51
2011 the pivotal year
disposal of Alkermes
Failed AIP program : stop
Bapineuzumab IV phase 3
Split Prothena
Tysabri sales and
stop collaboration
52
current
situation
time
2011 the pivotal year
disposal of Alkermes
53
current
situation
time
- Diminution of EDT revenue
- Loss of patents
CESSION OF EDT ACTIVITIES TO ALKERMES
54
Sale of a part of Elan’s
business that was no
longer profitable
Reduction of Elan’s debt:
$ 1.249.1 millions
55
Athlone
(Alkermes)
Dublin
Corp.adm
South San
Francisco
(Prothena)
Gainesville
(Alkermes)
King of Prussia
(Alkermes)
location still belonging to Elan
56
places remaining
The income statement financial information relating to EDT for the years
ended December 31, 2012, 2011and 2010,(in millions):
2012
2011
2010
“On January 31, 2013, we announced that we had agreed to sell all of our remaining
7.75 million ordinary shares of Alkermes plc.”
57
“The sale of our Elan Drug Technologies (EDT) business to Alkermes
represented the objective of fundamentaly adress our debt”
2011
2010
ROE
-28.3%
-175.2%
ROTA
37.1%
-12.3%
Dette ( $ millions)
603.9
1,249.1
« We reduced our total principal amount of debt by $660.5 million, or
51%, during the year.”
 Improvement of financial siuation of Elan corp plc at the end of 2011.
BUT…
58
2011 the pivotal year
disposal of Alkermes
Failed AIP program : stop
Bapineuzumab phase 3 IV
59
current
situation
time

On 06/08/2012, J&J announced the discontinuation of Phase 3 development of
bapineuzumab IV in mild to moderate Alzheimer's based on the co-primary
clinical endpoints not being met.
50.1 %
49.9 %
AIP
AIP = Alzheimer’s immunotherapy
programm
-Bapineuzumab
-AAB-003
-ACC-001
60
Study 301 with patients who do not carry the apolipoprotein E epsilon 4 (ApoE 4)
Study 302 with ApoE 4 carriers

Once, ONE of the TOP blockbuster contenders

Now, ONE of the TOP phase III disasters of 2012

⇒ Pharma counts just 3 Alzheimer's drug wins in 13 years (101 losses!)

A subcutaneous formulation of bapineuzumab is in Phase 2 testing.
61
http://www.fiercebiotech.com/special-reports/top-15-blockbuster-contenders/bapineuzumab-top-15-blockbuster-contenders
http://www.fiercebiotech.com/special-report/top-phase-iii-disasters-2012/2012-10-02
http://www.fiercebiotech.com/story/pharma-counts-just-3-alzheimers-drug-wins-13-years-101-losses/2012-09-14
- Failure of active immunotherapy with peptide Abeta (AN1792)
=> test with passive immunotherapy (Bapineuzumab)
- Failure Bapineuzumab Phase 2
- Failure of four phase 3 studies Bapineuzumab IV
=> Test Bapineuzumab SC phase 2
=> ACC001 vaccine Phase 2
Ccl : . We recorded a net loss of $101.2 million on the Janssen AI
equity method investment in 2012, relating to our share of the losses of
Janssen AI and we will never realize any return upon our economic
interest in the AIP collaboration
62
2011 the pivotal year
disposal of Alkermes
Failed AIP program : stop
Bapineuzumab IV phase 3
Split Prothena
63
current
situation
time
On December 20, 2012, we completed the separation of the Prothena Business
into a new, publicly traded company incorporated in Ireland.
Is that the split is appropriate? to do with the results of the first quarter
2013 ...
Prothena
corp
Protein
misfolding
Autoimmune
discovery and
development
of novel
antibodies:
Synucleinopathies (PD,
Lewy Body, multiple
system atrophy
64
amyloidosis
2. Scission de Prothena
a. Repay debt
b. Make a buyback
program of action for
shareholders to pay
dividence
c. invest
a. Elan: Enables clearer choices for
shareholders
b. Hypothesis: Segment activities to
better sell?
Prothena
Prothena
EDT
Tysabri
ELAN’s STRATEGY =
SEGMENTATION
AIP
ELND005
EDT
3. Tysabri sales
1. Disposal To Alkermes
Remediates financial ratios
Elan + EDT was a "ball"
financial
65
La cession de l’activité Prothena en 2012 : perte nette totale de 18 millions de $
Athlone
(Alkermes)
South San
Francisco
(Prothena)
King of
Prussia
Gainesville (Alkermes)
(Alkermes)
Dublin
Corp.adm
location still belonging to Elan
66
places remaining
2011 the pivotal year
disposal of Alkermes
Failed AIP program : stop
Bapineuzumab IV phase 3
Split Prothena
Tysabri sales and stop collaboration
67
current
situation
time
On february 6, 2013:
Elan Corp PLC and Biogen Idec announced restructuring of Tysabri collaboration.
 Biogen Idec will purchase all the rights of Tysabri from Elan Corp PLC for
$3.25billion. Elan will receive substantial royalty.
“Sales of our only marketed product
Tysabri represented approximately
80% of our total revenues”
Continuing increase of Tysabri’s market
over last years and expected growth for
the next years.
68

ELAN has sold :
o
ELAN DRUG TECHOLOGY (EDT) to ALKERMES
Alzheimer Immunotherapy Programme (AIP) to JANSSEN
o TYSABRI® to Biogen Idec
o

ELAN spinned out some of its drug discovery business
platform into PROTHENA

Failure of Bapineuzumab

ELAN kept :
o
ELND005 : Phase II in Bipolar Disorder and in Alzheimer’s disease
o
ACC-001 Immuno-conjugate : Phase II
o
AAB-003 Monoclonal Antibody : Phase I
PROBABLY
69
Upon the closing of the Tysabri transaction Elan will execute along three dimensions:
Strategic
initiatives
Debt
refinancing
Share
repurchase
• These assets
will diversify
Elan from a
product,
science/ clinical,
therapeutic, and
geographic
point of view
• Elan will
refinance its
oustanding debt
• Following closing,
we will institute a
share program by
utilizing $ 1 billion
of the proceeds
from the Tysabri
restructuring
“This provides Elan and our shareholders
significant near and longer term benefits”
70

Some of them debate on forums, they mainly
have negative opinion on the deal and often
blame the Board…
“Kelly Martin's
strategy is to
replace everything
in Elan except the
management.”
“I stayed in the
stock, as most did,
because of
Bapineuzumab.
It was not because
of great leadership
of Elan.”
71
72
73
New investments with
funds from the sale of
tysabri’s rights and
royalties
Buy by Royalty Pharma,
proposed on Feb
25,2013
Sale of Prothena® and
then, payout to
shareholders
 End of Elan Corp PLC
74
2011 the pivotal year
disposal of Alkermes
Failed AIP program : stop
Bapineuzumab IV phase 3
Split Prothena
Tysabri sales
75
current
situation
time
76
Athlone
(Alkermes)
South San
Francisco
(Prothena)
King of Prussia
(Alkermes)
Gainesville
(Alkermes)
Dublin
Corp.adm
locations owned by Elan
77
Number of employees over the years
1800
1600
1400
1200
1000
800
600
400
200
0
2007.5
2008
2008.5
2009
2009.5
2010
2010.5
2011
2011.5
2012
2012.5
78
Discovery
Preclinical
Phase I
Phase II
Phase III
Marketed
Beta
Secretase
Research
Onclave
Research
Tysabri®
SC
ELND005
AAB-003
Monoclonal
Antibody
AAB-001
Bapineuzumab
Tysabri®
(natalizumab)
Secondary
Progressive
Multiple
Sclerosis
Tysabri®
(natalizumab)
Relapsing
forms of
Multiple
Sclerosis
Parkinson’s
Research
Prothena
Neotope
Research
ACC-001
Immunoconjugate
corp
Tysabri®
(natalizumab)
U.S.
ELND005
Alzheimer’s disease
Parkinson’s disease
Neotope
Multiple Sclerosis
Onclave
Crohn’s disease
Alzheimer’s Immunotherapy
Program (AIP)
Bipolar disorder
79
80
Strengths
- ELND005, promising medicine.
- Strong liquidity following a resale rights
Tysabri.
- Investment possibilities.
- Bapineuzumab SC phase II.
- ELND005 agitation and aggression in AD
and in bipolar disorder.
- Prothena
Weakness
- Poor performance of Bapineuzumab > Financial losses.
- Misunderstanding and poor opinion
of shareholders and financial analysts.
- Debt ($ 600millions)
- Only molecule: ELND005
- Prothena
- Bapineuzumab failure.
- Redemption.
- Concurrent Tysabri, Biogen in the
application approval in September.
81
Opportunities
Threats
Conclusion :
Would we join Elan Corp PLC. ?
 Would we invest in ELAN Corp PLC. ?
82
BACK UP SLIDES
83
What are Engineered Nanoparticles?
Nanoscale particles of API:
•
characterized by an extremely high surface-area to mass ratio and stabilized
against agglomeration using surface modifiers
•
not naturally occurring; prepared by:
•
-
molecular deposition /complexation (“bottom up”)
-
attrition of larger non-nanoscale materials (“top down”)
range in size from ca. 80 to 1000 nm for many pharmaceutical applications
84
FDA Advisory Committee Meeting_22Jul08_Elan_SBR
©2008
Schematic of an Aqueous Nanoparticle Dispersion
85
FDA Advisory Committee Meeting_22Jul08_Elan_SBR
©2008
Parenteral delivery
Oral delivery
•
Increased bioavailability
•
Increased rate of absorption
•
Reduced fed/fasted variable
•
formulations (up to 45% w/w)
•
Improved dose proportionality
•
Avoidance of uncontrolled
Avoidance of harsh vehicles (e.g.
cosolvents, solubilizers, pH extremes)
absorption
•
High drug loading in aqueous
•
Readily syringable formulations
facilitate use of traditional small-bore
needles
precipitation after dosing
•
Safety established for IV, IM and SC
routes of administration
86