www.archive.org
`41 5.561.6767
`41 5.840-0391 c-fax
`
`Internet Archive
`300 Funston 1\ vcnuc
`San Francisco, CA 941 18
`
`AFFIDAVIT OF CHRISTOPHER BUTLER
`
`1. I am the Office Manager at the Internet Archive, located in San Francisco,
`California. I make this declaration ofmy own personal knowledge.
`2. The Internet Archive is a website that provides access to a digital library of
`Internet sites and other cultural artifacts in digital form. Like a paper library, we provide
`free access to researchers, historians, scholars, and the general public. The Internet
`Archive has partnered with and receives support from various institutions, including the
`Library of Congress.
`3. The Internet Archive has created a service known as the Wayback Machine. The
`Way back Machine makes it possible to surf more than 450 billion pages stored in the
`Internet Archive's web archive. Visitors to the Wayback Machine can search archives
`by URL (i.e., a website address). If archived records for a URL are available, the visitor
`wi ll be presented with a list of available dates. The visitor may select one of those
`dates, and then begin surfing on an archived version of the Web. The links on the
`archived tiles, when served by the Wayback Machine, point to other archived files
`(whether HTML pages or images). If a visitor clicks on a link on an archived page, the
`Wayback Machine will serve the archived file with the closest available date to the page
`upon wh ich the link appeared and was clicked.
`4. The archived data made viewable and browseable by the Wayback Machine is
`compiled using software programs known as crawlers, which surf the Web and
`automatically store copies of web files, preserving these files as they exist at the point of
`time of capture.
`5. The Internet Archive assigns a URL on its site to the arch ived files in the format
`http://web.archive.org/web/[Year in yyyy][Month in mm][Day in dd][Time code in
`hh:mm:ss]/[Archived URL]. Thus, the Internet Archive URL
`http://web.archive.org/web/ l 9970 l 26045828/http://www.archive.org/ would be the
`URL for the record of the Internet Archive home page HTML file
`(http://www.archive.org/) archived on January 26, 1997 at 4:58 a.m. and 28 seconds
`(1997 /0 I /26 at 04:58:28). A web browser may be set such that a printout from it will
`display the URL of a web page in the printout's footer. The date assigned by the Internet
`Archive applies to the HTML file but not to image files linked therein. Thus images that
`appear on a page may not have been archived on the same date as the HTML file.
`Likewise, if a website is designed with "frames," the date assigned by the Internet
`Archive applies to the frameset as a whole, and not the individual pages within each
`frame.
`6. Attached hereto as Exhibit A are true and accurate copies of printouts of the
`Internet Archive's records of the HTML files or PDF files for the URLs and the dates
`specified in the footer of the printout (HTM L) or attached coversheet (PDF).
`7. I declare under penalty of perjury that the foregoing is true and correct.
`
`DATE•#/t9
`
`Christopher Butler
`
`Sawai (IPR2019-0666), Ex. 1012, p. 001
`
`

`

`Exhibit A
`
`Exhibit A
`
`Sawai (IPR2019-0666), EX. 1012, p. 002
`
`Sawai (IPR2019-0666), Ex. 1012, p. 002
`
`

`

`http://web.archive.org/web/20041021033354/http://www.fumapharm.ch:80/pdf
`/BG-12_Schimrigk_Poster_Final.pdf
`
`Sawai (IPR2019-0666), Ex. 1012, p. 003
`
`

`

`P642
`
`A PROSPECTIVE, OPEN-LABEL, PHASE II STUDY OF ORAL FUMARATE THERAPY FOR THE TREATMENT
`OF RELAPSING-REMITTING MULTIPLE SCLEROSIS
`S. Schimrigk, N. Brune, K. Hellwig, M. Rieks, V. Hoffmann, D. Pöhlau, H. Przuntek, and the Fumarate Study Group for Multiple Sclerosis
`
`Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
`
`• Brain MRI scans were performed at screening, baseline visit, and weeks 12, 18, 22,
`46, and 70.
`• Data were analyzed using the nonparametric Wilcoxon test. Differences were
`considered statistically significant at a P value of .05.
`
`FIGURE 1. Study Design
`
`Table 2. Clinical Data
`
`Median EDSS score
`Median AI
`Median 9-HPT (right), sec
`Median 9-HPT (left), sec
`
`Baseline
`2.0
`2.0
`22.0
`21.0
`
`Week 12
`2.0
`2.0
`20.0
`20.5
`
`Week 18
`1.5
`1.0
`20.5
`20.5
`
`Week 22
`1.5
`1.0
`17.0
`18.0
`
`Week 46
`1.5
`1.0
`18.0
`19.0
`
`Week 70*
`1.5
`1.0
`19.0
`19.0
`
`FIGURE 3. Change in Volume of Gadolinium-Enhancing Lesions
`
`*
`
`*
`
`*
`
`*
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`-100
`
`Lesion Load in Pixel Volume (1 pixel = cbmm)
`
`Baseline Week 12 Week 18 Week 22
`Visit
`
`Week 46 Week 70
`
`*P<.018 compared with baseline.
`
`CONCLUSIONS
`
`• Oral fumarate therapy resulted in a significant improvement in the
`number and volume of Gd+ lesions compared with baseline.
`• Clinical measures of both function and disease progression
`appeared stable during the study, supporting the MRI results.
`• The positive results in this small, short-term study suggest that
`larger trials should be undertaken to determine the efficacy of oral
`fumarate therapy in patients with MS.
`
`References
`1. Noseworthy JH, Lucchinetti C, Rodriguez M, et al. N Engl J Med 2000;343:938-952.
`2. Prinz JC. J Eur Acad Dermatol Venereol 2003;17:257-270.
`3. Altmeyer PJ, Matthes U, Pawlak F, et al. J Am Acad Dermatol 1994;30:977-981.
`4. Altmeyer P, Hartwig R, Matthes U. Hautarzt 1996;47:190-196.
`5. Bayard W, Hunziker T, Krebs A, et al. Hautarzt 1987;38:279-285.
`6. Kolbach DN, Nieboer C. J Am Acad Dermatol 1992;27:769-771.
`7. Mrowietz U, Christophers E, Altmeyer P. Br J Dermatol 1998;138:456-460.
`
`Presentation of this study supported by Biogen Idec, Inc.
`
`*Calculated from 6 patients who completed the 70-week trial.
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`• 10 patients were enrolled, and 6 patients completed the 70-week study. Reasons
`for discontinuation were the following (one each):
`– Unplanned pregnancy
`– Side effects
`– Lack of compliance
`– Undetermined
`• A significant reduction in the number of Gd+ lesions was observed following 18 weeks
`of oral fumarate treatment, with a further reduction after 70 weeks (Figure 2).
`• The volume of Gd+ lesions was decreased at 22 weeks compared with baseline;
`this reduction was maintained at 46 and 70 weeks (Figure 3).
`• Patients who completed the study demonstrated stable or slightly improved clinical
`measures of disease, including EDSS score, AI, and 9-HPT over the course of the
`study (Table 2), although the changes did not achieve statistical significance.
`• Mild to moderate gastrointestinal side effects were experienced by 6 of 7 patients
`who completed >3 weeks of treatment but decreased during the first 12 weeks
`of treatment. In 1 patient these side effects were severe enough to discontinue
`treatment.
`• Other side effects were mild and transient. Four patients had a transient increase in
`liver enzymes.
`
`FIGURE 2. Change in Number of Gadolinium-Enhancing
`Lesions
`
`*
`
`*
`
`*
`
`*
`
`Baseline Week 12 Week 18 Week 22
`Visit
`
`Week 46 Week 70
`
`16
`
`14
`
`12
`
`10
`
`8 6 4 2 0
`
`-2
`
`Number of Gd+ Lesions
`
`*P<.02 compared with baseline.
`
`720 mg/day
`
`30 mg/day
`
`Fumarate
`
`30 mg/day
`
`360 mg/day
`
`Fumarate
`
`Enrollment
`
`70 weeks
`
`Baseline
`Phase
`(6 weeks)
`
`Treatment
`Phase
`(18 weeks)
`
`Washout
`Phase
`(4 weeks)
`
`Treatment
`Phase
`(42 weeks)
`
`Efficacy Outcomes
`• The primary outcome measure was the number and volume of gadolinium-
`enhancing (Gd+) lesions on MRI scans.
`• Secondary outcome measures were changes in EDSS score, AI, and 9-HPT.
`
`RESULTS
`
`• Demographic and baseline characteristics for patients enrolled in the study are
`presented in Table 1.
`
`Table 1. Baseline Characteristics (N = 10)
`
`Characteristic
`Sex, n (%)
`Female
`Male
`
`Median age, y (range)
`Median relapse rate in preceding 12 months (range)
`Median time since first event, y (range)
`Median EDSS score (range)
`
`Median AI
`
`Value
`
`5 (50)
`5 (50)
`
`29.5 (26–36)
`2 (1–3)
`4.5 (1–11)
`2.0 (2.0–4.5)
`
`2.0
`
`Median 9-HPT
`22
`Right
`21
`Left
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`INTRODUCTION
`• Multiple sclerosis (MS) is a chronic immune-mediated disease that results in
`focal areas of demyelination and axonal loss in the central nervous system
`(CNS), particularly in the brain.
`• Considerable evidence supports involvement of the immune system in the
`pathogenesis of MS1:
`– The presence of lymphocytic infiltrates in CNS lesions and perivascular cuffing
`suggests an autoimmune response
`– A role for immune function in the pathology of MS is supported by the efficacy of
`immune-modulating therapies in slowing disease progression
`• Psoriasis is a chronic T-cell–mediated disease in which immune suppressants have
`also been found to be effective and, similar to MS, a pro-inflammatory T-helper 1
`(Th1) cytokine profile predominates in lymphocytes isolated from psoriatic plaques.2
`• Several open and double-blind clinical studies have shown that oral fumarate therapy
`is effective in psoriasis.3-7
`• Given the involvement of immune-mediated responses and predominance of the
`Th1 cytokine profile in both psoriasis and MS, the objective of this study was to
`determine if oral fumarate therapy is effective in patients suffering from relapsing-
`remitting MS (RRMS).
`
`METHODS
`
`Patients
`• Patients were 18 to 55 years of age and had a clinically definite diagnosis of RRMS
`with ≥1 relapse within the previous year.
`• Patients must have had ≥1 active lesion on brain magnetic resonance imaging (MRI)
`and a baseline Expanded Disability Status Scale (EDSS) score ≥2 but <6.
`• Exclusion criteria for the study included
`– Infection
`– Chronic inflammatory diseases other than MS
`– Pregnancy or breast feeding
`– History of drug or alcohol abuse
`– Disease exacerbation within the previous 3 weeks
`– Corticosteroid treatment within the previous 30 days
`– Immunosuppressive therapy within the previous 12 weeks
`
`Study Design
`• The study design consisted of a 6-week baseline period and 2 treatment periods
`(18 weeks and 42 weeks) separated by a 4-week washout period without fumarate
`treatment (Figure 1).
`– Dimethylfumarate was administered orally in tablet form as a low-dose (30 mg
`Fumaderm initial®) and a high-dose (120 mg Fumaderm forte®) formulation
`• The dose of fumarate was slowly increased over the first 9 weeks to minimize
`gastrointestinal side effects.
`• The maximum dose of fumarate was 720 mg/day in the initial treatment phase and
`360 mg/day in the second treatment phase.
`• Physical examination, EDSS score, ambulatory index (AI), and 9-Hole Peg Test (9-HPT)
`were performed at screening, baseline visit, and weeks 3, 6, 12, 18, 22, 46, and 70.
`
`Sawai (IPR2019-0666), Ex. 1012, p. 004
`
`

`

`P642
`
`A PROSPECTIVE, OPEN-LABEL, PHASE II STUDY OF ORAL FUMARATE THERAPY FOR THE TREATMENT
`OF RELAPSING-REMITTING MULTIPLE SCLEROSIS
`S. Schimrigk, N. Brune, K. Hellwig, M. Rieks, V. Hoffmann, D. Pöhlau, H. Przuntek, and the Fumarate Study Group for Multiple Sclerosis
`
`Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
`
`INTRODUCTION
`• Multiple sclerosis (MS) is a chronic immune-mediated disease that results in
`focal areas of demyelination and axonal loss in the central nervous system
`(CNS), particularly in the brain.
`• Considerable evidence supports involvement of the immune system in the
`pathogenesis of MS1:
`– The presence of lymphocytic infiltrates in CNS lesions and perivascular cuffing
`suggests an autoimmune response
`– A role for immune function in the pathology of MS is supported by the efficacy of
`immune-modulating therapies in slowing disease progression
`• Psoriasis is a chronic T-cell–mediated disease in which immune suppressants have
`also been found to be effective and, similar to MS, a pro-inflammatory T-helper 1
`(Th1) cytokine profile predominates in lymphocytes isolated from psoriatic plaques.2
`• Several open and double-blind clinical studies have shown that oral fumarate therapy
`is effective in psoriasis.3-7
`• Given the involvement of immune-mediated responses and predominance of the
`Th1 cytokine profile in both psoriasis and MS, the objective of this study was to
`determine if oral fumarate therapy is effective in patients suffering from relapsing-
`remitting MS (RRMS).
`
`METHODS
`
`Patients
`• Patients were 18 to 55 years of age and had a clinically definite diagnosis of RRMS
`with ≥1 relapse within the previous year.
`• Patients must have had ≥1 active lesion on brain magnetic resonance imaging (MRI)
`and a baseline Expanded Disability Status Scale (EDSS) score ≥2 but <6.
`• Exclusion criteria for the study included
`– Infection
`– Chronic inflammatory diseases other than MS
`– Pregnancy or breast feeding
`– History of drug or alcohol abuse
`– Disease exacerbation within the previous 3 weeks
`– Corticosteroid treatment within the previous 30 days
`– Immunosuppressive therapy within the previous 12 weeks
`
`Study Design
`• The study design consisted of a 6-week baseline period and 2 treatment periods
`(18 weeks and 42 weeks) separated by a 4-week washout period without fumarate
`treatment (Figure 1).
`– Dimethylfumarate was administered orally in tablet form as a low-dose (30 mg
`Fumaderm initial®) and a high-dose (120 mg Fumaderm forte®) formulation
`• The dose of fumarate was slowly increased over the first 9 weeks to minimize
`gastrointestinal side effects.
`• The maximum dose of fumarate was 720 mg/day in the initial treatment phase and
`360 mg/day in the second treatment phase.
`• Physical examination, EDSS score, ambulatory index (AI), and 9-Hole Peg Test (9-HPT)
`were performed at screening, baseline visit, and weeks 3, 6, 12, 18, 22, 46, and 70.
`
`• Brain MRI scans were performed at screening, baseline visit, and weeks 12, 18, 22,
`46, and 70.
`• Data were analyzed using the nonparametric Wilcoxon test. Differences were
`considered statistically significant at a P value of .05.
`
`FIGURE 1. Study Design
`
`Table 2. Clinical Data
`
`Median EDSS score
`Median AI
`Median 9-HPT (right), sec
`Median 9-HPT (left), sec
`
`*Calculated from 6 patients who completed the 70-week trial.
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`• 10 patients were enrolled, and 6 patients completed the 70-week study. Reasons
`for discontinuation were the following (one each):
`– Unplanned pregnancy
`– Side effects
`– Lack of compliance
`– Undetermined
`• A significant reduction in the number of Gd+ lesions was observed following 18 weeks
`of oral fumarate treatment, with a further reduction after 70 weeks (Figure 2).
`• The volume of Gd+ lesions was decreased at 22 weeks compared with baseline;
`this reduction was maintained at 46 and 70 weeks (Figure 3).
`• Patients who completed the study demonstrated stable or slightly improved clinical
`measures of disease, including EDSS score, AI, and 9-HPT over the course of the
`study (Table 2), although the changes did not achieve statistical significance.
`• Mild to moderate gastrointestinal side effects were experienced by 6 of 7 patients
`who completed >3 weeks of treatment but decreased during the first 12 weeks
`of treatment. In 1 patient these side effects were severe enough to discontinue
`treatment.
`• Other side effects were mild and transient. Four patients had a transient increase in
`liver enzymes.
`
`FIGURE 2. Change in Number of Gadolinium-Enhancing
`Lesions
`
`720 mg/day
`
`30 mg/day
`
`Fumarate
`
`30 mg/day
`
`360 mg/day
`
`Fumarate
`
`Enrollment
`
`70 weeks
`
`Baseline
`Phase
`(6 weeks)
`
`Treatment
`Phase
`(18 weeks)
`
`Washout
`Phase
`(4 weeks)
`
`Treatment
`Phase
`(42 weeks)
`
`Efficacy Outcomes
`• The primary outcome measure was the number and volume of gadolinium-
`enhancing (Gd+) lesions on MRI scans.
`• Secondary outcome measures were changes in EDSS score, AI, and 9-HPT.
`
`RESULTS
`
`• Demographic and baseline characteristics for patients enrolled in the study are
`presented in Table 1.
`
`Table 1. Baseline Characteristics (N = 10)
`
`Characteristic
`Sex, n (%)
`Female
`Male
`
`Median age, y (range)
`Median relapse rate in preceding 12 months (range)
`Median time since first event, y (range)
`Median EDSS score (range)
`
`Median AI
`
`Value
`
`5 (50)
`5 (50)
`
`29.5 (26–36)
`2 (1–3)
`4.5 (1–11)
`2.0 (2.0–4.5)
`
`2.0
`
`Median 9-HPT
`22
`Right
`21
`Left
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`*P<.02 compared with baseline.
`
`Sawai (IPR2019-0666), Ex. 1012, p. 005
`
`

`

`A PROSPECTIVE, OPEN-LABEL, PHASE II STUDY OF ORAL FUMARATE THERAPY FOR THE TREATMENT
`
`S. Schimrigk, N. Brune, K. Hellwig, M. Rieks, V. Hoffmann, D. Pöhlau, H. Przuntek, and the Fumarate Study Group for Multiple Sclerosis
`
`• Brain MRI scans were performed at screening, baseline visit, and weeks 12, 18, 22,
`
`• Data were analyzed using the nonparametric Wilcoxon test. Differences were
`
`Table 2. Clinical Data
`
`Median EDSS score
`Median AI
`Median 9-HPT (right), sec
`Median 9-HPT (left), sec
`
`Baseline
`2.0
`2.0
`22.0
`21.0
`
`Week 12
`2.0
`2.0
`20.0
`20.5
`
`Week 18
`1.5
`1.0
`20.5
`20.5
`
`Week 22
`1.5
`1.0
`17.0
`18.0
`
`Week 46
`1.5
`1.0
`18.0
`19.0
`
`Week 70*
`1.5
`1.0
`19.0
`19.0
`
`FIGURE 3. Change in Volume of Gadolinium-Enhancing Lesions
`
`*
`
`*
`
`*
`
`*
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`-100
`
`Lesion Load in Pixel Volume (1 pixel = cbmm)
`
`Baseline Week 12 Week 18 Week 22
`Visit
`
`Week 46 Week 70
`
`*P<.018 compared with baseline.
`
`CONCLUSIONS
`
`• Oral fumarate therapy resulted in a significant improvement in the
`number and volume of Gd+ lesions compared with baseline.
`• Clinical measures of both function and disease progression
`appeared stable during the study, supporting the MRI results.
`• The positive results in this small, short-term study suggest that
`larger trials should be undertaken to determine the efficacy of oral
`fumarate therapy in patients with MS.
`
`References
`1. Noseworthy JH, Lucchinetti C, Rodriguez M, et al. N Engl J Med 2000;343:938-952.
`2. Prinz JC. J Eur Acad Dermatol Venereol 2003;17:257-270.
`3. Altmeyer PJ, Matthes U, Pawlak F, et al. J Am Acad Dermatol 1994;30:977-981.
`4. Altmeyer P, Hartwig R, Matthes U. Hautarzt 1996;47:190-196.
`5. Bayard W, Hunziker T, Krebs A, et al. Hautarzt 1987;38:279-285.
`6. Kolbach DN, Nieboer C. J Am Acad Dermatol 1992;27:769-771.
`7. Mrowietz U, Christophers E, Altmeyer P. Br J Dermatol 1998;138:456-460.
`
`Presentation of this study supported by Biogen Idec, Inc.
`
`*Calculated from 6 patients who completed the 70-week trial.
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`• 10 patients were enrolled, and 6 patients completed the 70-week study. Reasons
`for discontinuation were the following (one each):
`– Unplanned pregnancy
`– Side effects
`– Lack of compliance
`– Undetermined
`• A significant reduction in the number of Gd+ lesions was observed following 18 weeks
`of oral fumarate treatment, with a further reduction after 70 weeks (Figure 2).
`• The volume of Gd+ lesions was decreased at 22 weeks compared with baseline;
`this reduction was maintained at 46 and 70 weeks (Figure 3).
`• Patients who completed the study demonstrated stable or slightly improved clinical
`measures of disease, including EDSS score, AI, and 9-HPT over the course of the
`study (Table 2), although the changes did not achieve statistical significance.
`• Mild to moderate gastrointestinal side effects were experienced by 6 of 7 patients
`who completed >3 weeks of treatment but decreased during the first 12 weeks
`of treatment. In 1 patient these side effects were severe enough to discontinue
`treatment.
`• Other side effects were mild and transient. Four patients had a transient increase in
`liver enzymes.
`
`FIGURE 2. Change in Number of Gadolinium-Enhancing
`Lesions
`
`*
`
`*
`
`*
`
`*
`
`Baseline Week 12 Week 18 Week 22
`Visit
`
`Week 46 Week 70
`
`16
`
`14
`
`12
`
`10
`
`8 6 4 2 0
`
`-2
`
`Number of Gd+ Lesions
`
`*P<.02 compared with baseline.
`
`70 weeks
`
`• Demographic and baseline characteristics for patients enrolled in the study are
`
`Sawai (IPR2019-0666), Ex. 1012, p. 006
`
`

`

`http://web.archive.org/web/20041214102714/http://www.fumapharm.ch:80/pdf
`/BG-12_Schimrigk_Poster_Final.pdf
`
`Sawai (IPR2019-0666), Ex. 1012, p. 007
`
`

`

`P642
`
`A PROSPECTIVE, OPEN-LABEL, PHASE II STUDY OF ORAL FUMARATE THERAPY FOR THE TREATMENT
`OF RELAPSING-REMITTING MULTIPLE SCLEROSIS
`S. Schimrigk, N. Brune, K. Hellwig, M. Rieks, V. Hoffmann, D. Pöhlau, H. Przuntek, and the Fumarate Study Group for Multiple Sclerosis
`
`Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
`
`• Brain MRI scans were performed at screening, baseline visit, and weeks 12, 18, 22,
`46, and 70.
`• Data were analyzed using the nonparametric Wilcoxon test. Differences were
`considered statistically significant at a P value of .05.
`
`FIGURE 1. Study Design
`
`Table 2. Clinical Data
`
`Median EDSS score
`Median AI
`Median 9-HPT (right), sec
`Median 9-HPT (left), sec
`
`Baseline
`2.0
`2.0
`22.0
`21.0
`
`Week 12
`2.0
`2.0
`20.0
`20.5
`
`Week 18
`1.5
`1.0
`20.5
`20.5
`
`Week 22
`1.5
`1.0
`17.0
`18.0
`
`Week 46
`1.5
`1.0
`18.0
`19.0
`
`Week 70*
`1.5
`1.0
`19.0
`19.0
`
`FIGURE 3. Change in Volume of Gadolinium-Enhancing Lesions
`
`*
`
`*
`
`*
`
`*
`
`500
`
`400
`
`300
`
`200
`
`100
`
`0
`
`-100
`
`Lesion Load in Pixel Volume (1 pixel = cbmm)
`
`Baseline Week 12 Week 18 Week 22
`Visit
`
`Week 46 Week 70
`
`*P<.018 compared with baseline.
`
`CONCLUSIONS
`
`• Oral fumarate therapy resulted in a significant improvement in the
`number and volume of Gd+ lesions compared with baseline.
`• Clinical measures of both function and disease progression
`appeared stable during the study, supporting the MRI results.
`• The positive results in this small, short-term study suggest that
`larger trials should be undertaken to determine the efficacy of oral
`fumarate therapy in patients with MS.
`
`References
`1. Noseworthy JH, Lucchinetti C, Rodriguez M, et al. N Engl J Med 2000;343:938-952.
`2. Prinz JC. J Eur Acad Dermatol Venereol 2003;17:257-270.
`3. Altmeyer PJ, Matthes U, Pawlak F, et al. J Am Acad Dermatol 1994;30:977-981.
`4. Altmeyer P, Hartwig R, Matthes U. Hautarzt 1996;47:190-196.
`5. Bayard W, Hunziker T, Krebs A, et al. Hautarzt 1987;38:279-285.
`6. Kolbach DN, Nieboer C. J Am Acad Dermatol 1992;27:769-771.
`7. Mrowietz U, Christophers E, Altmeyer P. Br J Dermatol 1998;138:456-460.
`
`Presentation of this study supported by Biogen Idec, Inc.
`
`*Calculated from 6 patients who completed the 70-week trial.
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`• 10 patients were enrolled, and 6 patients completed the 70-week study. Reasons
`for discontinuation were the following (one each):
`– Unplanned pregnancy
`– Side effects
`– Lack of compliance
`– Undetermined
`• A significant reduction in the number of Gd+ lesions was observed following 18 weeks
`of oral fumarate treatment, with a further reduction after 70 weeks (Figure 2).
`• The volume of Gd+ lesions was decreased at 22 weeks compared with baseline;
`this reduction was maintained at 46 and 70 weeks (Figure 3).
`• Patients who completed the study demonstrated stable or slightly improved clinical
`measures of disease, including EDSS score, AI, and 9-HPT over the course of the
`study (Table 2), although the changes did not achieve statistical significance.
`• Mild to moderate gastrointestinal side effects were experienced by 6 of 7 patients
`who completed >3 weeks of treatment but decreased during the first 12 weeks
`of treatment. In 1 patient these side effects were severe enough to discontinue
`treatment.
`• Other side effects were mild and transient. Four patients had a transient increase in
`liver enzymes.
`
`FIGURE 2. Change in Number of Gadolinium-Enhancing
`Lesions
`
`*
`
`*
`
`*
`
`*
`
`Baseline Week 12 Week 18 Week 22
`Visit
`
`Week 46 Week 70
`
`16
`
`14
`
`12
`
`10
`
`8 6 4 2 0
`
`-2
`
`Number of Gd+ Lesions
`
`*P<.02 compared with baseline.
`
`720 mg/day
`
`30 mg/day
`
`Fumarate
`
`30 mg/day
`
`360 mg/day
`
`Fumarate
`
`Enrollment
`
`70 weeks
`
`Baseline
`Phase
`(6 weeks)
`
`Treatment
`Phase
`(18 weeks)
`
`Washout
`Phase
`(4 weeks)
`
`Treatment
`Phase
`(42 weeks)
`
`Efficacy Outcomes
`• The primary outcome measure was the number and volume of gadolinium-
`enhancing (Gd+) lesions on MRI scans.
`• Secondary outcome measures were changes in EDSS score, AI, and 9-HPT.
`
`RESULTS
`
`• Demographic and baseline characteristics for patients enrolled in the study are
`presented in Table 1.
`
`Table 1. Baseline Characteristics (N = 10)
`
`Characteristic
`Sex, n (%)
`Female
`Male
`
`Median age, y (range)
`Median relapse rate in preceding 12 months (range)
`Median time since first event, y (range)
`Median EDSS score (range)
`
`Median AI
`
`Value
`
`5 (50)
`5 (50)
`
`29.5 (26–36)
`2 (1–3)
`4.5 (1–11)
`2.0 (2.0–4.5)
`
`2.0
`
`Median 9-HPT
`22
`Right
`21
`Left
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`INTRODUCTION
`• Multiple sclerosis (MS) is a chronic immune-mediated disease that results in
`focal areas of demyelination and axonal loss in the central nervous system
`(CNS), particularly in the brain.
`• Considerable evidence supports involvement of the immune system in the
`pathogenesis of MS1:
`– The presence of lymphocytic infiltrates in CNS lesions and perivascular cuffing
`suggests an autoimmune response
`– A role for immune function in the pathology of MS is supported by the efficacy of
`immune-modulating therapies in slowing disease progression
`• Psoriasis is a chronic T-cell–mediated disease in which immune suppressants have
`also been found to be effective and, similar to MS, a pro-inflammatory T-helper 1
`(Th1) cytokine profile predominates in lymphocytes isolated from psoriatic plaques.2
`• Several open and double-blind clinical studies have shown that oral fumarate therapy
`is effective in psoriasis.3-7
`• Given the involvement of immune-mediated responses and predominance of the
`Th1 cytokine profile in both psoriasis and MS, the objective of this study was to
`determine if oral fumarate therapy is effective in patients suffering from relapsing-
`remitting MS (RRMS).
`
`METHODS
`
`Patients
`• Patients were 18 to 55 years of age and had a clinically definite diagnosis of RRMS
`with ≥1 relapse within the previous year.
`• Patients must have had ≥1 active lesion on brain magnetic resonance imaging (MRI)
`and a baseline Expanded Disability Status Scale (EDSS) score ≥2 but <6.
`• Exclusion criteria for the study included
`– Infection
`– Chronic inflammatory diseases other than MS
`– Pregnancy or breast feeding
`– History of drug or alcohol abuse
`– Disease exacerbation within the previous 3 weeks
`– Corticosteroid treatment within the previous 30 days
`– Immunosuppressive therapy within the previous 12 weeks
`
`Study Design
`• The study design consisted of a 6-week baseline period and 2 treatment periods
`(18 weeks and 42 weeks) separated by a 4-week washout period without fumarate
`treatment (Figure 1).
`– Dimethylfumarate was administered orally in tablet form as a low-dose (30 mg
`Fumaderm initial®) and a high-dose (120 mg Fumaderm forte®) formulation
`• The dose of fumarate was slowly increased over the first 9 weeks to minimize
`gastrointestinal side effects.
`• The maximum dose of fumarate was 720 mg/day in the initial treatment phase and
`360 mg/day in the second treatment phase.
`• Physical examination, EDSS score, ambulatory index (AI), and 9-Hole Peg Test (9-HPT)
`were performed at screening, baseline visit, and weeks 3, 6, 12, 18, 22, 46, and 70.
`
`Sawai (IPR2019-0666), Ex. 1012, p. 008
`
`

`

`P642
`
`A PROSPECTIVE, OPEN-LABEL, PHASE II STUDY OF ORAL FUMARATE THERAPY FOR THE TREATMENT
`OF RELAPSING-REMITTING MULTIPLE SCLEROSIS
`S. Schimrigk, N. Brune, K. Hellwig, M. Rieks, V. Hoffmann, D. Pöhlau, H. Przuntek, and the Fumarate Study Group for Multiple Sclerosis
`
`Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany
`
`INTRODUCTION
`• Multiple sclerosis (MS) is a chronic immune-mediated disease that results in
`focal areas of demyelination and axonal loss in the central nervous system
`(CNS), particularly in the brain.
`• Considerable evidence supports involvement of the immune system in the
`pathogenesis of MS1:
`– The presence of lymphocytic infiltrates in CNS lesions and perivascular cuffing
`suggests an autoimmune response
`– A role for immune function in the pathology of MS is supported by the efficacy of
`immune-modulating therapies in slowing disease progression
`• Psoriasis is a chronic T-cell–mediated disease in which immune suppressants have
`also been found to be effective and, similar to MS, a pro-inflammatory T-helper 1
`(Th1) cytokine profile predominates in lymphocytes isolated from psoriatic plaques.2
`• Several open and double-blind clinical studies have shown that oral fumarate therapy
`is effective in psoriasis.3-7
`• Given the involvement of immune-mediated responses and predominance of the
`Th1 cytokine profile in both psoriasis and MS, the objective of this study was to
`determine if oral fumarate therapy is effective in patients suffering from relapsing-
`remitting MS (RRMS).
`
`METHODS
`
`Patients
`• Patients were 18 to 55 years of age and had a clinically definite diagnosis of RRMS
`with ≥1 relapse within the previous year.
`• Patients must have had ≥1 active lesion on brain magnetic resonance imaging (MRI)
`and a baseline Expanded Disability Status Scale (EDSS) score ≥2 but <6.
`• Exclusion criteria for the study included
`– Infection
`– Chronic inflammatory diseases other than MS
`– Pregnancy or breast feeding
`– History of drug or alcohol abuse
`– Disease exacerbation within the previous 3 weeks
`– Corticosteroid treatment within the previous 30 days
`– Immunosuppressive therapy within the previous 12 weeks
`
`Study Design
`• The study design consisted of a 6-week baseline period and 2 treatment periods
`(18 weeks and 42 weeks) separated by a 4-week washout period without fumarate
`treatment (Figure 1).
`– Dimethylfumarate was administered orally in tablet form as a low-dose (30 mg
`Fumaderm initial®) and a high-dose (120 mg Fumaderm forte®) formulation
`• The dose of fumarate was slowly increased over the first 9 weeks to minimize
`gastrointestinal side effects.
`• The maximum dose of fumarate was 720 mg/day in the initial treatment phase and
`360 mg/day in the second treatment phase.
`• Physical examination, EDSS score, ambulatory index (AI), and 9-Hole Peg Test (9-HPT)
`were performed at screening, baseline visit, and weeks 3, 6, 12, 18, 22, 46, and 70.
`
`• Brain MRI scans were performed at screening, baseline visit, and weeks 12, 18, 22,
`46, and 70.
`• Data were analyzed using the nonparametric Wilcoxon test. Differences were
`considered statistically significant at a P value of .05.
`
`FIGURE 1. Study Design
`
`Table 2. Clinical Data
`
`Median EDSS score
`Median AI
`Median 9-HPT (right), sec
`Median 9-HPT (left), sec
`
`*Calculated from 6 patients who completed the 70-week trial.
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`• 10 patients were enrolled, and 6 patients completed the 70-week study. Reasons
`for discontinuation were the following (one each):
`– Unplanned pregnancy
`– Side effects
`– Lack of compliance
`– Undetermined
`• A significant reduction in the number of Gd+ lesions was observed following 18 weeks
`of oral fumarate treatment, with a further reduction after 70 weeks (Figure 2).
`• The volume of Gd+ lesions was decreased at 22 weeks compared with baseline;
`this reduction was maintained at 46 and 70 weeks (Figure 3).
`• Patients who completed the study demonstrated stable or slightly improved clinical
`measures of disease, including EDSS score, AI, and 9-HPT over the course of the
`study (Table 2), although the changes did not achieve statistical significance.
`• Mild to moderate gastrointestinal side effects were experienced by 6 of 7 patients
`who completed >3 weeks of treatment but decreased during the first 12 weeks
`of treatment. In 1 patient these side effects were severe enough to discontinue
`treatment.
`• Other side effects were mild and transient. Four patients had a transient increase in
`liver enzymes.
`
`FIGURE 2. Change in Number of Gadolinium-Enhancing
`Lesions
`
`720 mg/day
`
`30 mg/day
`
`Fumarate
`
`30 mg/day
`
`360 mg/day
`
`Fumarate
`
`Enrollment
`
`70 weeks
`
`Baseline
`Phase
`(6 weeks)
`
`Treatment
`Phase
`(18 weeks)
`
`Washout
`Phase
`(4 weeks)
`
`Treatment
`Phase
`(42 weeks)
`
`Efficacy Outcomes
`• The primary outcome measure was the number and volume of gadolinium-
`enhancing (Gd+) lesions on MRI scans.
`• Secondary outcome measures were changes in EDSS score, AI, and 9-HPT.
`
`RESULTS
`
`• Demographic and baseline characteristics for patients enrolled in the study are
`presented in Table 1.
`
`Table 1. Baseline Characteristics (N = 10)
`
`Characteristic
`Sex, n (%)
`Female
`Male
`
`Median age, y (range)
`Median relapse rate in preceding 12 months (range)
`Median time since first event, y (range)
`Median EDSS score (range)
`
`Median AI
`
`Value
`
`5 (50)
`5 (50)
`
`29.5 (26–36)
`2 (1–3)
`4.5 (1–11)
`2.0 (2.0–4.5)
`
`2.0
`
`Median 9-HPT
`22
`Right
`21
`Left
`AI = ambulatory index; EDSS = Expanded Disability Status Scale; 9-HPT = 9-Hole Peg Test.
`
`*P<.02 compared with baseline.
`
`Sawai (IPR2019-0666), Ex. 1012, p. 009
`
`

`

`A PROSPECTIVE, OPEN-LABEL, PHASE II STUDY OF ORAL FUMARATE THERAPY F