Transcript Le retrait du campath remplacé par l*Alentuzumab

BENTAIEB Fathi
FETRO Christine
LINDNER Lucie
MAAMAR Suina
RAME Blandine
Feb. 18th, 2014 - M2 AREIPS
1

September 17,2013 the European Commission has granted marketing
authorization for Lemtrada for patients with relapsing remitting MS

December 13, 2013 Health Canada has approved Lemtrada for the
management of adult patients with relapsing remitting multiple
sclerosis.

December 19, 2013 the Australian Therapeutic Goods Administration
has approved Lemtrada for the treatment of relapsing forms of
multiple sclerosis.

December 30, 2013 the FDA has rejected approval of the
investigational drug Lemtrada.
2

Approved in the US (Campath®) and the EU (MabCampath®)in May
2001 and July 2001 respectively

Withdrawn from all markets in 2012

ATU in France

Compassionate use in Europe

Campath access program in the US
3
Alemtuzumab
2001
Alemtuzumab
2013
4
5
SUMMARY
I.
Scientific Overview
II. Economic Strategy
III. Regulatory Overview
IV. Conclusion
6
I.
SCIENTIFIC OVERVIEW
1. ALEMTUZUMAB
2. LLC
3. MS
4. CLINICAL TRIALS
7
A LONG AND WINDING HISTORY…
1983 Originally
synthesized by
Herman Waldmann
at the Department of
Pathology in
Cambridge
University (hence
Cam-Path)
2011
A Long and Winding History ：Campath(Alemtuzumab) の数奇な運命
8
A LONG AND WINDING HISTORY…
1997 Joint-venture LeukoSite/Ilex
Onco
In 1999 Millennium purchased
Leukosite /Ilex
Joint clinical trials in B-CLL
http://www.whatisbiotechnology.org/exhibitions/campath/change
9
A LONG AND WINDING HISTORY…
Merger in 2004
Genzyme had to continue
working with Bayer.
Joint venture started by Ilex
with Schering AG for the
development of Campath-1H
in MS
http://www.whatisbiotechnology.org/exhibitions/campath/change
10
ALEMTUZUMAB

CAMPATH-1M
rat IgM

CAMPATH-1G
rat IgG2b

CAMPATH-1H
http://www.path.cam.ac.uk/~mrc7/campath/campath.html
humanized IgG1
11
ALEMTUZUMAB PROFILE
 Humanized monoclonal
antibody
Murine CDR’s
Targets CD52 antigen
abundant on the surface of B
and T lymphocytes
 Apoptosis
12
Alemtuzumab MoA - One target : CD52
Expert Opin. Biol. Ther. (2010) 10(3):421-429
13
FROM B-CLL TO MS
B-CLL
B-CLL
MS
Cross AH et al. (2001) B cells and antibodies in CNS demyelinating disease. J Neuroimmunol 112: 1–14
Nature Clinical Practice Neurology (2006) 2, 201-211 Immunopathogenesis and immunotherapy of multiple sclerosis Bernhard Hemmer
14
I.
SCIENTIFIC OVERVIEW
1. ALEMTUZUMAB
2. LLC
3. MS
4. CLINICAL TRIALS
15
CHRONIC LYMPHOCYTIC
LEUKEMIA
Disease
Epidemiology
Diagnostic
Complications
• Lymphocytes B, produced by the bone marrow, never die again.
• Accumulation in the blood, spleen, lymph and bone marrow.
• the most common leukemia occurring in adults
• approximately 3,000 new cases per year in France.
• It affects twice as many men than women, >50 years
•
•
•
•
no sign of disease, unnoticed.
CBC: too many B cell + immunophenotyping
3 stages: A, B, C
2/3 only treat
•Decreased hemoglobin: Anemia
•Infections
•decreased platelets: bleeding
16
CLL - TREATMENT
A
• No treatment
• Monitoring
B,C
• First line: Rituximab (Mabthera®,
Rituxan®) + Fludarabine +
Cyclophosphamide (Endoxan®)
• 2nd line:
-Campath® +/-corticotherapy ou
-Campath® +/- fluda+/ cyclophosphamide
• 2nd line :Rituximab + pentostatine +
cyclophosphamide
FDA – 2007  First line
17
I.
SCIENTIFIC OVERVIEW
1. ALEMTUZUMAB
2. LLC
3. MS
4. CLINICAL TRIALS
18
© Inserm19
EPIDEMIOLOGY
starts between 20 and 40 years and affects women more than men (ratio 3:2)
2 million patients
80 000 in France
20
DIAGNOSTIC
 Complications
Clinical Diagnostic
Visual
disorders
Loss of
motricity
Sensitivity
disorders
Balance
disorders
Functional
disorders
Mcdonald’s criterias
Number of
relapses
Number of
lesions
Existence of
an
inflammation
Biologic and Radiologic diagnostic
Lumbar
puncture
MRI
21
EDSS SCORE
22
3 DIFFERENT FORMS
85%
50% 15%
23
TREATMENT (1/2)
The treatment of MS generally falls into two categories
symptomatic treatments
+ Kinesitherapy
Treatments that change the
course of the disease
Flares:
Methilprednisolone IV
MS RelapsingRemitting
24
TREATMENT (2/2)
LEMTRADA®
Elsep®,
Tysabri®,
Gilenya®
Aubagio®
Betaferon®,
Avonex®,
Rebif®,
Copaxone®
Reco HAS
25
I.
SCIENTIFIC OVERVIEW
1. ALEMTUZUMAB
2. LLC
3. MS
4. CLINICAL TRIALS
26
EVALUATION IN B-CLL
A prospective, noncomparative phase II trial called CAM211
Primary objective: evaluate
Overall Response rate (OR)
Secondary objectives: safety
profile and clinical benefit
April-October 1998
93 patients (73 male, 20 female)
27
EVALUATION IN B-CLL:
SURVIVAL CURVE
CAM211 (n=93)
Response rate (95% IC)
33.3 % (23-43%) n=31
Complete response (CR)
2.2% n=2
Partial response
31.1% n=29
•Treatment of patients with chronic lymphocytic leukaemia (CLL) who
have been treated with alkylating agents and who have failed to
achieve a complete or partial response or achieved only a short
remission (less than 6 months) following fludarabine phosphate therapy
•Accelerated approval in US (final study report in Nov 2006)
For the treatment of B-cell CLL in patients who have been treated
with alkylating agents and who have failed fludarabine therapy
EMA
28
March
2001
FDA
7 May
2001
28
EVALUATION IN B-CLL: CAM307
A phase
III study
An international, multi-center, randomized, open-label trial
One observation :the worst disease progression and survival outcomes correlate with
deletions of 17p (the location of the p53 gene) and 11q
=> resistance to purine analogs
=>identify treatments for CLL that work through p53-independent
Primary end point: progression freesurvival (PFS)
Secondary end points: overall response
rate (ORR), and overall survival
JCO-2007-Hillmen 5616-23
29
EVALUATION IN B-CLL: CAM307
149 patients
received
Alemtuzumab (IV)
Dose escalation and
30mg/weeks for no
more than 12 weeks
148 patients
received
Chlorambucil (PO)
40mg/m²
297 patients
From December 2001 to July 2004
30
CAM307 : CHANGE IN LABELLING
07 July 2001
The treatment of patients with B-CCL for
whom fludarabine combination
chemotherapy are not appropriate
19 September 2007
expanded the labelling: indicated
as a single agent for the
treatment of B-CLL
31
EVALUATION IN MS: CARE-MS
STUDIES PHASE III
COMPARISON OF ALEMTUZUMAB AND REBIF EFFICACY IN MULTIPLE SCLEROSIS
CARE-MS 1 (S323)
CARE-MS 2 (S324)
Same design: A 2-year rater-masked, randomised, controlled phase 3 trial
Same Coprimary endpoints:
•relapse rate
•time to 6 month sustained accumulation of disability
defined as an increase from baseline of at least one
EDSS point confirmed over 6 months
32
EVALUATION IN MS : CARE-MS 1
with previously untreated relapsing-remitting MS (between
Sept 7,2007 and April 17,2009)
187 patients received interferon beta 1a
376 patients received alemtuzumab 12
mg
Baseline
Alemtuzumab
12
months
OR
Interferon
33
RESULTS
Lancet 2012; 380: 1819–28
34
CAMMS324 OR CARE-MS 2
for patients after disease-modifying therapy
Between Oct 20,2007 and Sept 18,2009
Same schedule of administration
202 patients received interferon beta 1a
426 patients received alemtuzumab 12 mg
170 patients received alemtuzumab 24 mg
decision to close recruitment into the arm was made by the Neurology Steering
Committee and Genzyme management without review of safety or efficacy data from
this study
35
RESULTS
Lancet 2012; 380: 1829–39
36
A SIMILAR SAFETY
CARE-MS 1
37
A SIMILAR SAFETY
CARE-MS 1
« The substantial efficacy of alemtuzumab in needs to be balanced
against potentially serious but treatable adverse effects »
38
TO SUMMARISE
CARE MS 1
CARE MS 2
Study design
Randomized, ratermasked phase 3
Randomized, ratermasked phase 3
Date
Sept 7,2007-April
17,2009
Oct 20, 2007- Sept
18, 2009
Coprimary endpoint:
-relapse rate
-ok
-SAD 6 months
-no
Safety
2 pivotal studies
2 different decisions
-ok
-ok
-infusion associated
reactions
-infections
-IS
-infusion associated
reactions
-infections
-IS
ALEMTUZUMAB
2013:Lemtrada®
39
II. Economic Strategy
1. SANOFI
2. GENZYME
3. COSTS CONSIDERATIONS
40
SANOFI RANK - 2005
2004 – Merge SanofiSynthelabo & Aventis
2005 – Sanofi reachs
the 3rd rank of Pharma
companies worldwide
under J-F Dehecq
41
MAIN REVENUES & PATENTS
PERSPECTIVES – 2005
PROTECTION END
US
EU
Revenues – 2005
(M€)
2143
LOVENOX® (enoxaparine)
2026
PLAVIX® (clopidogrel)
1609
TAXOTERE® (docetaxel)
1564
ELOXATINE® (oxaliplatine)
STILNOX® (zolpidem)
1519
LANTUS® (insuline glargine)
1214
2012
2011
2011
2013
2010
2010
2008
2006
2007
2004
2014
2014
COPAXONE® (glatiramère)
902
2014
2015
APROVEL® (irbésartan)
892
2011
2012
42
NEW DIRECTION
In 2008 : Christopher Viehbacher takes the Lead of Sanofi-Aventis
( Sanofi in 2011) while 6/7 main products lose protection within
next 2-4 years
He wants to direct the Groupe to :
OTC medicines
R&D reinforcement
Biotechnologies
43
THE POTENTIAL BIOTECHS
Revenues - 2005
Revenues - 2010
(B$)
(B$)
12.4
Amgen
15
Amgen
6.6
Genentech
4.7
Biogen
2.7
Genzyme
Biogen
MedImmune
1.2
Celgene
0.5
Alexion
0.01
Regeneron
Genzyme
4
Celgene
3.6
2.4
Alexion
0.5
Regeneron
0.4
0.07
MedImmune  AZ - 2007
Genetech
 Roche – 2009
44
GENZYME - ID
Genzyme : Biotechnology Compagny specialized in rare diseases
founded in 1981 at Boston (headquarter) by Henry Termeer
Presence in 40 countries
12 production sites : US (8) ; Australia (1) and Europe (3)
Products distributed in 100 countries
45
GENZYME – PORTFOLIO
Product
Pathology
Incidence
Revenues
2010 (M€)
End of
Protection
Cerezyme™/Cer
edase™
Gaucher disease
1/ 57 000
719.6
2001
www.genzyme.fr
46
GENZYME - PORTFOLIO
Product
Pathology
Incidence
Revenues
2010 (M€)
End of
Protection
Cerezyme™/Cer
edase™
Gaucher disease
1/ 57 000
719.6
2001
Renagel™
Hyperphosphoremia
10% world
population
697.7
2014 (US)
2015 (EU)
The Lancet – 2013
www.genzyme.fr
47
GENZYME - PORTFOLIO
Product
Pathology
Incidence
Revenues
2010 (M€)
End of
Protection
Cerezyme™/Cer
edase™
Gaucher disease
1/ 57 000
719.6
2001
Renagel™
Hyperphosphoremia
10% world
population
697.7
2014 (US)
2015 (EU)
1/50 000
188.2
2010
Fabrazyme™
The Lancet – 2013
www.genzyme.fr
Fabry disease
(a-galactosidase deficit)
48
GENZYME - PORTFOLIO
Product
Pathology
Incidence
Revenues
2010 (M€)
End of
Protection
Cerezyme™/Cer
edase™
Gaucher disease
1/ 57 000
719.6
2001
Renagel™
Hyperphosphoremia
10% world
population
697.7
2014 (US)
2015 (EU)
1/50 000
188.2
2010
1/40 000
≈315
2013 (US)
2016 (EU)
Fabrazyme™
Myozyme™
The Lancet – 2013
www.genzyme.fr
Fabry disease
(a-galactosidase deficit)
Pompe disease
(a-glucosidase deficit)
49
GENZYME - PORTFOLIO
Product
Pathology
Incidence
Revenues
2010 (M€)
End of
Protection
Cerezyme™/Cer
edase™
Gaucher disease
1/ 57 000
719.6
2001
Renagel™
Hyperphosphoremia
10% world
population
697.7
2014 (US)
2015 (EU)
1/50 000
188.2
2010
1/40 000
≈315
2013 (US)
2016 (EU)
1/100 000
≈150
2010 (US)
2013 (EU)
Fabrazyme™
Myozyme™
Aldurazyme™
The Lancet – 2013
www.genzyme.fr
Fabry disease
(a-galactosidase deficit)
Pompe disease
(a-glucosidase deficit)
Mucopolyscharidosis
(type 1)
50
CAMPATH®
2009
• Genzyme obtains the rights of Campath® for
$1.25B (over next 10 years) + royalties upon
worldwide sales (buy-out option = $900 M)
• Why did Bayer sell Campath ?
2010
• Campath® revenues is only less than $150M (max
revenues since its MA in 2001 in the US)
End of Protection :
2014 (EU) & 2015 (US)
51
SANOFI RANK - 2010

2010 – Sanofi is at the
6th rank of Pharma
companies worldwide
52
GENZYME ACQUISITION
20,1 billion $ en 2011 (74$ per share) +
Contingent Value Right (CVR – Certificat de valeur conditionnelle) based on Lemtrada®
sales (max 14$ per share) : $2.8B by 2020.
A long deal : 9-month !
A great deal : Genzyme is stucked with a contamination issue for months in 2009
(impact on Cerezyme™/Fabrazyme™ production) … but Sanofi can help with its
vaccine knowledge …
2013 : Sanofi reachs the 4th rank of pharmaceutical companies worldwide
53
Why does Sanofi prefer
Lemtrada® ?
54
COSTS CONSIDERATIONS
Campath®
Indication
Dose
Scheme
LLC
30mg/ml
W1 : 3 vials
W2-4-6-8-10-12 :
3 vials/week
Price
435 €
(1 vial)
Cost per
mg
14.50 €
Annual
Costs
9 135 €
SMR
aSMR
CT
opinion
II (important)
IV (mild – 1st line)
2008
55
COSTS CONSIDERATIONS
Indication
Dose
Scheme
Campath®
Campath®
LLC
SEP-RR
30mg/ml
10mg/ml (12mg)
W1 : 3 vials
W2-4-6-8-10-12 :
3 vials/week
Y1 : 5 vials
Y2 : 3 vials
Price
435 €
(1 vial)
435 €
(1 vial)
Cost per
mg
14.50 €
36.25 €
Annual
Costs
9 135 €
1 740 €
II (important)
NA
IV (mild – 1st line)
NA
2008
NA
SMR
aSMR
CT
opinion
56
COSTS CONSIDERATIONS
Indication
Dose
Scheme
Campath®
Campath®
Lemtrada®
LLC
SEP-RR
SEP-RR
30mg/ml
10mg/ml (12mg)
10mg/ml (12mg)
Y1 : 5 vials
Y2 : 3 vials
Y1 : 5 vials
Y2 : 3 vials
W1 : 3 vials
W2-4-6-8-10-12 :
3 vials/week
Price
435 €
(1 vial)
435 €
(1 vial)
10 650 €
(1 vial)
Cost per
mg
14.50 €
36.25 €
887.50 €
Annual
Costs
9 135 €
1 740 €
42 600 €
II (important)
NA
pending
IV (mild – 1st line)
NA
pending
2008
NA
pending
SMR
aSMR
CT
opinion
57
COSTS CONSIDERATIONS
Indication
Dose
Scheme
Tysabri®
Gilenya®
(natalisumab)
(fingolimod)
SEP-RR
SEP-RR
SEP-RR
10mg/ml (12mg)
10mg/ml (12mg)
20mg/ml (300mg)
0.5 mg
Y1 : 5 vials
Y2 : 3 vials
Y1 : 5 vials
Y2 : 3 vials
300mg / month
1cp / day
Campath®
Campath®
Lemtrada®
LLC
SEP-RR
30mg/ml
W1 : 3 vials
W2-4-6-8-10-12 :
3 vials/week
Price
435 €
(1 vial)
435 €
(1 vial)
10 650 €
(1 vial)
1 800 €
(1 vial)
1 923 €
(28 caps)
Cost per
mg
14.50 €
36.25 €
887.50 €
6€
137 €
Annual
Costs
9 135 €
1 740 €
42 600 €
21 600 €
23 076 €
II (important)
NA
pending
II (important)
II (important)
IV (mild – 1st line)
NA
pending
III (modéré)
IV (mineur)
2008
NA
pending
2007
2011
SMR
aSMR
CT
opinion
58
COSTS CONSIDERATIONS
Indication
Dose
Scheme
Tysabri®
Gilenya®
Aubagio®
(natalisumab)
(fingolimod)
(teriflunomide)
SEP-RR
SEP-RR
SEP-RR
SEP-RR
10mg/ml (12mg)
10mg/ml (12mg)
20mg/ml (300mg)
0.5 mg
14 mg
Y1 : 5 vials
Y2 : 3 vials
Y1 : 5 vials
Y2 : 3 vials
300mg / month
1cp / day
1 cp / day
Campath®
Campath®
Lemtrada®
LLC
SEP-RR
30mg/ml
W1 : 3 vials
W2-4-6-8-10-12 :
3 vials/week
Price
435 €
(1 vial)
435 €
(1 vial)
10 650 €
(1 vial)
1 800 €
(1 vial)
1 923 €
(28 caps)
1 251 €
(28 caps)
Cost per
mg
14.50 €
36.25 €
887.50 €
6€
137 €
3€
9 135 €
1 740 €
42 600 €
21 600 €
23 076 €
15 012 €
II (important)
NA
pending
II (important)
II (important)
pending
IV (mild – 1st line)
NA
pending
III (modéré)
IV (mineur)
pending
2008
NA
pending
2007
2011
2013
Annual
Costs
SMR
aSMR
CT
opinion
59
KEY POINTS
Campath® : LLC (MA : 2001 – US)
Genzyme gets Campath® rights from Bayer (2009)
Sanofi buys Genzyme (2011)
Lemtrada® : MS (MA : 2013 – EU) ; co-development Genzyme/Bayer
Alemtuzumab end of protection : 2014 (EU) & 2015 (US)
Lemtrada price may impact health insurance systems
Leukemia market < MS market
60
III. REGULATORY OVERVIEW
1. EMA
2. FDA
61
III. REGULATORY OVERVIEW
1. EMA
2. FDA
62
Start
Campath® / MabCampath®  B cells CLL (30 mg/ml)
=
ALEMTUZUMAB
=
Lemtrada®  MS (10 mg/ml)
63
Start
MAH intends to take
action to withdraw a
product from the
market
At the request of Genzyme
From 50 countries (including European market) in August 2012
To Prevent off-label use  risk for patients
 Commerical reasons : to launch Lemtrada in MS
64
Start
MAH intends to take
action to withdraw a
product from the
market
What is the
MA
procedure?
MabCampath® (alemtuzumab)
Agency product number : EMEA/H/C/000353
Rap. Dr J. Ersboll (Denmark) / Co-Rap. Prof. S. Garattini (Italy)
Product authorised through the CENTRALISED PROCEDURE
65
Start
MAH intends to take
action to withdraw a
product from the
market
What is the
MA
procedure?
Art. 116 &
117 of Dir.
2001/83/EC
?
NO
66
IN THE EUROPEAN UNION
European legal basis for the withdrawal:
Regulation (EC) No 726/2004
Article 13(4) :
The MHA is required to “notify the Agency if the product ceases to be placed
on the market of a Member State, either temporarily or permanently”.
“Such notification shall, otherwise than in exceptional circumstances, be made
no less than two months before the interruption in the placing on the market of
the product”.
Regulation (EU) 1027/2012
Article 14b :
The notification must include the reasons for such action.
67
68
ANY OTHER POSSIBILITIES ?
2 ≠ MA ?
RTU ?
Indication’s
extension ?
69
THE MA IS NO LONGER VALID IN
B-CELL CLL
BUT …
As NO standard alternative
therapies are available !!!
&
PATIENT FIRST !!!
Discussion between the EMA & Genzyme
PATIENT ACCESS PROGRAM in 50 countries: “Compassionate Use”
70
COMPASSIONATE USE IN THE EU
Definition
Legal
basis
Condition
• To cover the supply of an unlicensed medicinal
product to patients for whom no standard
alternative therapies are available
• Usually reserved for the treatment of serious,
often fatal diseases
• Directive 2001/83/EC
• Regulation (EC) No 726/2004
• The EMA manages a procedure for providing
recommendations to Member States
• Compassionate use programmes remain
coordinated and implemented by Member
States
71
IN FRANCE
Named
ATU
PTU
Campath®
access
72
IN FRANCE
Named
ATU
PTU
Campath®
access
Derogation
Permitted for medicinal products intended to treat severe or rare
diseases, in the absence of appropriate alternative treatment
Named patient ATU applications are made by the prescribing doctor for
a specific patient and transmitted to the ANSM by the hospital pharmacist
73
IN FRANCE
Named
ATU
PTU
Campath®
access
The authorisation implies the implementation of a “Protocol for Therapeutic Use &
Collection of Information”.
It should be signed between agency and industrial.
It describes practical information about prescription, delivery and monitoring
associated with treatment and collection of data on conditions of use.
Genzyme is required to transmit to ANSM every 6 months a report
74
IN FRANCE
Named
ATU
PTU
Campath®
access
How long ?
How much ?
75
IN FRANCE : HOW LONG ?
In theory
In practice
• The duration of a
named ATU must be
specified on the
authorisation
• No end date published
!!!
• This corresponds to the
treatment duration &
cannot exceed 1 year
• Until an alternative is
found …
• Interim solution
• If it is necessary to
prolong treatment, an
application for an ATU
renewal is submitted to
the ANSM
76
IN FRANCE : HOW MUCH ?
Fees
• ATU applications are free of charge
Cost
• Laboratory’s decision
• Free of Charge (for current & futur
users) …
77
EACH OBJECTION HAS ITS ANSWER
Campath withdrawal in August 2012 in
the EU & Sept. 2012 in the US
CLL comunity:
 Disapointment
 Group favoring
MS comunity:
 serious implications for vulnerable UK
patients with MS
 Patients already taking the drug offlabel could see their condition
deteriorate as they wait for the drug
to be re-launched as Lemtrada
Genzyme started informing US &
European doctors of the upcoming
withdrawal of campath & the patient
access plan in July 2012
All leukeamia patients will benefit from
free of charge programs that make sure
that all patients receive their much
needed medicine
«Lemtrada remains available to patients
who are taking part in clinical tests.» 
safety monitoring
Restores access to MS drug after
pressure from Neurologists
Focus on obtaining regulatory approval
as a ttt for MS  the best way to ensure
access for the greatest number of
patients.
78
 TIME CONSUMING !!! 79
THE MOST IMPORTANT… :
PATIENTS
« Programme run so far quite smoothly » (the German society for haematology &
oncoloogy)
“The companies had done a strong job of laying the groundwork for a transition from
commercial product to one available for free under a compassionate-use protocol”
“They’ve actually been quite supportive by telling us what the distribution is & how they have
communicated their plans to health care providers who treat our patients”
(Leukemia & Lymphoma Society)

An efficient communication’s strategy
80
LEMTRADA
Approved in the
EU (Sept. 2013)
RMP
Price & reimb.
(NICE & HAS)
81
III. REGULATORY OVERVIEW
1. EMA
2. FDA
82
US BACKGROUND
NO
Marketing Authorization
1 same active ingredient (alemtuzumab)
2 different diseases (B-CLL & MS)
1 initial MA (B-CLL)
1. FDA
Regulatory (B-CLL)
Process
►Withdrawn
September 4, 2012
2. Consequences
of
rejection
Submission
(MS)
►Rejected (MS)
Withdrawal (B-CLL)
December
27, 2013
- patient-access
program
83
US BACKGROUND
NO Marketing Authorization
1. FDA
Regulatory Process
2. Consequences
of rejection
84
FDA REGULATORY PROCESS
85
FDA REGULATORY PROCESS
86
COMPLETE RESPONSE LETTER
Code of Federal Regulations
- Title 21
• Sec. 314.110 Complete response letter to
the applicant
Drug will not be approved in its present
form
Changes must be made before an application
can be approved.
 The FDA does not divulge the
contents of a CRL
Press release from the company
Potayto—Potahto? The Meaning of the FDA's "Complete Response" Letters
September 2008, Vol 1, No 7 - FDA Watch Mark Senak, JD American Health & Drug Benefits
87
FDA REGULATORY PROCESS
88
FDA ADVISORY COMMITTEE
 Panels of independent experts
 Renewal at two-year intervals
 Recommendations (not legally
binding)
According to the FDA
Amendment Act of 2007
(FDAAA), the FDA should refer
new drugs to an advisory
committee meeting, or
alternatively justify why an
advisory committee meeting was
not requested
FDA Consumer Health Information www.fda.gov/consumer
89
THE KEY DATES
27/11/2012
• NDA
Alemtuzumab
applications
• Reviewing
process
• 3 FDA
reviewers
16/10/2013
• Alemtuzumab
Background
Package
13/11/2013
• Peripheral
and NCS
Drugs
Advisory
Committee
Meeting
90
ALEMTUZUMAB BACKGROUND
PACKAGE
Prepared by the FDA
Division of Neurology
Clinical safety, efficacy
and statistics reviews
To members of the
Advisory Committee
In preparation for the
meeting to discuss BLA
for alemtuzumab in MS
91
ADVISORY COMMITTEE MEETING
92
The ADVISORY COMMITTEE
voted
11-6- (1 abstention)
that Sanofi's clinical trials
were inadequate
12-6
that Lemtrada provided
substantial evidence of
effectiveness in relapsing
MS.
93
The ADVISORY COMMITTEE
voted
14-2- (2 abstentions)
against its benefits on
disability.
94
The ADVISORY COMMITTEE
voted
17 to 0 (1 abstention)
that, safety results would not
preclude approval.
95
The ADVISORY COMMITTEE
voted
16-0 with two abstentions
that Lemtrada should not be
indicated as a first-line MS
therapy.
96
ADVISORY COMMITTEE RECOS
□ METHODOLOGY
X
Potential Bias (unblinding of patients and physicians)
Double dummy design +++
□ EFFECTIVENESS / FLARES

□ DISABILITY
X
□ SAFETY

□ FIRST LINE
X
97
FDA REGULATORY PROCESS
98
OPEN PUBLIC HEARING
99
OPEN PUBLIC HEARING
“If one of your family
members had MS, wouldn’t you
want them to have a choice?
We, as patients, deserve the
right to have a choice of
therapy” Melissa Burdick
“Lemtrada has the potential to be a highly
“Other approved medicines
also carry safety risks”
http://www.mymsaa.org/news-msaa/
CODE OF FEDERAL REGULATIONS (21 CFR PART 14)
effective treatment for MS.
The determination of risk versus benefit is best
to be considered between the
treating physician and the informed patient.”
Doug Franklin, CEO
100
US BACKGROUND
NO Marketing Authorization
1. FDA Regulatory
Process
2. Consequences
of rejection
101
CONSEQUENCES

Return of alemtuzumab to the US market for
treatment of B-CLL

Off-label use of alemtuzumab for MS
 using a formulation intended for B-CLL
 from other countries (registered product)
102
103
CONSEQUENCES

Return of alemtuzumab to the US market for
treatment of B-CLL

Off-label use of alemtuzumab for MS
 using a formulation intended for B-CLL
 from other countries (registered product)

Appeal ….
104
SANOFI CEO CHRISTOPHER VIEHBACHER
January 23, 2014, Bloomberg TV
 (…) this is a drug that has been approved by
thirty countries around the world. We are seeing
patients that have gone five years without a relapse
so Sanofi believes that the drug actually is working
and it's important for patients and that's why for the
first time in my twenty-five years in the industry
we're thinking about doing an appeal with the
FDA.
 (…) We can't possibly go do the new trial so
the product comes to the market or it doesn't
come to the market. In the rest of the world though
the market is a little different. There are more MS
patients in Europe than in the US so Lemtrada can
still be a big success.
GENZYME CEO DAVID MEEKER
February 6, 2014, Annual report
 We did receive a complete response letter
from the FDA in late December. As you know,
we are in the process of appealing that
decision. (…)
 I think it's important to put this in a bit of
context. As we look at the overall franchise and
the unmet medical need in the multiple
sclerosis market, U.S. patients represent about
400,000 out of the 2.1 million patients affected
with MS (…) we'll continue to work with the
FDA to find hopefully a path forward.
http://seekingalpha.com/article/2000831-sanofi-management-discusses-q4-2013-results-earnings-call-transcript Feb 6, 2014
105
FDA APPEAL PROCESS
FDA is committed to the
principle that regulated
industry has a right to
disagree with an agency
decision, action, or
operation, and that full
and open discussion of
issues in controversy
produces a better
decision in the end.
Moreover, regulated
industry is entitled to
receive high quality
administrative practices
and procedures from all
parts of FDA.” (FDA
Ombudsman’s website)
Guidance for Industry – Formal Dispute Resolution: Appeals Above the Division Level
106
APPEAL PROCESS
FDA
Ombudsman
CDER/CBER
Ombudsman
Division Director
107
Regulatory Sclerosis
Time is short
1,000 Neurologists Were Asked About
Lemtrada; This Is What They Said
The FDA Nixes a Pathbreaking Drug for MS
http://seekingalpha.com/author/chris-demuth-jr/instablog/4
The Wall Street Journal
Friday, January 17, 2014
108
109
IV. CONCLUSION
To date :
• European MA
• Price & reimbursement pending
But FDA :
• Doesn’t seem to be willing to approve
• Patient First  FDA required Campath® re-introduction
To be continued…
110
111
Bibliography
www.sanofi.fr
www.genzyme.fr
www.ansm.sante.fr
www.ema.europa.eu
www.fda.gov
www.thelancet.com
www.nature.com
www.nejm.org
112