Beer et al. BMC Neurology 2011, 11:144
`http://www.biomedcentral.com/1471-2377/11/144
`
`RESEARCH ARTICLE
`Open Access
`The prevalence of injection-site reactions with
`disease-modifying therapies and their effect on
`adherence in patients with multiple sclerosis: an
`observational study
`Karsten Beer1*, Martin Müller2, Anna Marie Hew-Winzeler3, Adriano Bont4, Philippe Maire5, Xiaojun You6,
`Pamela Foulds6, Jessica Mårlind7 and Daniela Curtius7
`
`Abstract
`Background: Interferon beta (IFNb) and glatiramer acetate (GA) are administered by subcutaneous (SC) or
`intramuscular (IM) injection. Patients with multiple sclerosis (MS) often report injection-site reactions (ISRs) as a
`reason for noncompliance or switching therapies. The aim of this study was to compare the proportion of patients
`on different formulations of IFNb or GA who experienced ISRs and who switched or discontinued therapy because
`of ISRs.
`Methods: The Swiss MS Skin Project was an observational multicenter study. Patients with MS or clinically isolated
`syndrome who were on the same therapy for at least 2 years were enrolled. A skin examination was conducted at
`the first study visit and 1 year later.
`Results: The 412 patients enrolled were on 1 of 4 disease-modifying therapies for at least 2 years: IM IFNb-1a (n =
`82), SC IFNb-1b (n = 123), SC IFNb-1a (n = 184), or SC GA (n = 23). At first evaluation, ISRs were reported by fewer
`patients on IM IFNb-1a (13.4%) than on SC IFNb-1b (57.7%; P < 0.0001), SC IFNb-1a (67.9%; P < 0.0001), or SC GA
`(30.4%; P = not significant [NS]). No patient on IM IFNb-1a missed a dose in the previous 4 weeks because of ISRs,
`compared with 5.7% of patients on SC IFNb-1b (P = 0.044), 7.1% of patients on SC IFNb-1a (P = 0.011), and 4.3% of
`patients on SC GA (P = NS). Primary reasons for discontinuing or switching therapy were ISRs or lack of efficacy.
`Similar patterns were observed at 1 year.
`Conclusions: Patients on IM IFNb-1a had fewer ISRs and were less likely to switch therapies than patients on other
`therapies. This study may have implications in selecting initial therapy or, for patients considering switching or
`discontinuing therapy because of ISRs, selecting an alternative option.
`
`Background
`Interferon beta (IFNb) and glatiramer acetate (GA) are
`first-line therapies for the long-term treatment of multi-
`ple sclerosis (MS) and are generally believed to have
`comparable efficacy. IFNb-1b, IFNb-1a, and GA are
`administered by either intramuscular (IM) or subcuta-
`neous (SC) injection, the frequency of which varies from
`daily to weekly depending on the product. The injection
`of these therapies can be associated with severe adverse
`
`* Correspondence: praxis.beer@bluewin.ch
`1Private practice, Obere Bahnhofstrasse, CH 9500, Wil, Switzerland
`Full list of author information is available at the end of the article
`
`skin reactions, such as necrosis and lipoatrophy [1-4],
`which patients may experience after years of treatment.
`The frequency of injections and injection-site reactions
`(ISRs) can be burdensome for patients and these reac-
`tions are, among other side effects, a major reason for
`poor adherence with these medications over the long
`term [5-7]. O’Rourke and Hutchinson reported that
`patients stopped IFNb therapy because of side effects
`after a median of 13 months [6]. Since poor medication
`adherence or discontinuation can lead to treatment fail-
`ure and ultimately poorer long-term prognosis, it is cri-
`tical that patients persist with treatment to achieve
`
`© 2011 Beer et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
`Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
`any medium, provided the original work is properly cited.
`
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`maximum benefit from therapy. The objective of this
`observational study was to compare the proportion of
`patients on different formulations of IFNb or GA who
`experienced ISRs and who switched or discontinued
`therapy because of ISRs.
`
`Methods
`Study design and participants
`The Swiss MS Skin Project was an observational study
`supported by Biogen Idec Inc. and conducted at 31 sites
`in Switzerland. This was a noninterventional and obser-
`vational study; therefore, approval from an ethics com-
`mittee or health authority was not required. Written
`informed consent was obtained from all patients before
`any study-related procedures were performed.
`Men or women between the ages of 18 and 55 years
`with relapsing MS or clinically isolated syndrome (CIS)
`were enrolled. Information on demographic characteris-
`tics, current MS therapy and duration, and concomitant
`disease and medication were collected at study entry.
`Patients were not naive to therapy and were required
`to be on 1 of 4 disease-modifying therapies (DMTs) for
`at least 2 years prior to enrollment: IM IFNb-1a (Avo-
`nex®), SC IFNb-1b (Betaseron®/Betaferon®), SC IFNb-
`1a (Rebif®), or SC GA (Copaxone®). Rebif New Formu-
`lation was not approved in Switzerland at the time of
`this study. A thorough skin exam was performed on
`patients who met all inclusion criteria. During this first
`evaluation, all observed ISRs were recorded, with addi-
`tional data (number of occurrences and severity) col-
`lected for cases of necrosis and lipoatrophy. Patients
`were asked whether an injection was omitted in the pre-
`vious 4 weeks because of skin reactions, and, if so, the
`number of injections missed was recorded. Changes in
`therapy,
`including treatment discontinuation, or a
`patient’s desire to change or discontinue treatment and
`the reason were also noted. A follow-up skin evaluation
`specific for necrosis and lipoatrophy was performed 1
`year later or at early termination from the study. At the
`follow-up evaluation, changes in treatment and the rea-
`son for the change were recorded.
`The primary outcomes of this study were to evaluate
`the proportion of patients on IFNb or GA who experi-
`enced ISRs and who switched or discontinued therapy
`because of ISRs.
`
`Statistical methods
`A chi-square test and a Fisher exact test were used for
`comparisons between categorical variables (gender, ISR,
`necrosis, lipoatrophy, injection omitted, and treatment
`changed). t tests were used for comparisons between
`continuous variables (age, duration of disease, and treat-
`ment duration).
`
`Results
`Patient disposition and disease characteristics
`Of the 501 patients screened at the start of the study,
`412 met per-protocol entry criteria. Patients were cur-
`rently on 1 of 4 DMTs: IM IFNb-1a (n = 82), SC IFNb-
`1b (n = 123), SC IFNb-1a (n = 184), or SC GA (n = 23).
`There were no significant differences in any study entry
`demographic or disease characteristic across treatment
`groups (Table 1). The overall mean age at enrollment
`was 44.3 years (standard deviation [SD] 10.12) and the
`majority of patients (69.7%) were women. The overall
`mean duration of MS disease was 9.3 years (SD 6.22)
`and the overall mean duration of treatment was 5.9
`years (SD 2.97). Overall, 88 of 412 patients (21.4%) were
`taking comedication for a concomitant disease.
`The end-of-study visit was completed for 351 patients:
`73 patients on IM IFNb-1a, 107 patients on SC IFNb-
`1b, 156 patients on SC IFNb-1a, and 15 patients on SC
`GA. The reasons for study discontinuation included lost
`to follow-up (n = 37), stopped therapy (n = 8), changed
`physicians (n = 6), switched therapy to natalizumab (n =
`3) or mitoxantrone (n = 1), withdrew consent (n = 3),
`pregnancy (n = 1), deterioration of general condition (n
`= 1), and protocol violation (inclusion criteria not met,
`n = 1).
`
`First evaluation
`Of the 412 patients enrolled in this study, 214 (51.9%)
`reported an adverse skin reaction at the first evaluation.
`ISRs were reported for fewer patients on IM IFNb-1a
`(11 of 82 patients, 13.4%) than on SC IFNb-1b (71 of
`123 patients, 57.7%; P < 0.0001), SC IFNb-1a (125 of
`184 patients, 67.9%; P < 0.0001), or SC GA (7 of 23
`patients, 30.4%; P = not significant [NS]) (Figure 1). The
`proportion of SC GA-treated patients who experienced
`ISRs was also significantly lower than that for SC IFNb-
`1b (P = 0.016) and SC IFNb-1a (P < 0.001). Of the 214
`patients who experienced an ISR, 123 (57.5%) reported
`that ISRs occurred “several times,” 74 (34.6%) reported
`that they occurred “frequently,” and 8 (3.7%) reported
`that they occurred “once.” Data were not available for 9
`patients (4.2%).
`Necrosis was reported for 18 of 412 patients (4.4%) at
`the first evaluation (Table 2). No patients on IM IFNb-
`1a or SC GA experienced necrosis, compared with 7 of
`123 patients (5.7%) treated with SC IFNb-1b and 11 of
`184 patients (6.0%) treated with SC IFNb-1a. Most of
`the patients who experienced necrosis (77.8%) had 1-2
`occurrences. The severity of necrosis was rated as mild
`or moderate in the majority (83.3%) of these patients;
`severe necrosis was reported in 1 of 7 patients (14.3%)
`treated with SC IFNb-1b and 1 of 11 patients (9.1%)
`treated with SC IFNb-1a. Data on the frequency and
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`Table 1 Demographic and disease characteristics of patientsa at study entry
`IM IFNb-1a
`SC IFNb-1b
`SC IFNb-1a
`(n = 82)
`(n = 123)
`(n = 184)
`44.7 (10.35)
`45.9 (10.23)
`43.2 (9.72)
`64 (78.0)
`84 (69.4)
`122 (66.7)
`9.9 (7.37)
`10.0 (6.29)
`8.6 (5.74)
`5.5 (2.56)
`6.8 (3.06)
`5.5 (2.93)
`
`Mean age, years (SD)
`Gender, female (%)
`Mean duration of MS disease, years (SD)
`Mean duration of treatment, years (SD)
`
`aThere were no statistically significant differences between the groups.
`
`SC GA
`(n = 23)
`43.1 (11.25)
`15 (65.2)
`9.5 (4.92)
`5.6 (3.24)
`
`Overall
`(N = 412)
`44.3 (10.12)
`285 (69.7)
`9.3 (6.22)
`5.9 (2.97)
`
`1a (P = 0.011), and 1 of 23 patients (4.3%) treated with
`SC GA (P = NS) (Table 2). Overall, 39 of 412 patients
`(9.5%) reported wanting to switch therapies or discon-
`tinue therapy at the first evaluation: 4 of 82 patients
`(4.9%) treated with IM IFNb-1a, 13 of 123 patients
`(10.6%) treated with SC IFNb-1b, 18 of 184 patients
`(9.8%) treated with SC IFNb-1a, and 4 of 23 patients
`(17.4%) treated with SC GA (Figure 2A). The primary
`reasons for wanting to switch therapy were ISRs (30.8%)
`and lack of efficacy (15.4%). Other reasons included
`injection fatigue (7.7%), flu-like symptoms (5.1%), abnor-
`mal liver function (5.1%), and cardiovascular problems
`(2.6%) (Figure 3A). One patient on IM IFNb-1a switched
`therapy because of ISRs or injection fatigue, compared
`with 7 patients on SC IFNb-1b and 7 patients on SC
`IFNb-1a. No patients on SC GA switched therapy
`because of an ISR or injection fatigue.
`
`Follow-up skin evaluation at 1 year
`Adherence was comparable among the 4 DMTs at 1
`year. However, a significantly higher proportion of
`patients who started on IM IFNb-1a were still on the
`same therapy (86.6%) compared with patients on SC
`IFNb-1b (79.7%), patients on SC IFNb-1a (83.2%), and
`patients on SC GA (60.9%) (overall P = 0.036 [chi-
`square test]) (Figure 4).
`Data on necrosis were collected from 345 patients.
`Ten of 345 patients (2.9%) experienced necrosis at the
`injection site: 5 of 104 patients (4.8%) treated with SC
`IFNb-1b and 5 of 154 patients (3.2%) treated with SC
`IFNb-1a (Table 3). No patients on IM IFNb-1a or SC
`GA experienced necrosis. The majority of patients who
`experienced necrosis (80.0%) reported 1-2 occurrences,
`and the severity was mild or moderate in most patients
`(70.0%). Severe necrosis was observed in only 1 patient
`treated with SC IFNb-1b. Data on the frequency and
`severity of necrosis were unknown for 1 patient on SC
`IFNb-1b and 1 patient on SC IFNb-1a.
`Data on lipoatrophy were collected from 344 patients.
`Lipoatrophy was reported in 33 of 344 patients (9.6%): 9
`of 104 patients (8.7%) treated with SC IFNb-1b, 23 of
`153 patients (15.0%) treated with SC IFNb-1a, and 1 of
`14 patients (7.1%) treated with SC GA (Table 3). No
`patient on IM IFNb-1a experienced lipoatrophy, which
`
`severity of necrosis were unknown for 1 patient receiv-
`ing SC IFNb-1a.
`At the first evaluation, lipoatrophy was reported for 34
`of 412 patients (8.3%) (Table 2): 1 of 82 patients (1.2%)
`treated with IM IFNb-1a, 11 of 123 patients (8.9%) trea-
`ted with SC IFNb-1b, 19 of 184 patients (10.3%) treated
`with SC IFNb-1a, and 3 of 23 patients (13.0%) treated
`with SC GA. Lipoatrophy was experienced by signifi-
`cantly fewer patients on IM IFNb-1a than on SC IFNb-
`1b (P = 0.021), on SC IFNb-1a (P = 0.009), or on SC
`GA (P = 0.032). The majority of patients who experi-
`enced lipoatrophy (73.5%) had 1-3 occurrences. Five or
`more occurrences of lipoatrophy were seen in 2 of 11
`patients (18.2%) treated with SC IFNb-1b and 6 of 19
`patients (31.6%) treated with SC IFNb-1a. The severity
`of lipoatrophy was rated as mild or moderate in most
`patients (91.2%); severe lipoatrophy was reported for 1
`of 11 patients (9.1%) treated with SC IFNb-1b. Data on
`severity were unknown for 2 patients receiving SC
`IFNb-1b.
`At the first evaluation, no patient on IM IFNb-1a had
`missed a dose in the previous 4 weeks, compared with 7
`of 123 patients (5.7%) treated with SC IFNb-1b (P =
`0.044), 13 of 184 patients (7.1%) treated with SC IFNb-
`
`67.9*
`
`57.7*
`
`13.4
`
`30.4†
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Patients with injection-site reactions (%)
`
`IM IFNβ-1a
`
`SC IFNβ-1b
`
`SC IFNβ-1a
`
`SC GA
`
`Figure 1 Results of skin examination at the first evaluation. The
`number of patients experiencing ISRs at the first evaluation was
`recorded for each therapy. At the first evaluation examination,
`patients had been on their current DMT for at least 2 years. *P <
`0.0001 vs IM IFNb-1a; chi-square test. †P = 0.016 vs SC IFNb-1b; P <
`0.001 vs SC IFNb-1a; P = NS vs IM IFNb-1a; chi-square test.
`
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`Table 2 Skin status at first evaluation examination
`IM IFNb-1a
`(n = 82)
`11 (13.4)
`0 (0)a
`
`Any ISR, n (%)
`Necrosis, n (%)
`Number of occurrences
`1
`2
`3
`4
`Unknown
`Severity
`Mild
`Moderate
`Severe
`Unknown
`Lipoatrophy, n (%)
`Number of occurrences
`1
`2
`3
`4
`≥5
`Severity
`Mild
`Moderate
`Severe
`Unknown
`Injection omitted during last 4 weeks, n (%)
`
`SC IFNb-1b
`(n = 123)
`71 (57.7)
`7 (5.7)
`
`SC IFNb-1a
`(n = 184)
`125 (67.9)
`11 (6.0)
`
`SC GA
`(n = 23)
`7/23 (30.4)
`0 (0)
`
`1/7 (14.3)
`4/7 (57.1)
`1/7 (14.3)
`1/7 (14.3)
`0
`
`3/7 (42.9)
`3/7 (42.9)
`1/7 (14.3)
`0
`11 (8.9)
`
`1/11 (9.1)
`6/11 (54.5)
`2/11 (18.2)
`0
`2/11 (18.2)
`
`6/11 (54.5)
`2/11 (18.2)
`1/11 (9.1)
`2/11 (18.2)
`7 (5.7)
`
`6/11 (54.5)
`3/11 (27.3)
`1/11 (9.1)
`0
`1/11 (9.1)
`
`6/11 (54.5)
`3/11 (27.3)
`1/11 (9.1)
`1/11 (9.1)
`19 (10.3)
`
`5/19 (26.3)
`6/19 (31.6)
`2/19 (10.5)
`0
`6/19 (31.6)
`
`10/19 (52.6)
`9/19 (47.4)
`0
`0
`13 (7.1)
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`3 (13.0)
`
`1/3 (33.3)
`1/3 (33.3)
`1/3 (33.3)
`0
`0
`
`2/3 (66.7)
`1/3 (33.3)
`0
`0
`1 (4.3)
`
`Overall
`(N = 412)
`214 (51.9)
`18 (4.4)
`
`7/18 (38.9)
`7/18 (38.9)
`2/18 (11.1)
`1/18 (5.6)
`1/18 (5.6)
`
`9/18 (50.0)
`6/18 (33.3)
`2/18 (11.1)
`1/18 (5.6)
`34 (8.3)
`
`7/34 (20.6)
`13/34 (38.2)
`5/34 (14.7)
`1/34 (2.9)
`8/34 (23.5)
`
`19.34 (55.9)
`12/34 (35.3)
`1/34 (2.9)
`2/34 (5.9)
`21 (5.1)
`
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`1 (1.2)b
`
`0
`0
`0
`1/1 (100)
`0
`
`1/1 (100)
`0
`0
`0
`0 (0)c
`
`At the first evaluation examination, patients had been on their current DMT for at least 2 years.
`aP = 0.028 vs SC IFNb-1b; P = 0.020 vs SC IFNb-1a.
`bP = 0.021 vs SC IFNb-1b; P = 0.009 vs SC IFNb-1a; P = 0.032 vs SC GA.
`cP = 0.044 vs SC IFNb-1b; P = NS vs SC GA; P = 0.011 vs SC IFNb-1a.
`
`was significantly lower than the rate of lipoatrophy on
`SC IFNb-1b (P = 0.011) and SC IFNb-1a (P < 0.0001).
`At least 5 occurrences of lipoatrophy were observed in 1
`of 9 patients (11.1%) treated with SC IFNb-1b and 3 of
`23 patients (13.0%) treated with SC IFNb-1a. The sever-
`ity of lipoatrophy was rated as mild or moderate in the
`majority of patients (78.8%); severe lipoatrophy was
`experienced by 1 patient treated with SC IFNb-1b and 1
`patient treated with SC IFNb-1a. Frequency data were
`unknown for 1 patient and severity data were unknown
`for 5 patients in the SC IFNb-1a-treated group.
`Data on switching or discontinuing therapy were col-
`lected from 346 patients. Overall, 28 of 346 patients
`(8.1%) reported wanting to switch or discontinue ther-
`apy at the 1-year follow-up: 4 of 73 patients (5.5%) trea-
`ted with IM IFNb-1a, 6 of 104 patients (5.8%) treated
`with SC IFNb-1b, 16 of 154 patients (10.4%) treated
`with SC IFNb-1a, and 2 of 15 patients (13.3%) treated
`with SC GA (Figure 2B). The primary reasons for want-
`ing to switch or discontinue therapy were lack of
`
`efficacy (46.4%) and ISRs (17.9%) (Figure 3B). Other rea-
`sons included injection fatigue (3.6%), flu-like symptoms
`(3.6%), and abnormal liver function (3.6%). No patients
`on IM IFNb-1a switched therapy because of ISRs or
`injection fatigue during the 1-year study, compared with
`1 patient on SC IFNb-1b, 4 patients on SC IFNb-1a,
`and 1 patient on SC GA.
`A logistic regression model was used to evaluate
`potential relationships between stopping or switching
`initial treatment at the year 1 follow-up and baseline
`age, ISRs, initial treatment, gender, and disease duration.
`Significant interactions were found for gender and IM
`IFNb-1a versus GA. The odds of stopping or switching
`initial MS treatment at the year 1 follow-up were 2.876
`times higher for female patients than for male patients
`(P = 0.0115). Likewise, the odds of stopping or switching
`initial treatment at the year 1 follow-up were 4.877
`times higher for patients on GA than for patients on IM
`IFNb-1a (P = 0.0215). No significant interactions were
`found for the other baseline variables.
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`30.8
`
`15.4
`
`7.7
`
`5.1
`
`5.1
`
`2.6
`
`ISRs
`
`Lack of
`efficacy
`
`Injection
`fatigue
`
`Flu-like
`symptoms
`
`Abnormal
`liver test
`
`CV issues
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`A
`
`Reasons for switching or discontinuing
`
`therapy at first evaluation (%)
`
`3.6
`
`3.6
`
`3.6
`
`Abbreviations: CV, cardiovascular.
`
`46.4
`
`17.9
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`B
`
`discontinuing therapy at 1 year (%)
`
`Reasons for switching or
`
`ISRs
`
`Lack of
`Injection
`Flu-like
`Abnormal liver
`efficacy
`fatigue
`symptoms
`test
`Figure 3 Reasons for switching or discontinuing therapy at the
`first evaluation (A) and 1 year (B). At the first evaluation
`examination, patients had been on their current DMT for at least 2
`years.
`
`common reason for switching or discontinuing therapy,
`followed by lack of efficacy and injection fatigue. At the
`1-year follow-up, similar patterns of ISRs and of switch-
`ing or discontinuing therapy were seen. Patients on IM
`IFNb-1a were significantly less likely to have necrosis or
`lipoatrophy than patients on SC IFNb-1b or SC IFNb-
`1a. More patients remained on IM IFNb-1a than on the
`other injectable therapies. Although lack of efficacy was
`
`*
`86.6
`
`79.7
`
`83.2
`
`60.9
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Patients remaining on original
`
`treatment at 1 year (%)
`
`IM IFNβ-1a
`
`SC IFNβ-1b
`
`SC IFNβ-1a
`
`SC GA
`
`Figure 4 Patients remaining on original treatment at 1-year
`follow-up. *Overall P = 0.036 (chi-square test).
`
`17.4
`
`10.6
`
`9.8
`
`4.9
`
`IM IFNβ-1a
`
`SC IFNβ-1b
`
`SC IFNβ-1a
`
`SC GA
`
`13.3
`
`10.4
`
`5.5
`
`5.8
`
`20
`18
`16
`14
`12
`10
`
`02468
`
`20
`18
`16
`14
`12
`10
`
`02468
`
`A
`
`Patients who switched or discontinued
`
`therapy at first evaluation (%)
`
`B
`
`discontinued therapy at 1 year (%)
`
`Patients who switched or
`
`IM IFNβ-1a
`
`SC IFNβ-1b
`
`SC IFNβ-1a
`
`SC GA
`
`Figure 2 Patients wanting to switch or discontinue therapy at
`first evaluation (A) and 1 year (B). At the first evaluation
`examination, patients had been on their current DMT for at least 2
`years.
`
`Discussion
`The Swiss MS Skin Project study is the first study to
`evaluate the relative frequency and severity of ISRs asso-
`ciated with the 4 injectable DMTs available for patients
`with MS. In our large patient population of more than
`400 patients, approximately half of the patients experi-
`enced ISRs at the first evaluation even though they had
`been on the same therapy for at least 2 years (mean
`treatment duration = 5.9 years). This finding suggests
`that ISRs continue to be a concern for patients with MS
`even after they have been on therapy for several years.
`Indeed, ISRs and lack of efficacy were the 2 most com-
`mon reasons for patients’ discontinuing treatment or
`wanting to switch therapy at the first evaluation and 1-
`year follow-up.
`We report potentially clinically important differences
`in the proportion of patients experiencing ISRs with
`injectable DMTs. At the first evaluation examination,
`significantly fewer patients on IM IFNb-1a than on
`other IFN formulations experienced ISRs. A trend
`toward lower rates of ISRs with IM IFNb-1a than with
`SC GA was also reported. Missed doses in the previous
`4 weeks appeared to be associated with twice the likeli-
`hood of discontinuing or switching therapy for patients
`on SC IFNb-1b, SC IFNb-1a, or SC GA as compared
`with patients on IM IFNb-1a. ISRs were the most
`
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`Beer et al. BMC Neurology 2011, 11:144
`http://www.biomedcentral.com/1471-2377/11/144
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`Table 3 Skin status at one-year follow-up examination
`IM IFNb-1a
`SC IFNb-1b
`(n = 73)
`(n = 104)
`0 (0)
`5 (4.8)
`
`0
`0
`0
`
`0
`0
`0
`0
`0 (0)a
`
`0
`0
`0
`0
`0
`0
`
`Necrosis, n (%)
`Number of occurrences
`1
`2
`Unknown
`Severity
`Mild
`Moderate
`Severe
`Unknown
`Lipoatrophy, n (%)
`Number of occurrences
`1
`2
`3
`4
`≥5
`Unknown
`Severity
`0
`Mild
`0
`Moderate
`0
`Severe
`0
`Unknown
`aP = 0.011 vs SC IFNb-1b; P < 0.0001 vs SC IFNb-1a.
`bLipoatrophy status was not collected for 1 SC IFNb-1a patient (n = 153).
`
`SC IFNb-1a
`(n = 154)
`5 (3.2)
`
`2/5 (40.0)
`2/5 (40.0)
`1/5 (20.0)
`
`1/5 (20.0)
`3/5 (60.0)
`0
`1/5 (20.0)
`23 (15.0)b
`
`4/23 (17.4)
`11/23 (47.8)
`3/23 (13.0)
`1/23 (4.3)
`3/23 (13.0)
`1/23 (4.3)
`
`11/23 (47.8)
`6/23 (26.1)
`1/23 (4.3)
`5/23 (21.7)
`
`SC GA
`(n = 14)
`0 (0)
`
`0
`0
`0
`
`0
`0
`0
`0
`1 (7.1)
`
`0
`1/1 (100)
`0
`0
`0
`0
`
`0
`1/1 (100)
`0
`0
`
`Overall
`(N = 345)
`10 (2.9)
`
`5/10 (50.0)
`3/10 (30.0)
`2/10 (20.0)
`
`4/10 (40.0)
`3/10 (30.0)
`1/10 (10.0)
`2/10 (20.0)
`33 (9.6)
`
`7/33 (21.2)
`14/33 (42.4)
`6/33 (18.2)
`1/33 (3.0)
`4/33 (12.1)
`1/33 (3.0)
`
`17/33 (51.5)
`9/33 (27.3)
`2/33 (6.1)
`5/33 (15.2)
`
`3/5 (60.0)
`1/5 (20.0)
`1/5 (20.0)
`
`3/5 (60.0)
`0
`1/5 (20.0)
`1/5 (20.0)
`9 (8.7)
`
`3/9 (33.3)
`2/9 (22.2)
`3/9 (33.3)
`0
`1/9 (11.1)
`0
`
`6/9 (66.7)
`2/9 (22.2)
`1/9 (11.1)
`0
`
`the most common reason for switching or discontinuing
`therapy, ISRs were also a common reason.
`Our findings that ISRs are common and that fewer
`patients treated with IM IFNb-1a than the other inject-
`able therapies experience ISRs are consistent with the
`findings of previous randomized, controlled studies
`comparing the therapies pairwise. The EVIDENCE trial
`compared IM IFNb-1a 30 μg once weekly to SC IFNb-
`1a 44 μg three times weekly [1]. In this study, ISRs were
`the most commonly reported adverse event. ISRs were
`experienced by significantly fewer patients on IM IFNb-
`1a than on SC IFNb-1a (28% vs 83%, P < 0.001) [1].
`Similarly, the INCOMIN open-label trial compared IM
`IFNb-1a 30 μg once weekly with SC IFNb-1b 250 μg
`every other day. In this study, ISRs were reported in 8%
`of patients treated with IM IFNb-1a compared with 37%
`of patients treated with SC IFNb-1b (P < 0.0001) [2].
`These data are further supported by Milanese et al, who
`showed occurrence of local reactions in 8% of IM IFNb-
`1a-treated patients versus 33% of SC IFNb-1b-treated
`patients [3]. Finally, BEYOND, a study of SC IFNb-1b
`(250 μg or 500 μg every other day) versus SC GA (20
`mg daily), reported that 48%-58% of patients across
`treatment groups experienced ISRs [4]. The current
`study is limited by its observational nature and the low
`
`number of patients on SC GA, which may be reflective
`of low utilization of SC GA at the study sites in Switzer-
`land. Given the overall mean treatment duration of 5.9
`years, study patients may have received other treatments
`prior to the current DMT. This possibility is important,
`since a patient may have different expectations with the
`first therapy than with the second or third therapy. In
`addition, these results may not reflect the prevalence of
`ISRs at the initiation of treatment or early in the treat-
`ment regime. Nevertheless, the results are generally con-
`sistent with, and may be more reflective of, clinical
`practice than results from controlled clinical trials. At
`both the first evaluation and 1-year follow-up examina-
`tions, patients on IM IFNb-1a had fewer skin reactions
`and were less likely to switch therapies than patients on
`other therapies.
`Maintaining patients with MS on DMTs can be chal-
`lenging, particularly in the early stage of treatment,
`when the benefits of therapy may not be obvious to
`patients and such patients are still adjusting to their
`medication. Patients with MS commonly cite the fre-
`quency of injections and ISRs as reasons for missing
`doses or switching or discontinuing therapies [5-8].
`Patients discontinuing therapy because of side effects,
`such as ISRs, often do so early during in the course of
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`Beer et al. BMC Neurology 2011, 11:144
`http://www.biomedcentral.com/1471-2377/11/144
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`Page 7 of 7
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`therapy [6]. Selecting therapy with a lower risk for ISRs
`and educating patients on strategies to minimize their
`occurrence may help patients adhere to treatment, thus
`improving their chances for optimal treatment of MS
`over the long term. Although many factors are involved
`when making treatment decisions, our study may have
`implications in selecting initial therapy or, for patients
`considering switching or discontinuing therapy because
`of ISRs, selecting an alternative option.
`
`Conclusions
`More patients remained on IM IFNb-1a compared with
`other DMTs over the 1-year study. Patients on IM
`IFNb-1a had fewer skin reactions and better compliance
`and were less likely to switch to other DMTs compared
`with patients on other therapies. Minimizing the impact
`of adverse effects is crucial in helping patients adhere to
`their treatment regimens and in improving their chances
`of better health over the longer term.
`
`Acknowledgements
`This study, the Swiss MS Skin Project, was supported by Biogen Idec Inc. The
`authors wish to acknowledge editorial support from Marie Geissler of
`Infusion Communications, which was funded by Biogen Idec Inc.
`
`Author details
`1Private practice, Obere Bahnhofstrasse, CH 9500, Wil, Switzerland.
`2Department of Medicine, Canton Hospital of Lucerne, Lucerne, Switzerland.
`3Private practice, Todistrasse 46, CH 8002, Zurich, Switzerland. 4Private
`practice, Brunngasse 6, CH 8400, Winterthur, Switzerland. 5Hirslanden Clinic
`Aarau, Schanisweg, CH 5001, Aarau, Switzerland. 6Biogen Idec Inc., 133
`Boston Post Road, Weston, MA, USA. 7Biogen-Dompé AG, Bundesplatz 9, CH
`6300, Zug, Switzerland.
`
`Authors’ contributions
`DC, JM, PF, and XY were responsible for the concept and design of the
`study; DC and JM were responsible for study coordination; XY was
`responsible for the data analysis; KB, MM, AMHW, AB, and PM collected the
`clinical data. All authors had full access to the study data, contributed to the
`interpretation of data, contributed to and critically reviewed the manuscript
`during its development, and approved the final version of the manuscript
`for submission.
`
`Competing interests
`MM has received grants from Biogen Idec, Teva Neuroscience, Bayer-
`Schering, and Merck-Serono. XY and PF are employees of Biogen Idec Inc.
`JM and DC are employees of Biogen-Dompé AG. KB, AMHW, AB, and PM
`declare that they have no competing interests.
`
`Received: 2 May 2011 Accepted: 10 November 2011
`Published: 10 November 2011
`
`References
`Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P,
`1.
`Monaghan E, Li D, Weinshenker B, EVIDENCE (EVidence of Interferon Dose-
`response: European North American Comparative Efficacy) Study Group;
`University of British Columbia MS/MRI Research Group: Randomized,
`comparative study of interferon β-1a treatment regimens in MS: the
`EVIDENCE trial. Neurology 2002, 59(10):1496-1506.
`Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Ghezzi A, Montanari E,
`Zaffaroni M, Independent Comparison of Interferon (INCOMIN) Trial Study
`Group: Every-other-day interferon beta-1b versus once-weekly interferon
`beta-1a for multiple sclerosis: results of a 2-year prospective randomised
`multicentre study (INCOMIN). Lancet 2002, 359(9316):1453-1460.
`
`2.
`
`4.
`
`5.
`
`3. Milanese C, La Mantia L, Palumbo R, Martinelli V, Murialdo A, Zaffaroni M,
`Caputo D, Capra R, Bergamaschi R, the North Italy Multiple Sclerosis Group:
`A post-marketing study on interferon β 1b and 1a treatment in relapse-
`remitting multiple sclerosis: different response in drop-outs and treated
`patients. J Neurol Neurosurg Psychiatry 2003, 74:1689-1692.
`O’Connor P, Filippi M, Arnason B, Comi G, Cook S, Goodin D, Hartung HP,
`Jeffery D, Kappos L, Boateng F, Filippov V, Groth M, Knappertz V, Christian
`Kraus C, Sandbrink R, Pohl C, Bogumil T, for the BEYOND Study Group: 250
`μg or 500 μg interferon beta-1b versus 20 mg glatiramer acetate in
`relapsing-remitting multiple sclerosis: a prospective, randomized,
`multicentre study. Lancet Neurol 2009, 8(10):889-897.
`Tremlett HL, Oger J: Interrupted therapy: stopping and switching of the
`beta-interferons prescribed for MS. Neurology 2003, 61(4):551-554.
`O’Rourke K, Hutchinson M: Stopping beta-interferon therapy in multiple
`sclerosis: an analysis of stopping patterns. Mult Scler 2005, 11(1):46-50.
`Girouard N, Théorêt G: Management strategies for improving the
`tolerability of interferons in the treatment of multiple sclerosis. Can J
`Neurosci Nurs 2008, 30(4):18-25.
`Rio J, Porcel J, Tellez N, Sánchez-Betancourt A, Tintoré M, Arévalo MJ,
`Nos C, Montalban X: Factors related with treatment adherence to
`interferon β and glatiramer acetate therapy in multiple sclerosis. Mult
`Scler 2005, 11(3):306-309.
`
`6.
`
`7.
`
`8.
`
`Pre-publication history
`The pre-publication history for this paper can be accessed here:
`http://www.biomedcentral.com/1471-2377/11/144/prepub
`
`doi:10.1186/1471-2377-11-144
`Cite this article as: Beer et al.: The prevalence of injection-site reactions
`with disease-modifying therapies and their effect on adherence in
`patients with multiple sclerosis: an observational study. BMC Neurology
`2011 11:144.
`
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