J Neurol (20l0) 257':l9l'.«‘—l923
`D01 10.10077300415-U10-5779-x
`
`
`ORIGINAL COMMUNICATION
`
`Tolerability and safety of novel half milliliter formulation
`of glatiramer acetate for subcutaneous injection: an open-label,
`multicenter, randomized comparative study
`
`G. Anderson - D. Meyer - C. E. Herrman -
`C. Sheppard - R. Murray - E. J. Fox -
`
`J. Mathena - J. Conner - P. 0. Buck
`
`Received: 18 May 2010/Revised: 17‘ August 2010/Accepted: 29 September 2010/Published online: 16 October 20l0
`© The Author[s) 2010. This article is published with open access at Springerlinl-Lcom
`
`Abstract Daily glatiramer acetate (GA) 20 mgfl.0 1nL is
`a first-line treatment for relapsing—remitting multiple scle-
`rosis {RRMS). To reduce the occurrence of injection pain
`and local injection site reactions (LISRS), a reduced volume
`formulation of GA was developed. This study compared
`pain and LISRS after injecting the marketed and the novel
`formulations. RRMS patients
`currently injecting GA
`participated in this multieenter,
`randomized, crossover
`comparative study. All patients administered once—daily
`subcutaneous injections of GA 20 mg/1.0 mL (marketed
`
`Electronic supplementary material The online version of this
`article (doizltll(lll7/slll)4l5-lll0-5779-X) contains supplementary
`material, which is available to authorized users.
`
`G. Anderson (IE)
`Associates in Neurology PSC, 102] Majestic Dr. Suite #200,
`Lexington, KY 40513, USA
`e-mail: Greg.l.anderson@insightl'Jh.corn
`
`D. Meyer
`Triad Neurological Associates, Winston—Salem, NC, USA
`
`C. E. I-lernnan
`
`Josephson Wallaek Munshnwer Neurology PC,
`Indianapolis. IN. USA
`
`C. Sheppard
`The Oak Clinic for MS. Uniontown. OH, USA
`
`R. Murray
`MS Clinic of Colorado. lst lnternational Research Centers,
`Centennial, CO, USA
`
`E. J. Fox
`Central Texas Neurology Consultants,
`Round Rock, TX, USA
`
`J. Mathena - J. Conner ' P. 0. Buck
`Medical Affairs, Teva Neuroscience, Kansas City, MO, USA
`
`formulation) or GA 20 mg/0.5 ml- (reduced volume for-
`mulation) for 14 days. Patients were crossed-over to the
`alternate treatment for an additional 14 days. Using a
`Visual Analog Scale (VAS), patients recorded in daily
`diaries the severity of injection pain immediately and 5 min
`post-injection, and the presence and severity of LISRS
`(swelling, redness, itching, lump) within 5 min and 24 h
`poseinjcction. VAS pain scores were ranked significantly
`lower immediately and 5 min after GA 20 mg/0.5 mL
`injections (p < 0.0001). Although LISRs were rare for both
`preparations, the severity of reactions ranked significantly
`lower and fewer syntptoms occurred within 5 min and 24 h
`of using the reduced volume formulation (p < 0.0001). GA
`injected subcutaneously in a reduced volume formulation is
`a more tolerable option.
`
`Keywords Relapsing-remitting multiple sclerosis -
`Glatiramer acetate - Copaxone - Subcutaneous injections -
`Local injection site reactions - Injection pain
`
`Introduction
`
`Glatiramer acetate (GA) injection (Copaxone, Teva Phar-
`maceuticals lne., Petah Tiqva,
`Israel)
`is indicated for
`reducing the frequency of relapses in patients with relaps-
`ing—remitting multiple sclerosis (RRMS), and in patients
`who have experienced a first clinical episode and have MR1
`features consistent with multiple sclerosis (MS) [1]. This
`first-line treatment has proven efflcaey and safety [2%>]. As
`with all therapeutics, patient adherence to the treatment
`regimen is very important. Patients with chronic diseases
`have lower drug adherence and persistence rates [7], with
`studies of MS patients reporting that almost 40% of patients
`with MS miss injections [S-1 0]. Many factors can lead to
`
`Q Springer
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 1
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`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 1
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`

`
`1918
`J Neurol (2010) 257:]917—l923
`
`poor adherence with any medication L7]; patients have
`reported that
`local
`in_jection site reactions (LISRs) and
`injection site pain are a couple of the reasons why they miss
`in_jections [10,
`I 1].
`LISRs, including pain, are the most Common adverse
`reactions reported by patients receiving GA [1]. In con-
`trolled studies, the proportion of subjects reporting these
`reactions at least once was higher following treatment with
`GA than following placebo [2, 4, 5]. Although the etiology
`of injection site pain is multi-factorial, an increase in the
`volume of an injectable agent has been associated with
`increased injection site pain [12]. A study assessing fou1'
`volumes of a subcutaneous injection found that increasing
`the volume from 0.5 to L0 mL increased injection pain
`significantly [12]. ln an attempt to potentially reduce the
`occurrence of injection pain and other injection site reac-
`tions, a reduced volume of the GA formulation was
`
`developed. The new formulation contains 20 mg GA and
`20 mg mannitol in 0.5 mL whereas the marketed formu-
`lation contains 20 mg GA and 40 mg mannitol in 1.0 mL
`solution. The objective of this study was to assess injection
`pain and other LlSRs associated with the reduced volume
`formulation by comparing it to the marketed formulation.
`
`Methods
`
`Study design
`
`The study was a multiccntcr, randomized, two-arm, single
`crossover study designed to compare the tolerability and
`safety of GA 20 mg/0.5 mL versus GA 20 mg! l .0 mL when
`administered subcutaneously by patients with RRMS. Dur-
`ing the 7-day run-in period preceding the two treatment
`periods, all patients administered a daily subcutaneous dose
`of GA 20 mg} 1.0 mL. During this period they were
`instructed on a 7-site injection rotation, manual injection
`techniques, and how to complete the patient diary. They
`were also randomized at a ratio of 1:1 to one of two cross-
`
`over sequences of either GA 20 mg! 1.0 mL or GA 20 mg!
`0.5 ml. (Sequences 1 and 2) for the two treatment periods.
`During the treatment periods, patients administered one of
`the formulations of GA for 14 days and then the patients
`were crossed-over to the alternate formulation for an addi-
`
`tional 14-day treatment period. Total GA treatment duration
`in the study was 5 weeks,
`including the 1-week run-in
`period. Block randomization stratified by study site was
`done according to a computer—generated schedule to ensure
`that patients of each site were distributed equally between
`the formulation sequences. Blinding in this study was not
`possible due to the patients’ ability to detect difference in the
`volumes of each formulation, The study was conducted
`following the principles of the Declaration of Helsinki, ICH
`
`@ Springer
`
`guidelines on good clinical practices, and all applicable laws
`and regulations. All patients gave written informed consent
`after the procedures had been fully explained, and prior to
`performing any study related procedures.
`
`Patients
`
`Men or women, aged :18 years, with a diagnosis of RRMS
`and taking GA 20 mg! 1.0 mL per day subcutaneously with
`the Autoject®2 for glass syringe or by a manual injection
`technique for a minimum of 90 days were eligible for
`inclusion. They also had to be willing to switch from using
`an At1toject®2 for glass syringe to using a manual injection
`technique or to continue with a manual injection technique
`during the course of the study. Patients were excluded if in
`the 30 days prior to screening (1) they were treated with
`another immunomodulating therapy in conjunction with
`GA, (2) they used intermittent or pulse courses of cortico-
`steroids by any route of administration (corticosteroids were
`prohibited for the duration of the study), or (3) used any
`other parenteral medications. Patients with a presence or
`history of skin necrosis or a known extensive dermatolog-
`ical condition were excluded to prevent a potential con-
`founding factor in the assessment of LISRs.
`
`Treatments
`
`During the 7-day run-in period preceding the two treatment
`periods, all patients administered a daily subcutaneous dose
`of GA 20 mg/1.0 mL. After the run-in period all patients
`received once-daily subcutaneous administration of 20 mg
`GA, as either 20 mg/1.0 mL or 20 1ngl0.S mL, for a 14-day
`treatment period, and then received the second (alternate)
`treatment as per the randomization schedule for an addi-
`tional 14-day treatment period. Both the 20 mg/l.(J mL and
`20 mgf0.5 ml. formulations of GA have a pH range of
`approximately 5.5-7.0 and are stable for up to 1 month at
`room temperature with no adverse impact on product
`potency, appearance, pH, clarity or other physicochemical
`characteristics. All
`treatments were adrninistered via a
`
`injection technique. Compliance with the dosing
`manual
`regimen for each period was determined by counting
`returned unused study drug syringes.
`
`Ol.llLC0l’I1B I1'1BElSLlI’€S
`
`Using daily diaries, patients recorded the severity of pain
`occurring immediately and 5 min after injection, and the
`presence and severity of LlSRs that occurred within 5 min
`and 24 h post—injection. Daily diaries were collected at the
`end of the run-in period, at the end of Treatment Period 1
`(before they were crossed-over to Period 2), and at the end
`of Treatment Period 2.
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 2
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`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 2
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`

`
`1919
`J Ncurol (2010) 257:l9l'.Ll923
`
`the difference
`The primary clinical outcome was
`between the two GA formulations in the total injection pain
`rating occurring immediately after injection as reported on
`a Visual Analog Scale (VAS). Daily injection pain was
`rated by the patients with a I00 mm VAS, where 0 mm
`represented “no pain” and l(l0 mm represented “worst
`possible pain.” Injection pain occurring 5 min after the
`injection was also recorded daily on a 100 mm VAS
`(secondary outcome variable). Patients reported the pres-
`ence or absence of LISRS and the degree of LISR severity
`that occurred within the 5 min and 24 h periods following
`the injection. LISR total presence scores could r'ange from
`0 to 4 for an individual patient depending on how many of
`the following symptoms were experienced: redness, itch-
`ing, swelling, and lunrp. LISR total severity scores could
`range from 0 to l2 for an individual patient depending on
`the severity (rated 0—3, with 0 = none to 3 : severe) of
`each of the following symptoms experienced:
`redness,
`itching, swelling, and lump.
`
`Safety measures
`
`Safety was monitored at each study site by assessing adverse
`events (AE5), evaluating laboratory values (hematology,
`chemistry, and urinalysis), conducting general physical
`exanrinations, and conducting nervous system examinations
`(including mental status, pupil and fundi, cranial nerves,
`motor examination, gait, coordination, reflexes, and sensory
`function).
`
`Statistical analysis
`
`The sample size (60 patients per group) was estimated to
`provide 80% power of detecting an effect of size 18% with
`a two-tailed I test for correlated sample means with an
`alpha value of 0.05. Four trained individuals at a central
`location measured the VAS ratings for all study patients
`and calculated the patient daily scores (inter~rater eonsis—
`tency was confirmed). Daily scores within each period
`were averaged to provide total pain ratings for each patient.
`Also daily scores within each period for LISRS were
`averaged to provide total LISR ratings.
`All statistical analyses were performed using SAS®
`(SAS Institute lne., Cary, NC), Version 8. The normality
`assumption was checked using data plots and the Shapiro-
`Willt test for the primary clinical outcomes variable. Due to
`the non—normality of the data, ANOVA with mean ranked
`average scores and least square means (LS means) were
`used to compare the treatment outcomes. The ANOVA
`model for a two-treatment crossover study was run with
`treatment, sequence, and period as fixed effects, and patient
`within sequence as a random effect. The corresponding
`95% confidence interval
`for
`treatment difference was
`
`calculated. Descriptive statistics for continuous variables
`consisted of it, mean, median, standard deviation (SD),
`standard error of the mean (SEM), minimum, and maxi—
`mum values. Statistical significance was declared when
`p < 0.05.
`
`Results
`
`Patient characteristics
`
`The study was conducted from July 2009 to September
`2009. Patients were recruited from 21 centers in the United
`
`States. A total of 148 patients were randomly assigned to
`Sequence 1
`(H. = 76, Period 1: GA 20 mg/1.0 mL, Period
`2: GA 20 mg/0.5 mL) or Sequence 2 (n : 72, Period 1:
`GA 20 mg/0.5 mL, Period 2: GA 20 mg/1.0 mL). Nearly
`all (95.9%, 142/148) of the patients completed the study.
`Of the six patients who discontinued from the study,
`five patients withdrew consent and one did not meet the
`inclusion criteria but was mistakenly randomized. The majority
`of patients (81.0%) were women, 90.5% of the population was
`Caucasian, and the mean age was 46.0 years (Table l). The
`groups receiving Sequence 1 and Sequence 2 were comparable
`in demographic characteristics. Overall, 99.5 % of patients were
`compliant in the administration of 20 mg/0.5 mL GA and
`99.6% of patients were compliant when administering the
`20 mg/1.0 1nL GA during the study.
`
`Table 1 Patient demographics
`
`Sequence 1"
`(n = 76)
`
`Sequence 2h
`(n : 71)
`
`Total
`(N : 147')
`
`45.1 :: 10.64
`45.0
`
`46.9 i 9.64
`48.0
`
`46.0 :: 10.1?‘
`47.0
`
`2/l—7l
`
`22%.?
`
`2241
`
`15 (19.7)
`61 (80.3)
`
`13 (18.3)
`58 (81.7)
`
`28 (19.0)
`119 (81.0)
`
`Age (years)
`Mean :1: SD
`Median
`
`Range
`Gender. :2 (9%)
`
`Male
`Female
`Race, :1 (%]
`
`Asian
`Black or African
`American
`
`0 (0.0)
`2 (2.6)
`
`71 (93.4)
`Caucasian
`3 (3.9)
`Other
`SD Standard deviation
`
`l (1.4)
`4 (5.6)
`
`l (0.7)
`6 (4.1)
`
`62 (87.3)
`4 (5.6)
`
`133 (90.5)
`7 (4.8)
`
`3 Sequence 1: Period 1, GA 20 mg/1.0 mL; Period 2, GA 2.0 mg/'
`0.5 rnL
`
`h Sequence 2: Period l, GA 20 mg1'0.5 IIIL; Period 2, GA 20 mg!
`1.0 mL
`
`Q Springer
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`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 3
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`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 3
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`

`
`J Neurol (2010) 25':':19l7—1923
`
`daily mean immediate pain score was consistently lower
`when the 20 mg/0.5 mL GA preparation was used than
`when the 20 mg/1.0 mL GA preparation was used (Fig. 2).
`
`Secondary outcomes
`
`V/1.5‘ pain score
`
`As illustrated in Fig. 1, mean VAS total pain scores 5 min
`after administration were 11.85 mm after
`the 20 mg.’
`0.5 mL GA preparation and 17.19 mm after the 20 mg.’
`1.0 ml. GA preparation. The 20 mgi0.5 mL GA prepara-
`tion was associated with significantly less pain 5 min post-
`injection than with the 20 mg/1.0 mL GA preparation; the
`mean ranked VAS scores differed by 27.2 (p < 0.0001; LS
`mean 130.4, 95% CI l16.9—1-43.9; and LS mean 157.6,
`95% CI 144.1—171.2; respectively). There were no signif-
`icant effects associated with the treatment period or
`sequence of formulation.
`
`Presence of LISR.s-
`
`When treated with 20 mg1'il.5 ml, GA the mean occurrence
`(presence) of LlSRs within 5 min posteinjection was 1.41
`symptoms
`(maximum four symptoms), whereas when
`treated with 20 mgfl .0 ml. GA the mean occurrence within
`5 min post-injection was 1.85 symptoms (Fig. 3). As
`indicated by the LS mean analysis for treatment effect, the
`20 mg/0.5 mL GA preparation produced significantly
`fewer l.1SRs within 5 min post-injection than the 20 mg!
`1.0 mL GA preparation (p < 0.0001; mean ranked average
`5 min LISR scores were 126.2 for the 20 mg/0.5 mL GA,
`
`2
`
`E|2GmgJ1.0rnI_.
`
`I 20 m,g;'0.5 mL
`
`.
`
`|\.I u
`
`21]
`
`Lr.
`
`D
`
`Cl
`
`
`
`
`
` 0 vi- Mean(:1;SEM)LISRTnlzdPresnxeSears‘
`D.
`
`5 min
`
`24 hours
`
`Fig. 3 Mean (iSEM) occurrence of LISRS 5 min and 24 h after
`injection of 20 mgl0.5 mJ.. GA or 20 mg/1.0 mL GA. “As indicated
`on the Y axis, the presence of symptoms scores could range from (1
`“no symptoms” to 4 “all four symptoms occurred.“ *1: < 0.0001;
`20 1ngI0.5 1111., LS mean 126.2 symptoms, 95% CI 1]2.9—-139.6; and
`20 mg/1.0 mL LS mean 161.3 symptoms, 95% Cl
`I47.9—l74.7.
`lp <: 0.0001; 20 mg/0.5 ml. LS mean 132.0 symptoms, 95% C1
`11S.5—145.6; and 20 mg."I.0 mL LS mean 155.8 symptoms, 95% C1
`1422-1693
`
`1920
`
`Primary outcome
`
`The mean immediate VAS total pain score was 8.64 mm
`after administration of 20 mg/0.5 1nL GA and 11.89 mm
`after administration of 20 mgfl .0 ml. GA (Fig. 1). Because
`of the non—normal distribution of the VAS scores, the rank
`
`than observed scores, were statistically
`rather
`scores,
`compared. LS mean ranked immediate VAS scores were
`significantly lower after administration of 20 mg/0.5 mL
`GA than after 20 mg/1.0 mL GA ifp <: 0.0001; LS mean
`133.6, 95% CI l2{).U—l47.2; and LS mean 154.7, 95% CI
`
`respectively). There were no significant
`l41.(P168.3;
`effects associated with the treatment period or sequence of
`formulation. Throughout the 14-day treatment period, the
`
`:1 20rrtg/].0mI.
`I2‘.0mgJO.5mL
`
`[J
`
`Immediate
`
`5 min
`
`‘E H10 1
`E 20-
`::
`E .4
`m 12
`
`-
`
`g 10
`E s
`g
`5
`3.
`-1
`E
`2
`
`U E
`
`Fig. I WAS total pain scores (mean + SEM) recorded immediately
`and 5 min after injection of 20 mgI0.5 mL GA or 20 mg/'1 .0 mL GA.
`"As indicated on the Y axis, the rating scale for VAS total pain scores
`was 0 "no pain" to 100 mm "worst possible pain." *p < 0.0001;
`20 mg/0.5 mL LS mean 133.6 mm, 95% CI 120.0—147.2; and 20 mg}
`1.1) mL LS mean 154.7 mm, 95% Cl 141.0—16R.3.
`lp < 0.0001;
`20 mg/0.5 mL LS mean 130.4 mm, 95% C1 116.9 143.9; and 20 mg}
`1.0 mL LS mean 157.6 mm, 95% Cl 144-.l—l71.2
`
`
`
`
`
`Mean[iSEM)ImmediateFus1:—]n'je:i:'nn
`
`VASScare
`
`truth)‘
`
`20mg/'l.0mL -—20mgf0.5mI..
`
`1:
`._l_
`
`
`
`
`
`Fig. 2 Daily mean (::SEM) immediate pain scores after injection of
`20 mg/0.5 mL GA or 20 mg/1.0 n1L GA. “As indicated on the Yaxis,
`the rating scale for VAS total pain scones was 11 “no pain" to 100 mm
`“worst possible pain.”
`
`Q Springer
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`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 4
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`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 4
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`
`I921
`J Neurol (2010) 257:l91'i'—I923
`
`95% Cl lI2.9—l39.6 and 161.3 for the 20 mg/1.0 mL GA,
`95% CI I4"i‘.9—I74.7'). Neither treatment period nor prep-
`aration sequence affected the findings.
`Within the 24-h time period,
`treatment with 20 mg]
`0.5 mL GA was associated with a mean presence of 0.92
`LISR symptoms, whereas treatment with 20 mg/1.0 mL
`GA was associated with a mean presence of 1.19 LISR
`symptoms (Fig. 3). As indicated by the LS mean for
`treatment effect,
`the 20 mgl0.5 ml. GA preparation pro-
`duced significantly fewer LISRS within 24 h post-injcction
`than the 20 mg! 1.0 mL GA preparation (p < 0.0001; mean
`ranked scores were 132.0, 95% C] I
`I 8.5—l45.6, and 155.3,
`
`95% CI l42.2—l69.3, respectively, no effects of treatment
`period and formulation sequence).
`
`Severity of LIS'R,r
`
`The mean LISR total severity score within 5 min after
`administration was rated 1.64 for 20 mg/0.5 mL. GA and
`rated 2.30 for 20 mg/1.0 mL GA (Fig. 4, maximum score
`could be 12). The 20 mg/0.5 ml. GA preparation was
`associated with a significantly lower mean LISR symptom
`severity score than the 20 mg/1.0 mL GA within 5 min
`post—injection (p < 0.0001; mean ranked scores were 125.3,
`95% CI
`ll2.0—l38.6 and 162.2, 95% Cl
`l48.9—l75.6,
`respectively, with no treatment period and formulation
`sequence effects).
`
`treatment with 20 mg!
`Within the 24-11 time point,
`0.5 mL GA was associated with a mean LISR severity
`score of 1.10, whereas treatment with 20 mg/l.(] mL GA
`was associated with a mean LISR severity score of 1.47
`(Fig. 4). As indicated by the LS mean for treatment effect,
`the 20 mg/0.5 mL GA preparation produced a significantly
`less severe mean LISR score within 24 h post-injection
`than the 20 mg/1.0 mL GA preparation (p < 0.0001; mean
`ranked scores were 132.0, 95% CI ll8.5—l45.6 and 155.8,
`95% CI l42.2—l69.3, respectively, with no treatment per-
`iod and formulation sequence effects).
`
`No syntpmms
`
`Most patients reported some LISR symptoms within 5 min
`following injection of either formulation. It is interesting to
`note, though, that the percentage of patients reporting no
`symptoms within 5 min of the 20 mg/0.5 mL GA injection
`was twice the percentage of patients reporting no symp—
`toms within 5 min of the 20 mg/1.0 ml, GA (Fig. 5).
`Likewise, within 24 h post-injections,
`the majority of
`patients reported LISR symptoms; however, more patients
`reported no symptoms after injecting 20 mg/0.5 IDL GA
`than after injecting 20 mg/1.0 mL GA (Fig. 5).
`
`m-;—-I
`
`5 cu
`
`5_,_t :-
`
`D-I
`
`um
`
`t\.| G
`
`KI‘
`
`C
`
`3 \.'I
`
`C! 1:-
`
`I
`
`E|2{)rrtgfl.0tnL
`
`I2omgJo.5mt.
`
`:-
`
`—I-
`
`5 n-in
`
`24 hours
`
`
`
`
`
`Mean(:1:SEM)LISRTotalSeverityStores‘
`
`
`
`
`
`Fig. 4 Mean (J.SEM) LISR total severity score 5 min and 24 h after‘
`injection of 20 mgI'0.5 mL GA or 20 mg/1.0 n‘1L GA. “As indicated
`on the Y axis, LISR total severity scores could range from 0 to 12 per
`patient depending on the severity (0 "nonc“ to 3 “scvcrc") for each
`of the four l,ISRs cxpcricnccd: redness, itching, swelling and lump.
`*p <: 0.0001; 20 ntgI'0.5 mL LS mean 125.3, 95% Cl
`Il2.0—I3-8.6;
`and 20 mg/1.0 mL LS mean
`162.2,
`95% (‘.1
`148.9 175.6.
`1p < 0.000]; 20 mg/0.5 rn.L LS mean 132.0, 95% Cl 1185-1456; and
`20 t11gIi.C|n1L LS mean 155.8, 95% Cl l42.2—169.3
`
`
`
` ozomytons.
`nzomgxnsmt
`
`
`
`
`
`'u’«9
`4-6
`‘J9
`4-6
`7-9
`
`
`
`5 min Post-injection
` 24 his Posbinjeclion
`Day httentals (days)
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 5
`
`Q Springer
`
`PdLa)La)U13LA
`a-....3
`
`C 5
`
`
`
`PatientswithNoLISRSymptoms(9/0)
`
`Fig. 5 Percentage of patients
`reporting no LISR symptoms
`5 min and 24 h after injection of
`20 mg;'0.5 1111.. GA or 20 mg.’
`1.0 mL GA on days 0—3, days
`4—6, days 7 9. and days >9
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 5
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`

`
`1922
`
`Adverse evemir
`
`Both formulations of GA were well tolerated. During the
`study there were no deaths, serious adverse events (SAEs),
`or AEs that lead to discontinuation. No significant changes
`in the laboratory parameters, vital signs, physical examina-
`tions, or neurological examinations were noted compared
`to baseline assessments or between formulations. The per-
`centage of patients reporting AEs was low (<20%) for both
`treatments. During the entire period of the study, 27 AEs
`were reported for 18 (12.5%) patients treated with 20 mg’
`1.0 ml_. GA, and 38 A135 were reported for 26 (18.1%)
`patients treated with 20 mg/0.5 ml. GA. The most fre-
`quently reported AEs after administration of 20 mg/0.5 mL
`GA were urinary tract infection (2.8%), viral upper respira-
`tory tract infection (1.4%), arthralgia (1.4%), and headache
`(1.4%). The most frequently reported AEs after adminis-
`tration of 20 mg/1.0 mL GA were contusion (1.4%), mus-
`cttlar weakness (1.4%), and ataxia (1.4%). Two severe AEs
`were reported during the study: severe biliary dyskinesia
`during the run-in period and severe hypertonia after admin-
`istration of 20 mg/1.0 mL GA. Both events were not related
`to the study treatment and resolved within 2 days. All other
`AEs were either mild or moderate in intensity.
`Treatment-related AEs were reported for two patients
`during the run-in period (20 mg/1.0 mL GA): one patient
`had biliary dyskincsia and one patient had presyncope.
`Treatment-related Aljs were reported for three patients
`(2.1%) during the 20 mg} 1.0 mL GA treatment period:
`increased hepatic enzyme (:1. = I), anxiety and panic attack
`(:1 = 1 patient), and headache (:1 : 1). Similarly,
`treat-
`ment-related AEs were reported for four patients (2.8%)
`during the 20 mg:'O.5 mL GA treatment period: headache
`and injection site nodule (I2 = 1 patient), panic attack
`(:1
`1 patient), dyspnca (rt: 1 patient), and constipation
`(ti. : 1 patient). None of the treatment-related AEs were
`severe in intensity.
`Two AEs related to the injection-site were reported
`during the study. One patient
`reported injection site
`necrosis on day 2 of the run-in period. The event was mild
`in intensity and not considered to be related to the study
`treatment. Another patient reported injection site nodule on
`day 1 of Period 1 of the 20 mg/0.5 mL GA treatment. The
`event was mild in intensity, considered to be related to the
`study treatment, and spontaneously resolved after 10 days.
`
`Discussion
`
`Overall, the results demonstrate a significant improvement
`in injection pain and LlSRs (swelling, redness, itching, and
`lump) with the novel
`formulation compared with the
`marketed formulation. The mean pain scores were low for
`
`Q Springer
`
`J Neurol (2010) 25?:l9l7'—l923
`
`both formulations; however,
`
`the mean immediate VAS
`
`total pain score was significantly lower after administration
`of 20 mg/0.5 mL GA injection compared with the 20 mgr’
`1.0 mL GA injection. The lower immediate VAS pain
`score associated with the novel formulation was consistent
`
`the
`indicating that
`study,
`the
`14 days of
`all
`over
`improvement in injection pain did not diminish over time.
`The reduced VAS pain score associated with the novel
`formulation was also evident 5 min post-injection.
`The initial onset of LISRS experienced by patients can lead
`them to discontinue treatment or miss injections. Witlt the
`realization that LlSRs may lead to non-adherence, research-
`ers have been investigating ways to limit LISRs [I3, 14]. Use
`of warm compresses and rotating the injection site seem to
`have a moderate effect [13]. As evidenced by the present
`study, reducing the volume may also provide a moderate
`benefit. The incidence and severity of L1SRs within 5 min
`and 24 h post-injection were significantly less for the novel
`formulation than the marketed formulation. Moreover, even
`though most patients reported some LlSRs following injec-
`tion of either formulation, a greater percentage of patients
`treated with the reduced volume solution reported no symp-
`toms within 5 min and 24 h after injection. A longer study
`duration would be needed to detemiine whether the improve-
`ment in injection pain and LlSRs associated with the novel
`formulation improves quality of life, incidence of lipoatrophy,
`and long-term drug adherence.
`A limitation of the study is that it was not blinded.
`Although blinding of the administered volume of the dose
`represents a superior experimental design, it was not pos-
`sible to implement in the present trial for several reasons.
`First, the patients would have been required to be seen at
`the clinic every day, for a total of 35 days, to receive their
`injection. It would have been logistically very difficult for
`the large number of patients required for this trial, and
`place too great a burden on these patients to undertake
`daily visits. Second, to blind the volume of the formulation
`in the syringe, it would not have been sufficient to cover
`the syringe with opaque tape, or use a syringe with opaque
`glass, as the differences in the length of the syringe plun-
`ger, related to differences in the volume, would have been
`noticed by the patients. A new syringe with a redesigned
`plunger was not available for this study. However‘,
`it
`is
`important to note that, although the patients were able to
`detect a difference in the volume of the formulation,
`the
`trial investigators took care not to present one fortntllation
`as “better” or “superior” than the other formulation. In
`addition, patient diaries were collected after each period of
`the trial so that patients did not have the results of the
`previous entries for comparison purposes.
`Both formulations had a good tolerability and safety
`profile. The percentage of subjects reporting AEs was
`low (<20%) for both treatments. All AEs were reported
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 6
`
`MYLAN PHARMS. INC. EXHIBIT 1073 PAGE 6
`
`

`
`I923
`J Ncurol (2010) 25'.":lEll7—1923
`
`previously and there were no unexpected laboratory values.
`The novel formulation has the potential to improve patient
`adherence by producing less pain, and fewer and less
`severe LISRs. The 20 mg/0.5 ml, formulation is a more
`tolerable option for patients using subcutaneous injections
`of GA. Since injection site reactions,
`including pain, are
`the most frequently reported ALis in subjects receiving
`daily injections of GA for RRMS. the 20 tng/0.5 ml_. for-
`mulation may offer clinical benefits for patients.
`
`Acknowledgments The authors thank Stephen Glenski, PharmD. of
`the Medical Affairs division of Teva Neuroscience {Kansas City,
`M0] for assistance with the design, conduction, and analysis of the
`study. The statistical analyses were conducted by i3 Research (a
`division of lngenix Research Pharmaceutical Services, Inc. Basking
`Ridge. NJ). The authors thank Heather 3. Oliff, Phi) (Science Con-
`sulting Group LLC, North Tustin. CA) and Pippa Loupe, PhD
`(Medical Affairs, Teva Neuroscience, Kansas City, M0) for assis-
`tance with this article. The study was funded by Teva Neuroscience,
`Kansas City, MO.
`
`(‘ncgory Anderson has received honoraria and!
`Conflict of interest
`or research funding from the following companies: Teva Neurosci-
`ence. Glaxo Smith Kline, Biogen ldec, Johnson and Johnson, Eli
`l.illy, Genzyme. Opexa, Merck, Supernus, Boehringer Ingelheim,
`Janssen. and Elan. Ronald Murray has received honoraria andfor
`research funding from the following companies: Teva Neuroscience,
`Pfizer, Bayer Health Care. and Biogen Idec. David Meyer has
`received honoraria and/or research funding from the following cont-
`panies: Teva Neuroscience, Biogen Idec. Bayer, EMD Serono, Forest,
`Novat'tis. Pfizer, and Eli Lilly. Craig I-Iern-nan has received honoraria
`from l-tiogen ldce and research funding from Teva Neuroscience.
`Christopher Sheppard ltas received honoraria and/or research funding
`from Teva Neuroscience, Hiogcn Idec, and EMD Serono Phat‘n1a—
`ceuticals. Edward Fox has received a honoraria and/or research
`
`funding front the following companies: Bayer, l-liogen-ldcc, EMD
`Serono, Genayme, Opexa Therapeutics. Pfizer. Teva Neuroscience,
`Eli Lilly. Ono, and Sanofi—Aventis. Jill Conner is an employee of
`Teva Neuroscience (Kansas City, MO), a division of Teva Pham1a—
`eeuticals. Inc, Petah Tiqva. Israel. Julie Maltitena is an employee of
`Teva Neuroscience (Kansas City, MD), a division of Teva Phanna-
`ceuticals, lnc, Pctah 'l‘iqva, Israel. Phil Bttck is an employee of Teva
`Neuroscience (Kansas City, MO), a division of Teva Pharmaceuticals,
`Inc, Petah Tiqva, Israel.
`
`'l‘his article is distributed under the tcrnts of the
`Open Access
`Creative Commons Attribution Noncommercial License which per-
`mits any noncommercial use, distribution. and reproduction in any
`mcdittm. provided the original ant]tor{s) and source are credited.
`
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