Transcript Document

®
COPAXONE
Glatiramer acetate
Is it possible to make a generic of a non-fully characterized drug?
Can it be a threat to TEVA,
the world's leading generic pharmaceutical company?
Marie Delattre
Laëtitia Lemaire
Juliette Morawiec
The triggering event
1974
1995 1996 1997
Copaxone
first patent
Launch
Last patent,
expiring 2014
Dec
2007
July
2008
FDA accepted to
review the ANDA
ANDA* Submission
of Momenta/Sandoz’s M356
FDA approval
*ANDA = Abbreviated New Drug Application
2
Copaxone®:
TEVA’s blockbuster
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18% of TEVA’s sales…
total sales=$9.4bn
6%
API (external only)
synergies
75%
Generic pharmaceuticals
balance
19%
Innovative pharmaceuticals
Copaxone®: $1.71B
Azilect®
(2007)
QVAR®
Albuterol® HFA
4
…and a major contribution to its
profits
Génériques
Copaxone
24%
24% of Teva's profits in 2008
(32% expected in 2010)
5
®
Copaxone :
a complex mixture drug
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Unexpected properties
• 1960,Weizmann Institute : tried to induce
Experimental Allergic Encephalomyelitis (animal
model of MS)
• Synthetic copolymer mimicking MBP
=> no encephalitogenic activity but high efficacy
in suppressing EAE
• 1987: agreement with TEVA for development
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A random copolymer
• amino acid sequence vary from one peptide to another
• Potential sequence:
ALGTLTGLALALGAGTGLATGGTLLAGTGLAGTLAG…
50 to 100 amino acids
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• 20 mg subcutaneous daily

reduces the frequency of relapses in RRMS
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Proposed mechanism of action
IMMUNOMODULATION
displaces
myelin Ag
GA-reactive
CD4 Th2
NEUROPROTECTION
Proinflammatory
cytokines
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Anergy, apoptosis
Momenta/Sandoz’s M356:
a generic drug of Copaxone?
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• Biotechnology company
• Duplicate; Re-engineer; Create
• Specializing in characterization and engineering
of complex sugars
• ANDA for M-Enoxaparin (generic of Lovenox®)
filled in 2005
12
Sandoz
• Generic drug subsidiary of Novartis
• First company to launch a biosimilar :
Omnitrope (recombinant human growth
hormone)
13
ANDA process with paragraph IV
Dec 2008
July 2008
FDA:
Acceptable &
Complete?
NDA holder
(TEVA)
lawsuit for
patent
infringment
FDA 45 days
ANDA
submission accepts
for
review
Jan 2009
Patent
infringement
litigation
2011
2014
Momenta
eligible for
180 days
exclusivity
30 months stay If FDA
or until court
accepts
decision
ANDA
Patent
expiration
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ANDA = Abbreviated New Drug Application
Requirements for an ANDA:
1. Pharmaceutical Equivalence:

Same active ingredient

Same conditions of use, route of administration,
dosage form, strength, labeling
2. Bioequivalence
3. Patent certification (I to IV)
PE + BE = Therapeutic Equivalence
=>Safety & Effectiveness presumed
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But it is not easily applicable to
Copaxone…
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Requirements for an ANDA:
1. Pharmaceutical Equivalence:

Same active ingredient

Same conditions of use, route of administration,
dosage form, strength, labeling
2. Bioequivalence
3. Patent certification (I to IV)
PE + BE = Therapeutic Equivalence
=>Safety & Effectiveness presumed
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1. Chemical sameness
Problem: Copaxone = random copolymer
=> not fully characterized
M 356 cannot be identical to Copaxone since
Copaxone’s composition is not precisely
defined!
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Copaxone’s synthesis: polymerization
O
R1
O
HN
R1
O
O
O
H2N
O
N-carboxyanhydride
+
N
N
H
H3C
CH3
CH3
CH3
O
R1
CO2
Diethylamine
O
R2
R1
O
HN
H2N
O
O
O
O
H2N
R2
N
H
O
N
N
CH3
CH3
CH3
CH3
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Synthesis (1): Polymerisation in anhydrous
dioxane
H
CH3
O
O
O
O
N-carboxyanhydride of L-Alanine
N
O
O
O
O
H3C
N
N
H
H
N-carboxyanhydride de L-lysine
X
O
O
O
O
X
H N
H
O
O
O
H3C
N
H
HN
CH3
O
NH
O
O
O
H
N
F
O
F F
HN
O
N-carboxyanhydride of L-glutamate
OH
N
O
O
O
N-carboxyanhydride de L-tyrosine
OH
protected copolymer
Molecular ratio: 1,4 :3,4 :4,2 :1,0
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Synthesis (2): Deprotection
H3C
H3C
X
HO
O
NH
NH
O
O
O
O
HN
O
Hydrogenation
Pd/C
AcOH
H
N
NH
O
O
O
NH2
NH
O
H3C
HN
X
H3C
O
HN
HN
OH
O
OH
O
CH3
protected copolymer
CH3
acetate salt of copolymer 1
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Synthesis (3): Separation
and purification
• Dialysis against water
• Gel permeation chromatography
• Average molecular weight: 5000 - 9000 Da
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Exact chain composition: unknown
NCA amino acids react in an unpredictable order :
K
Y
100
amino
acids
Y
E
E
A
K
Y
E
A
A
K
Y
E
K
A
KY E
A
K
YEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAKYEAK
(4)100 possible combinations!
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Exact chain length: unknown
R1
CH3
NH
R1
O
H2N
N
CH3
O
HN
CH3
Diethylamine
O
CH3
R1
O
N-carboxyanhydride
H2N
O H
O
OH
H
• In theory, 1% diethylamine
1 chain of 100 aa
• water can start polymerization: more chains but shorter ones
Average length= 50 to 100 amino acids
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Analysis with current analytical
methods: impossible
•
Peptides highly similar in size, charge and
hydrophobicity
•
Even multidimentionnal analysis and mass
spectrometry unable to separate (4)100 peptide
sequences
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COPAXONE:
A product defined by its process!
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Process control
• In theory:
1 diethylamine
100 NCA of aa
1 chain of 100 aa with
diethylamide at C-term
• In reality:
1 diethylamine
100 NCA of aa
2 chains of 50 aa,
one with carboxyl at C term
1 H2O
Ratio diethylamides / C-term carboxylates : 13 to 38%
(according to Momenta’s patent « Methods of evaluating peptide
mixtures »)
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Biological way of characterization
- Biological activity mediated by
immunomodulation on T cells
- Measurement of potency
between 2 batches: comparing
IL-2 release
- Process patented: impossible to
compare glatiramer acetate and
a generic version without
infringing the patent!!
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Requirements for an ANDA:
1. Pharmaceutical Equivalence:

Same active ingredient

Same conditions of use, route of administration,
dosage form, strength, labeling
2. Bioequivalence
3. Patent certification (I to IV)
PE + BE = Therapeutic Equivalence
=>Safety & Effectiveness presumed
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2. Bioequivalence
Impossible to measure Copaxone’s blood concentration:
- injection of (4)100 peptides, quickly degraded to free amino
acids: no systemic plasma concentrations, urinary or faecal
excretion detectable
- no analytical method in biological fluids
- no human PK studies in Copaxone’s NDA: studies conducted
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in animals using radiolabelled Copaxone
Requirements for an ANDA:
1. Pharmaceutical Equivalence:

Same active ingredient

Same conditions of use, route of administration,
dosage form, strength, labeling
2. Bioequivalence
3. Patent certification (I to IV)
PE + BE = Therapeutic Equivalence
=>Safety & Effectiveness presumed
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3. Patent certification
• Copaxone composition: patents in Orange book, expiring 2014
• Momenta/Sandoz have to invalidate those patents to obtain a
generic
 original patents expired in 1991
 lower molecular weights said to be less toxic:
new patents stretching into 2014
 but all molecular weight ranges equally safe and effective
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From a generic to a biosimilar?
Approvals in USA
Small molecule
products
Biological Products
NDA
BLA
ANDA
No regulation yet for
Follow-on Biologics
NDA 505(b)2
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From a generic to a biosimilar?
• Modest change in the process: slightly higher molecular weight
=> Systemic toxicity (organ damage, death): completely
distinct immunoreactive and toxicological profile!
• Biosimilar: clinical studies required to prove efficacy and safety
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Previous FDA decisions
in similar cases
Examples :
-Premarin
-Lovenox
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Another uncharacterized mixture drug
• conjugated estrogens, derived from the
urine of pregnant mares
• the most widely prescribed drug in the USA
for estrogen replacement (menopause)
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Premarin
1942
1970
FDA approval
1992
Nowadays
quantitative
composition of
Premarin has not
been defined
other constituents
described as "concomitant
components"
mixture of sodium estrone
sulfate and sodium equilin
sulfate
If one component disappears, the drug will have a
different activity.
Qualitative
FDA has not approved the generic version
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The case of Lovenox
• Enoxaparin sodium
a Low-Molecular-Weight Heparin
• Sourced from porcine intestinal mucosa
• Antithrombosis drug : prevention and treatment of deep
vein thrombosis
• Glycosaminoglycan
Can a generic version be approved?
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Lovenox: an uncharacterized mixture
• Mixture of sulfated polysaccharide chains
• Vary in length and made of repeating disaccharide units
• The complex set of oligosaccharides have not yet been
completely characterized
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Momenta’s generic version of Lovenox:
M-enoxaparin
March
1993
FDA approval
August
2005
ANDA
submission of
M-enoxaparin
Nov
2007
FDA nonapprovable
letter
April
2008
Sept
2008
Sandoz submitted
the amendment
FDA: additional
Momenta duplicates
animal studies
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What are the topics prone to discussion?
Sanofi-Aventis
Teva/Amphastar
Momenta/Sandoz
1. Lack of “full characterization”
2. Structural fingerprints
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1. Lack of “full characterization”
Sanofi-Aventis :
Lovenox has chemical characteristics entirely dependent on its
manufacturing process.
Rivals :
Aventis’ ” product by process” theory is contradicted by the known
variability of Lovenox itself
(2 batches of Lovenox are not identical)
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2. “Structural Fingerprints”
Sanofi-Aventis :
The generic product has to contain a 1,6 anhydro ring structure at the
reducing ends of between 15% and 25% of its polysaccharide chains.”
1,6-Anhydro-β-D-glucopyranose
 this “fingerprint” is unachievable with any process other than Aventis’.
Rivals :
Momenta’s enoxaparin oligosaccharide profile has been compared
to that of Aventis’ Lovenox .
Both enoxaparin products show essentially the same variability.
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Not approved
Approved
Glatiramoids?
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Glatiramoids?
Premarin’s example
- Piperazine estrone sulfate
- Micronized estradiol
Same indications
Not the same active ingredients
Not interchangeable with Premarin
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Glatiramoids? : Lovenox’s example
March
1993
August
2005
FDA approval
ANDA
submission of
M-enoxaparin
July
2006
Momenta re-engineer
Nov
2007
April
2008
FDA nonapprovable
letter
Sept
2008
Sandoz submitted
the amendment
FDA additional animal
studies
Momenta submitted an IND to begin a
Phase I human clinical study of M118
Might do the same with M 356 if FDA does not approve the ANDA
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Conclusion
Copaxone : - a chemically synthesized mixture
- uncharacterized
- defined by its process
=> Almost impossible to make a generic version
Approve Copaxone like a biosimilar would require
clinical studies to prove efficacy and safety
For rivals the path to follow could be glatiramoids…
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PI-2301 : a threat for TEVA ?
• Second-generation peptide copolymer
• New patent in July 2008
• Designed to be more efficacious and more convenient (weekly
versus daily dosing) than Copaxone
• Currently in Phase 1b development
• Peptimmune has granted Novartis exclusive option to License
PI-2301 for Multiple Sclerosis the 15th of January 2009…
THANK YOU FOR
YOUR ATTENTION!
ANY QUESTIONS?
Marie Delattre
Laëtitia Lemaire
Juliette Morawiec
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