Case No. IPR2015-00644
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS, INC.
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`Petitioner
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`v.
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`YEDA RESEARCH AND DEVELOPMENT CO. LTD.
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`Patent Owner
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`Case No. IPR2015-00644
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`Patent No. 8,399,413
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`DECLARATION OF EDWARD J. FOX, M.D., PH.D. IN SUPPORT OF
`PATENT OWNER YEDA’S RESPONSE TO INSTITUTION OF INTER
`PARTES REVIEW
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`YEDA EXHIBIT NO. 2129
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`TABLE OF CONTENTS
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`INTRODUCTION ............................................................................................................... 1 
`I. 
`QUALIFICATIONS AND EXPERIENCE ......................................................................... 1 
`II. 
`THE PERSON OF ORDINARY SKILL IN THE ART ...................................................... 4 
`III. 
`LEGAL PRINCIPLES ......................................................................................................... 4 
`IV. 
`SUMMARY OF OPINIONS ............................................................................................... 5 
`V. 
`VI.  BACKGROUND ................................................................................................................. 7 
`A.  Multiple Sclerosis is a Debilitating Disease of the Central Nervous System ..................... 7 
`B.  Multiple Sclerosis Treatment .............................................................................................. 9 
`C.  Benefits of GA 40 mg tiw ................................................................................................. 15 
`VII.  OPINIONS ......................................................................................................................... 17 
`A.  GA 40 mg tiw Satisfied a Long-Felt Need for a Safe and Effective Treatment that Was
`More Tolerable and More Convenient .............................................................................. 17 
`B.  GA 40 mg tiw Provides Benefits that were Unexpected in August, 2009 ........................ 22 
`It Was Unexpected that GA 40 mg tiw Would Result in Fewer and Less Severe Adverse
`i. 
`Events than GA 20 mg Daily ......................................................................................... 22 
`It Was Unexpected that GA 40 mg tiw Would Result in a Decrease in Brain Grey
`Matter Atrophy............................................................................................................... 27 
`VIII.  CONCLUSION .................................................................................................................. 29 
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`ii. 
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`I.
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`INTRODUCTION
`1.
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`I, Edward J. Fox, M.D., Ph.D., have personal knowledge of the facts
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`set forth in this Declaration and am competent to testify to the same.
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`2.
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`I have been retained by counsel for Teva (Teva Pharmaceuticals USA,
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`Inc., Teva Pharmaceutical Industries Ltd., Teva Neuroscience, Inc.) on behalf of
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`Yeda Research and Development Co. Ltd. (“Patent Owner”) in this proceeding
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`regarding U.S. Patent No. 8,399,413 (“the ’413 patent”).
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`3.
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`I hereby offer this Declaration in support of Patent Owner’s Response
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`to Institution of Inter Partes Review.
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`4.
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`A list of materials that I have reviewed is attached hereto as Exhibit
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`A.
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`II. QUALIFICATIONS AND EXPERIENCE
`5.
`I have been involved in research and clinical treatment of patients
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`suffering from multiple sclerosis (“MS”) for more than 25 years. I specialize in the
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`diagnosis and treatment of MS, and my research is directed toward various facets
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`of MS, including the study of pharmaceutical agents, including glatiramer acetate,
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`and their mechanism of action, as well as methods of managing MS as it
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`progresses.
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`6.
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`I was named Clinical Assistant Professor of Neurology at the
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`University of Texas Medical Branch in 2004. I am currently the Director of the
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`MS Clinic of Central Texas. I also maintain a private neurology practice at Central
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`Texas Neurology Consultants.
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`7.
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`For the last 25 years, I have specialized in the diagnosis and treatment
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`of multiple sclerosis, during which time I have treated thousands of patients with
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`multiple sclerosis. In my private neurology practice at Central Texas Neurology
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`Consultants, I currently have approximately 1,000 patients. I have been
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`prescribing Copaonxe 20 mg to patients with multiple sclerosis since 1997. I have
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`been prescribing Copaxone 40 mg to patients with multiple sclerosis since 2014.
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`8.
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`I graduated from Washington University in St. Louis in 1981, after
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`which I attended the M.D./Ph.D. Medical Scientist Training Program at Baylor
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`College of Medicine. I received a Ph.D in Immunology in 1987 and an M.D. in
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`1988.
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`9.
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`I finished my internship in Internal Medicine at Baylor in 1989, and I
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`was a Resident in the Neurology Residency Program at Baylor from 1989 through
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`1992. In 1991, I was appointed to the position of Chief Resident.
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`10.
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`Throughout my career, I have held multiple appointments to various
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`committees and advisory boards that deal with neurology and MS, and I am
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`currently a Fellow with the American Academy of Neurology as well as a member
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`of the Executive Board of the American Academy of Neurology’s MS Section. I
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`am also on the Healthcare Advisory Committee for the Five Star Chapter of the
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`National Multiple Sclerosis Society (NMSS) and am on the Board of Directors of
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`the Texas Neurological Society.
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`11.
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`I have authored or co-authored over 250 articles and abstracts related
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`to neurology, MS, and the treatment of MS with pharmaceutical agents such as
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`glatiramer acetate.
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`12.
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`In my capacity as Director of the MS Clinic of Central Texas, I serve
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`as an Investigator in Phase I, II, III and IV studies. I have participated in more
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`than one hundred clinical trials and extensions as principal investigator, including
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`several major trials involving Copaxone including the following:
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` Phase IIIb, ENCORE: Evaluation of Two Copaxone Formulations
`Plus Autojects in Relapsing-Remitting Multiple Sclerosis Patients
`(“ENCORE”);
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` Phase IV, A Multicenter, Open-Label, Two-Arm Prospective Study to
`Evaluate the Impact of Patient Readiness to Self-Inject on Outcomes
`When Using the Copaxone Prefilled Syringes (“READY”);
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` Phase III, A Multinational, Multicenter, Randomized, Parallel-Group,
`Double-Blind Study to Compare the Efficacy, Tolerability and Safety
`of Glatiramer Acetate Injection 40 mg/ml to That of Glatiramer
`Acetate Injection 20 mg/ml Administered Once Daily by
`Subcutaneous Injection in Subjects With Relapsing Remitting (R-R)
`Multiple Sclerosis (MS) (“FORTE”);
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` Phase IIIb, An Open-Label, Multicenter Randomized Study
`Evaluating the Tolerability and Safety of Two Formulations of
`Glatiramer Acetate (GA) for Subcutaneous Injection (“SONG”); and
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` Phase IV, A Multi-Centered, Randomized, Double-Blind, Placebo
`Controlled Study Assessing the Add-on Effect of Oral Steroids in
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`Relapsing Remitting Multiple Sclerosis Subjects Treated With
`Glatiramer Acetate (“ASSERT”).
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`A copy of my current curriculum vitae is attached (Exhibit 2100).
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`13.
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`III. THE PERSON OF ORDINARY SKILL IN THE ART
`14.
`I have been informed that the Patent Trial and Appeals Board has
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`determined that a person of ordinary skill in the art (“POSA”) pertaining to the
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`subject matter of the ’413 patent as of August 20, 2009 (the provisional filing date
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`of the application that led to the ’413 patent) would have had: (1) several years of
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`experience in the pharmaceutical industry or in practicing medicine; (2) experience
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`with the administration or formulation of therapeutic agents, dosing schedules and
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`frequencies, and drug developmental study and design; (3) a Ph.D. in
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`pharmacology or be a physician with experience in clinical pharmacology; and (4)
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`knowledge of and experience with both multiple sclerosis and its pathophysiology
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`and glatiramer acetate.
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`IV. LEGAL PRINCIPLES
`15.
`I have been informed that a patent claim is invalid as obvious if it can
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`be shown that the differences between the patented subject matter and the prior art
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`are such that the subject matter as a whole would have been obvious, at the time
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`the invention was made, to a person having ordinary skill in the art.
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`16.
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`I understand that an obviousness analysis involves consideration of
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`four factors: (1) the scope and content of the prior art; (2) the differences between
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`the prior art and the claims; (3) the level of ordinary skill in the art; and (4) the
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`existence of objective indicia of nonobviousness. I understand that these objective
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`indicia are also known as “secondary considerations of non-obviousness.”
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`17.
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`I further understand that these secondary considerations of non-
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`obviousness include, among other considerations, “long-felt but unresolved need,”
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`which can be demonstrated by showing that there was a problem in the relevant
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`field for a considerable time and the claimed invention solved the problem; and
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`“unexpected results,” which can be demonstrated by showing that the claimed
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`invention exhibits some superior property or advantage that a person of ordinary
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`skill in the relevant art would have found surprising or unexpected.
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`18.
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`I also understand that any alleged secondary conditions must have a
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`nexus with the invention as claimed.
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`V.
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`SUMMARY OF OPINIONS
`19.
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`It is my opinion that as of August, 2009, there was a long-felt but
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`unmet need for a multiple sclerosis treatment option that had the same safety and
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`efficacy profile as the Copaxone 20 mg daily glatiramer acetate product (“GA 20
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`mg daily”), but with improved tolerability and convenience. In my opinion, this
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`need was met with the introduction of the Copaxone 40 mg/mL three times per
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`week glatiramer acetate product (“GA 40 mg tiw”) that is claimed in the ’413
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`patent. GA 40 mg tiw has been shown to be as safe and effective as GA 20 mg
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`daily while reducing injection-related adverse effects and the inconvenience caused
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`by daily administration of glatiramer acetate.
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`20.
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`It is also my opinion that the GA 40 mg tiw product claimed in the
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`’413 patent has produced unexpected results. First, GA 40 mg tiw has been
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`demonstrated to induce less severe and less frequent injection site and post-
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`injection adverse events compared to daily 20 mg GA treatment. A POSA would
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`not have expected this result because as of August, 2009, POSAs believed that
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`these adverse events were dose dependent and would worsen as a result of
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`increasing the dose of GA from 20 mg to 40 mg. Further, a POSA would have
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`expected that less frequent GA injections would likely worsen the severity of
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`injection site reactions because the cells responsible for those reactions would have
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`more time to recover, resulting in a more severe response. For this additional
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`reason, the results seen with the claimed regimen have been unexpected.
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`21.
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`In addition, GA 40 mg tiw’s ability to reduce grey matter brain
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`atrophy is another unexpected benefit provided by the claimed invention. To date,
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`no other treatment for MS has been demonstrated to have such an effect in rigorous
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`clinical testing.
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`6
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`VI. BACKGROUND
`A. Multiple Sclerosis is a Debilitating Disease of the Central Nervous
`System
`22. Multiple sclerosis is a disease in which the immune system attacks the
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`central nervous system. The underlying mechanism of the disease is not fully
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`understood, but its clinical manifestations are well characterized. MS affects
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`between two and three times as many women as men, with the first symptoms most
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`commonly appearing between the ages of twenty and forty years. The disease
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`affects people in the Northern hemisphere with a higher frequency than those in the
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`Southern hemisphere. Caucasian people have a higher incidence of MS than those
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`of African or Asian descent.1
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`23.
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`Clinically, MS is characterized by a gradual worsening of symptoms
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`over the course of the disease. The symptoms of MS can be life altering and may
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`include motor disability, sensory dysfunction, bowel dysfunction, bladder
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`dysfunction, sexual dysfunction, vision problems, extreme fatigue (“MS fatigue”),
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`depression and cognitive dysfunction. Motor dysfunction includes weakness,
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`tremors, spasticity, and ataxia (lack of voluntary coordination). In the absence of
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`1 Rumrill, “Multiple sclerosis: Medical and psychosocial aspects, etiology,
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`incidence, and prevalence,” Journal of Vocational Rehabilitation, 31, 75-82
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`(2009). (Exhibit 2090)
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`7
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`disease modifying therapies, fifty percent of patients are wheelchair bound after 25
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`years living with the disease.2
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`24.
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`Pathologically, as viewed with MRI technology, MS is characterized
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`by lesions in the central nervous system caused by the destruction of the fatty
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`tissue, or myelin, that surrounds the nerve cells. This destruction of the myelin
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`causes the electrical impulses that coordinate mental and physiological processes
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`to be blocked or slowed.
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`25.
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`In addition to the lesions, MS patients also experience brain atrophy,
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`or a loss of tissue in the brain. Brain atrophy occurs in two tissue types in the
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`brain, the grey matter and white matter. Recent studies have shown that the loss in
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`grey matter is more closely related to accumulation of disability than loss of white
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`matter and may also be more indicative of disability than lesions.3
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`26. MS is categorized as either relapsing disease or progressive disease.
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`Most patients are initially diagnosed with relapsing disease. In the relapsing form
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`of MS, relapses, or periods of time during which the symptoms of the disease
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`suddenly worsen, are followed by periods of remission during which the symptoms
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`abate. Relapses are separated by remission periods that last anywhere from months
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`2 Id.
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`3 Leonora K. Fisniku, et al, Gray Matter Atrophy is Related to Long-Term
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`Disability in Multiple Sclerosis, Ann Neurol 2008, 64:247-254. (Exhibit 2088)
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`8
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`to years. Although clinical symptoms decrease during periods of remission, the
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`symptoms may not entirely resolve, such that a patient’s condition during each
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`period of remission is worse than it was in the preceding period. Additionally, a
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`patient’s condition may worsen gradually during remission periods. In this way, a
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`patient’s condition steadily worsens over time, with discrete set-backs in disability.
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`Further, the brain lesions and atrophy characteristic of MS continue to increase
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`even during remission periods. In the progressive form of MS, the patient’s
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`condition gradually continues to worsen, with no discrete relapses and no periods
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`of remission.
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`B. Multiple Sclerosis Treatment
`27. MS is a chronic disease and patients must continue therapy for the
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`duration of their lives. The expected lifespan of the average person with MS is
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`only slightly lower than the expected lifespan of healthy individuals, so patients
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`diagnosed with MS face decades of treatment. There is no available treatment that
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`will stop the progression of the disease or reverse the accumulation of disability.
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`28.
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`Treatments are divided into three categories, based on their purpose
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`and action on the disease. First, corticosteroids are used to decrease inflammation
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`and shorten the duration of relapses. Second, various medications including pain
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`relievers and muscle relaxants are used to treat common symptoms. Third,
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`“disease modifying” or immunomodulatory agents are used in an attempt to reduce
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`the number of future relapses and to slow disease progression. The currently
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`approved disease modifying agents have only been shown to be effective in the
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`relapsing form of the disease.
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`29.
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`Relatively few disease modifying therapies are used to reduce the
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`number of future relapses and slow the progression of the disease. While none of
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`these agents have been shown to be effective in every patient with MS, individual
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`patients may respond well to different therapies. Doctors have generally
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`prescribed either Interferon--1 (“interferon”) or glatiramer acetate (“GA”) – those
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`treatments with the best safety profile – to patients that are newly diagnosed with
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`MS. Although other treatments are now available, they pose a greater risk of
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`potentially severe side effects that, in some cases, may be fatal. These treatments
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`have therefore not historically been the first choice therapy for many physicians
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`and patients.
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`30.
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`Interferon therapies were first introduced into the United States
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`market in 1993. Treatment with interferon has been shown to reduce the rate of
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`relapses in relapsing MS by 31-32% when compared with placebo.4 However, a
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`small but not insignificant number of patients on interferon therapy develop
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`neutralizing anti-interferon antibodies, which negate the clinical benefit of the
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`4 Paty, D.W., The interferon- 1b clinical trial and its implications for other trials,
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`Ann Neurol., 1994, 36 Suppl: S113-14. (Exhibit 2087)
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`10
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`therapy.5 The most common side effects of interferon treatment include flu-like
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`symptoms, liver and bone marrow abnormalities, injection site reactions such as
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`redness and swelling, and an exacerbation of preexisting conditions such as
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`depression, spasticity, pain, headaches and MS fatigue.6
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`31.
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`Glatiramer acetate was approved in the United States in 1996, under
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`the trade name Copaxone. Copaxone has been shown to reduce the rate of relapses
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`in relapsing MS by one-third when compared with placebo.7 Other trials have
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`shown that GA delays disease progression, including by reducing by 45% the risk
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`that patients with a first disease flare up, called “clinically isolated syndrome,” will
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`5 Sorensen, P. et al., Clinical importance of neutralising antibodies against
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`interferon beta in patients with relapsing-remitting multiple sclerosis, 362 Lancet
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`9391, 1184-1191 (2003). (Exhibit 2101)
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`6 See current Prescribing Information for Betaseron®, Avonex ®, Rebif®, and
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`Extavia®, the brand names under which Interferon--1 is sold. (Exhibits 1048,
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`2097, 2098, and 2099, respectively)
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`7 Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces relapse rate and
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`improves disability in relapsing-remitting multiple sclerosis: Results of a phase III
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`multicenter, double-blind, placebo-controlled trial. Neurology 1995; 45: 1268-76.
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`(Exhibit 1018)
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`11
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`develop into clinically definite MS when compared with placebo.8 The most
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`common side effects with GA are injection-related adverse events (“IRAEs”) such
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`as immediate post-injection reactions (“IPIRs”) and injection site reactions
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`(“ISRs”). IPIRs include flushing, chest pain, palpitations, anxiety, dyspnea,
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`constriction of the throat, and urticaria (chronic hives). The IPIRs associated with
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`Copaxone are generally self-limiting and cease shortly after a patient is dosed.
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`ISRs range from redness, swelling and pain, to lipoatrophy (deterioration of fat
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`tissues under the skin) and skin necrosis (death of an area of skin).9 Studies have
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`indicated that the IRAEs are caused by local histamine release from dermal mast
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`cells.10
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`32.
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`Glatiramer acetate is sold in two dosages, 20 mg/mL injected every
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`day and 40 mg/mL injected three times per week with at least one day between
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`8 Comi G, Martinelli V, Redegher M, et al. Effect of glatiramer acetate on
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`conversion to clinically definite multiple sclerosis in patients with clinically
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`isolated syndrome (PreCISe study): A randomised, double-blind, placebo-
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`controlled trial, Lancet 2009, Oct 31; 374 (9700): 1503-11. (Exhibit 2123)
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`9 See current Prescribing Information for Copaxone®. (Exhibit 2005)
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`10 M. Shalit et al, Copolymer-1 (Copaxone®) induces a non-immunologic
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`activation of connective tissue type mast cells, J. Allergy Clin. Immunol., 97(1),
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`part 3, abstract 650 (1996). (Exhibit 2054)
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`12
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`injections.11 Both dosages are sold under the Copaxone trade name. The 20 mg
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`injection was introduced in 1996. The 40 mg injection was introduced in 2014.
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`Thus, only the 20 mg daily injection was available in 2009, the time that I have
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`been told is relevant in this proceeding.
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`33.
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`As of 2009, when GA 20 mg daily was the only regimen of GA
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`treatment available, doctors frequently prescribed both interferon and GA.
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`However, GA was the treatment of choice for many patients, for a few reasons.
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`First, interferon treatment does not work for many patients, who do see
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`improvement with GA. Second, interferon treatment is associated with side
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`effects, such as flu-like symptoms and exacerbations of MS fatigue, that may be
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`more difficult for patients than the self-limiting IRAEs and localized ISR’s caused
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`by GA. Further, GA has some benefits over interferon treatment, including having
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`a pregnancy category B rating, which indicates no fetal risk from animal studies,
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`having no known drug-drug interactions, and having lasting efficacy as patients are
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`not known to develop treatment failure related to neutralizing antibodies to GA.
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`The development of GA was thus a tremendous advance in the treatment and
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`management of MS.
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`11 Note that this dosing regimen results in one two-day drug free interval and two
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`one-day drug free intervals per each seven-day period.
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`13
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`34.
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`Despite the notable advantages that GA 20 mg daily offered over
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`other disease modifying treatments available in 2009, many patients could not
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`tolerate the adverse effects, particularly the injection site reactions, which at times
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`cause permanent tissue damage. And, understandably, many patients had difficulty
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`with daily injections, which may be painful, and which comprise daily, continuous
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`reminders of a patient’s disease. Some patients also had trouble remembering to
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`take their medication on a daily basis.
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`35.
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`Because of the difficulty that many patients experienced with daily
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`GA injections, a few small studies exploring alternate day injections were
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`described in the literature as of 2009.12 However, none of these studies changed
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`the standard of care concerning GA as of 2009. Persons of skill in the art
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`continued to administer daily injections of GA 20 mg daily dose because robust
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`12 See, e.g., Khan, O., et al., Randomized, prospective, rater-blinded, four-year, pilot
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`study to compare the effect of daily versus every-other-day glatiramer acetate 20
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`mg subcutaneous injections in relapsing-remitting multiple sclerosis, Multiple
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`Sclerosis, S295, P902 (2009) (Exhibit 1010); Flechter, S., et al., Copolymer 1
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`(Glatiramer Acetate) in Relapsing Forms of Multiple Sclerosis: Open Multicenter
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`Study of Alternate-Day Administration, 25 Clin. Neuropharmacol 1,11-15 (2002).
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`(Exhibit 1008)
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`14
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`clinical trial data supported the safety and efficacy of daily injections of 20 mg of
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`GA while such robust clinical data did not exist for other dosing regimens. Thus,
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`practitioners worked diligently to support patients and to remind them to take their
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`medication daily.
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`C. Benefits of GA 40 mg tiw
`36.
`In 2014, the FDA approved GA 40 mg tiw, a 40 mg/mL dose of GA
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`which contains 40 mg of the active ingredient GA and is dosed three times per
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`week, based on a Phase III Glatiramer Acetate Low Frequency Administration
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`(GALA) study involving 142 sites in 17 countries and about 1,400 patients that
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`assessed the efficacy, safety, and tolerability of GA injection 40 mg/mL
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`administered three times per week compared to placebo. GA 40 mg tiw represents
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`a huge step forward for patients suffering from MS, in terms of both convenience
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`and tolerability.
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`37. My patients have shared with me a few ways in which their lives have
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`improved because of the new, 40 mg tiw treatment regimen. They explained that
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`they could “take the weekend off” from worrying about their disease by scheduling
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`all three injections for weekdays. They explained how packing for an overnight
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`trip has become so much easier because they don’t need to have an injection every
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`day. They explained that outdoor excursions, such as camping, have again become
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`possible because they don’t have to worry about storing their medication every
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`night. These benefits reflect a significant improvement in the quality of life for
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`patients living with MS. And these benefits accrue to the large population of
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`patients whose disease is managed by glatiramer acetate.
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`38.
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`In addition to the life-style benefits described above, researchers have
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`documented statistics that clearly show that IRAEs are diminished in both
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`frequency and severity with GA 40 mg tiw as compared with GA 20 mg daily.
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`And many of my own patients have observed a decrease in the severity and
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`frequency of ISRs upon switching from GA 20 mg daily to GA 40 mg tiw.
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`Further, a research study has shown that GA mg tiw reduces grey matter atrophy in
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`MS patients, which has been shown to have a direct relationship to accumulated
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`disability.13
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`39.
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`The multiple sclerosis patient population lives with a chronic,
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`debilitating disease that affects much more than just their physical well-being. It
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`may also affect their emotional well-being, their interpersonal relationships, and
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`their ability to be gainfully employed. For this long-suffering population,
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`improvements in the tolerability and convenience of treatment make an enormous
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`13 Daniel Wynn, et al., Patient Experience with Glatiramer Acetate 40 mg/1 mL
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`Three-Times Weekly Treatment for Relapsing-Remitting Multiple Sclerosis:
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`Results from the GLACIER Extension Study, The 8th Congress of PACTRIMS, P-
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`40, Nov. 19-21, 2015 (Exhibit 2096); see also Fisniku, supra note 3.
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`16
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`YEDA EXHIBIT NO. 2129
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`IPR2015-00644
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`difference in the outlook and mood of individual patients. The improved
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`convenience and tolerability of the three times per week dosing regimen claimed in
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`the ’413 patent is the reason why I and other physicians prescribe GA 40 tiw and is
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`also the reason why large number of patients already on 20 mg GA therapy have
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`switched to the new 40 mg product.
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`VII. OPINIONS
`A. GA 40 mg tiw Satisfied a Long-Felt Need for a Safe and Effective
`Treatment that Was More Tolerable and More Convenient
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`40.
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`In my opinion, as of August, 2009, there was a long felt but unmet
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`need for an MS treatment option that offered the same safety and efficacy as GA
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`20 mg daily, but was more convenient and tolerable. This need was not met until
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`the Phase III GALA study was performed and GA 40 mg tiw was subsequently
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`approved by the FDA and introduced to patients and physicians.
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`41.
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`As mentioned above, the literature included suggestions for altered
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`dosing regimens of GA. However, the studies and trials described in that literature
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`were either too small or poorly run to alter the standard of care or to convince a
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`POSA to change treatment regimens with a reasonable expectation of success. For
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`example, one study followed thirty patients that were randomized to receive either
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`the standard treatment of GA 20 mg daily or an alternate treatment of GA 20 mg
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`every other day. That study concluded that, while 20 mg of GA given on alternate
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`days may be as effective as 20 mg of GA given daily, “large, multi-center studies
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`17
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`are warranted to confirm” the findings.14 Another study followed 68 patients
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`dosed with 20 mg GA every other day. That study was uncontrolled and also
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`concluded that larger scale studies were needed.15 Because disability accumulates
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`with each relapse and is irreversible, doctors and patients would not risk a
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`treatment regimen that had not been proven effective at decreasing the frequency
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`of relapses.
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`42.
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`Prior to August, 2009, the FDA approved new regimens for interferon
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`treatment, which included fewer weekly injections. However, as discussed above,
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`many patients prefer GA over interferon due to efficacy or tolerability. Therefore,
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`advances in treatment regimens for interferon did not meet the long felt need of
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`patients that required a treatment option that had the same safety and efficacy
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`profile as GA 20 mg daily, but with improved tolerability and convenience.
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`43.
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`Newly approved agents for the treatment of MS including Tysabri
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`(natalizumab), Gilenya (fingolimod), and Tecfidera (dimethyl fumarate), also did
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`not satisfy this need. These drugs offer the benefit over GA in that they are taken
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`orally instead of via injection. However, all of these agents have been shown to
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`have severe side effects, including the risk of developing progressive multifocal
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`leukoencephalopathy (PML), a serious and possibly fatal infection of the brain.
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`14 Khan, supra note 12.
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`15 Flechter, supra note 12.
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`18
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`Because of this possibility for severe side effects, which may increase with
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`increased duration of treatment, the labelling of these drugs include warnings of
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`potentially fatal side effects. Many patients view these risks as unacceptable, and
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`therefore, these treatments did not meet the needs of patients that required a
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`treatment option that had the same safety and efficacy profile as GA 20 mg daily,
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`but with improved tolerability and convenience.
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`44.
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`In my opinion, GA 40 mg tiw is the first treatment that fills the long-
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`felt need of MS patients because it has been shown to be as safe and effective as
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`GA 20 mg daily while reducing injection-related adverse effects and the
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`inconvenience caused by daily administration of glatiramer acetate.
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`45.
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`The GALA study that led to FDA approval of GA 40 mg tiw
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`established that GA 40 mg tiw is a safe and effective alternate regimen for the
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`treatment of MS. Further, this new regimen was more convenient, with only three
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`injections per week. GALA also found the new regimen increased tolerability over
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`GA 20 mg daily: the incidence of injection site reactions was approximately 20 to
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`50% lower compared with previous studies of patients treated with GA 20 mg
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`daily, and IPIRs, which occurred in the GALA study in 7.6% of patients, were
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`19
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`lower than the incidence of IPIRs found in previous placebo controlled studies
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`with GA 20 mg daily (15%).16
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`46.
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`A further study with GA 40 mg tiw provides additional evidence of its
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`tolerability advantage. The GLACIER study (GLatiramer Acetate low frequenCy
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`safety and patIent ExpeRience) measured IRAEs as its primary endpoint.
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`GLACIER researchers reported that the rate of moderate and severe reactions, as
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`opposed to mild reactions, was 60% lower with GA 40 mg tiw than with GA 20
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`mg daily. Further, they observed a 50% decrease in the rate of injection related
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`adverse events in the GA 40 mg tiw group vs. the GA 20 mg daily group. This
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`represented a 50% reduction in the rate of ISRs, and a decrease i