RMD Open: first published as 10.1136/rmdopen-2014-000037 on 12 August 2015. Downloaded from
`
`http://rmdopen.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`Rheumatoid arthritis
`
`EXTENDED REPORT
`
`Efficacy and safety of tabalumab,
`an anti-BAFF monoclonal antibody,
`in patients with moderate-to-severe
`rheumatoid arthritis and inadequate
`response to TNF inhibitors: results
`of a randomised, double-blind,
`placebo-controlled, phase 3 study
`
`Michael Schiff,1 Bernard Combe,2 Thomas Dörner,3 Joel M Kremer,4
`Thomas W Huizinga,5 Melissa Veenhuizen,6 Anne Gill,7 Wendy Komocsar,7
`Pierre-Yves Berclaz,8 Robert Ortmann,7 Chin Lee7
`
`To cite: Schiff M, Combe B,
`Dörner T, et al. Efficacy and
`safety of tabalumab, an anti-
`BAFF monoclonal antibody,
`in patients with moderate-to-
`severe rheumatoid arthritis
`and inadequate response to
`TNF inhibitors: results
`of a randomised, double-
`blind, placebo-controlled,
`phase 3 study. RMD Open
`2015;1:e000037.
`doi:10.1136/rmdopen-2014-
`000037
`
`▸ Prepublication history
`and additional material is
`available. To view please visit
`the journal (http://dx.doi.org/
`10.1136/rmdopen-2014-
`000037).
`
`Received 11 December 2014
`Revised 3 May 2015
`Accepted 18 June 2015
`
`For numbered affiliations see
`end of article.
`
`Correspondence to
`Chin Lee;
`leechinhyok@lilly.com
`
`ABSTRACT
`Background: Tabalumab is a human monoclonal
`antibody that neutralises B-cell activating factor.
`Objectives: To evaluate tabalumab efficacy and safety
`in patients with rheumatoid arthritis (RA).
`Methods: This phase 3, randomised, double-blind,
`placebo-controlled study evaluated 456 patients with
`active RA after 24-week treatment with subcutaneous
`tabalumab (120 mg every 4 weeks (120/Q4W) or
`90 mg every 2 weeks (90/Q2W)) versus placebo, with
`loading doses (240 or 180 mg) at week 0. Patients
`were allowed background disease-modifying
`antirheumatic drugs and previously discontinued ≥1
`tumour necrosis factor α inhibitors for lack of efficacy/
`intolerance. Primary end point was American College of
`Rheumatology 20% (ACR20) response at 24 weeks.
`This study was terminated early due to futility.
`Results: Most patients had moderate-to-high baseline
`disease activity. There was no significant difference in
`week 24 ACR20 responses between 120/Q4W, 90/
`Q2W, and placebo (17.6%, 24.3%, 20%) per non-
`responder imputation analysis. Mean percent changes
`in CD20+ B-cell count (−10.8%, −9.6%, +10.9%)
`demonstrated expected pharmacodynamic effects.
`Treatment-emergent adverse events (AEs) were similar
`(59.5%, 51.7%, 52.6%), as were AE discontinuations
`(2.6%, 2.7%, 2.6%), serious AEs (4.6%, 4.1%, 3.9%),
`serious infectious events (1.3%, 0, 0) and events of
`interest: infections (23.5%, 25.9%, 24%), injection site
`reactions (13.1%, 25.8%, 11%) and allergy/
`hypersensitivity (3.9%, 4.1%, 3.9%) reports. Incidence
`of treatment-emergent antidrug antibodies was similar
`to placebo (3.9%, 4.8%, 3.9%). No deaths or new/
`unexpected safety findings were reported.
`Conclusions: Tabalumab did not demonstrate clinical
`efficacy in patients with RA in this phase 3 study,
`
`Key messages
`
`What is already known about this subject?
`B cells contribute to the immunopathology of auto-
`immune disorders including rheumatoid arthritis
`(RA), which may be related to increased B-cell acti-
`vating factor (BAFF) signalling. Earlier phase clinical
`trials of anti-BAFF monoclonal antibodies showed a
`clinical effect in RA.
`
`What does this study add?
`BAFF targeting via tabalumab did not provide clin-
`ical benefit in this phase 3 trial for patients with
`moderate-to-severe RA with
`prior
`inadequate
`response
`to
`tumour
`necrosis
`factor
`(TNF)
`inhibitors.
`
`How might this impact on clinical practice?
`In patients with prior inadequate response to TNF
`inhibitors, targeting the BAFF pathway alone was
`not an effective approach to treating RA. Targeting
`BAFF may not be a viable therapeutic approach.
`
`despite evidence of biological activity. There were no
`notable differences in safety parameters between
`tabalumab treatment groups and placebo.
`Trial registration number: NCT01202773.
`
`INTRODUCTION
`B cells contribute to the immunopathology
`of autoimmune disorders including rheuma-
`toid arthritis (RA), which may be related to
`increased B-cell activating factor (BAFF)
`
`Schiff M, et al. RMD Open 2015;1:e000037. doi:10.1136/rmdopen-2014-000037
`
`1
`
`Lassen - Exhibit 1026, p. 1
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`

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`RMD Open: first published as 10.1136/rmdopen-2014-000037 on 12 August 2015. Downloaded from
`
`http://rmdopen.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`RMD Open
`
`signalling.1 Dysregulated BAFF expression contributes to
`autoimmunity primarily via effects on survival of imma-
`ture and transitional B cells and the resulting failure to
`eliminate self-reactive B cells. Conversely, blocking BAFF
`has been shown to reverse autoimmune disease in
`animal models.2 3 Furthermore, many patients with RA
`have elevated BAFF in blood and synovial fluid.3 4
`Disease-modifying antirheumatic drugs (DMARDs) are
`a part of the standard of care to treat RA, including the
`class of biologics (bDMARDs) that
`target
`tumour
`necrosis factor (TNF).5 Though numerous RA therapies
`are currently available, 20–50% of patients do not
`achieve significant clinical improvement,6–12 or they fail
`to maintain efficacy after initial therapeutic benefit.13
`Thus, new treatment options for RA are needed.
`Tabalumab is a fully human immunoglobulin G sub-
`class 4 (IgG4) monoclonal antibody that binds and neu-
`tralises both soluble and membrane-bound BAFF.14 In
`phase 2 studies, tabalumab demonstrated evidence of
`both biological and clinical activity in patients with
`active RA and inadequate response to methotrexate.15 16
`This phase 3 study was designed to evaluate efficacy and
`safety of tabalumab in patients with RA who had an inad-
`equate response to one or more TNF inhibitors.
`
`METHODS
`Study design
`H9B-MC-BCDV (FLEX V; NCT01202773) was a phase 3,
`double-blind, placebo-controlled study comprised of a
`screening period of 7–28 days, a 24-week treatment
`period and post-treatment follow-up for up to 48 weeks.
`Participants were randomly assigned (1:1:1) to treatment
`groups by a computer generated random sequence
`using the Interactive Voice Response System (IVRS); the
`randomisation code was held by the vendor performing
`IVRS functions.
`This study evaluated two subcutaneous (SQ) tabalu-
`mab doses: 120 mg every 4 weeks (120/Q4W) or 90 mg
`every 2 weeks (90/Q2W), versus placebo. At week 0,
`patients assigned to a tabalumab regimen received a SQ
`loading dose that was twice the treatment dose (ie,
`240 mg or 180 mg).
`
`Patient eligibility
`of
`in American College
`Eligible patients were
`Rheumatology (ACR) functional class I, II, or III; had at
`least 8/68 tender and at least 8/66 swollen joints; had
`been treated at approved doses with at least 1 biological
`TNF inhibitor therapy; and stopped prior anti-TNF treat-
`ment due to either (1) insufficient efficacy or loss of effi-
`cacy after ≥90 days of treatment or (2) intolerance to
`treatment regardless of treatment duration. If patients
`were on conventional DMARDs, they were required to
`have been on a stable dose for ≥8 weeks prior to study
`baseline.
`This study was conducted in accordance with local
`institutional review board ethical standards, good clinical
`
`practices and the Declaration of Helsinki. All patients
`provided written informed consent before
`study
`participation.
`
`Study assessments
`The primary objective was to demonstrate the superiority
`of either tabalumab regimen over placebo as measured
`by a 20% response rate in a core set of measures
`(ACR20) after 24 weeks of treatment.
`Secondary efficacy end points were to demonstrate super-
`iority of either tabalumab regimen over placebo after
`24 weeks of
`treatment as measured by ACR50 and
`ACR70 (ie, 50% and 70% ACR response rates), ACR-N
`( per cent improvement on the ACR), individual compo-
`nents of the ACR core set, Disease Activity Score based
`on a 28-joint count (DAS28) and C reactive protein
`(CRP) level (DAS28-CRP), time to ACR20 response and
`European League Against Rheumatism Responder
`Index based on the 28-joint count (EULAR-28).
`Health utilisation and outcomes evaluated as second-
`ary end points included the Medical Outcomes Study
`36-Item Short Form Health Survey (SF-36), Brief Fatigue
`Inventory (BFI), Brief Pain Inventory Modified Short
`Form (BPI-SF modified), duration of morning stiffness
`and the use of concomitant medications specifically for
`RA taken during the treatment period.
`Biological activity of tabalumab was assessed over time
`via changes in serum immunoglobulins, CD20+ B-cell
`absolute counts and relative percentages ( percentages
`of the total lymphocyte population), compared between
`each treatment regimen and placebo.
`Safety assessments were treatment-emergent adverse
`events (TEAEs), TEAEs of
`special
`interest, clinical
`laboratory tests including immunogenicity testing, vital
`signs and concomitant medications.
`
`Statistical analyses
`A sample size of 555 randomised patients (185 patients
`each per tabalumab regimen and placebo group) was
`calculated to provide ≥99% power to detect a ≥30% dif-
`ference in ACR20 response rates at week 24 for each
`tabalumab regimen versus placebo, assuming a placebo
`response rate of 18%. ACR20 significance testing used
`the Dunnett procedure at an overall 2-sided α level of
`0.05, with each tabalumab regimen versus placebo com-
`parison made at a two-sided α level of 0.0272. All other
`statistical
`tests of
`treatment effects and interaction
`effects were performed at two-sided significance levels of
`0.05 and 0.10, respectively, unless otherwise stated.
`Primary and key secondary analyses followed a gatekeep-
`ing testing strategy to control the overall type I error
`rate at a two-sided α level of 0.05. Treatment group com-
`parisons used Fisher’s exact test for categorical data and
`analysis of variance (ANOVA) for continuous data,
`unless otherwise stated.
`Efficacy and health outcome analyses were conducted
`following the intention-to-treat principle. Primary effi-
`cacy analysis was
`repeated on the per protocol
`
`2
`
`Schiff M, et al. RMD Open 2015;1:e000037. doi:10.1136/rmdopen-2014-000037
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`Lassen - Exhibit 1026, p. 2
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`RMD Open: first published as 10.1136/rmdopen-2014-000037 on 12 August 2015. Downloaded from
`
`http://rmdopen.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`population, a subset of the intent-to-treat (ITT) popula-
`tion excluding patients with significant protocol viola-
`tions. Safety analyses were conducted on the safety
`population including all patients who received at least
`one dose of assigned study drug. Primary end point ana-
`lyses of continuous efficacy and health outcome data
`were conducted using a modified baseline observation
`carried forward (mBOCF) approach; all other analyses
`were conducted using the modified last observation
`carried forward (mLOCF) approach. Non-responder
`imputation (NRI) was used for ACR analyses; non-
`responders (NR) were defined by <20% improvement in
`tender joint count and swollen joint count at week 16.
`Non-responders at week 16, patients who discontinued
`study treatment at any time and randomised patients
`with no postbaseline observations were defined as NR
`for all ACR end point analyses.
`
`RESULTS
`Patient population
`In total, 456 patients met enrolment criteria and were
`randomised, and comprised the ITT population: 153
`patients in the 120/Q4W group, 148 patients in the 90/
`Q2W group and 155 patients in the placebo group
`( figure 1). Two randomised patients (1 patient each in
`the 90/Q2W and placebo groups) did not receive study
`treatment and were excluded from the safety population
`of 454 patients. The study was conducted from 28
`January 2011 to 12 March 2013.
`Baseline demographic and disease characteristics are
`summarised for each treatment group in table 1.
`Patients were a mean age of 53 years,
`the majority
`(84%) were women; most were located in North
`America (58.8%) with a mean time since RA diagnosis
`of 8.2 years. At baseline, most patients (75.4%) were
`seropositive for both RF+ and anti-CCP+. Patients for
`whom data were available had disease severity charac-
`terised as
`very
`active RA (75.3%), defined by
`DAS28-CRP >5.1, whereas the remaining patients had
`disease that was moderately active RA (24.7%), defined
`as DAS28-CRP >3.2–≤5.1. Demographic variables and
`clinical characteristics were generally balanced between
`treatment groups, with no significant difference between
`placebo and tabalumab treatment groups.
`
`Efficacy assessments
`ACR20 responders at the week 24 end point in the ITT
`population included: 17.6% in the 120/Q4W group,
`24.3% in the 90/Q2W group and 20% in the placebo
`group ( figure 2). Fisher’s exact test was used at the week
`24 end point because the sample size was not sufficient
`for logistic regression due to week 16 non-response,
`drop out and sponsor decision. There were no signifi-
`cant differences in the ACR20 response rate at the week
`24 end point
`for either tabalumab treatment group
`versus the placebo group; therefore, the primary end
`point of this study was not met. While a significant
`
`Rheumatoid arthritis
`
`ACR20 response rate at week 12 was observed for
`patients in the 90/Q2W treatment group (28.4%) versus
`the placebo group (18.1%; p=0.030), this benefit was
`not sustained at week 24.
`In the ITT population, mean changes from baseline at
`the week 24 mBOCF on individual ACR components—
`tender and swollen joint count, patient global assess-
`ment (PtGA), physician global assessment (PhGA), pain
`VAS—were similar across all treatment groups (data not
`shown). There were no significant differences for either
`tabalumab treatment group versus placebo in ACR50,
`ACR70, CRP, HAQ-DI or DAS28-CRP scores, or propor-
`tions of patients who reported a good to moderate
`rating on the EULAR-28 (mLOCF). After an interim
`analysis that was prompted by lack of efficacy in a separ-
`ate
`tabalumab study
`(H9B-MC-BCDM;
`FLEX M;
`NCT01198002), the present study was terminated by the
`sponsor due to futility evidenced by insufficient efficacy.
`
`Biological activity
`In the safety population, both tabalumab groups showed
`an expected initial increase in mean CD20+ B-cell abso-
`lute counts at week 1 (median per cent change from
`baseline: 37.6–56.3%) compared with placebo (−2.6%),
`followed by a subsequent decrease back to baseline or
`lower starting at week 4 ( figure 3). At week 24 (exclud-
`ing week 16 non-responders), CD20+ B-cell absolute
`count median per cent change from baseline was
`−43.2%, −53.2% and −1.1% for 120/Q4W, 90/Q2W and
`placebo groups, respectively. Significant differences were
`observed at week 24 (mLOCF) in tabalumab groups
`versus placebo for mean CD20+ B-cell count change
`from baseline (−62.0 cells/µL, −65.2 cells/µL, and −3.8
`cells/µL; p<0.001 vs placebo for each comparison) and
`change from baseline in CD20+ B cells as percentage of
`total lymphocytes (−3%, −3.4%, and 0.1%; p<0.001 vs
`placebo for each comparison).
`For week 16 non-responders initially randomised to
`tabalumab, the patterns of absolute CD20+ B-cell count
`median percent change from baseline and median time
`to B-cell nadir were similar with B-cell changes observed
`for the responders.
`For this study, B-cell recovery was defined as <43 cells/
`µL and <50% of B-cell baseline values. Fifteen patients
`(excluding week 16 non-responders) had 1 or more low
`B-cell counts: 8, 5 and 2 patients, respectively. These
`patients were further evaluated to determine the time
`from nadir to recovery. The median time from B-cell nadir
`to recovery (Kaplan-Meier estimates, excluding week 16
`non-responders) was 11.9 weeks (95% CI 8.4 weeks to not
`available) for 120/Q4W group and 12.3 weeks (95% CI
`12.1 weeks to 22.4 weeks) for 90/Q2W group.
`In the safety population, both tabalumab groups
`demonstrated decreases in mean serum immunoglobu-
`lins over the 24-week treatment period ( figure 3B–D).
`At the week 24 end point (mLOCF), the IgA mean per
`cent change from baseline was −9%, −9% and +1.6%,
`respectively ( p<0.001 vs placebo, each comparison); IgG
`
`Schiff M, et al. RMD Open 2015;1:e000037. doi:10.1136/rmdopen-2014-000037
`
`3
`
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`RMD Open: first published as 10.1136/rmdopen-2014-000037 on 12 August 2015. Downloaded from
`
`http://rmdopen.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`RMD Open
`
`Figure 1 Patient disposition. Eligibility was assessed during screening, then randomisation to 24 weeks of treatment
`(or 16 weeks for non-responders) in 1 of 2 tabalumab regimens or placebo and 48 weeks of follow-up. 120/Q4W=120 mg
`subcutaneous (SQ) tabalumab injection every 4 weeks; 90/Q2W=90 mg SQ tabalumab injection every 2 weeks.
`
`mean per cent change from baseline was −7.2%, −7.9%
`and +1.4%, respectively ( p<0.001 vs placebo, each com-
`parison); and IgM mean percent change from baseline
`was −15%, −14.8% and +0.2%, respectively ( p<0.001 vs
`placebo, each comparison).
`No correlation was observed between immunoglobulin
`changes from baseline to the week 24 mLOCF end point
`and number of treatment-emergent infections or anti-
`drug (tabalumab) antibodies (ADA) for either tabalu-
`mab group versus placebo during the treatment and
`follow-up periods.
`
`Safety profile
`During the 24-week treatment period, the incidence of
`treatment-emergent adverse events (TEAEs) and serious
`AEs were similar across treatment groups (table 2). The
`incidence of TEAEs was 59.5%, 51.7% and 52.6% in the
`120/Q4W, 90/Q2W and placebo groups, respectively.
`The majority of TEAEs were mild or moderate in sever-
`ity. The most
`frequently reported TEAEs (≥5% of
`patients in any group) were exacerbation of RA (5.9%,
`4.8% and 7.8%) and upper respiratory tract infection
`(5.9%, 4.8% and 5.8%; table 2). There were no signifi-
`cant differences between either tabalumab group versus
`placebo for either of
`these events. Possibly-related
`
`TEAEs reported by ≥5% of patients in either tabalumab
`group included infections and infestations (7.2%, 9.5%
`and 11.7%), and general disorders and administration
`site conditions (7.2%, 9.5% and 5.8%). TEAEs were the
`reason for study discontinuation in four patients in each
`treatment group among responders. No significant
`dose-related increase in TEAEs was observed for any
`single event or grouping of TEAEs evaluated.
`AEs of special interest that deserve mention include
`infections, allergic/hypersensitivity events, injection site
`reactions, cardiovascular events and depression. The
`incidence of
`treatment-emergent
`infections (23.5%,
`25.9% and 24%) and non-anaphylactic allergic/hyper-
`sensitive reactions (3.9%, 4.1% and 3.9%) were similar
`across 120/Q4W, 90/Q2W and placebo groups, respect-
`ively. Two major cardiovascular adverse events were
`reported during the treatment period: a serious arrhyth-
`mia (1 patient in the 90/Q2W group) and coronary
`revascularisation (1 patient
`in the placebo group).
`Twenty-one patients who received tabalumab (7 (13.1%)
`in the 120/Q4W group and 14 (25.8%) in the 90/Q2W
`group) and 6 (11%) patients in the placebo group
`reported a treatment-emergent injection site reaction
`during the treatment period. The exposure-adjusted rate
`of injection site reactions per 100 patient-years exposure
`
`4
`
`Schiff M, et al. RMD Open 2015;1:e000037. doi:10.1136/rmdopen-2014-000037
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`Lassen - Exhibit 1026, p. 4
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`RMD Open: first published as 10.1136/rmdopen-2014-000037 on 12 August 2015. Downloaded from
`
`http://rmdopen.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`Table 1 Patient baseline characteristics
`
`Baseline characteristic
`
`Tabalumab 120/Q4W
`N=153
`
`Tabalumab 90/Q2W
`N=148
`
`Placebo
`N=155
`
`Rheumatoid arthritis
`
`54.2±11.6
`124 (81.0)
`
`119 (78.8)
`14 (9.3)
`10 (6.6)
`8 (5.3)
`0
`
`89 (58.2)
`25 (16.3)
`20 (13.1)
`8 (5.2)
`11 (7.2)
`79.6
`29.9
`8.1±4.3
`19.5±12.2
`28.6±15.8
`62.3±17.3
`63.7±23.0
`62.8±22.2
`16.29
`1.67±0.58
`5.84±1.02
`11 (7.2)
`19 (12.4)
`114 (74.5)
`223±171
`
`3 (2.0)
`94 (61.4)
`30 (19.6)
`26 (17.0)
`
`140 (91.5)
`13 (8.5)
`0
`82 (53.6)
`
`Age, mean years±SD
`Female, n (%)
`Race, n (%)
`White
`Black
`Asian
`American Indian/Alaska native
`Multiracial
`Geographic region, n (%)
`North America
`Central/South America
`Eastern Europe
`Western Europe
`Rest of world*
`Weight, mean kg
`Body mass index, mean kg/m2
`Time since RA diagnosis, mean years±SD
`Swollen joint count (66), mean±SD
`Tender joint count (68), mean±SD
`PhGA (VAS), mean±SD
`PtGA (VAS), mean±SD
`Patient assessment of pain (VAS), mean±SD
`C reactive protein, mg/L, mean±SD
`HAQ-DI, mean±SD
`DAS28-CRP, mean±SD
`Only RF+, n (%)
`Only anti-CCP+, n (%)
`Both RF+ and anti-CCP+, n (%)
`Absolute CD20+ B-cell count (cells/μL) mean±SD
`Number of previous TNF treatment failures, n (%)
`0
`1
`2
`≥3
`Background DMARDS, n (%)
`1
`2
`≥3
`Background corticosteroids, n (%)
`Mean daily dose of background medications
`15.5 (n=126)
`15.5 (n=131)
`Methotrexate, mg/week
`360.0 (n=10)
`376.5 (n=17)
`Hydroxychloroquine, mg/day
`1900.0 (n=10)
`1419.6 (n=8)
`Sulfasalazine, mg/day
`*Rest of world=Russia, Australia, Japan, Korea, Malaysia, New Zealand, South Africa and Taiwan.
`120/Q4W=120 mg subcutaneous (SQ) tabalumab injection every 4 weeks; 90/Q2W=90 mg SQ tabalumab injection every 2 weeks.
`ACR, American College of Rheumatology; CCP, cyclic citrullinated peptide; DAS28-CRP, Disease Activity Score based on a 28 joint count
`and C reactive protein level; DMARD, disease-modifying antirheumatic drug; EULAR-28, European League Against Rheumatism Responder
`Index in 28 joints; HAQ-DI, Health Assessment Questionnaire-Disability Index; PhGA, physician global assessment; PtGA, patient global
`assessment; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumour necrosis factor; VAS, visual analogue scale.
`
`51.3±11.7
`126 (85.1)
`
`108 (74.0)
`16 (11.0)
`9 (6.2)
`9 (6.2)
`4 (2.7)
`
`90 (60.8)
`21 (14.2)
`18 (12.2)
`8 (5.4)
`11 (7.4)
`80.3
`29.9
`7.9±3.9
`19.8±12.2
`30.1±17.1
`63.9±17.0
`65.3±21.6
`66.0±21.6
`14.57
`1.68±0.60
`5.88±1.04
`8 (5.4)
`15 (10.1)
`112 (75.7)
`210±154
`
`1 (0.7)
`95 (64.2)
`27 (18.2)
`25 (16.9)
`
`136 (93.2)
`10 (6.8)
`0
`85 (57.4)
`
`54.0±11.1
`131 (84.5)
`
`112 (74.2)
`18 (11.9)
`13 (8.6)
`6 (4.0)
`2 (1.3)
`
`89 (57.4)
`25 (16.1)
`18 (11.6)
`7 (4.5)
`16 (10.3)
`77.6
`29.3
`8.7±4.2
`18.3±11.7
`28.7±15.7
`62.4±19.0
`68.1±20.1
`65.1±21.6
`19.11
`1.66±0.56
`5.89±0.97
`9 (5.8)
`13 (8.4)
`117 (76.0)
`223±153
`
`4 (2.6)
`86 (55.5)
`42 (27.1)
`23 (14.8)
`
`133 (86.9)
`17 (11.1)
`3 (2.0)
`86 (55.5)
`
`15.8 (n=135)
`336.8 (n=19)
`1590.9 (n=11)
`
`for the 90/Q2W treatment group (25.8) was almost
`double the rate for the 120/Q4W (13.1) and placebo
`treatment groups (11.0). No patients discontinued study
`treatment due to an injection site reaction. All injection
`site reactions were mild to moderate in severity. The inci-
`dence of depression or suicidal
`ideation was similar
`across the treatment groups (2%, 0.7% and 2.6%).
`
`Serious AEs were reported in seven patients (4.6%)
`in the 120/Q4W group, 6 (4.1%) in the 90/Q2W
`group and 6 (3.9%) in the placebo group, during the
`24-week treatment period. Serious infections (2 cases of
`pneumonia, 1.3%) were reported in the 120/Q4W
`group only. Opportunistic infections were reported in 3
`(2%), 6 (4.1%) and 6 (3.9%) patients, respectively, in
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`Schiff M, et al. RMD Open 2015;1:e000037. doi:10.1136/rmdopen-2014-000037
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`5
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`Lassen - Exhibit 1026, p. 5
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`Figure 2 ACR20 response rates. ACR20 response rates
`based on non-responder imputation (NRI) for the 120/Q4W,
`90/Q2W and placebo groups over 24 weeks of treatment.
`Response rates are based on the ITT population.
`ACR20=20% improvement in American College of
`Rheumatology criteria; 120/Q4W=120 mg subcutaneous (SQ)
`tabalumab injection every 4 weeks; 90/Q2W=90 mg SQ
`tabalumab injection every 2 weeks.
`
`the treatment and follow-up periods. Individual events
`included investigator reported pneumonia, nail
`infec-
`tion, herpes zoster, upper respiratory infection,
`influ-
`enza, erysipelas, UTI, nasopharyngitis, sinusitis, cellulitis
`and device-related infection. No deaths were reported
`in this study.
`
`No notable differences or trends were identified for
`vital signs, ECG, or clinical laboratory test results during
`the study treatment period.
`
`Immunogenicity
`Over the 24-week treatment period, 6 (3.9%), 7 (4.8%)
`and 6 (3.9%) patients in the 120/Q4W, 90/Q2W and
`placebo groups, respectively, developed persistent or tran-
`sient treatment-emergent ADA (defined as ≥2 dilutions/
`fourfold increase from baseline). Four patients (2.6%), 2
`(1.4%) and 4 (2.6%) patients, respectively, were classified
`as treatment-emergent ADA-persistent defined as 2 or
`more positive samples of at least 12 weeks duration.
`Blood samples from patients who developed ADA
`were also evaluated for neutralising antidrug antibodies
`(NAb). One (0.3%) tabalumab-treated patient had a
`positive NAb result and 2 (0.7%) had negative results.
`Samples
`from 13 (4.3%) patients were inconclusive
`because drug concentrations exceeded the drug toler-
`ance limit for the assay. Given the low frequency of
`ADA, it was difficult to assess the effect of ADA on the
`serum pharmacokinetics of tabalumab. No association
`was found between patients with treatment-emergent
`ADAs and reports of allergic/hypersensitivity (non-
`anaphylaxis) events or injection site reactions in the
`treatment or follow-up period.
`
`Figure 3 (A–D). B-cell and Ig changes. Mean changes in total CD3-CD20+ B-cells (A) and immunoglobulin (Ig) subclasses
`levels (B-D) were measured over 24 weeks of treatment. Mean per cent changes are based on the safety population. 120/
`Q4W=120 mg subcutaneous (SQ) tabalumab injection every 4 weeks; 90/Q2W=90 mg SQ tabalumab injection every 2 weeks;
`mLOCF=modified last observation carried forward. *p<0.001 tabalumab groups versus placebo (both comparisons) at week 24
`(mLOCF).
`
`6
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`Schiff M, et al. RMD Open 2015;1:e000037. doi:10.1136/rmdopen-2014-000037
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`Lassen - Exhibit 1026, p. 6
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`RMD Open: first published as 10.1136/rmdopen-2014-000037 on 12 August 2015. Downloaded from
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`http://rmdopen.bmj.com/
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` on 19 July 2019 by guest. Protected by copyright.
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`Table 2 Summary of adverse events during the treatment period
`
`Events, n (%)
`
`All safety population patients*
`Tabalumab 120/Q4W
`Tabalumab 90/Q2W
`N=153
`N=147
`
`Placebo
`N=154
`
`Week 16
`Non-responders†
`N=93
`
`Rheumatoid arthritis
`
`91 (59.5)
`4 (2.6)
`7 (4.6)
`0
`
`76 (51.7)
`4 (2.7)
`6 (4.1)
`0
`
`Patients with ≥1 TEAE
`Discontinuations due to TEAE
`Patients with ≥1 SAE
`Deaths
`TEAEs in ≥5% of patients (any group)
`4 (4.3)
`12 (7.8)
`7 (4.8)
`9 (5.9)
`Rheumatoid arthritis
`2 (2.2)
`9 (5.8)
`7 (4.8)
`9 (5.9)
`Upper respiratory tract infection
`120/Q4W=120 mg subcutaneous (SQ) tabalumab injection every 4 weeks; 90/Q2W=90 mg SQ tabalumab injection every 2 weeks.
`*Safety data include events up to week 1 for week 16 non-responders; data are reported for the safety population.
`†Safety data collected after week 16 are reported.
`SAE, serious adverse event; TEAE, treatment-emergent adverse event.
`
`81 (52.6)
`4 (2.6)
`6 (3.9)
`0
`
`38 (40.9)
`2 (2.2)
`4 (4.3)
`0
`
`DISCUSSION
`Prior phase two studies of tabalumab in patients with
`moderate-to-severe RA showed evidence of clinical effi-
`cacy, reporting higher ACR20 response rates and signifi-
`cant differences in response rates for ACR50, ACR70,
`DAS-28 CRP and EULAR scores in tabalumab groups
`versus placebo.15 16 Biological activity was also demon-
`strated in these earlier studies, including reductions in
`B-cell counts and serum immunoglobulins.
`While there is no obvious explanation for the discrep-
`ant results in this study relative to the earlier phase two
`studies, there are some differences between the phase 2
`and 3 studies to consider. The baseline characteristics
`for disease activity in the earlier phase 2 studies were
`generally comparable to the current study; however, this
`study was a global study, while some of the phase 2
`studies enrolled patients from less diverse geographic
`regions and were smaller in size. In terms of study drug
`administration,
`in one phase 2 study of patients with
`inadequate response to TNF inhibitors, tabalumab was
`administered as either a 30 mg or 80 mg intravenous
`infusion at weeks 0, 3 and 6,17 while the current phase 3
`study evaluated two subcutaneous (SQ) tabalumab doses
`of 120 mg every 4 weeks (120/Q4W) or 90 mg every
`2 weeks (90/Q2W), versus placebo. A separate phase 2
`tabalumab study of patients with inadequate response to
`methotrexate, which also applied intravenous adminis-
`tration and the same dosing frequency, demonstrated
`that all tabalumab doses were significantly more effective
`than placebo through week 24.15 It is notable that clin-
`ical efficacy corresponded to peak drug concentrations
`following infusion of tabalumab.
`The
`current phase
`3
`study of patients with
`moderate-to-severe RA and prior treatment
`failure or
`intolerance to 1 or more TNF inhibitors did not meet its
`primary objective, as tabalumab treatment was not super-
`ior to placebo for the primary end point of ACR20
`response at week 24 and did not meet any secondary effi-
`cacy objective. The efficacy of tabalumab in special patient
`subgroups (eg, prior prednisolone use, smoking status,
`RF/anti-CCP seropositivity status and number of previous
`
`inconclusive
`failures), was
`treatment
`TNF inhibitor
`because data were insufficient due to early termination of
`the trial. The findings in this study corroborate prelimin-
`ary reported data from other BAFF inhibitor trials in
`patients with RA showing a lack of significant efficacy18 or
`efficacy that was restricted to a bDMARD-naïve sub-
`group.19 Despite the lack of efficacy, the biological activity
`of tabalumab was confirmed, but did not differ between
`the 2 dosing regimens in all parameters tested. Over the
`24-week treatment period, CD20+ B-cells initially increased
`then gradually and significantly declined in response to
`tabalumab but not placebo administration, and without
`total B-cell depletion. This was expected, based on the
`mechanism of action of tabalumab: binding and neutralis-
`ing BAFF,14 an essential B-cell survival signal, and has also
`been reported for other BAFF/B-lymphocyte stimulator
`atacicept).20
`(BLyS)
`inhibiting
`agents
`(belimumab,
`Notably, these other BAFF blocking agents also showed a
`lack of correlation between different dosages and bio-
`marker changes.21 22 In the current study, B-cell decline
`correlated with significant decreases in circulating IgA,
`IgG and IgM levels after tabalumab treatment. Despite
`decreases in biological parameters, there was no difference
`in infection rates for either tabalumab group compared
`with placebo. Tabalumab treatment was associated with a
`low incidence of ADA, and there was no association
`between treatment-emergent ADA and any reports of AEs.
`Frequencies of TEAEs and SAEs were similar across
`tabalumab and placebo groups, and the incidence of
`AEs leading to study discontinuation was low across all
`treatment groups. The safety profile of tabalumab in this
`RA population was consistent with prior studies, and no
`new or unexpected safety findings were observed.15–17
`Compared with prior phase 3 studies of other biological
`therapies in patients with RA, the present study of taba-
`lumab had a similar
`incidence of TEAEs (range:
`51.7-59.5%), discontinuations due to TEAEs (range: 2.6–
`2.7%), infections (range: 23.5–25.9%) and SAEs (range:
`3.9–4.6%).6 23–26
`There were limitations to the design and interpretation
`of results of this study, which was terminated early. The
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`Schiff M, et al. RMD Open 2015;1:e000037. doi:10.1136/rmdopen-2014-000037
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`7
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`Lassen - Exhibit 1026, p. 7
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`RMD Open: first published as 10.1136/rmdopen-2014-000037 on 12 August 2015. Downloaded from
`
`http://rmdopen.bmj.com/
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` on 19 July 2019 by guest. Protected by copyright.
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`RMD Open
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`effects of background DMARD treatment, and prior and
`concomitant RA medications, may limit interpretation of
`results. In addition, patients were previously treated with
`1 or more TNF inhibitors and had discontinued due to
`treatment failure or intolerance; there may be patients in
`this population who are refractory to immunomodulatory
`biological therapy for RA, including tabalumab.
`In this phase 3 study in patients with previous failure
`of biological therapy, tabalumab did not demonstrate
`clinical efficacy in either dosing regimen, despite evi-
`dence of biological activity. Targeting BAFF may not be
`a viable therapeutic approach. Alternatively, the dose of
`active study drug and/or duration of the study may not
`have been optimal to observe a clinical effect. No new
`or unexpected safety findings were reported for patients
`with RA who received tabalumab.
`
`Author affiliations
`1Rheumatology Division, School of Medicine, University of Colorado, Denver,
`USA
`2Department of Rheumatology, Lapeyronie Hospital, Montpellier 1 University,
`Montpellier, France
`3Department of Medicine/Rheumatology and Clinical Immunology, Charité–
`Universitätsmedizin Berlin, Berlin, Germany
`4Division of