1. 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 1

2. The triggering event 1997 1974 1996 1995 Dec 2007 July 2008
Copaxone first patent
1997
Last patent,
expiring 2014
1974
1996
1995
FDA approval
Launch
Dec
2007
July
2008
ANDA* Submission
of Momenta/Sandoz’s M356
FDA accepted to
review the ANDA
dépôt NDA par momenta / TEVA répond par une pétition / FDA accepte NDA / Information à TEVA qui fait appel à la cours de justice « infraction de son brevet »
These patents expire on May 24, 2014
contains a Paragraph IV patent certification, referring to key patents (chemical composition, pharmaceutical composition, method of use)
an ANDA has been accepted for review by the FDA le 11 juillet 2008
- Petition de Teva le 26 septembre 2008
- Teva va engager un procès contre Momenta et Sandoz pour infraction de ses brevets valable jusqu’en 2014.et ceci, within the 45-day period provided under the Hatch-Waxman legislation.
*ANDA = Abbreviated New Drug Application

3. Copaxone®: TEVA’s blockbuster
A blockbuster drug is a drug generating more than $1 billion of revenue for its owner each year.

4. 18% of TEVA’s sales… Copaxone®: $1.71B total sales=$9.4bn
API (external only) 6%
synergies
Generic pharmaceuticals
75%
balance
Established 1901, Israelian company Among the top 20 pharmaceutical companies
$9.4bn 2007 sales
the world's leading generic pharmaceutical company 
Reconverting into innovative R&D (branded and proprietary pharmaceuticals)
Copaxone : MS
Azilect : Parkinson
QVAR et Albuterol HFA : Respiratory
19%
Innovative pharmaceuticals
Copaxone®: $1.71B
Azilect®
QVAR®
Albuterol® HFA
(2007)

5. …and a major contribution to its profits
USA & Canada : distributed by Sanofi-Aventis until march 08, now by Teva
sales in North America reached $1.37 billion during the first quarter accounting for 53% of Teva's sales in the region
The drug accounted for $667 million, or 26% of Teva's European sales.
All together Copaxone is responsible for 20% of Teva's net profits in 2007.
Copaxone increasingly becoming a larger contributor to Teva's corporate profits, an estimated 24% in 2008 to 32% in 2010, investor sensitivity has recently become justifiably heightened regarding this product." (
Net Income for 2007 reached $1.952 billion, a 5% increase over 2006
Net sales for 2007 were $9.4 billion, with global Copaxane sales of $1.713 billion
Copaxone + Azilect pr Parkinson
Copaxone® est licencié par Teva à sanofi-aventis et commercialisé par le biais d’une alliance avec Teva En Europe et en Australie, Copaxone® est commercialisé par sanofi-aventis et Teva Pharmaceutical Industries Aux États-Unis et au Canada, Copaxone® est promu par Teva et sera distribué par sanofi-aventis jusqu’en mars Puis, Teva reprendra la distribution et comptabilisera les ventes de Copaxone® (aux États-Unis et au Canada).
24% of Teva's profits in 2008
(32% expected in 2010)

6. Copaxone®: a complex mixture drug

7. 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
D-Cop 1 : devoid of any suppressive effect on EAE, nor cross reactive with MBP
Major pb: to adapt the lab's synthetic procedure to an industrial scale (took 2 years to develop a production process
Weizmann institute:centre majeur de recherche scientifique et d'études supérieures situé à Rehovot en Israël.
se positionne comme le leader israélien et l’un des leaders mondiaux en termes de commercialisation de brevets
2 500 chercheurs
1000 projets de rechercheDvpmt
a polypeptide composed of amino acids found
in MBP, and possessing a net positive electrical charge (as
does MBP), might induce EAE similarly to the crude injections
of myelin-containing tissue. To test this hypothesis they synthesized
three random copolymers by reacting together various
combinations of appropriately protected amino acids.
EAE is an acuteneurological autoimmune disease, induced by theinjection in complete Freund’s adjuvant (CFA) of brain- or spinal cord-derived substances which constitutethe encephlitogenic antigens. These include severalproteins such as myelin basic protein (MBP),proteolipid protein (PLP), myelin oligodendriticglycoprotein (MOG) and others. The disease ismediated by CD4+ autoreactive T cells, whichrecognize the encephalitogenic antigen(s) inassociation with major histocompatibility complex(MHC) class II molecules. These autoreactive cellsmigrate into thecentral nervous system (CNS) and mediate the pathogenic process (THE CHEMISTRY OF THE COPAXONE DRUG
Ruth Arnon and Michael Sela)
High binding activity to HLA-DR2 (MHC protein expressed by 60% of the general MS population)
binding data to purified HLA-DR proteins suggest that Y and K as well as A are important for binding to the three DR haplotypes
Cop 1 demonstrated high binding activity to HLA-DR2 (MHC protein expressed by 60% of the general MS population)
Antibody structure and function were just being revealed
elaborate studies on the structural aspects of antigens were conducted (immunochemistry) to arrive at better understanding of their interaction with the antibodies.
In parallel, information on the cellular compartment of the immune
system was just starting.
In our laboratory we were deeply involved in studies on the structural basis of the antigenicity of proteins,
utilizing synthetic antigens comprising polymers and copolymers of amino acids [l].
Research with these polymers had been pioneered by Prof. Ephraim Katchalski, in whose laboratory both Michael Sela and
myself received our training. Employing these synthetic protein-like molecules we could induce immune responses of almost any desired specificity, including that of non-protein moieties.
Already in 1937 Rivers [5] hadobserved that a single inoculation of laboratory animal with brain or spinal cord tissue in Complete Freund’sadjuvant (CFA) led to an acute neurological autoimmune disease resembling MS, which was designated Experimental Allergic Encephalomyelitis (EAE)
Ruth Arnon 7

8. ALGTLTGLALALGAGTGLATGGTLLAGTGLAGTLAG…
A random copolymer
amino acid sequence vary from one peptide to another
Potential sequence:
ALGTLTGLALALGAGTGLATGGTLLAGTGLAGTLAG…
50 to 100 amino acids
As for the chemistry angle of this drug, it is of interest that Copaxone is the first drug of a polymeric nature
approved for treatment of a disease. This is a macromolecular preparation obtained by polymeric
techniques, in which probably no two molecules are completely identical. The microheterogeneity of Cop 1 can actually be part of its success, as it may contain sufficient different amino acid sequences that could successfully compete with the encephalitogenic antigens for class II MHC antigens of many different genetic backgrounds. The Chemistry of the Copaxone drug , Ruth Arnon, Michael Sela
Has been associated with
preservation of normal
brain volume (Wolinsky et
al, 2001) and significant
reduction in development
of new T-1 enhancing
lesions on magnetic
resonance imaging (Comi
et al, 2001a; Wolinsky et
al, 2001 8

9. reduces the frequency of relapses in RRMS
20 mg subcutaneous daily
reduces the frequency of relapses in RRMS
Diminution nombre d’exacerbations
Diminution nombre de lésions à l’IRM
Ralentissement score EDSS

10. Proposed mechanism of action
IMMUNOMODULATION
displaces
myelin Ag -
GA-reactive
CD4 Th2
EN périphérie : le GA se fixe avec une forte affinité au CMH et induit une population de lymphocytes TH2 AI qui lui est spécifique
Ces TH2, parcequ’ils st activés par une immunisation quotidienne, passent la BHE.
Dans le SNC : les LTh2-AG spécifiques sont réactivés par les Ag du SNC tels que la MBP. Une fois réactivés, ces LTh2 libèrent des cytokines AI( IL4,6,10 TGFbeta), qui vont inhiber la prolifération des LTh1 autoréactifs à la myéline présents dans le SNC.
A simplified diagrammatic representation of the immunopharmacology of GA in MS therapeutics. The Pre-Rx portion of the panel emphasizes the baseline state in MS with CD4+ Th1 myelin antigen-reactive cells being activated by systemic antigen processing cells, including macrophages, that present foreign antigens that are myelin-like (‘myelin’ Ag) in the context of surface MHC to TCR; invoking the concept of molecular mimicry. Stimulated CD4+ Th1 ‘myelin’ Ag-reactive cells secrete a number of pro-inflammatory cytokines (IL-2, IFN-γ, TNF-α, and LT). With GA therapy, GA may displace some ‘myelin’ Ag. More importantly, on presentation and stimulation of GA and ‘myelin’ Ag-reactive CD4+ Th1 cells, GA silences cross-reacting CD4+ Th1 ‘myelin’ Ag-reactive cells through anergy, apoptosis, or antigen-specific mechanisms. Concomitantly, GA stimulates and expands a population of GA-reactive CD4+ Th1 cells (dark grey curved arrows).
With continued therapy the net result is a reduced proportion of CD4+ Th1 and an increased proportion of GA and ‘myelin’ cross-reactive CD4+ Th2 cells. When these GA and ‘myelin’ cross-reactive CD4+ Th2 cells gain access to the CNS by trafficking across the blood–brain barrier, they are re-stimulated by true myelin Ags processed and presented by microglia, a brain-resident macrophage. On re-stimulation, the GA-reactive CD4+ Th2 cells secrete anti-inflammatory cytokines to inhibit ‘myelin’ Ag-reactive CD4+ Th1 cells within the CNS and also secret topic factors, such as BDNF that may facilitate neuronal survival (light grey curved arrow). Reproduced from Wolinsky JS 2004a. Glatiramer acetate for the treatment of multiple sclerosis. Expert Opin Pharmacother, 5:875–91. Copyright © 2004 with
permission from Ashley Publications.
Abbreviations: Ag, antibody; BDNF, brain-derived neutrophic factor; GA, glatiramer acetate; IFN, interferon; LT, leukotriene; MHC, major histocompatibility
complex; MS, multiple sclerosis; Rx, treatment; TCR, T cell receptor; TNF, tumor necrosis factor.
Inmunomodulation: Induction of GA specific Th2 cells in periphery which cross BBB and down regulate inflammation.
Neuroprotection : stimulation of neurotrophin secretion in the central nervous system that may promote neuronal repair.
Glatiramer acetate is designed to mimic the effects of the main proteins in myelin. Once injected, the drug is thought to work by connecting to cells in the immune system that can reach the myelin sheath under attack. These cells are thought to switch off inflammation occurring in the central nervous system (brain and spinal cord), and so help brain and spinal column cells recover. (MS ressource center)
High affinity binding to MHC : competition with MBP at the APC level.
Inhibition of MBP specific T-cell activation through competition with TCR : clonal anergy & deletion of Myelin-Ag specific T-cells
Induction & Activation of GA reactive T-cell and shift from Th1 to Th2 response( anti-inflammatory)
Preferential migration of GA-reactive T-cells into CNS : decrease local inflammation
Neuronal & Axonal protection by secretion of neurotrophic factors ( BDFN)
Mécanisme d’action précis non connu
Fonctionne comme une vaccination thérapeutique
Change la réponse immunitaire initialement dirigée vers les peptides de la gaine de myéline et entraînant une démyélinisation
L'acétate de glatiramère est un agent immunomodulateur. Chez l'animal, il a été montré que cette molécule était
efficace dans la guérison, la prévention et la réduction de l'intensité des formes aiguës et rémittentes
d'encéphalomyélite allergique expérimentale (EAE) chez la souris, le rat, le cobaye, le lapin et le primate (singe
Rhésus et babouin). Le suivi de l'IRM cérébrale a montré la réduction de la formation de nouvelles lésions (à la fois
en séquences pondérées T1 ou T2) deux mois après le début du traitement.
Un total de 269 patients ont été traités par l'acétate de glatiramère dans trois études cliniques contrôlées. La
première était une étude d'une durée deux ans sur 50 patients (L'acétate de glatiramère 20 mg n = 25, placebo n =
25). La deuxième étude comprenait 251 patients traités pendant au moins 2 ans (L'acétate de glatiramère 20 mg n
= 125, placebo n = 126) et la troisième, une étude de 9 mois comprenant 239 patients (L'acétate de glatiramère 20
mg n = 119, placebo n = 120).
L'acétate de glatiramère a un effet statistiquement significatif sur la diminution du nombre de poussées après deux
ans de traitement contre placebo (diminution d'environ 30 % du nombre moyen de poussées versus placebo soit une
différence de 0,5 poussées sur deux ans). Cet effet est confirmé par une diminution d'environ 30 % des principaux
paramètres de suivi des lésions en IRM.
Il n'a pas été démontré d'effet bénéfique de l'acétate de glatiramère sur la progression du handicap chez les patients
atteints de sclérose en plaques évoluant par poussée.
Il n'a pas été démontré qu'un traitement par l'acétate de glatiramère ait un effet bénéfique sur la durée ou la gravité
des poussées.
Ppté bio de ce produit= critère global (autres médic: individuel)
Préste au SI qqch ttalement nveau: occupe ttes poches du CMH ms pas concentration suffisante pour décl quoi que ce soit
NEUROPROTECTION
Proinflammatory
cytokines
Anergy, apoptosis

11. Momenta/Sandoz’s M356: a generic drug of Copaxone?

12. Biotechnology company
Duplicate; Re-engineer; Create
Specializing in characterization and engineering of complex sugars
ANDA for M-Enoxaparin (generic of Lovenox®) filled in 2005

13. Sandoz Generic drug subsidiary of Novartis
First company to launch a biosimilar : Omnitrope (recombinant human growth hormone)
En 2006

14. ANDA process with paragraph IV
ANDA submission
FDA: Acceptable & Complete?
FDA accepts for review
45 days
NDA holder (TEVA)
lawsuit for patent infringment
30 months stay or until court decision
Patent infringement litigation
If FDA accepts ANDA
Momenta eligible for 180 days exclusivity
July 2008
Dec 2008
Jan 2009
2011
2014
Patent expiration
The statute provides an incentive of 180 days of market exclusivity to the "first" generic applicant who challenges a listed patent by filing a paragraph IV certification and running the risk of having to defend a patent infringement suit.
The statute provides that the first applicant to file a substantially complete ANDA containing a paragraph IV certification to a listed patent will be eligible for a 180-day period of exclusivity beginning either from the date it begins commercial marketing of the generic drug product, or from the date of a court decision finding the patent invalid, unenforceable or not infringed, whichever is first. These two events - first commercial marketing and a court decision favorable to the generic - are often called "triggering" events, because under the statute they can trigger the beginning of the 180-day exclusivity period.
In some circumstances, an applicant who obtains 180-day exclusivity may be the sole marketer of a generic competitor to the innovator product for 180 days. But 180-day exclusivity can begin to run - with a court decision - even before an applicant has received approval for its ANDA. In that case, some, or all, of the 180-day period could expire without the ANDA applicant marketing its generic drug. Conversely, if there is no court decision and the first applicant does not begin commercial marketing of the generic drug, there may be prolonged or indefinite delays in the beginning of the first applicant's 180-day exclusivity period. Approval of an ANDA has no effect on exclusivity, except if the sponsor begins to market the approved generic drug. Until an eligible ANDA applicant's 180-day exclusivity period has expired, FDA cannot approve subsequently submitted ANDAs for the same drug, even if the later ANDAs are otherwise ready for approval and the sponsors are willing to immediately begin marketing. Therefore, an ANDA applicant who is eligible for exclusivity is often in the position to delay all generic competition for the innovator product.Only an application containing a paragraph IV certification may be eligible for exclusivity. If an applicant changes from a paragraph IV certification to a paragraph III certification, for example upon losing its patent infringement litigation, the ANDA will no longer be eligible for exclusivity.
ANDA = Abbreviated New Drug Application

15. 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

16. But it is not easily applicable to Copaxone…

17. 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

18. 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!
ANDA : section 505(j)2 :
ANDA must provide “ information to show that the active ingredient of the new drug of the same as that of the listed drug”= sameness requirement
FDA regulations : same as means identical in Active Ingredient, dosage form, strength, route of administration, and conditions od use.
Donc : ANDA doit prouver que leur générique de Copaxone a la même séquence d’aa.
Regulatory Agencies might require stringent clinical standards in demonstrating equivalence due to complex chemistry
Chemical sameness
Pour déterminer épitopes actifs :- devrait séparer et séquencer les aa de chaque épitope : impossible avec les méthodes anaytiques actuelles de séparer tous ingrédients actifs potentiels du GA. En plus ont taille, charge et hydrophobicité similaires.
- synthétiser et screener les épitopes potentiels
- faire études précliniques et cliniques pr tester activité chaque épitope( pas marquers pt efficacité)

19. Copaxone’s synthesis: polymerization19

20. Synthesis (1): Polymerisation in anhydrous dioxane
Polymerisation in anhydrous dioxane, initiator=diéthylamine
L-glutamic acid, L-lysine, L-alanine, and L-tyrosine with a defined molar
residue ratio of 0.14:0.34:0.43:0.09 and an average length of
45 to 100 amino acids
Molecular ratio: 1,4 :3,4 :4,2 :1,0 20

21. Synthesis (2): Deprotection
Debloking of carboxyl group by hydrogen bromide in glacial acetic acid 21

22. Synthesis (3): Separation and purification
Dialysis against water
Gel permeation chromatography
Average molecular weight: Da
Poids moléculaire moyen augmente on constate alors que l’augmentation du poids moléculaire entraine une toxicité.
On a 2 lots avec une masse moyenne de 7700 Da et Da.
Ces 2 lots ont des enveloppes de masse moléculaire différentes = si la masse moléculaire est supérieure, le profil de répartition est différent.
Or on ne peut pas démontrer qu’on a le même produit (pas d’analyse point de vue ni analytique ni chimique car la molécule se décompose en milliard de produits), donc il faut faire des tests biologiques globaux = c’est sa capacité à induire une réaction qui est mesurée.
Gel permeation chromatography: determination of molecular weight
Poly [ L-Glu13-15, L-Ala39-46, L-Tyr8.6-10, L-Lys30-37 ].n(CH3CO2H
Pour reproductiblité lots : 2 lost qui ont M.M à 7,7KDA
Contrairement aux méthodes de chromatographie conventionnelle, le phénomène physique permettant la séparation des différentes macromolécules constituant le polymère n'est pas basé sur l'affinité chimique avec le support, mais simplement sur la taille des macromolécules (leur volume hydrodynamique). En effet, suivant leur taille, les molécules éluées peuvent ou non pénétrer dans les billes poreuses dont sont remplies les colonnes. Ainsi, les molécules les plus petites sont retenues alors que les plus grosses éluent plus rapidement. En sortie de colonne, des détecteurs (viscosimètre, photomètre, réfractomètre...) nous fournissent le nombre de macromolécules sortant de la colonne à un instant donné

23. Exact chain composition: unknown
NCA amino acids react in an unpredictable order :
(4)100 possible combinations!
100
amino
acids
The copolymers range from 40 to 90 amino acids in length and the molecular weight ranges between 4.7 and 10 kDa
La nature chimique du générique peut être différente d ’un lot à l’autre!!!!!
L’enchainement des acides aminés représente de sous-ensembles pas encore définis.
On ne connaît pas à l’heure actuelle quel enchainement est responsable.
2 points : - une grande variation
- une variation dans la longueur de la chaine elle même
Donc : pas de méthode analytique individuelle, juste une méthode globale.

24. Exact chain length: unknown
In theory, 1% diethylamine chain of 100 aa
water can start polymerization: more chains but shorter ones
Average length= 50 to 100 amino acids
Les anhydrides d'acide sont issus de la réunion de deux fonctions acides carboxyliques, suivant la réaction de déshydratation:
Cette réaction est réversible : les anhydrides formés peuvent subir une hydrolyse très facilement, y compris avec l'humidité de l'air, ce qui leur confère parfois un gout piquant.
On peut aussi former des anhydrides d'acide en utilisant un chlorure d'acyle et un carboxylate.

25. 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
Peut évaluer la molécule globale, mais il n’existe pas de méthode individuelle!
Tests biologiques : pourrait envisager de définir des UI par rapport à l’activité IL2.

26. COPAXONE: A product defined by its process!
Et pas l’analyse!

27. Process control Ratio diethylamides / C-term carboxylates : 13 to 38%
1 diethylamine
100 NCA of aa
1 chain of 100 aa with
diethylamide at C-term
1 H2O
2 chains of 50 aa,
one with carboxyl at C term
In theory:
In reality:
1. Process
In theory : 1 diethylamine : 100 aa : all chains end with diethylamine
Determine the mole percent of polypeptides having a diethylamide group at C-term: In Copaxone, 13% to 38%
Water : termination of polymerization => shorter chains ending with carboxylate
Ratio diethylamides / C-term carboxylates : 13 to 38%
proprietary test!

28. 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!!
T cells recognise immunogenic peptides complexed to the MHC, class I or II
Specificity of antigen recognition by T cells defined by
affinity Tcell receptor/MHC peptide complex
primary sequence of the antigenic peptide
Biological activity of copaxone mediated by immunomodulation on T cells
Measurement of potency between 2 batches of glatiramer: comparing IL-2 release secreted by T-cells
Strategy: process patented: impossible to compare glatiramer acetate and a generic version without infringing the patent!! 28

29. 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

30. 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 in animals using radiolabelled Copaxone
Equivalence in
Extent : quantity of API in the blood circulation =>AUC
Rate : Speed => Cmax Tmax
Biodisponibilité : Quantité de PA qui atteint la circulation générale après administration de la forme médicamenteuse étudiée et vitesse à laquelle le PA y parvient.
Se mesure par rapport à une forme pharmaceutique de même tupe : F relative
une solution IV : F absolue.
FDA requirements : ANDA must demonstrate the purported generic product’s bioequivalence to a previsously approved drug
Intended to assure that every approved generic is as safe and effective as the Reference Listed product.
After subcutaneous
administration, GA is quickly degraded to free amino acids
and small oligopeptides with only 10% remaining at the
injection site after 1 h [29]. No systemic plasma concentrations
nor any urinary or faecal excretion are detectable. Due
to its high polarity and hydrophilic nature, the penetration of
GA through the blood–brain barrier is impeded [29]. Thus,
GA is most unlikely to reach the central nervous system and
most probably initiates its major immunological effects in
the periphery [30].
there is currently no direct and sensitive analytical method for measuring COPAXONE in biological fluids. Therefore all pharmacokinetic studies have been conducted in animals using radiolabelled COPAXONE. The methodology is limited because the radiolabel dissociates rapidly from COPAXONE and re-associates with other macromolecules. However the studies indicate that COPAXONE is readily absorbed; repetitive dosing has no effect on absorption; Cmax and AUC are linearly dependent across the administered COPAXONE dose range and there is no evidence of any tissue accumulation of COPAXONE.

31. 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

32. 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

33. From a generic to a biosimilar?
Approvals in USA
Small molecule
products
Biological Products
NDA
BLA
ANDA
NDA 505(b)2
No regulation yet for
Follow-on Biologics
Chemical drugs have a well-defined structure whereas
the structure of biotechnological medicines is much more
complex and heterogeneous.
The manufacturing process leading to the production
of a biotechnological medicine is also much more complex.
A controlled manufacturing process is intrinsically
important to biotechnological medicines. Manufacturing
biotechnological medicines is complex, lengthy and
expensive. Each manufacturer must make their own
unique cell line which is a clone to a single cell. The cell
line is constructed using a unique proprietary DNA expression
vector. The characteristics of the incorporation
of DNA is unique for each cell. The cell line is evaluated
for product integrity, activity and overall quality. In addition
to product quality, the cell line is chosen based on
expected performance in manufacturing such as growth
and viability. It is also clear that even minor variations
could produce vastly different products since the process
is extremely sensitive to changes in both manufacturing
and production [7] .

34. 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
impossible de génériquer 1 produit qui n’a pas ete caracterisé
On ne peut pas le reproduire puisque compo non définie
Chemical drugs are in most cases relatively easy to reproduce
as their structure is precisely defined and expressed
by the chemical formula. The unique multi-dimensional
structure of the proteins and, in consequence,
their complicated mode of action are never fully reproducible.
In fact biotechnological medicines, even with the
same molecular weight and produced by the same type of
cells or microorganisms, can possess different pharmacokinetic
and pharmacodynamic properties [8]
the first biosimilars entered the
market in 2006 after having been approved by the European
Agency for the Evaluation of Medicinal Products
(EMEA). Those first biosimilars were Omnitrope (biosimilar
to Genotropin) and Valtropin (biosimilar to Humatrope)
[9, 10] . It is of note, however, that EMEA has
recently rejected the biosimilar Alpheon (interferon- )
due to a higher number of side effects and more frequent
recurrence of the disease in patients treated with Alpheon
than with its reference product Roferon-A, and the lack of
appropriate validation of the manufacturing process and
the test used to evaluate a potential immunologic response
to the drug [11] .
The most important issue of the EMEA guidelines is
the notion that biotechnological medicines cannot simply
be copied as has been the case with conventional
chemical medicines [12, 14] . However the guidelines accept
minor differences in the active substance, such as
variability in post-translational modifications. This recognition
is crucial with respect to the safety of the new
biotechnological products which will be approved in the
near future. The overview of the EMEA guidelines on biosimilars
is given in figure 1 .
The other important part of the guidelines indicates
that biosimilar manufacturers need to identify a single
reference product and conduct tests to demonstrate biophysical
similarity. It is also obligatory for the manufacturer
to provide sufficient non-clinical (in vitro and in
vivo pharmacodynamic and toxicological studies) and
clinical data to demonstrate the clinical similarity to the
reference product.
Also a risk management/pharmacovigilance
plan with attention paid to immunogenicity
and potential rare serious adverse events should be presented
before approval [15, 16] . Furthermore an efficacy
study with an appropriate indication is required if the
reference product has multiple indications. Biosimilar
manufacturers may extrapolate to other indications if the
mechanism of action is the same and if appropriately justified.
Most importantly the guidance also requires immunogenicity
data to be provided before approval.
Synthetic polypeptide with a modestly higher molecular weight distribution
Developed by making slight changes to manufacturing process following the polymerization reaction
Significantly increased the product’s immunoreactivity
Systemic toxicity (organ damage, death)
Completely distinct immunoreactive and toxicological profile
Even the most minor changes in the manufacturing of GA will produce a new molecular entity

35. Previous FDA decisions in similar cases
Examples :
Premarin
Lovenox

36. 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)
symptoms of menopause including hot flashes, night sweats, and vaginal dryness, or to prevent and treat osteoporosis
Subcutaneous injection.

37. FDA has not approved the generic version
Premarin
1942
1970
1992
Nowadays
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"
Pour la petite histoire :
Premarin contains several different estrogens. Precisely how these various estrogens contribute to the drug’s effectiveness has not been definitively determined.
In 1942, Premarin's approval was based on acceptable chemistry, manufacturing, and controls information and a showing, from reports of clinical investigations, that the drug was safe for its intended use in the treatment of menopausal symptoms and related conditions.
Previously it was thought that two estrogens--sodium estrone sulfate and sodium equilin sulfate, were the sole active ingredients in Premarin.
In 1970, conjugated estrogens were officially defined in a U.S. Pharmacopeia monograph as a mixture of sodium estrone sulfate and sodium equilin sulfate.
In 1992, in addition to those components, other constituents were described as "concomitant components" and as impurities.
The quantitative composition of Premarin with respect to potentially pharmacologically active components has not been defined.
FDA Premarin : These generic products have not been shown to contain the same active ingredients, and therefore to work the same.
If one component disappears, the drug will have a
different activity.
Qualitative
FDA has not approved the generic version

38. Sourced from domestic animals, mainly from porcine intestinal mucosa
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?
Lovenox binds to and accelerates the activity of antithrombin III. By activating antithrombin III, enoxaparin preferentially potentiates the inhibition of coagulation factors Xa and IIa. Factor Xa catalyzes the conversion of prothrombin to thrombin, so enoxaparin s inhibition of this process results in decreased thrombin and ultimately the prevention of fibrin clot formation.
Heparin is a highly sulfated glycosaminoglycan that is used as an important clinical anticoagulant.
Gag: chaine lineaire sulfatees composees de la repetition d un dissacharide de base et un ose : ici ac uronique et d glucosamine
Sourced from domestic animals, mainly from porcine intestinal mucosa

39. 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
L enoxaparine sodique est le sel de sodium d'une héarine de bas poids moléculaire.
La masse moléculaire moyenne de lenoxaparine sodique correspond au tiers de celle de l heparine non fractionnee
L’enoxaparine sodique est constituee d’un mélange de chaines de polysaccharides sulfates de longueurs variables et formées d’unités disaccharidiques récurrentes.
La séquence complexe des oligosaccharides n’a pas encore été entièrement déterminée.
Le monomére des disaccharides se compose de 1 molécule d’acide uronique et de 1 molécule de D-glucosamine, liéss en position 1-4. L’acide uronique peut être l’acide D-glucuronique ou l’accide L-iduronique, lequel peut être sulfaté en position 2. La glucosamine peut 黎re N-sulfat馥, N-ac騁yl馥, 6-0-sulfat馥 ou 3-0- sulfat馥.
Selon les connaissances actuelles, la majorit� des composants ont une structure 4- 駭opyranosuronique � l弾xtr駑it� non r馘uctrice de leur cha�e. Environ 20 % des composants comportent un d駻iv� 1,6-anhydro � l弾xtr駑it� r馘uctrice de leur cha�e, dans une proportion comprise entre 15 % et 25 %. La masse mol馗ulaire moyenne se situe entre et daltons; la valeur relative s帝tablissant � environ daltons. Le pourcentage des cha�es ayant une masse de � daltons se situe entre 68,0 % et 82,0 %. L帝noxaparine sodique est le sel de sodium d'une h駱arine de bas poids mol馗ulaire, obtenue par d駱olym駻isation alcaline de l'ester benzylique d'h駱arine sodique provenant de la muqueuse intestinale de porc. La masse mol馗ulaire moyenne de l帝noxaparine sodique correspond au tiers de celle de l檀駱arine non fractionn馥. L帝noxaparine sodique est constitu馥 d置n m駘ange de cha�es de polysaccharides sulfat駸 de longueurs variables et form馥s d置nit駸 disaccharidiques r馗urrentes. La s駲uence complexe des oligosaccharides n誕 pas encore 騁� enti鑽ement d騁ermin馥. Le monom鑽e des disaccharides se compose de 1 mol馗ule d誕cide uronique et de 1 mol馗ule de D-glucosamine, li馥s en position 1-4. L誕cide uronique peut 黎re l誕cide D-glucuronique ou l誕cide L-iduronique, lequel peut 黎re sulfat� en position 2. La glucosamine peut 黎re N-sulfat馥, N-ac騁yl馥, 6-0-sulfat馥 ou 3-0- sulfat馥. Selon les connaissances actuelles, la majorit� des composants ont une structure 4- 駭opyranosuronique � l弾xtr駑it� non r馘uctrice de leur cha�e. Environ 20 % des composants comportent un d駻iv� 1,6-anhydro � l弾xtr駑it� r馘uctrice de leur cha�e, dans une proportion comprise entre 15 % et 25 %. La masse mol馗ulaire moyenne se situe entre et daltons; la valeur relative s帝tablissant � environ daltons. Le pourcentage des cha�es ayant une masse de � daltons se situe entre 68,0 % et 82,0 %.

40. Momenta’s generic version of Lovenox: M-enoxaparin
March 1993
August 2005
Nov 2007
April 2008
Sept 2008
FDA non-approvable letter
FDA approval
ANDA submission of M-enoxaparin
Sandoz submitted the amendment
Lovenox a obtenu une AMM le 31 mars 1993.
Momenta in collaboration with Sandoz, is developing M-enoxaparin, a technology- enabled generic version of sanofi-aventis’s low molecular weight fraction of heparin Lovenox.
Le 31 juillet 2006 : July 2006, Momenta submitted an electronic Investigational New Drug (IND) application to begin a Phase I human clinical study of M118.
Momenta Pharmaceuticals is a biotechnology company specializing in the detailed structural analysis of complex mixture drugs. Momenta is applying its technology to the development of generic versions of complex drug products, as well as to the discovery and development of novel drugs. The Company's most advanced product candidate, M-Enoxaparin, is designed to be a technology-enabled generic version of Lovenox(r). Momenta's first novel drug candidate is M118, a rationally engineered anticoagulant specifically designed for acute coronary syndromes. Through its discovery program, the Company is seeking to discover and develop novel therapeutics by applying its technology to better understand sugars' functions in biological processes, with an initial focus in oncology. Momenta was founded in 2001 based on technology initially developed at Massachusetts Institute of Technology and is headquartered in Cambridge, MA.
Our ability to sequence and analyze complex mixtures of sugars has allowed us to analyze Lovenox and develop a process that we have used to make a generic version of Lovenox that we believe will meet the FDA requirements for approval through the abbreviated New Drug Application (ANDA) process. We have collaborated with Sandoz, a division of Novartis (NYSE: NVS), to jointly develop, manufacture, and commercialize M-Enoxaparin in the U.S. and the European Union.
Momenta said they had “both complex generic and novel products to our growing pipeline”.
B28E-DCB C/Annual%20Report%20Final% pdf
M 118 : next generation versions of drugs containing sugars.
= heparin designated
Nov 2007 : Lack of potential for immunogenicity of the product
FDA: additional animal studies
Momenta duplicates

41. What are the topics prone to discussion?
Sanofi-Aventis
Momenta/Sandoz
Process is the product
Clinical studies batch modified ≠manufactured batch***(guideline europe)
known variability of Lovenox itself : schema par momenta
1)Against : Aventis argues that Lovenox has certain chemical characteristics and speculates that such characteristics must be entirely dependent on its manufacturing process.process is the product
2) Against : Aventis’ ” product by process” theory is contradicted by the known variability of Lovenox itself.
For : Momenta Pharmaceuticals’ International Patent Application WO 03/ A2 contains results of studies of the variability of Lovenox’s disaccharide “building blocks”concluding that the variation between batches of commercially available Lovenox is substantial.
the term "same as" means, among other things, "identical in active ingredient(s).
Pétition du 20 aout 2004.
For determining the suitability of an abbreviated new drug application, the term same as means identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use.
1.The sameness standard for ANDA approvals
Aventis: Lovenox has certain chemical characteristics and speculates that such characteristics must be entirely dependent on its manufacturing process.
Rivals : Aventis’ ” product by process” theory is contradicted by the known variability of Lovenox itself.
2. Lack of “full characterization”
Aventis : failure to characterize approximately 20% to 30% of the components of their product should be cause for FDA to delay generic competition.
Rivals : In reality, an ANDA may be submitted, and approved, even for a drug which is not fully characterized, so long as FDA, concludes that the generic product meets all criteria, including “sameness” of the active ingredient.
it is important that the generic products are manufactured in strict compliance with the manufacturing specification of the branded product. Furthermore, regulatory agencies should require additional data on the chemical biologic, pharmacologic/toxicologic, and dose-response relationship in specific settings.
1. Lack of “full characterization”
2. Structural fingerprints

42. 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)

43. 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’.
eva痴 enoxaparin oligosaccharide profile has been compared to that of Aventis� Lovenoxｮ using ion-pair HPLC- separation with TOF-MS methodology/detection.
Rivals :
Momenta’s enoxaparin oligosaccharide profile has been compared to that of Aventis’ Lovenox .
Both enoxaparin products show essentially the same variability.

44. Moving from that, isn’t it a smatter strategy a bit different ?
Not approved
Approved
Glatiramoids?
Moving from that, isn’t it a smatter strategy a bit different ?

45. Glatiramoids? Premarin’s example - Piperazine estrone sulfate
- Micronized estradiol
Same indications
Not the same active ingredients
Not interchangeable with Premarin
On sait que Momenta et Sandoz essaient de génériquer Copaxone.
La molécule n’étant pas caractérisable, cela ne sera pas forcément possible.
La solution serait alors de développer un médicament différent ayant la même action que Copaxone.
Comme ça si la FDA refuse l’AMM, ils font leurs études cliniques et développent un médicament de la même famille.
L’idée serait de faire comme Premarin.
Although the label indications of these products are very similar, they do not contain the same active ingredients as Premarin, nor could they be said to be the same as, or interchangeable with, Premarin.

46. Glatiramoids? : Lovenox’s example
March 1993
August 2005
July 2006
Nov 2007
April 2008
Sept 2008
FDA approval
FDA non-approvable letter
ANDA submission of M-enoxaparin
Sandoz submitted the amendment
FDA additional animal studies
Momenta re-engineer
Lovenox a obtenu une AMM le 31 mars 1993.
Momenta in collaboration with Sandoz, is developing M-enoxaparin, a technology-enabled generic version of sanofi-aventis’s low molecular weight fraction of heparin Lovenox.
Le 31 juillet 2006 : July 2006, Momenta submitted an electronic Investigational New Drug (IND) application to begin a Phase I human clinical study of M118.
Momenta Pharmaceuticals is a biotechnology company specializing in the detailed structural analysis of complex mixture drugs. Momenta is applying its technology to the development of generic versions of complex drug products, as well as to the discovery and development of novel drugs. The Company's most advanced product candidate, M-Enoxaparin, is designed to be a technology-enabled generic version of Lovenox(r). Momenta's first novel drug candidate is M118, a rationally engineered anticoagulant specifically designed for acute coronary syndromes. Through its discovery program, the Company is seeking to discover and develop novel therapeutics by applying its technology to better understand sugars' functions in biological processes, with an initial focus in oncology. Momenta was founded in 2001 based on technology initially developed at Massachusetts Institute of Technology and is headquartered in Cambridge, MA.
Our ability to sequence and analyze complex mixtures of sugars has allowed us to analyze Lovenox and develop a process that we have used to make a generic version of Lovenox that we believe will meet the FDA requirements for approval through the abbreviated New Drug Application (ANDA) process. We have collaborated with Sandoz, a division of Novartis (NYSE: NVS), to jointly develop, manufacture, and commercialize M-Enoxaparin in the U.S. and the European Union.
Momenta said they had “both complex generic and novel products to our growing pipeline”.
M 118 : next generation versions of drugs containing sugars.
= heparin designated
Nov 2007 : Lack of potential for immunogenicity of the product
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

47. 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…
Operating influence only by 2014
On an operating level Copaxone is protected by patent in the US until 2014 and in Europe until 2015.
After the patent will expire any generic company will be able to submit a request to the FDA for
distributing generics and it will have to meet the matching tests the FDA is holding and prove that its
product is similar to Copaxone. Proving the match is not an easy task.
If the company will wish to distribute a generic version before 2014 it will have to submit a request to
he FDA in a different track called Paragraph IV, this is a track in which patents are challenged. When a
company submits a request to the FDA to distribute before the patent protection period is over it
informs the innovative company (in this case – Teva) and if a company sues (if Teva sues) a 30
months stay period is triggered. This means that if tomorrow a company will ask to distribute generics,
we will not see generics in the market before 2011, at the earliest.
Natco which signed a distribution agreement for the distributing the product in the US with Mylan has
not yet submitted a request to the FDA.
In addition, we must bear in mind that Teva is a generic company, and if a generic company will
receive an approval for distributing Copaxone generics Teva will immediately change the products'
categorization form an innovative product to a generic one and will wisely win over a larger market
share and maintain significant profitability.
As for products under development for treating MS, Novartis's oral product FTY720, reported two
cases of death as a result of Encephalitis (brain inflammation) during the clinical trials. In this context,
an article was published in Lancet magazine which presents Laquinimod as a promising development
for oral treatment for the MS sector.
Until 2014 Copaxone's weight in Teva's overall product basket is expected to decline
In 2007 Copaxone sales, in terms of market sales, totaled $1.7 B. We estimate Teva notes ca. 50% of
revenues, so that Copaxone sales constitute ca. 9% of sales. In 2014 Copaxone sales are expected to
surpass $20 B and the weight of Copaxone within the product basket is expected to decline. In terms
of profit margins Copaxone's profit is high but by 2014 Teva will have additional products with high
profitability whose weight within the total product basket will rise. Among the products we can name
Azilect which showed good results in the clinical trial and proved it can halt the progression of the
Parkinson's disease. Presently, Teva has two oral products for treating MS which are at phase III of
clinical trials and in the past couple of years it invested in many small companies, so it has accessibility
to many developments if they are proven successful.

48. 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

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

50. 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 50