Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209668 on 26 September 2016. Downloaded from
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`http://ard.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
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`Clinical and epidemiological research
`
`EXTENDED REPORT
`Efficacy and safety of an interleukin 6 monoclonal
`antibody for the treatment of systemic lupus
`erythematosus: a phase II dose-ranging randomised
`controlled trial
`Daniel J Wallace,1 Vibeke Strand,2 Joan T Merrill,3 Serghei Popa,4 Alberto J Spindler,5
`Alicia Eimon,6 Michelle Petri,7 Josef S Smolen,8 Joseph Wajdula,9 Jared Christensen,10
`Cheryl Li,10 Annette Diehl,9 Michael S Vincent,10 Jean Beebe,10 Paul Healey,11
`Sudhakar Sridharan12
`
`ABSTRACT
`Objectives This phase II trial evaluated the efficacy
`and safety of an interleukin (IL) 6 monoclonal antibody
`for systemic lupus erythematosus (SLE).
`Methods Patients with active disease were randomised
`to placebo or PF-04236921 10 mg, 50 mg or 200 mg,
`subcutaneously, every 8 weeks with stable background
`therapy. SLE Responder Index (SRI-4; primary end point)
`and British Isles Lupus Assessment Group-based
`Composite Lupus Assessment (BICLA) were assessed at
`week 24. Post hoc analysis identified an enriched
`population based upon planned univariate analyses.
`Results 183 patients received treatment ( placebo,
`n=45; 10 mg, n=45; 50 mg, n=47; 200 mg, n=46).
`The 200 mg dose was discontinued due to safety
`findings and not included in the primary efficacy
`analysis. The SRI-4 response rates were not significant
`for any dose compared with placebo; however, the
`BICLA response rate was significant for 10 mg
`( p=0.026). The incidence of severe flares was
`significantly reduced with 10 mg (n=0) and 50 mg (n=2)
`combined versus placebo (n=8; p<0.01). In patients
`with greater baseline disease activity (enriched
`population), the SRI-4 ( p=0.004) and BICLA ( p=0.012)
`response rates were significantly different with 10 mg
`versus placebo. Four deaths (200 mg, n=3; 10 mg, n=1)
`occurred. The most frequently reported adverse events
`included headache, nausea and diarrhoea.
`Conclusions PF-04236921 was not significantly
`different from placebo for the primary efficacy end point
`in patients with SLE. Evidence of an effect with 10 mg
`was seen in a post hoc analysis. Safety was acceptable
`for doses up to 50 mg as the 200 mg dose was
`discontinued due to safety findings.
`Trial registration number NCT01405196;
`Pre-results.
`
`INTRODUCTION
`Systemic lupus erythematosus (SLE) is a chronic,
`systemic autoimmune disease associated with het-
`erogeneous immunological and clinical manifesta-
`tions, leading to sporadic and unpredictable flares
`of multisystem inflammation. SLE has a substantial
`detrimental impact on health-related quality of life
`
`(HRQOL) and participation in daily activities,
`including work within and outside the home.1
`The pleiotropic cytokine interleukin (IL) 6 has a
`range of biological effects and is primarily pro-
`duced by monocytes, fibroblasts and endothelial
`cells, and by T cells, B cells, keratinocytes and
`mesangial cells.2 IL-6 acts alone or alongside other
`cytokines to promote differentiation of B cells into
`immunoglobulin-producing cells, as well as prolif-
`eration and differentiation of T cells.3
`The spontaneous production of autoantibodies
`plays an important role in SLE pathogenesis,4 5
`which has been attributed to B cell hyperactivity.6
`Studies suggest that IL-6 is critically involved in the
`B cell hyperactivity of SLE, and may also mediate
`tissue damage.7 Moreover, IL-6 regulates hepatic
`synthesis of acute phase reactants,
`including the
`inflammatory biomarker C reactive protein (CRP),8
`and is involved in the differentiation of T helper 17
`(Th17) cells, which are understood to be pivotal in
`the induction of autoimmune diseases.9 Consistent
`with these observations, IL-6 production is higher in
`patients with active SLE than in healthy individuals,
`and serum IL-6 levels, as well as IL-6 levels mea-
`sured in skin lesions and the kidney, correlate with
`disease activity.10–14
`Targeting IL-6 signalling may offer a novel thera-
`peutic approach for SLE, supported by promising
`clinical and serological responses observed with the
`soluble IL-6 receptor inhibitor tocilizumab in a
`small, open-label phase I study.15 In this study, 16
`patients with mild-to-moderate SLE received one of
`three dose regimens of tocilizumab every 2 weeks
`for 12 weeks. Improvements in disease activity were
`seen and antidouble-stranded DNA (anti-dsDNA)
`levels decreased. It was noted that there was a clear
`dose-related reduction in complement
`levels and
`neutrophil count.
`PF-04236921 is a fully human immunoglobulin
`G2 monoclonal antibody that binds and neutralises
`IL-6 as demonstrated in the early phase I trials.16
`Here, we report the results of a phase II dose-
`ranging randomised controlled trial to assess the effi-
`cacy and safety of PF-04236921 in patients with
`active SLE.
`
`Handling editor Tore K Kvien
`
` (cid:377) Additional material is
`published online only. To view
`please visit the journal online
`(h t t p : / / d x . d o i . o r g / 1 0 . 1 1 3 6 /
`a n n r h e u m d i s - 2 0 1 6 - 2 0 9 6 6 8 )
`
`For numbered affiliations see
`end of article.
`
`Correspondence to
`Dr Daniel J Wallace, Division of
`Rheumatology, Cedars-Sinai
`Medical Center, Los Angeles,
`CA, 90048, USA;
`danielwallac@gmail.com
`
`Received 5 April 2016
`Revised 30 June 2016
`Accepted 11 July 2016
`Published Online First
`26 September 2016
`
`To cite: Wallace DJ, Strand V,
`Merrill JT, et al. Ann Rheum
`Dis 2017;76:534–542.
`
`534
`
`Wallace DJ, et al. Ann Rheum Dis 2017;76:534–542. doi:10.1136/annrheumdis-2016-209668
`
`Lassen - Exhibit 1029, p. 1
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`

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`Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209668 on 26 September 2016. Downloaded from
`
`http://ard.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`METHODS
`Study design
`Following a 4-week screening period, patients were randomised
`(1:1:1:1) to receive placebo or PF-04236921 10 mg, 50 mg or
`200 mg. Randomisation was performed through an interactive
`voice response system according to a computer-generated ran-
`domisation schedule, with stratification by baseline disease activ-
`ity (SLE Disease Activity Index (SLEDAI)-2K score 6–9 vs ≥10;
`anti-dsDNA antibodies greater than vs less than the upper limit
`of normal (120 IU/mL)). Doses were administered as two sub-
`cutaneous injections at day 1, week 8 and week 16 over a
`24-week double-blind treatment phase, during which efficacy
`and safety data were recorded. Patients subsequently entered a
`28-week follow-up period.
`Consistent with entry criteria, stable (≥30 days before base-
`line) standard-of-care SLE medications including immunosup-
`pressives,
`antimalarials
`and corticosteroids were
`allowed.
`Corticosteroid doses were limited to prednisone ≤25 mg/day at
`baseline. Supplemental corticosteroids were allowed at baseline
`to no more than 10 mg/day above prestudy doses, but had to be
`tapered to the baseline dose by day 28. Subsequent dose increases
`were not allowed thereafter, and tapering was recommended
`based upon clinical
`judgement during the treatment phase,
`however no changes were permitted during the last 4 weeks of
`the 24-week treatment phase. Rescue medications for disease
`worsening were allowed during the treatment phase at investiga-
`tor discretion; however, such patients were considered treatment
`failures and non-responders for the efficacy analyses.
`
`Entry criteria
`Eligible patients were aged 18–75 years, had a clinical diagnosis
`of SLE according to American College of Rheumatology criteria,
`were serologically positive based upon current or historical posi-
`tive test results for antinuclear antibodies (ANA, human epithelial
`type 2; titre ≥1:80) and/or anti-dsDNA antibodies (>120 IU/L),
`and had active disease (SLEDAI-2K score of ≥6 and British Isles
`Lupus Assessment Group (BILAG) 2004 A disease in ≥1 organ
`system or BILAG B disease in ≥2 organ systems if no level A
`disease activity was present). Detailed exclusion criteria are
`included in the online supplementary material.
`
`End points
`The primary efficacy end point was the proportion of patients
`achieving the SLE Responder
`Index (SRI-4) at week 24.
`
`Figure 1 Patient disposition.
`*Treatment group terminated
`prematurely. AE, adverse event.
`
`Clinical and epidemiological research
`
`Responders were defined by a ≥4-point reduction in SLEDAI-2K
`score, no new BILAG A or two new BILAG B organ domain
`scores, and no significant deterioration (<0.3-point increase) in
`Physician’s Global Assessment score compared with baseline. In
`addition, responders could not be treatment failures, defined as:
`new or increased use of corticosteroids after day 28; new or
`increased use of immunosuppressives and/or antimalarials; death
`or hospitalisation due to worsening SLE; treatment discontinuation
`due to SLE; or a flare that would interfere with trial participation.
`Key secondary efficacy end points assessed at week 24 in-
`cluded the proportion of patients achieving BILAG-based
`Composite Lupus Assessment
`(BICLA) responses (responders
`defined by BILAG 2004 improvement (all A scores at baseline
`improved to B/C/D and all B scores improved to C or D), no
`new BILAG A scores and ≤1 new B score, no worsening of
`modified SLEDAI-2K score (modified to omit ‘low complement’
`and ‘leukopoenia’ parameters), no significant deterioration in
`Patient’s Global Assessment score (<10% worsening), and no
`treatment
`failure); ≥10%, ≥30% or ≥50% reductions
`in
`anti-dsDNA antibody levels; mean changes in complement
`levels (C3 and C4); the proportion of patients whose cortico-
`steroid dose was reduced by ≥25% from baseline, and to
`≤7.5 mg/day, for at least one visit up to and including week 24;
`mean changes in 36-item Short Form Health Survey (SF-36;
`V.2) summary and domain scores; mean changes in European
`Quality of Life 5 Dimensions (EQ-5D) visual analogue scale
`(VAS) scores; and mean changes in Functional Assessment of
`Chronic Illness Therapy (FACIT)-Fatigue scores.
`Exploratory efficacy end points at week 24 included the
`incidence of
`severe SLE flares using modified Safety of
`Estrogens
`in Lupus Erythematosus: National Assessment-
`SLEDAI Flare Index (SFI) or BILAG (defined for this proto-
`col as one new BILAG A or two new BILAG B organ domain
`scores).
`Additional details on pharmacokinetic, pharmacodynamic,
`biomarker and safety assessments are provided in the online
`supplementary material.
`
`Post hoc analysis of enriched population
`Prespecified descriptive univariate analyses were performed
`on the following baseline parameters to identify a population
`with an increased likelihood of achieving efficacy: age, gender,
`race, ethnicity, baseline SLEDAI-2K score, corticosteroid use,
`
`Wallace DJ, et al. Ann Rheum Dis 2017;76:534–542. doi:10.1136/annrheumdis-2016-209668
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`Clinical and epidemiological research
`
`Table 1 Patient demographics and disease characteristics at baseline
`
`Mean age, years (SD)
`
`Female, n (%)
`
`Race, n (%)
`
`White
`
`Black
`
`Asian
`
`Other
`Mean BMI, kg/m2 (SD)
`
`Mean SLE duration, years (SD)
`
`Mean SLEDAI-2K score (SD)
`
`SLEDAI-2K ≥10, n (%)
`
`BILAG 2004
`
`Placebo (n=45)
`
`10 mg (n=45)
`
`50 mg (n=47)
`
`200 mg (n=46)
`
`42.3 (13.0)
`
`38 (84.4)
`
`33 (73.3)
`
`4 (8.9)
`
`1 (2.2)
`
`7 (15.6)
`
`29.6 (7.1)
`
`9.1 (6.9)
`
`9.5 (2.2)
`
`22 (48.9)
`
`39.9 (11.5)
`
`43 (95.6)
`
`37 (82.2)
`
`3 (6.7)
`
`1 (2.2)
`
`4 (8.9)
`
`28.6 (6.9)
`
`7.9 (8.1)
`
`9.6 (2.7)
`
`22 (48.9)
`
`38.3 (10.5)
`
`43 (93.6)
`
`36 (76.6)
`
`8 (17.0)
`
`0 (0.0)
`
`3 (6.4)
`
`27.4 (6.9)
`
`7.5 (6.0)
`
`9.0 (2.7)
`
`19 (40.4)
`
`41.3 (11.3)
`
`43 (93.5)
`
`33 (71.7)
`
`9 (19.6)
`
`0 (0.0)
`
`4 (8.7)
`
`29.9 (8.1)
`
`8.6 (6.1)
`
`10.1 (3.9)
`
`22 (47.8)
`
`19 (42.2)
`
`16 (34.0)
`
`25 (54.3)
`
`BILAG A in ≥1 organ system, n (%)
`
`BILAG B in ≥2 organ systems, n (%)
`
`Mean BILAG numerical score (SD)
`
`BILAG A or B in organ domain, n (%)
`
`Cardiorespiratory
`
`Constitutional
`
`Gastrointestinal
`
`Haematological
`
`Mucocutaneous
`
`Musculoskeletal
`
`Neuropsychiatric
`
`Ophthalmic
`
`Renal
`
`20 (44.4)
`
`25 (55.6)
`
`18.4 (3.3)
`
`0 (0.0)
`
`3 (6.7)
`
`0 (0.0)
`
`1 (2.2)
`
`39 (86.7)
`
`44 (97.8)
`
`0 (0.0)
`
`1 (2.2)
`
`1 (2.2)
`
`27 (60.0)
`
`18.5 (4.1)
`
`33 (70.2)
`
`18.3 (4.1)
`
`26 (56.5)
`
`20.0 (5.2)
`
`2 (4.4)
`
`3 (6.7)
`
`0 (0.0)
`
`0 (0.0)
`
`39 (86.7)
`
`45 (100.0)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (2.2)
`
`4 (8.5)
`
`2 (4.3)
`
`0 (0.0)
`
`0 (0.0)
`
`41 (87.2)
`
`46 (97.9)
`
`0 (0.0)
`
`1 (2.1)
`
`2 (4.3)
`
`6 (13.0)
`
`1 (2.2)
`
`0 (0.0)
`
`0 (0.0)
`
`37 (80.4)
`
`45 (97.8)
`
`5 (10.9)
`
`0 (0.0)
`
`3 (6.5)
`
`1.8 (0.3)
`
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`Mean PhGA score (SD)
`
`Serologically positive (ANA ≥1:80 and/or anti-dsDNA >120 IU/mL), n (%)
`
`Anti-dsDNA >ULN (120 IU/mL), n (%)
`
`Detectable anti-dsDNA (≥28 IU/mL), n (%)
`
`Low C3 (<90 mg/dL), n (%)
`
`Low C4 (<16 mg/dL), n (%)
`
`Corticosteroid use, n (%)
`
`Corticosteroids >7.5 mg/day, n (%)
`
`Immunosuppressive use, n (%)
`
`Antimalarial use, n (%)
`
`Mean SF-36 score (SD)
`
`PCS score
`
`1.6 (0.4)
`
`36 (80.0)
`
`13 (28.9)
`
`27 (60.0)
`
`13 (28.9)
`
`10 (22.2)
`
`31 (68.9)
`
`23 (51.1)
`
`20 (44.4)
`
`34 (75.6)
`
`34.6 (10.2)
`
`1.7 (0.4)
`
`35 (77.8)
`
`7 (15.6)
`
`28 (62.2)
`
`12 (26.7)
`
`9 (20.0)
`
`32 (71.1)
`
`14 (31.1)
`
`18 (40.0)
`
`35 (77.8)
`
`1.6 (0.4)
`
`38 (80.9)
`
`10 (21.3)
`
`28 (59.6)
`
`11 (23.4)
`
`5 (10.6)
`
`36 (76.6)
`
`24 (51.1)
`
`21 (44.7)
`
`34 (72.3)
`
`32 (71.1)
`
`11 (23.9)
`
`21 (45.7)
`
`12 (26.7)*
`
`7 (15.6)*
`
`34 (73.9)
`
`18 (39.1)
`
`23 (50.0)
`
`26 (56.5)
`
`34.0 (8.0)
`
`39.6 (11.8)
`
`34.5 (8.4)
`
`42.7 (9.9)
`
`33.9 (9.6)
`
`39.2 (12.2)
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`
`MCS score
`
`Physical functioning
`
`Role physical
`
`Body pain
`
`General health
`
`Vitality
`
`Social functioning
`
`Role emotional
`
`Mental health
`
`Mean EQ-5D VAS score (SD)
`
`Mean FACIT-Fatigue score (SD)
`
`39.9 (9.7)
`
`51.4 (27.8)
`
`43.8 (26.8)
`
`39.5 (22.5)
`
`34.4 (18.7)
`
`35.0 (22.1)
`
`51.7 (25.2)
`
`61.3 (24.6)
`
`57.7 (18.7)
`
`56.7 (22.9)
`
`26.0 (11.8)
`
`48.6 (25.2)
`
`38.5 (24.8)
`
`37.8 (20.3)
`
`34.6 (19.0)
`
`38.9 (21.4)
`
`54.4 (24.5)
`
`56.5 (30.0)
`
`55.0 (20.6)
`
`55.2 (21.5)
`
`25.9 (11.4)
`
`51.3 (24.3)
`
`47.1 (21.7)
`
`39.9 (20.8)
`
`33.9 (11.9)
`
`41.2 (17.8)
`
`57.7 (22.1)
`
`61.2 (27.1)
`
`63.2 (16.2)
`
`57.6 (18.5)
`
`29.4 (10.3)
`
`45.0 (24.3)
`
`42.4 (25.9)
`
`36.3 (19.6)
`
`36.8 (18.7)
`
`37.2 (18.6)
`
`49.7 (24.8)
`
`53.6 (27.9)
`
`57.6 (21.4)
`
`49.8 (20.4)
`
`24.7 (11.6)
`
`*n=45 for the 200 mg group.
`ANA, antinuclear antibody; BILAG, British Isles Lupus Assessment Group; BMI, body mass index; dsDNA, double-stranded DNA; EQ-5D, European Quality of Life 5 Dimensions; FACIT,
`Functional Assessment of Chronic Illness Therapy; MCS, mental component summary; PCS, physical component summary; PhGA, Physician’s Global Assessment; SF-36, 36-item Short Form
`Health Survey; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; ULN, upper limit of normal; VAS, visual analogue scale.
`
`immunosuppressive use, anti-dsDNA antibodies, ANA and
`hypocomplementaemia. A post hoc analysis was conducted to
`evaluate whether influential covariates could define a more
`responsive population.
`
`Statistical analyses
`The primary analysis of SRI-4 responders at week 24 was based
`upon a generalised linear mixed model (GLMM) with stratifica-
`tion variables as covariates for each active treatment versus
`
`536
`
`Wallace DJ, et al. Ann Rheum Dis 2017;76:534–542. doi:10.1136/annrheumdis-2016-209668
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`Lassen - Exhibit 1029, p. 3
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`

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`Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209668 on 26 September 2016. Downloaded from
`
`http://ard.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`placebo comparison. Forty-five patients per group provided
`approximately 80% power to detect a 25% difference in SRI-4
`responder rates between PF-04236921 and placebo at week 24
`using a one-sided α of 0.05. No multiple comparison adjust-
`ments were made for multiple doses. Similar modelling was
`used for the secondary analysis of BICLA responders at week
`24. GLMM analyses for SRI and BICLA included all available
`data before each patient completed week 24 or discontinued.
`The model likelihood was adjusted for missed visits by discon-
`tinued patients based on patients with similar data patterns.
`The incidences of severe SFI flares and BILAG flares were com-
`pared across treatment groups using Fisher’s exact test. Mean
`changes in EQ-5D VAS, FACIT-Fatigue and SF-36 scores for each
`active treatment group were compared with placebo using an ana-
`lysis of covariance model, adjusted for baseline scores.
`Efficacy analyses were performed on the modified intent-
`to-treat population, which included all randomised patients who
`received at least one dose of study drug. After the 200 mg dose
`was stopped, prior to unblinding, the statistical analysis plan
`was amended to exclude this dose group from the primary ana-
`lysis. The safety population included all patients who received at
`least one dose of study drug.
`
`RESULTS
`Patients
`Of 423 screened patients, 183 were randomised and received
`treatment (figure 1).
`
`Clinical and epidemiological research
`
`Baseline characteristics were balanced between groups (table 1).
`Approximately 78% of patients were serologically positive at
`baseline; the remaining patients had historically positive ANA
`or anti-dsDNA, with current active SLE confirmed by independ-
`ent experts (based upon clinical history and SLE serologies).
`Rates of discontinuation due to adverse events (AEs), with-
`drawal of consent and loss to follow-up were generally low
`across groups (figure 1). Premature termination of the 200 mg
`dose accounted for 22 of the 50 study discontinuations. Based
`upon an assessment of fatalities due to serious infections and
`thromboembolic events, the data monitoring committee advised
`discontinuation of the 200 mg dose group (see safety outcomes
`for further details). Therefore, the primary efficacy outcomes
`are based upon a full analysis set of 137 patients who received
`placebo, 10 mg or 50 mg.
`
`Efficacy outcomes
`SRI-4 response rates (GLMM) at week 24 were numerically
`greater for 10 mg versus placebo; however, statistical signifi-
`cance was not achieved ( p=0.076; figure 2). There were signifi-
`cantly more BICLA responders
`for 10 mg versus placebo
`( p=0.026; figure 2). Neither outcome was significant for 50 mg
`versus placebo. A sensitivity analysis was performed for the SRI
`and BICLA using a logistic regression model; details are
`included in the online supplementary materials. The observed
`proportion of responders in the 200 mg group who had com-
`pleted week 24 prior to premature termination (n=22) was
`
`Figure 2 SRI-4 and BICLA responder rates at week 24 (A) in the total population, and (B) in the enriched population (GLMM model). *p<0.05 vs
`placebo; **p<0.01 vs placebo. BICLA, British Isles Lupus Assessment Group-based Composite Lupus Assessment; GLMM, generalised linear mixed
`model; SRI, Systemic Lupus Erythematosus Responder Index.
`
`Wallace DJ, et al. Ann Rheum Dis 2017;76:534–542. doi:10.1136/annrheumdis-2016-209668
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`537
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`Clinical and epidemiological research
`
`Table 2 Summary of efficacy outcomes at week 24
`
`SRI response rate, n/N (%)*
`
`OR vs placebo (90% CI)
`
`p Value
`
`BICLA response rate, n/N (%)*
`
`OR vs placebo (90% CI)
`
`p Value
`
`Treatment failures, n/N (%)
`
`p Value
`
`Patients with disease flares, n/N (%)
`
`Severe BILAG flares (new BILAG A or two new BILAG B organ domain scores)
`
`Severe SFI flares
`
`Proportion of patients with reductions in anti-dsDNA from baseline, n/N (%)‡
`
`≥10% reduction
`
`≥30% reduction
`
`≥50% reduction
`
`Mean change in C3 concentration from baseline, g/L (SD)§
`
`Mean change in C4 concentration from baseline, g/L (SD)§
`
`Placebo (n=45)
`
`10 mg (n=45)
`
`50 mg (n=47)
`
`16/42 (40.1)
`
`20/35 (59.9)
`
`14/36 (39.2)
`
`11/42 (25.1)
`
`11/45 (24.4)
`
`5/45 (11.1)
`
`8/45 (17.8)
`
`7/17 (41.2)
`
`3/16 (18.8)
`
`1/15 (6.7)
`
`2.2 (0.89 to 5.62)
`
`0.96 (0.38 to 2.41)
`
`0.076
`
`18/35 (49.7)
`
`0.528
`
`15/36 (40.5)
`
`2.95 (1.18 to 7.41)
`
`2.03 (0.82 to 5.06)
`
`0.026
`
`1/45 (2.2)
`
`0.005
`
`2/43 (4.7)
`
`0/43 (0.0)†
`
`9/15 (60.0)
`
`7/14 (50.0)
`
`4/14 (28.6)
`
`0.10
`
`4/47 (8.5)
`
`0.031
`
`0/44 (0.0)
`2/44 (4.5)†
`
`11/18 (61.1)
`
`6/18 (33.3)
`
`1/16 (6.3)
`
`−0.021 (0.176)
`
`0.0002 (0.0417)
`
`−0.100 (0.163)
`
`−0.169 (0.161)
`
`−0.0096 (0.0516)
`
`−0.0551 (0.0491)
`
`4/15 (26.7)
`
`5/24 (20.8)
`
`Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209668 on 26 September 2016. Downloaded from
`
`http://ard.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`Patients whose corticosteroid dose was reduced by ≥25% from baseline, and to ≤7.5 mg/day,
`for at least one visit up to and including week 24, n/N (%)¶
`
`2/23 (8.7)
`
`LS mean change in SF-36 score from baseline (SE)
`
`PCS score
`
`MCS score
`
`Physical functioning
`
`Role physical
`
`Body pain
`
`General health
`
`Vitality
`
`Social functioning
`
`Role emotional
`
`Mental health
`
`LS mean change in EQ-5D VAS score from baseline (SE)
`
`LS mean change in FACIT-Fatigue score from baseline (SE)
`
`Placebo (n=45)
`
`10 mg (n=43)
`
`50 mg (n=46)
`
`3.08 (1.2)
`
`2.95 (1.4)
`
`4.87 (3.4)
`
`10.62 (3.4)
`
`7.92 (3.3)
`
`7.01 (2.5)
`
`6.42 (3.0)
`
`7.62 (3.5)
`
`6.49 (3.4)
`
`4.90 (2.5)
`
`5.99 (2.8)
`
`2.82 (1.5)
`
`6.04 (1.2)
`
`2.94 (1.4)
`
`10.96 (3.5)
`
`15.28 (3.5)
`
`13.38 (3.3)
`
`12.53 (2.6)
`
`10.30 (3.1)
`
`6.78 (3.5)
`
`6.65 (3.5)
`
`6.96 (2.6)
`
`10.30 (2.9)
`
`4.43 (1.6)
`
`5.67 (1.2)
`
`2.12 (1.4)
`
`12.49 (3.4)
`
`16.06 (3.3)
`
`13.94 (3.2)
`
`5.15 (2.5)
`
`7.45 (3.0)
`
`9.58 (3.4)
`
`10.80 (3.3)
`
`2.72 (2.5)
`
`6.18 (2.7)
`
`3.47 (1.5)
`
`Bold italic text denotes changes that were greater than the minimum clinically important difference (SF-36 PCS and MCS >2.5-point change from baseline;17 SF-36 domain scores
`>5-point change from baseline;17 EQ-5D >10-point change from baseline; FACIT-Fatigue score >4-point change from baseline).
`*Estimates from generalised linear mixed model. n/N represents the observed number of responders (n) for patients who completed through week 24 (N). Patients who discontinued from
`the study were not included in the denominator. Estimates from the generalised linear mixed model include all available data from completed and discontinued patients.
`†p<0.01 for combined 10 mg and 50 mg groups versus placebo (Fisher’s exact test).
`‡Patients with baseline anti-dsDNA above 31 IU/mL were included in the ≥10% reduction analysis (n=50); patients with baseline anti-dsDNA above 40 IU/mL were included in the ≥30%
`reduction analysis (n=48); patients with baseline anti-dsDNA above 54 IU/mL were included in the ≥50% reduction analysis (n=45).
`§Patients with complement data were included in the analyses of changes in C3 and C4 concentrations (placebo, n=41; 10 mg, n=39; 50 mg, n=38).
`¶Patients with a baseline corticosteroid dose >7.5 mg/day were included in the corticosteroid reduction analysis (n=62).
`BICLA, BILAG-based Composite Lupus Assessment; BILAG, British Isles Lupus Assessment Group; dsDNA, double-stranded DNA; EQ-5D, European Quality of Life 5 Dimensions; FACIT,
`Functional Assessment of Chronic Illness Therapy; LS, least squares; MCS, mental component summary; PCS, physical component summary; SF-36, 36-item Short Form Health Survey; SFI,
`modified Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA)-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index; SRI, Systemic Lupus
`Erythematosus Responder Index; VAS, visual analogue scale.
`
`similar to or worse than placebo for both SRI-4 (18.2% vs
`38.1% for placebo) and BICLA (27.3% vs 26.2% for placebo).
`Key efficacy outcomes
`are
`summarised in table 2.
`Treatment failure rates were significantly lower with 10 mg
`( p<0.01) and 50 mg ( p<0.05) versus placebo. No patients
`receiving 10 mg, and two receiving 50 mg experienced a
`severe SFI flare, compared with eight patients receiving
`placebo; severe SFI flare incidence was significantly lower for
`pooled 10 mg and 50 mg doses versus placebo ( p<0.01).
`Severe BILAG flare rates were also lower with PF-04236921
`vs placebo, although statistical significance was not achieved.
`Dose-dependent
`reductions
`in C3, C4 and CRP were
`observed.
`
`Across all groups, mean baseline SF-36 physical component
`summary (PCS) score (SD) was 34.3 (9.0) and mental compo-
`nent summary (MCS) score was 40.4 (10.9), which were
`approximately 1.5 SD and 1.0 SD <normative scores of 50,
`respectively.17 At week 24, trends towards improvements in
`SF-36 PCS scores, most SF-36 domain scores, FACIT-Fatigue
`and EQ-5D VAS scores were reported with 10 mg or 50 mg
`versus placebo. All HRQOL changes from baseline with 10 mg
`exceeded minimum clinically important differences (MCIDs).18
`
`Post hoc analysis of the enriched population
`Four univariate baseline parameters were associated with signifi-
`cant improvements in SRI-4 response rates for 10 mg versus
`
`538
`
`Wallace DJ, et al. Ann Rheum Dis 2017;76:534–542. doi:10.1136/annrheumdis-2016-209668
`
`Lassen - Exhibit 1029, p. 5
`
`

`

`Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209668 on 26 September 2016. Downloaded from
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`http://ard.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`Table 3 Summary of efficacy outcomes at week 24 in the enriched population
`
`Clinical and epidemiological research
`
`SRI response rate, n/N (%)*
`
`OR vs placebo (90% CI)
`
`p Value
`
`BICLA response rate, n/N (%)*
`
`OR vs placebo (90% CI)
`
`p Value
`
`Patients with disease flares, n (%)
`
`Placebo (n=33)
`
`10 mg (n=30)
`
`8/30 (27.7)
`
`15/21 (73.1)
`
`50 mg (n=38)
`
`12/28 (43.1)
`
`6/30 (19.7)
`
`7.09 (2.11 to 23.85)
`
`1.98 (0.67 to 5.86)
`
`0.004
`
`12/21 (55.7)
`
`0.151
`
`10/28 (34.7)
`
`5.11 (1.56 to 16.72)
`
`2.16 (0.71 to 6.59)
`
`0.012
`
`0.127
`
`BILAG flares (new BILAG A or two new BILAG B organ domain scores)
`
`Severe SFI flares
`
`5/33 (15.2)
`
`8/33 (24.2)
`
`0/30 (0.0)†
`
`0/28 (0.0)†
`
`Placebo (n=33)
`
`10 mg (n=28)
`
`LS mean change in SF-36 score from baseline (SE)
`
`PCS score
`
`MCS score
`
`Physical functioning
`
`Role physical
`
`Body pain
`
`General health
`
`Vitality
`
`Social functioning
`
`Role emotional
`
`Mental health
`
`LS mean change in EQ-5D VAS score from baseline (SE)
`
`LS mean change in FACIT-Fatigue score from baseline (SE)
`
`2.80 (1.4)
`
`2.04 (1.6)
`
`4.62 (4.0)
`
`8.44 (3.9)
`
`6.43 (3.9)
`
`6.80 (2.7)
`
`3.45 (3.5)
`
`5.80 (4.1)
`
`3.62 (3.7)
`
`4.20 (3.0)
`
`2.30 (3.2)
`
`1.16 (1.8)
`
`7.60 (1.5)‡
`
`2.69 (1.7)
`
`15.09 (4.4)
`
`14.63 (4.3)
`
`17.79 (4.2)
`
`14.13 (3.0)
`
`12.05 (3.8)
`
`10.02 (4.5)
`
`5.89 (4.1)
`
`6.78 (3.3)
`
`11.47 (3.5)
`
`5.28 (2.0)
`
`0/38 (0.0)†
`
`2/35 (5.7)†
`
`50 mg (n=37)
`
`5.07 (1.3)
`
`1.56 (1.5)
`
`12.44 (3.8)
`
`13.83 (3.7)
`
`11.56 (3.7)
`
`4.59 (2.6)
`
`4.19 (3.3)
`
`9.54 (3.9)
`
`8.98 (3.6)
`
`2.75 (2.9)
`
`6.10 (3.0)
`
`3.68 (1.8)
`
`Bold italic text denotes changes that were greater than the minimum clinically important difference (SF-36 PCS and MCS >2.5-point change from baseline;17 SF-36 domain scores
`>5-point change from baseline;17 EQ-5D >10-point change from baseline; FACIT-Fatigue score >4-point change from baseline).
`*Estimates from generalised linear mixed model. n/N represents the observed number of responders (n) for patients who completed through week 24 (N). Patients who discontinued from
`the study were not included in the denominator. Estimates from the generalised linear mixed model include all available data from completed and discontinued patients.
`†p<0.01 for combined 10 mg and 50 mg groups versus placebo (Fisher’s exact test).
`‡p<0.05 vs placebo.
`BICLA, BILAG-based Composite Lupus Assessment; BILAG, British Isles Lupus Assessment Group; EQ-5D, European Quality of Life 5 Dimensions; FACIT, Functional Assessment of Chronic
`Illness Therapy; LS, least squares; MCS, mental component summary; PCS, physical component summary; SF-36, 36-item Short Form Health Survey; SFI, modified Safety of Estrogens in
`Lupus Erythematosus: National Assessment (SELENA)-Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) Flare Index; SRI, Systemic Lupus Erythematosus Responder Index; VAS,
`visual analogue scale.
`
`placebo and defined an enriched population with greater disease
`activity at baseline: SLEDAI-2K score ≥10, corticosteroids
`≥7.5 mg/day, anti-dsDNA ≥28 IU/mL or hypocomplementaemia
`(C3 and C4). This included 101 patients ( placebo, n=33;
`10 mg, n=30; 50 mg, n=38), approximately 74% of the total
`population who had one or more of these characteristics.
`Efficacy outcomes in the enriched population are summarised
`in table 3. With 10 mg, SRI-4 and BICLA placebo-corrected
`response rates (GLMM) were greater in the enriched population
`than in the total population (45.4 vs 19.8 for SRI-4 and 36.0 vs
`24.6 for BICLA; figure 2) and significantly different
`than
`placebo for both SRI-4 ( p=0.004) and BICLA ( p=0.012).
`However, response rates in the 50 mg group were only margin-
`ally higher in the enriched population than in the total popula-
`tion. Notably, 10 mg was also associated with significant
`improvements in SF-36 PCS scores versus placebo ( p<0.05)
`and trends towards improvements in SF-36 MCS and domain
`scores. Changes from baseline in most SF-36 domain scores,
`EQ-5D VAS and FACIT-Fatigue scores exceeded MCID.
`
`Safety outcomes
`Rates of deaths, treatment-emergent AEs (TEAEs), serious AEs
`(SAEs) and AEs leading to treatment discontinuation during the
`treatment phase are summarised in table 4. The most frequent
`TEAEs (excluding infections and injection-site reactions) were
`headache, nausea and diarrhoea (nausea and diarrhoea were
`
`most commonly reported with placebo), and the most frequent
`infectious TEAEs were upper respiratory infection, cystitis and
`pharyngitis/laryngitis. More patients experienced non-infectious
`SAEs with placebo or 200 mg than with 10 mg or 50 mg. The
`higher SAE rate for placebo was largely due to a greater number
`of SLE flares. Serious infections occurred most frequently with
`200 mg. There were no cases of herpes zoster or malignancies.
`Four deaths occurred during the study. A 32-year-old woman
`died after receiving a single 10 mg dose due to a suspected pul-
`monary embolism (PE). A 54-year-old woman experienced
`severe shortness of breath and died on the way to the hospital
`after receiving a single 200 mg dose. Two additional patients
`(a 61-year-old woman and a 24-year-old woman) died after
`receiving two doses of 200 mg due to infectious causes
`combined with PEs (sepsis with PE and disseminated tubercu-
`losis with PE). A causal relationship with study medication
`could not be excluded for any of the events; therefore, the data
`monitoring committee recommended stopping further dosing of
`the 200 mg group. Additional details on the deaths are included
`in the online supplementary materials. In addition to the three
`deaths due to PEs listed above, there was one additional SAE
`that was due to a PE in a patient who received placebo.
`
`DISCUSSION
`While none of the treatment arms were significantly different
`than placebo for the primary end point, results of this trial
`
`Wallace DJ, et al. Ann Rheum Dis 2017;76:534–542. doi:10.1136/annrheumdis-2016-209668
`
`539
`
`Lassen - Exhibit 1029, p. 6
`
`

`

`Clinical and epidemiological research
`
`Table 4 TEAEs during the 24-week treatment phase
`
`Deaths, n (%)
`
`SAEs (excluding infections),
`n (%)*
`
`Serious infections, n (%)
`
`Sepsis
`
`Bronchitis
`
`Tuberculosis
`
`Bronchopneumonia
`
`Cellulitis
`
`Clostridium difficile colitis
`
`Placebo
`(n=45)
`
`0 (0.0)
`
`5 (11.1)
`
`2 (4.4)
`
`1 (2.2)
`
`1 (2.2)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (2.2)
`
`10 mg
`(n=45)
`
`1 (2.2)
`
`2 (4.4)
`
`1 (2.2)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (2.2)
`
`0 (0.0)
`
`50 mg
`(n=47)
`
`0 (0.0)
`
`1 (2.1)
`
`2 (4.3)
`
`1 (2.1)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`1 (2.1)
`
`0 (0.0)
`
`200 mg
`(n=46)
`
`3 (6.5)
`
`5 (10.9)
`
`4 (8.7)
`
`1 (2.2)
`
`0 (0.0)
`
`1 (2.2)
`
`1 (2.2)
`
`1 (2.2)
`
`0 (0.0)
`
`Sinusitis
`
`1 (2.2)
`
`0 (0.0)
`
`0 (0.0)
`
`0 (0.0)
`
`Any AEs (excluding
`infections and ISRs), n (%)
`
`34 (75.6)
`
`34 (75.6)
`
`32 (68.1)
`
`31 (67.4)
`
`Common AEs (≥5% in any treatment group, excluding infections and ISR), n (%)
`
`Headache
`
`Nausea
`
`Diarrhoea
`
`SLE
`
`Arthralgia
`
`Dizziness
`
`Cough
`
`2 (4.4)
`
`5 (11.1)
`
`5 (11.1)
`
`3 (6.7)
`
`3 (6.7)
`
`2 (4.4)
`
`2 (4.4)
`
`1 (2.2)
`
`4 (8.9)
`
`2 (4.4)
`
`2 (4.4)
`
`3 (6.7)
`
`1 (2.2)
`
`1 (2.2)
`
`4 (8.9)
`
`1 (2.2)
`
`5 (10.6)
`
`3 (6.4)
`
`2 (4.3)
`
`2 (4.3)
`
`2 (4.3)
`
`3 (6.4)
`
`0 (0.0)
`
`4 (8.5)
`
`5 (10.9)
`
`5 (10.9)
`
`3 (6.5)
`
`1 (2.2)
`
`2 (4.3)
`
`2 (4.3)
`
`1 (2.2)
`
`1 (2.2)
`
`Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209668 on 26 September 2016. Downloaded from
`
`http://ard.bmj.com/
`
` on 19 July 2019 by guest. Protected by copyright.
`
`hospitalisation and are associated with significant morbidity and
`mortality.19 Trends towards improved HRQOL were reported
`with 10 mg by SF-36 PCS, FACIT-Fatigue and EQ-5D.
`Although a greater percentage of patients receiving 10 mg or
`50 mg achieved ≥10% decreases in anti-dsDNA antibodies from
`baseline versus placebo, applying a higher level of response
`(≥30% or ≥50%) did not reveal a clear effect. Dose-dependent
`decreases in complement were noted, consistent with results
`with another IL-6 inhibitor.15
`To determine if there was a subgroup of patients with higher
`response rates, a post hoc analysis of patients with high disease
`activity at baseline was performed. Efficacy of 10 mg appeared
`more pronounced in this enriched population based upon sig-
`nificantly greater SRI-4 and BICLA response rates versus
`