March 31, 2015
`
`VIA ELECTRONIC SUBMISSION
`
`Dockets Management Branch, HFA-3 05
`
`Food and Drug Administration
`
`Department of Health and Human Services
`
`5630 Fishers Lane, Room 1061
`
`Rockville, MD 20852
`
`Re:
`
`Citizen Petition Requesting That FDA Consider New Scientific Information
`and Refrain From Approving Any Abbreviated New Drug Application
`Referencing Copaxone® (glatiramer acetate injection) Until Certain
`Conditions Are Met
`
`Dear Sir or Madam:
`
`On behalf of Teva Pharmaceutical Industries Ltd., Teva Neuroscience, Inc. (“Teva”)1
`hereby submits this Citizen Petition pursuant to 21 C.F.R. § 10.30 and sections 5050) and 505(q)
`of the Federal Food, Drug, and Cosmetic Act (“FFDCA”), 21 U.S.C. §§ 355(j) and 355(q). For
`the reasons that follow, Teva respectfully requests that the Commissioner of Food and Drugs
`consider the new scientific information submitted with this Petition and refrain from approving
`any abbreviated new drug application (“ANDA”) that references any Copaxone® (glatiramer
`acetate injection) product unless and until the conditions specified in this Petition are satisfied to
`assure that follow-on products are safe and effective? Teva manufactures and distributes
`Copaxone®, a treatment for the reduction of frequency of relapses in relapsing-remitting multiple
`sclerosis (“RRMS”).
`
`This Petition is submitted in accordance with guidance from the Food and Drug
`Administration (“FDA” or “the Agency”) that new scientific information from Teva’s ongoing
`research regarding Copaxone® and various follow—on glatiramer acetate products (“FOGAS”)
`should be made available for FDA’s consideration and public comment in the form of a Citizen
`
`is a global pharmaceutical company specializing in the development,
`1 Teva Pharmaceutical Industries Ltd.
`production, and marketing of generic, proprietary, and branded pharmaceuticals, and active pharmaceutical
`ingredients. Teva is among the top 20 pharmaceutical companies and is the leading generic pharmaceutical company
`in the world. Teva Neuroscience is the branded neurological products subsidiary of Teva Pharmaceutical Industries
`Ltd. and is responsible for the clinical development, registration, and marketing of Teva’s branded neurological
`products in North America, including Copaxone®.
`
`2 Copaxone is available in two presentations, a 20 mg/mL product and a 40 mg/mL product. Because the active
`ingredient is the same in both presentations, this Petition is intended to apply to purported generic versions of both
`products.
`
`Teva Pharmaceuticals
`
`11100 Nall/Xvenue I Overland Park. KS 66211 I Tel. 800.221.4026 1 www.te\NI35TaifoPharInS. Inc.
`
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`In a June 9, 2014 letter, FDA stated that it is “most appropriate to consider the issues
`Petition.
`raised in your submission in a public setting [because this] will allow others the opportunity to
`comment and participate in the decision—making process, will allow Teva the opportunity to
`comment publicly on the views and opinions of others, and will facilitate creation of an
`administrative record on which the Agency may base future decisions.”3 Moreover, in its response
`to Teva’s most recent Citizen Petition, FDA recognized the value of Teva’s ongoing research and
`encouraged Teva to continue to submit new scientific data as it becomes available.
`In particular,
`the Agency stated: “As Teva’s successive petitions demonstrate, scientific information regarding
`this complex drug continues to accumulate, which in turn means that FDA would continue to
`update the information available to it in evaluating each ANDA that is submitted for approval.”4
`
`In accordance with FDA’s guidance, this new Citizen Petition reports novel data from
`extensive gene expression studies conducted to compare Copaxone® with Synthon’s Polimunol, a
`FOGA that is currently marketed in Argentina as a purported generic glatiramer acetate product
`and presumably is the FOGA that is the subject of Synthon’s pending ANDA referencing
`Copaxone®. Despite Synthon’s assertions that Polimunol is equivalent to Copaxone®, these
`studies found hundreds of genes to be differentially expressed by the strictest measures of
`statistical significance. These differentially expressed genes enrich for key biological pathways
`clearly linked to safety and efficacy.
`These gene expression differences are particularly
`concerning when considered together with the physicochemical differences between Polimunol
`and Copaxone described in Teva’s November 13, 2014 comment to its prior Citizen Petition
`(Docket No. FDA-2014-P-0933). Given the extent and biological relevance of the observed
`differences, it is clear that any claims of equivalence between Synthon’s product and Copaxone®
`warrant careful investigation in order to protect the well-being of patients with multiple sclerosis.
`These results also suggest that Synthon’s GATE study, which had numerous methodological
`deficiencies that undermine its validity, was also premature since active ingredient sameness has
`not been established via rigorous analytical testing methodologies.
`
`I.
`
`Actions Reguested
`
`Teva respectfully requests that the Commissioner:
`
`Review and consider the new scientific data and information contained in this
`A.
`Petition prior to approving any ANDA that relies upon Copaxone® as the reference listed drug
`(“RLD”); and
`
`Based upon the additional scientific information and data contained in this Petition,
`B.
`as well as the information and arguments set forth in Teva’s prior Petitions regarding Copaxone®
`(which are incorporated herein by reference), refrain from approving any ANDA that relies upon
`Copaxone® as the RLD unless and until the ANDA contains:
`
`3 Letter from Nancy K. Hayes, Acting Director, Office of Regulatory Policy, CDER, FDA, to Dennis Ahern, MS,
`Senior Director, Regulatory Affairs, Teva Pharmaceuticals USA, at 2 (June 9, 2014) (Exhibit 1).
`
`4 FDA Response to Seventh Copaxone Petition, FDA-2014-P-0933, p. 7 n. 39 (Nov. 26, 2014) (Exhibit 2); see also
`FDA Response to Sixth Copaxone Petition, FDA-2013-P-1641, pp. 5-6 n.2O (May 2, 2014).
`
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`Information demonstrating that the proposed generic product contains the
`identical active ingredient as Copaxone®, not merely an active ingredient
`that is similar (or even highly similar) to Copaxone®’s, including data from
`high-resolution physicochemical, biological and genome-wide expression
`methods;
`
`including in—depth
`investigations,
`Results of non-clinical and clinical
`analyses of comparative gene expression profiles in several relevant
`preclinical systems, demonstrating that the immunogenicity risks associated
`with the proposed generic product are no greater than the risks associated
`with Copaxone®, including a demonstration that the risks of alternating or
`switching between use of the proposed product and Copaxone® are not
`greater than the risks of using Copaxone® without such alternation or
`switching; and
`
`investigations in RRMS patients using
`Results of comparative clinical
`relevant safety and effectiveness endpoints demonstrating that the proposed
`generic drug is bioequivalent to Copaxone®.
`
`The grounds for these requests are set forth below, in the attached memorandum
`reporting Teva’s new scientific findings, and in Teva’s prior Citizen Petitions, which are
`incorporated herein by reference?
`
`II.
`
`Statement of Grounds
`
`Copaxone® is a non-biologic complex drug (“NBCD”) and first—generation nanomedicine
`composed of an uncharacterized mixture of immunogenic polypeptides in a colloidal suspension.
`The active ingredient in Copaxone® ~ glatiramer acetate — is not a single molecular entity but
`rather a heterogeneous mixture ofpotentially millions of distinct, synthetic polypeptides of varying
`lengths, some containing up to 200 amino acids, with structural complexity comparable to that of
`proteins. The complexity of glatiramer acetate is amplified by the fact that its exact mechanisms
`of action are unknown, and the specific amino acid sequences (epitopes) responsible for its efficacy
`and safety cannot be identified. Accordingly, like many biological products, glatiramer acetate is
`defined, in large part, by its well-controlled manufacturing process, which has been used by Teva
`for more than twenty years.
`
`5 The prior Citizen Petitions were submitted in 2008, 2009, 2010, 2012, 2013, and 2014 respectively, and are
`incorporated herein by reference. See FDA-2008-P-0529 (Sept. 26, 2008) (Exhibit 3); FDA-2009-P-0555 (Nov. 13,
`2009) (Exhibit 4); FDA-2010-P-0642 (Dec. 10, 2010) (Exhibit 5); FDA-2012-P-0555 (June 4, 2012) (Exhibit 6);
`FDA—2013-P-1128 (Sept. 12, 2013) (Exhibit 7); FDA-2013-P-1641 (Dec. 5, 2013) (Exhibit 8); and FDA-2014-P-
`0933 (July 2, 2014) (Exhibit 9). Teva also incorporates by reference any exhibits to those petitions although, for
`efficiency’s sake, such exhibits are not being re-submitted because they are either FDA documents that are routinely
`available to the public (e.g., approved labeling, guidance documents and petition responses) or recognized medical
`or scientific textbooks or articles that are readily available to the agency. See 21 C.F.R. § 10.20(c)(1)(iii), (iv).
`
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`As part of its ongoing commitment to better characterize Copaxone®, Teva continues to
`evaluate the physicochemical and biological properties of Copaxone® using state-of—the-art
`technology.
`In prior Petitions, Teva submitted the results of new gene expression studies
`comparing Copaxone® and purported, foreign, generic glatiramer acetate products.6 Those studies
`produced multiple lines of evidence suggesting that purported “generic” products have a
`significantly more variable biological impact than Copaxone®, particularly with respect to immune
`cells associated with inflammatory response and beneficial tolerance. The results from these tests
`thus raise significant concerns that proposed generic products manufactured via different processes
`and using different starting materials may have undetected structural and compositional
`differences from Copaxone® that could compromise safety, immunogenicity, and effectiveness.
`
`In this Petition Teva reports new data from recently conducted gene expression studies that
`found extensive gene expression differences between Copaxone® and Polimunol across multiple
`model systems, thereby further confirming the concerns identified in Teva’s prior studies and
`Petitions. The new studies were conducted in both mouse splenocytes and human monocytes. The
`observed differences were both statistically significant and biologically important, occurring in
`pathways with clear connections to Copaxone®’s mechanism of action and in pathways with
`implications for possible adverse events. The gene expression findings suggest that regardless of
`the many issues in the design and conduct of Synthon’s GATE study that render the results
`unreliable, the study itself was premature because it was conducted on a glatiramoid that is almost
`certainly not equivalent to Copaxone®. Together, these data warrant further investigation, and
`emphasize the need for clinical trials, conducted only upon the establishment of quality and
`pharmaceutical equivalence, including multi-year safety studies with standard clinical endpoints
`for multiple sclerosis (“MS”), to ensure the safety and well-being of MS patients.
`
`It should be emphasized that in both the new and prior gene expression studies, Teva
`studied the effect of Copaxone® and various FOGAs available in foreign countries at the level of
`gene expression across the entire genome (unbiased, without prior hypothesis about the genes for
`which expression pattern may be altered and without choosing which genes to focus on or study)
`in a variety of immunologically relevant model systems, including mouse splenocytes and human
`monocytes. The genome-wide approach is critical, because two glatiramoids can appear identical
`based on a small panel of genes, yet differ significantly in their impact on other genes that are
`potentially highly relevant to safety and/or efficacy. Using multiple model systems is equally
`critical, since acting as an antigen, Copaxone® significantly impacts a variety of immunological
`cell types. The unbiased approach allows identification of genes and pathways with subtle, yet
`robust, differential expression patterns following stimulation by different glatiramoids in different
`experimental contexts. The functionality of identified genes and pathways is then described based
`on experimental data reported in the peer-reviewed literature. As described in Teva’s prior
`Petitions and the attached report, the research has also shown that various model systems capture
`different aspects of Copaxone®’s mechanism of action, such that no single cell type or system
`tested was sufficient to fully characterize the biological impact of this medicine.
`
`6 See Docket Nos. FDA-2014-P—0933 (July 2, 2014) and FDA-2013-P-1641 (Dec. 5, 2013) (Exhibits 9 and 8,
`respectively).
`In an earlier petition, Teva submitted the results of traditional colloidal assessment experiments to
`confirm that Copaxone® is a colloidal suspension rather than a true solution. See Docket No. FDA—2013—P-1 128
`(Sept. 12,2013) (Exhibit 7).
`
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`The core analysis methods used for these studies are validated and considered standard in
`the field (experimental design methodologies: Churchill, Nat. Genet., 2002; microarray data
`normalization method: Quackenbush, Nat. Genet., 2002; batch correction methodology: Johnson
`et al, Biostat, 2007; differential expression methodology: Smyth, Stat Appl Genet Mol Biol.,
`2004). Novel,
`innovative approaches were developed by Immuneering Corporation so as to
`address particular questions.
`
`The null hypothesis in traditional gene—expression studies, including Teva’s studies with
`the glatiramoids, is that there are no significant gene expression differences induced between the
`treatments. As such, the expectation is that regardless of the biological system used for testing,
`genes would show no statistically significant, nor biologically meaningful, differences among the
`various treatments purported as equivalent and already used to treat patients in certain territories.
`Only in cases where the treatments induce significant observable effects, genes differentially
`expressed between treatments will pass the stringent statistical tests, and false discovery rate
`(FDR) correction for multiple hypotheses.7 These stringent requirements were imposed a priori
`across all
`tests to ensure robustness of results and minimizing of spurious findings. Such
`statistically significant differences, if biologically meaningful (e.g., related to the disease biology
`or any of the drug’s known or putative targets and downstream pathways), warrant further studies,
`as two drugs that have identical activities in biological systems should not induce statistically
`observable and biologically enriched differences when compared against each other.
`
`It should be emphasized that these studies were not designed to establish a particular set of
`genes in a specific model system as a panel
`to evaluate “sameness” between differently
`manufactured glatiramoids. Instead, these were designed to assess the degree of similarity in the
`impact of two glatiramoids on relevant biological pathways. The application of robust
`methodology (high number of replicates and conditions, where relevant) was aimed to describe
`pathways changed by different treatments out of the entire milieu of genomic patterns. The results
`obtained across the tested experimental models revealed statistically significant differences
`between glatiramoids, which were intended to be similar and to perform the same function, despite
`stringent statistical threshold requirements. This was noteworthy, particularly in genes highly
`relevant to disease processes and drug response mechanisms. In addition, the differences observed
`revealed a complex interplay between immunological pathways, such that some differences were
`common to multiple systems, while many others were dependent on the specific model system (for
`example, some key genes modulated in T cells were not the same as in monocytes). This is not
`surprising for a process that involves multifaceted interactions between many immune system
`components, and is also exemplified in experimental studies of Copaxone®’s mechanism of action.
`Thus, no single model system, characterization method, or set of genes tested was sufficient to
`comprehensively capture the differences (or “sameness”) between the drugs. These observations
`indicate a need for in-depth investigation of comparative gene expression profiles in several
`relevant pre-clinical systems as key indicators of similarity and/or sameness between generic
`candidates and the original drug within the context of NBCDs. Ideally, the concordance between
`high—resolution physicochemical measures (e.g. ion motility mass spectrometry, IMMS), gene
`
`7 Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to
`multiple testing. Journal of the Royal Statistical Society Series B (Methodological): 289-300.
`
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`expression profiling and clinical trials would allow a more definitive assessment of equivalence in
`terms of patient benefit and safety.
`
`Teva previously has raised the above issues regarding active ingredient sameness,
`immunogenicity and bioequivalence with FDA in a series of Citizen Petitions dating back to 2008
`(supra note 5). In its responses to Teva’s prior Petitions, FDA has taken the position that it would
`be “premature and inappropriate” to provide a substantive decision on the approval requirements
`for ANDAS for glatiramer acetate while FDA is still reviewing pending applications.3 Teva’s prior
`Petitions thus remain largely unanswered, although the Agency has been receptive to reviewing
`and considering new scientific data.
`
`Accordingly, in light of the new scientific data and information discussed in the attached
`report, Teva is hereby renewing and supplementing the arguments made in its prior Petitions
`regarding active ingredient sameness, immunogenicity and bioequivalence testing.9 At bottom,
`Teva believes it would be contrary to the public health for FDA to approve a purported generic
`glatiramer acetate product that, based on current analytical technologies, can only be shown to be
`similar, rather than identical, to Copaxone® — particularly without valid and rigorous clinical
`testing to address residual uncertainty regarding immunogenicity, bioequivalence, safety or
`effectiveness.
`
`III.
`
`Environmental Impact
`
`Petitioner claims a categorical exclusion under 21 C.F.R. §§ 25.30 and 25.3 1(a).
`
`IV.
`
`Economic Impact
`
`Petitioner will submit economic information upon request of the Commissioner.
`
`V.
`
`Certification
`
`I certify that, to my best knowledge and belief: (a) this petition includes all information
`and views upon which the petition relies; (b) this petition includes representative data and/or
`information known to the petitioner which are unfavorable to the petition; and (c) I have taken
`reasonable steps to ensure that any representative data and/or information which are unfavorable
`to the petition were disclosed to me.
`I further certify that the information upon which I have based
`the action requested herein first became known to the party on whose behalf this petition is
`submitted on or about the following date: March 16, 2015.
`If I received or expect to receive
`payments, including cash and other forms of consideration, to file this information or its contents,
`I received or expect to receive those payments from the following persons or organization: my
`
`3 See, e. g., FDA’s Response to Sixth Copaxone Petition, FDA-2013-P-1641 (May 2, 2014).
`
`9 Because this submission contains new scientific information, Teva is required to file it as a new Citizen Petition
`rather than as a Petition for Reconsideration. See 21 C.F.R. § 10.33(e).
`
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`I verify under penalty of perjury that the foregoing is true and correct as of the
`employer, Teva.
`date of the submission of this petition.
`
`Respectfully submitted,
`
`% M 121»?
`
`42/,/{av/’/41¢
`
`J. Michael Nicholas, Ph.D.,
`
`Vice President, Global Specialty Medicines
`/l
`
`Janet Woodcock, M.D.
`
`Director, Center for Drug Evaluation and Research
`
`Robert Temple, M.D.
`
`Deputy Center Director for Clinical Science
`
`Acting Deputy Director, Office of Drug Evaluation 1
`
`Lawrence Yu, Ph.D.
`
`Acting Director, Office of Pharmaceutical Science
`
`William Dunn, M.D.
`
`Director, Division of Neurology Products
`
`Kathleen Uhl, M.D., Acting Director
`Office of Generic Drugs
`
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`% REPORT OF
`
`GENE EXPRESSION STUDIES
`
`COMPARING
`
`POLIMUNOL AND COPAXONE®
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`
`TABLE OF CONTENTS
`
`1.
`
`INTRODUCTION ................................................................................................... 5
`
`2.
`
`EXECUTIVE SUMMARY ......................................................................................... 8
`
`3. MOUSE SPLENOCYTE GENE EXPRESSION STUDIES .............................................. 10
`
`3.1.
`
`Introduction.............................................................................................................................................. 10
`
`3.2.
`
`Copaxone-modulated genes (MoA) .................................................................................................. 10
`
`3.3.
`
`Copaxone-modulated pathways ........................................................................................................ 13
`
`3.4.
`
`Copaxone MoA discussion ................................................................................................................... 14
`
`3.5.
`Polimunol and Copaxone comparison: differentially expressed genes, under Copaxone
`immunization ........................................................................................................................................................... 14
`
`3.6.
`Polimunol and Copaxone comparison: differentially expressed genes, under
`Polimunol immunization ..................................................................................................................................... 16
`
`3.7.
`Polimunol and Copaxone comparison: differentially expressed pathways, under
`Copaxone immunization ...................................................................................................................................... 19
`
`3.8.
`Polimunol/Copaxone comparison: differentially expressed pathways, Polimunol
`immunization ........................................................................................................................................................... 20
`
`3.9.
`
`Polimunol and Copaxone comparison: discussion ..................................................................... 21
`
`4. METHODS FOR MOUSE SPLENOCYTE STUDIES .................................................... 24
`
`Experimental Methods.......................................................................................................................... 24
`4.1.
`4.1.1. Mice ............................................................................................................................................................................ 24
`4.1.2. Preparation of mouse spleen cell cultures ............................................................................................... 24
`4.1.3.
`In vitro cell activation ........................................................................................................................................ 24
`
`Analysis Methods .................................................................................................................................... 25
`4.2.
`4.2.1. Outlier identification and normalization ................................................................................................... 25
`4.2.2. Batch correction ................................................................................................................................................... 25
`4.2.3. Differential expression analysis .................................................................................................................... 25
`4.2.4. Pathway enrichment analysis ........................................................................................................................ 25
`
`5. HUMAN MONOCYTE (THP-1) GENE EXPRESSION STUDIES .................................. 26
`
`5.1.
`
`Introduction.............................................................................................................................................. 26
`
`5.2.
`
`Copaxone-modulated genes (MoA) .................................................................................................. 26
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`5.3.
`
`Copaxone-modulated pathways ........................................................................................................ 28
`
`5.4.
`
`Copaxone MoA discussion ................................................................................................................... 31
`
`5.5.
`
`Polimunol and Copaxone comparison: differentially expressed genes ............................. 31
`
`5.6.
`
`Polimunol and Copaxone comparison: differentially expressed pathways ..................... 34
`
`5.7.
`
`Polimunol and Copaxone comparison: discussion ..................................................................... 37
`
`6. METHODS FOR HUMAN MONOCYTE STUDIES: ................................................... 39
`
`Experimental design .............................................................................................................................. 39
`6.1.
`6.1.1. A priori power analysis ..................................................................................................................................... 39
`6.1.2. Outlier identification and normalization ................................................................................................... 39
`6.1.3. Batch correction ................................................................................................................................................... 39
`6.1.4. Differential expression analysis .................................................................................................................... 39
`6.1.5. Pathway enrichment analysis ........................................................................................................................ 40
`
`7. CONCLUSIONS ................................................................................................... 41
`
`8. REFERENCES ...................................................................................................... 44
`
`9. APPENDIX .......................................................................................................... 46
`
`Abstracts to be presented at the American Academy of Neurology 2015 Conference --
`9.1
`Teva Response …………………………………………………………………………………………………………………….. 46
`9.1.1.
`Introduction ........................................................................................................................................................... 46
`9.1.2. Abstract #1 ............................................................................................................................................................. 46
`9.1.3. Abstract #2 ............................................................................................................................................................. 49
`9.1.4. Abstracts in order of response: ..................................................................................................................... 52
`
`THP-1 Results ........................................................................................................................................... 55
`9.2.
`9.2.1. Pathways significantly enriched among top probesets differentially expressed by
`Copaxone relative to mannitol control in THP-1 cells. ......................................................................................... 55
`9.2.2. Probesets significantly differentially expressed between Polimunol and Copaxone
`treatment (corrected for mannitol control) in THP-1 cells ................................................................................ 64
`9.2.3. Pathways significantly enriched among top probesets differentially expressed between
`Polimunol and Copaxone in THP-1 cells. .................................................................................................................... 98
`
`9.3.
`Mouse Splenocyte Results ................................................................................................................ 106
`9.3.1 Pathways enriched among top probesets modulated by Copaxone relative to mannitol in
`splenocytes from mice immunized with Copaxone …………………………………………………………………106
`9.3.2. Top probesets significantly differentially expressed between Polimunol and Copaxone
`treatment (corrected for medium control) in splenocytes from Copaxone-immunized mice......... 114
`9.3.3. Pathways enriched among top probesets upregulated by Polimunol relative to Copaxone
`(in Copaxone-immunized mice) ................................................................................................................................... 124
`9.3.4. Pathways enriched among top probesets upregulated by Polimunol relative to Copaxone
`(in Polimunol-immunized mice) .................................................................................................................................. 125
`
`
`
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`LIST OF TABLES
`Table 1: Top 25 Probesets Upregulated by Polimunol versus Copaxone in Splenocytes from
`Copaxone-immunized Mice ................................................................................................................................... 15
`Table 2: Fifteen Probesets Downregulated by Polimunol versus Copaxone in Splenocytes from
`Copaxone-immunized Mice ................................................................................................................................... 16
`Table 3: Top 25 Probesets Upregulated by Polimunol versus Copaxone in Splenocytes from
`Polimunol-immunized Mice .................................................................................................................................. 17
`Table 4: Top 25 Probesets Downregulated by Polimunol versus Copaxone in Splenocytes from
`Polimunol-immunized Mice .................................................................................................................................. 18
`Table 5: Top Probesets Modulated by Copaxone are Significantly Enriched Among the Top Probesets
`Modulated by Copaxone in Prior THP-1 Studies ......................................................................................... 28
`Table 6: Top Pathways Enriched Among Top Probesets Upregulated by Copaxone ................................... 29
`Table 7: Probesets Significantly Upregulated in Polimunol versus Copaxone ............................................... 32
`Table 8: Probesets Significantly Downregulated in Polimunol versus Copaxone ......................................... 33
`Table 9: Top 25 Pathways Significantly Enriched Among Top Probesets Differentially Expressed
`between Polimunol and Copaxone..................................................................................................................... 35
`
`
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`11
`
`12
`
`13
`
`20
`
`LIST OF FIGURES
`Figure 1: Expression of Anti-Inflammatory Cytokines (Il10 and Il4) Following Copaxone or
`Polimunol Immunization
`Figure 2: Expression of Markers of Regulatory T cells (Foxp3 and Gpr83) Following Copaxone or
`Polimunol Immunization
`Figure 3: Expression of Pro-inflammatory Cytokine Il12a Following Copaxone or Polimunol
`Immunization
`Figure 4: Pathways Enriched Among Probesets Modulated by Copaxone Relative to Medium in
`14
`Splenocytes from Mice Immunized with Copaxone
`Figure 5:
`IL18 Expression is Reduced to a Greater Extent by Copaxone than Polimunol, Regardless
`