Transcript Diapositive 1 - Moodle Lille 2

Campath® Withdrawal
Anatomy of a Brainstorming
Coralie Duriez, Philippine Guillier, Valentine Ripert, Pierre Titeca
August 2012
« Arrêter la commercialisation de la spécialité
ISSUES :
Scientific
« décision n’est pas prise pour des motifs de tolérance ni
d’efficacité, ni d’approvisionnement
Strategic »
« se consacrer au développement
Ethic dans le traitement de la
MabCampath »
sclérose en plaque »
2
-1- Alemtuzumab, Scientific aspect
3
Introducing Campath
= Alemtuzumab, AcM
• 3 generations, 3 isotypes
1980
Campath-1M
IgM (rat)
1986
Campath-1G
IgG (rat)
1987
Campath-1H
IgG1 (human)
• First humanized antibody
• Ac => Ag
4
Targeting CD52
CD52
Glycosylphosphatidylinositol (GPI)
anchored protein
12 amino-acids, negative charged
Expressed on
B-cells, T-cells, Monocytes
Fonction
anti-adhesion
• Monoclonal Ab humanisé recombinant
de type IgG1 kappa
• CDR-L3 : Dominant role in Antigen
Binding
• Ionic interactions
• An optimized Paratop
5
Alemtuzumab
6
General mecanism of Mab
7
8
Prospects
• Immunosuppression potentiel known since 90’s
• Kill lymphocytes by
– Complemet-mediated lysis
– Cell-mediated lysis
• Extensive research :
–
–
–
–
Leukemia
Vascularitis (1990)
Marrow and organ transplantation (1991)
Treatment of various autoimmune diseases
• Rhematoid arthritis(1992)
• Multiple sclerosis (1994)
9
B-CLL
10
Several targeted treatments options of B-CLL
11
Chronic Lymphocytic Leukemia
• Accumulation in the blood, bone marrow and
secondary lymphoid organs of small B-cell
monoclonal mature morphology but
immunophenotype characteristic.
– B lymphocytosis > 5000/mm3
– Surface markers characteristic : IgM, IgD, CD19,
CD20, CD23, CD5+
• Incurable disease
12
Figures
• Incidence : 4,1 pour 100 000 (Australia, USA,
Ireland, Italy)
• Elderly (60 years old)
• Male predominance (2/3 of cases).
• The 5-year relative survival is about 80%.
13
Symptoms
•
•
•
•
•
•
•
Fever, fatigue
Weight loss
shortness of breath
Night sweats
Lymphadenopathy
Thrombocytopenia
Anemia, splenomagalie.
• Asymptomatic
25% of cases not
treated
Complications
• Infections
• Auto immune:
hemolitique
Anémia,
Thrombopenia
• Lymphoma
14
Main Treatments
–Fludarabine
–Chlorambucil
Deletion 17p  resistance
–Cyclophosphamide
–Allogeneic hematopoietic stem cell
15
Development ?
Strong need of New Chemicals for B-CLL
Clinical development of
Gets a TUA already used - 2001
16
CAM 307
To verify clinical benefit in an open-label,
international, multicenter, randomized trial.
J Clin Oncol 25:5616-5623. © 2007 by American Society of Clinical Oncology
17
CAM 307 : Phase III study
From 2001 to 2004
Annual Cycle
CAM 307
297 naive
patients
RAI I to IV
Alemtuzumab® 3mg ; 10mg ;
30 mg i.v
Chlorambucil ® 40 mg/m² oraly
- 3 times/week
12 weeks
- Once every 28
days
maximum of 12
month
18
Procedure
Primary
Endpoint
Secondary
Endpoint
Progression- free survival (PFS) Duration.
Overall and Complete response rates
OR and CR > 2 months
19
Kaplan-Meier estimates of progression-free survival (PFS) based on Independent
Response Review Panel.
20
21
22
Other treatements depends on "suicide gene" 17p53
Deletion  resistance
Campath independent from gene TP 53 17th chromosome
locus P53
23
Alemtuzumab as First line therapy for B-CLL ?
- 2007 -
« Alemtuzumab has been shown to be
an effective monotherapy in both firstline and refractory chronic lymphocytic
leukaemia. »
« Notably, in patients who had the
cytogenetic deletion of 17p (p53),
there was a three-fold increase in
OR with alemtuzumab (64%)
compared with chlorambucil
(26%) »
24
In practice
• The therapeutic strategy depends on the existence
of comorbidity(s), the presence of 17p deletion and
the nature of prior treatments
• 17p deletion: 10% of patients
25
Marketing authorization approval
• FDA : September 2007
• EMA : July 2001
• « MabCampath is used to treat patients with B-cell chronic
lymphocytic leukaemia [...] MabCampath is used in patients
for whom treatment combinations including fludarabine
(another medicine used in leukaemia) are not appropriate. »
RCP
26
Multiple sclerosis
27
MS & autoimmunity
Molecular mimicry Hypothesis
• High involvment of
Lymphocytes (CD52)
28
Autoimmunity & Pathogenicity
 Inflamation reaction
In the MS, the cells of the immune system
cross the hémato-meningeal barrier and
affect the girdle of myélin surrounding
nerves.
 Démyélinisation
Myelin: Protect these fibers and accelerate
the transmission of the nervous messages
 Change of the impulse transmission
29
Multiple Sclerosis Worldwide
• + 2,5 millions people
diagnosed
• 2000 per year in France
• Affects 20 to 40 years old
people
• Incapacitating disease ++
1st cause of neurological disability
Environmental Factors? Hygien, UV-, Tobacco
30
Clinical signs
Motor disorders
muscle weakness, motor
control, loss of balance
Sensory disorders
numbness, tingling, loss of
sensitivity of certain
parts of the body
Visual disorders
decrease of sight, mouth, optic
neuritis
Cognitive disorders
memory loss, decrease in
attention
Urinary and sexual problems
incontinence, impotence,
dysuries
31
3 upgradable forms
• Relapsing-remitting stage RRMS (70%)
• Relapsing-persistant deficits SPMS (20%)
• Progressive persistant stage PPMS (10%)
RRMS
SPMS
PPMS
32
How to score MS
• Score of quality of life
• EDSS Scale Quantifiing Disability
33
Background treatments
Main treatments
 Relapses treatments
Corticoïdes IV méthylprednisolone
 Background treatments ( RR forms )
Immunomodulators IM or SC
Interféron Béta : Rebif, Betaferon, Avonex
prevent cells of immunity to cross this BHE
Acétate de glatiramère : COPAXONE
Protein which looks like the protein of the myéline
 plays the role of delusion
34
1991-2002: Cambridge Experience
Firsts trials for « Campath-IH » in MS
7 patients with MS, 10-day intravenous course
• Central nervous system lesions of MS detected by MRI with
gadolinium
M-3
+51 active lesions
Treatment
M+3
+15 active lesions
M+6
+2 active lesions
BUT :
– Rate Ratio significantly reduced in only 3 patients
– First infusion : exacerbation or re-awakening of preexisting symptoms, TNF, IFN (H+2), IL-6 (delayed H+4)
35
Early MS only ?
Results of a first open label Study of
Alemtuzumab in MS patients limits the
applications
RRMS patients
SPMS patients
Study fomat
Open label
Open label
Number of patients
36
22
Reduction in ARR
94 %
97%
Mean evolution of
EDSS score after 2
years
( per patient per
year)
-1,2
+ 0,2
A.J.Coles, et Al J.Neurol.253 (2006) 98-108
• BUT infusion causes :
• acute cytokine-release syndrome consisting of pyrexia, headache,
malaise and an urticarial rash
• exacerbation of neurological symptoms
=> Substancially ameliorated by pre-treatment with corticosteroids36
CAMMS 223 : Phase II Study
blind, randomized, 2002-2007 (2 years follow-up)
Annual Cycle
111 - IFN B 1a Rebif ® 44μg, SC
3 times a week
113 - Alemtuzumab 12mg, IV
- Month 1 :
1/d for 5 days
CAMM 223
334 naive treatments
patients
MSRR
EDSS ≤ 3.0
- Month 12 :
1/d for 3 days
110 - Alemtuzumab 24mg, IV
- Month 24 :
1/d for 3 days
37
Procedure
Primary
Endpoint
Secondary
Endpoint
-Annualized relapse rate
-Time to sustained accumulation of disability
-Lesion load on T2-weighted MRI at 12/24/36
month
-Brain volume on T1 weighted MRI
EDSS reevaluated every 3 months
MRI every years
38
Outstanding results
- Reduction in relapse rate and sustained disability
- Could even be better than approved therapies
39
ECTRIMS Investor Presentation October,14,2010
Persistance of effect in Time – 5years
5years follow up of CAMM 223
40
“ It is the first time when by treating early sick
young people, we observe a decrease of the
handicap. The images by MRI of the brain of
the patients taking the experimental medicine,
show an increase of the cerebral volume, so
the brain repairs ”. Dr Alasdair Coles
Clinical trials : until 2010
41
Alemtuzumab : neuroprotective effects ?
• Increased concentration of :
– Brain Derived Neurotrophic
Factor related to nerve growth
factor
• Increased axonal lengh :
myelinisation
– Ciliary Neurotrophic factor
• survival factor for neurones and
oligodendrocytes
Brain 2010/ 133;2232-2247
Neuroprotective Action strongly suspected
42
Studies of phase III
Same Endpoints
43
Etude CARE MS I ( 2007-2011)
Résults :
After two years of alemtuzumab with regard to IFB beta 1a :
 Rate of relapse reduces of 55 %
Etude CARE MS II : Rate of relapse reduces of 49%
44
Alemtuzumab : Side effects
Much more effective than INF in terms of results
BUT many questions concerning its tolerance !!
• DEATH due to immune thrombocytopenic purpura
• Infections
• Events affecting thyroid ( hypertyroidism, hypotyroidism )
45
A step forward?
Current competitors used in RRMS:
• Natalizumab Tysabri (Biogen Idec et Elan ) IV : approved in 2007
• Fingolimod Gilenya (Novartis ) : approved end 2011
46
New Therapeutics marketed in Active MS
Natalizumab TYSABRI
Fingolimod GILENYA
Biogen
(FTY720, Novartis)
Mechanism
Monoclonal antibody anti-A4
integrin
Modulator of the
sphingosine-1-phosphate
receivers
Route of administration
Intravenous way
Oral route
Efficacity
Side Effects
WARNING FDA
Decrease of 70% of pushes
number
Decrease of 90 % of new
inflammations
Reduction of 70 % of pushes
frequency
Stabilization of the brain
damages
• Hypersensitivity reactions
• Bradycardia after first dose
• Risk of Progressive Multifocal • Infections
Leukoencephalopathy
• Eye Macular oedema
• Basal-cell carcinomas
2005 : 2 PML
Suspension, then Black Box
warning
2011 : reported death after
administration
47
Comparision of both indications
Alemtuzumab for
Disease
CLL
RRMS
+ 60 years
25 -35 years
Prevalence
+
+++
Incidence
4 per 100.000
80 per 100.000
+
++
CAM 307
Care-MS 1 et 2
Age
Position on Market
Clinical Trials
Adverse Events
Lymphopenia,
neutropenia, Infections
Thrombocytopenia
Anemia
An obvious lucrative 2nd indication
Thrombocytopenic purpura
Infections
Hypotyroidism
Hypertyroidism
GO FOR MS ?
48
Context
• The biotechnology pharmaceutical companie
Genzyme : the manufacturer of alemtuzumab
• In August 2010, Sanofi makes a friendly
takeover bid for Genzyme
49
Acquisition of Genzyme by Sanofi-aventis
• The acquisition was delayed by a dispute between the
two companies regarding the value of alemtuzumab.
Business Unit
Therapeutic Area
Products
Research Pipeline
Rare diseases
Genetic diseases
Cerezyme, Fabrazyme,
Aldurazyme, Myozyme,
Lumizyme, Elaprase
Eliglustat
Mipomersen
Endocrine
Thyrogen
Cardiovascular
Cholestage
Multiple Sclerosis
Aubagio
Alemtuzumab
50
Genzyme and Sanofi agree on deal outline
• February 16, 2011: definitive agreement : Sanofi-aventis bought
Genzyme for $20.1 billion in cash ($74 per share), plus payments
contingent on the success of some of Genzyme's drugs
• => Sanofi acquires a molecule with dual indication, how will be
use its potential ?
51
- 2 – Strategic aspects
How to market alemtuzumab for MS ?
52
Extending the indication?
Y1
- No Y2
First infusion
Campath
30 mg/injection / 36 injections
Alemtuzumab in MS
12mg/injection / 5+3 injections
Different dosage = Different M.A.
53
Marketing Authorization
• Requires
– Registration dossier : Clinical studies
• drug safe and effective in its proposed use(s) benefits
of the drug outweigh the risks
– Appendixes : labelling, SPC, drug instruction
– Drug Monitoring and Risk Management Plan
– Price
– A Trademark name
No Restraint !
54
55
Drug Value
What’s the acceptable cost of an effective medicine ?
• Drug value evaluated by:
– QALY =Quality Adjusted Life Year
– ICER = incremental cost-effectiveness
ratio
• a measure that assesses the
additional cost for a new treatment
• ∆Cost / ∆Efficacy
• In UK
ICER per QALY
>30.000
Not Cost-Effective
<30.000
Cost-Effective
56
Informal Care
12%
Adaptations
5%
Services
2%
Other Drug
6%
DMTs
22%
Global Costs of MS
Sick Leave /
Reduced
Work
10
%
Early
Retirement
34
%
Hospital Inpatient Care 3%
Ambulatory Care
4%
Tests
2%
57
ICER of Tysabri
Tysabri Compared with
IFN
Copaxone
RES-RRMS
32.000 £
34.600 £
Suboptimal therapy group
43.400 £
44.300 £
Natalizumab for the treatment of adults with highly active relapsing– remitting multiple sclerosis,
NHS, June 2010
Course of
20 years
30 years
ICER Natalizumab vs B-INF
32.000 £
24.600 £
COST-EFFECTIVENESS FOR ACTIVE MS
RES-RRMS : Rapidly Evolving and Severe RRMS
58
Cost of a 1 year treatment
Natalizumab (Tysabri®)
Fingolimod (Gylenia®)
Dose per pack
1/4w, injection
1/d, oral route
WAC per package
$ 3.076
$ 3.688
WAC per Year
$ 39.985
$ 47.951
Ken O’Day and al. Cost-effectiveness of natalizumab versus fingolimod for the treatment of relapsing multiple
sclerosis. Journal of Medical Economics Vol. 14, No. 5, 2011, 617–627.
What to expect for Lemtrada?
59
What to expect for Alemtuzumab in MS?
If QALY >>>, then the Cost-effectiveness rises
Price ↗↗
60
When 1mg of powder is worth gold…
Campath® - BCLL
Lemtrada® - MS
Tysabri® - MS
Weight per vial
30 mg
12
300mg
Number of vials
36
8
13
Per mg
$55
$55
$416
$15
WAC per package
$1.666
$660
$4.998
$4.576
WAC per year
$60.000
$5.280
$39.985
$39.985
• If we assess that Lemtrada will cost at least what costs
Tysabri :
– Then price per mg for the same chemical would
increase by $55 to $416 : x8
– Price of APIs are only connected with pathologies 61
Same chemical
+
$/mg (Lemtrada) = 8 times $/mg (Campath)
+
Clinical Studies for both indications
= Off-Label Risk
OR :
A pharmaceutical industry is liable for
the off-label uses of its products, and is
to manage or prevent them
Avastin / Lucentis
“Given the known safety profile of alemtuzumab, I think MS doctors will be reluctant
to use it off label.” Til Menge, University Hospital Dusseldorf
62
Off-label-use : hefty bill
• Avoid the use of Alemtuzumab before & after the
MS-indication approval ?
Total dose
60mg (Y1) + 36mg (Y2)
Number of Campath®
30mg vials
Total Cost ($1.666)
4
$6.666
• Estimated Losses : from $30.000 to $35.000 per patient
(compared to Tysabri®)
• Potential market : 700.000 patients
63
Campath®-Alemtuzumab Patent
Expires in 2014
64
Biosimilars
• Estimated
price
for
biosimilar products will be
65%-85% of their originators.
• FDA : Patient Protection and Affordable Care Act (2010)
– Abbreviated licensure pathway for biological products
that are demonstrated to be “biosimilar” to or
“interchangeable” with an FDA-licensed biological
product.
• Pending arrival of Biosimilars
– A Campath’s biosimilar could cause off-label uses for MS
65
Avoiding off-label use
Reglementary concerns ?
or
Financial protection ?
66
• A different Market Authorization for Lemtrada®:
– A different Trademark name
– A price legitimataly corresponding to MS-market
But
• 2 indications requiring different doses :
– A previous indication ruining the price/mg
– A high-risk of off-label use of Campath® for MS
67
Decision
Sanofi withdraws Campath
68
Financial report, August 2012
• « Campath est actuellement approuvé aux États-Unis, en
Europe et dans quelques autres juridictions dans certaines
indications oncologiques. Genzyme mettra fin à la
commercialisation de Campath. Cette décision n'a pas été
prise pour des raisons liées à la qualité du produit, sa sécurité,
son efficacité ou son approvisionnement dans les indications
actuellement approuvées, mais parce que Sanofi et Genzyme
ont décidé de se concentrer sur Lemtrada™ pour la sclérose en
plaques, et il existe des différences dans le dosage et le profil
d’innocuité entre Campath et Lemtrada. Compte tenu de
l’arrêt de la commercialisation de Campath, Sanofi travaille
avec les autorités de santé pour mettre en place des
programmes d’accès au médicament par le biais desquels
Sanofi fournira Campath gratuitement pour les indications
dans lesquelles le produit est actuellement approuvé. Dans le
69
cadre de ce processus, les autorisations de commercialisation
- 3 – Regulation, ethical approach and
risk management
70
Regulation
• « Should a marketing authorisation holder decide withdraw it
from the market before the expiry of its marketing
authorisation, he shall accordingly inform the Agency six
months in advance. »
• Will prevent the off-label use (laboratory is responsible for offlabel uses of their products)
• Additional security against the potential future generic
71
Patients First
72
Consequences for patients
• Patient without treatment
• Ethically, it is unthinkable for Leukemia Patients to
deny the access to their treatment.
• First line in 17p deletion
73
Incredible patient access program
• Patient access program : for all patients who need it (
current users and future users)
• Free of charge : $0
• For oncologists for CLL
and malignancies
74
Incredible patient access program
• Nominative TUA
– Second TUA
– TUP
• monitoring and surveillance of patients
• terms of drug dispensing and monitoring of patients
• Product request form (basic patient information, the
intended use, the number of vials requested and agree to the
terms and conditions of the program)
75
76
Incredible patient access program
• Nominative TUA
• Product request form (basic patient information, the
intended use, the number of vials requested and agree to the
terms and conditions of the program)
• Genzyme is required to transmit to ANSM every 6 months a
report
• How long time ? No end date published
77
Patient associations and prescriber reactions
CLL
MS
-Hildy Dillon, vice president of patient
services for the Leukemia & Lymphoma :
«They’ve actually been quite supportive to
us and our constituents »
-Three British Neurologists have written to
the Health Minister, Jeremy Hunt, to protest
against Genzyme
- Prescriber : addition of more paperwork,
Loss of time
-Multiple sclerosis research blogspot : a blog
for people with MS ans their families
=> + FAVORABLE
=> +++ UNFAVORABLE
78
Therapeutic alternative
ARZERRA (ofatumumab) IV
monoclonal antibody (CD20)
• Treatment of patients with CLL who have not responded to
fludarabine and alemtuzumab.
• Side effects : Infection ++, Infusion reactions, Low blood cell
counts, Bowel problems
79
Work in MS
80
Alemtuzumab, MS
• This stoppage shows Sanofi's confidence in
the approval of Alemtuzumab in multiple
sclerosis
81
Focus in preparation for global launch
Japan
Spain
four key countries
Italy
France
7%
UK
9%
57%
660,000
diagnosed
patients
16%
USA
Positive initial
conservations with
stakeholders
Germany
MS prevalent populations across 7 majors pharmaceutical
markets
100% = 740 000 patients in 7 major markets
82
Alemtuzumab, MS
• FDA : action expected on the application in the
second half of 2013 (in August 2012, the FDA asked
Sanofi to resubmit its application)
• Genzyme has already submitted its marketing
authorization application for Lemtrada to the EMA
and the review process is underway.
• Expected price after negociation :
– 45 000 to 50 000/year
83
Risk management
• Estimated sales
Campath®
2011
$76.000.000
Lemtrada®
2018
$500.000.000
• Return on investisment
– Purchase price of Genzyme : $20.1 billion
– + CVR
84
Objectives of Sanofi
• The withdraw of Campath was already programmed by
Genzyme. While negociating, Genzyme required their
prerogatives.
• Terms of the CVR agreement call for additional cash payments
under certain circumstances :
• The CVR terminates on December 31, 2020
• $14 per CVR : $3,8 billion
$1.00 per CVR
if specified Cerezyme®/Fabrazyme® production levels
are met in 2011
$1.00 per CVR
upon final FDA approval of LemtradaTM for multiple
sclerosis indication
$2.00 per CVR
if net sales post launch exceed an aggregate of $400
million within specified periods per territory
$3.00 per CVR
if global net sales exceed $1.8 billion
$4.00 per CVR
if global net sales exceed $2.3 billion
$3.00 per CVR
if global net sales exceed $2.8 billion
85
Prospect in MS
Molecules in MS :
• Natalizymab (Tysabri*)
• Fingolimod (Gilenya*)
MARKET IN MS DRUGS
in 2013
in 2022 (estimation)
$13,8 billion
$19,6 billion
Pipeline in MS :
•
•
•
•
Ocrelizumab (OPERA and ORATORIO Phase 3 : ORCHESTRA)
Daclizumab (SELECT Phase 2b and DECIDE Phase 3)
Fampyra (MS-F203 and MS-F204 Phase 3)
BG-12 (Fumarate de diméthyl) : Currently under regulatory
review (DEFINE and CONFIRM Phase 3)
86
Sanofi in MS
• Teriflunomide (Aubagio*)
• once-daily pill
• Sept, 2012 : Market authorization in US and Australia
• Alemtuzumab (Lemtrada*)
• « When you walk in the display area, we are
as prominent as any other company. We are a
player now ». Bill Sibold, Genzyme head of MS
87
MERCI DE VOTRE ATTENTION
88