COPAXONE

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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
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The triggering event
ANDA Abbreviated New Drug Application
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Copaxone TEVAs blockbuster
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18 of TEVAs sales
total sales9.4bn
API (external only)
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synergies
Generic pharmaceuticals
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Copaxone 1.71B Azilect QVAR Albuterol HFA
Innovative pharmaceuticals
(2007)
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and a major contribution to its profits

• 24 of Teva's profits in 2008
• (32 expected in 2010)

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Copaxonea 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
• gt 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
Anergy, apoptosis
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Momenta/Sandozs 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

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Sandoz

• Generic drug subsidiary of Novartis
• First company to launch a biosimilar Omnitrope
  (recombinant human growth hormone)

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ANDA process with paragraph IV
ANDA Abbreviated New Drug Application
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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
• gtSafety 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
• gtSafety Effectiveness presumed

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1. Chemical sameness

• Problem Copaxone random copolymer
• gt not fully characterized
• M 356 cannot be identical to Copaxone since
  Copaxones composition is not precisely defined!

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Copaxones synthesis polymerization
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Synthesis (1) Polymerisation in anhydrous dioxane
Molecular ratio 1,4 3,4 4,2 1,0
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Synthesis (2) Deprotection
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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
• (4)100 possible combinations!

100 amino acids
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Exact chain length unknown

• 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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COPAXONEA product defined by its process!
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Process control
Ratio diethylamides / C-term carboxylates 13
to 38 (according to Momentas 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
• gtSafety Effectiveness presumed

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2. Bioequivalence

• Impossible to measure Copaxones 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 Copaxones NDA studies
  conducted in animals using radiolabelled 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
• gtSafety 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?
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From a generic to a biosimilar?

• Modest change in the process slightly higher
  molecular weight
• gt 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
Nowadays
1942
1970
1992
FDA approval
quantitative composition of Premarin has not been
defined
mixture of sodium estrone sulfate and sodium
equilin sulfate
other constituents described as "concomitant
components"

• 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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Momentas generic version of Lovenox M-enoxaparin
Nov 2007
April 2008
Sept 2008
August 2005
March 1993
FDA non-approvable letter
FDA approval
Sandoz submitted the amendment
ANDA submission of M-enoxaparin
FDA additional animal studies
Momenta duplicates
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What are the topics prone to discussion?
Teva/AmphastarMomenta/Sandoz
Sanofi-Aventis
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-ß-D-glucopyranose
? this fingerprint is unachievable with any
process other than Aventis.
Rivals Momentas 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?

• Premarins example
• - Piperazine estrone sulfate
• - Micronized estradiol
• ?Same indications
• ?Not the same active ingredients
• ?Not interchangeable with Premarin

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Glatiramoids? Lovenoxs example
Nov 2007
April 2008
Sept 2008
July 2006
August 2005
March 1993

FDA non-approvable letter
FDA approval
ANDA submission of M-enoxaparin
Sandoz submitted the amendment
FDA additional animal studies
Momenta re-engineer
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
• gt 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

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THANK YOU FOR YOUR ATTENTION! ANY QUESTIONS?
Marie Delattre Laëtitia Lemaire Juliette Morawiec