Safety, tolerability, efficacy and pharmacodynamics ... - SAGE Journals

Lupus (2016) 25, 1420–1430 http://lup.sagepub.com

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Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus L Kahl1,*, J Patel2, M Layton2, M Binks3, K Hicks4, G Leon5, E Hachulla6, D Machado7, D Staumont-Salle´6, M Dickson2, L Condreay8,y, L Schifano8, S Zamuner9 and RF van Vollenhoven10; on behalf of the JAK115919 Study Team 1 Clinical Development in Infectious Diseases, GSK, Uxbridge, UK; 2Immuno-Inflammation Therapeutic Area Unit, GSK, Stevenage, UK; Worldwide Research and Development, Pfizer Inc., Cambridge, MA, USA; 4Clinical Statistics Medicines Research Centre, GSK, Stevenage, UK; 5 Instituto de Ginecologia y Reproduccion, Lima, Peru; 6Claude Huriez Hospital, University of Lille, FHU IMMINeNT, Lille, France; 7Instituto Centralizado de Asistencia e Investigacion Clinica Integral, CAICI, Rosario, Santa Fe, Argentina; 8GSK, Research Triangle Park, NC, USA; 9 Clinical Pharmacology Modelling and Simulation Department, GSK, Uxbridge, UK; 10Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, Sweden; *Current affiliation: ViiV Healthcare, Brentford, UK; and y Current affiliation: PAREXEL International LLC, Durham, NC, USA 3

We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral GSK2586184 50– 400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes in Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index score, and number/severity of adverse events. A prespecified interim analysis was performed when 5 patients per group completed 2 weeks of treatment. In total, 84–92% of patients were high baseline expressors of the interferon transcriptional biomarkers evaluated. At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients. Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index scores were not analysed due to the small number of patients completing the study. The study futility and safety data described for GSK2586184 do not support further evaluation in patients with SLE. Study identifiers: GSK Study JAK115919; ClinicalTrials.gov identifier: NCT017 77256. Lupus (2016) 25, 1420–1430. Key words: DRESS syndrome; interferon; JAK1 inhibitor; systemic lupus erythematosus

Introduction The Janus kinase (JAK) family of tyrosine kinases (of which there are four members: JAK1, JAK2, JAK3 and TYK2) are activated via stimulation of cytokine and growth factor receptors.1 The JAK1 signalling pathway in particular is involved in mediating the intracellular signalling of interferon Correspondence to: Lesley Kahl, ViiV Healthcare, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. Email: [email protected] Received 28 September 2015; accepted 23 February 2016 ! The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

(IFN) alpha (IFNa),2 a key mediator in the pathogenesis of autoimmune conditions such as systemic lupus erythematosus (SLE) and psoriasis.3–6 Modulation of the JAK-STAT pathway could therefore potentially diminish IFNa-mediated effects in patients with SLE.7,8 A number of JAK inhibitors are under development or have been approved for the treatment of inflammatory conditions, including rheumatoid arthritis (RA), psoriasis, inflammatory bowel disease and high-risk myelofibrosis.9–12 The efficacy of first-generation pan-JAK inhibitors was limited by potential side effects such as anaemia and 10.1177/0961203316640910

GSK2586184 safety/efficacy/pharmacodynamics in SLE L Kahl et al.

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neutropenia, which may be related to inhibition of erythropoiesis resulting from JAK2 inhibition.14,15 Recent observations that JAK1 is dominant in JAK1/JAK3/ c signalling,16 and that JAK1 kinase activity is involved in IFNa, interleukin (IL) 6, IL10 and IL22 signalling,2 suggest that inhibition of these signalling pathways may be important in determining the efficacy of JAK inhibitors in immune or inflammatory diseases. A selective JAK1 inhibitor may avoid side effects related to the mode of action of pan-JAK inhibitors, and therefore may be effective in treatment of SLE. GSK2586184 (GLPG0788), generically known as solcitinib, is an orally active, competitive, potent, selective JAK1 inhibitor that was evaluated for treatment of inflammatory and auto-immune diseases. GSK2586184 has demonstrated selective JAK1 inhibition in preclinical and human in vitro enzyme, cellular and tissue assay systems17 and was well tolerated in healthy volunteers (GSK, data on file) and patients with psoriasis.18 In in vivo IFNa challenge studies in healthy volunteers, significant inhibition of IFNa-induced increases of neopterin and b2-microglobulin levels was observed with GSK2586184 doses greater than 100 mg and 200 mg twice daily (BID), respectively, compared with placebo (GSK, data on file). Induction of multiple IFNa-dependent genes was also suppressed in subjects treated with GSK2586184 400 mg BID, and transcriptomic analysis demonstrated that basal expression of IFNa target genes (but not control genes) was reduced by 10 days of treatment with GSK2586184 800 mg, compared with placebo (GSK, data on file). Here, we report the results of a study evaluating GSK2586184 in adult patients with active SLE.

Methods Study design This was an adaptive, randomized, double-blind, multicentre, placebo-controlled, dose-ranging Phase II study (GSK JAK115919; ClinicalTrials.gov NCT01777256 (March 2013– February 2014)), conducted at 22 centres across Argentina, Czech Republic, Estonia, France, Greece, Hungary, Korea, Peru and Poland. Patients were randomized 1:1:1:1:1 to receive oral GSK2586184 50 mg, 100 mg, 200 mg, 400 mg or placebo BID with food (immediately after a meal), for up to 12 weeks. Interim Analysis 1 was conducted when at least five patients in each treatment group had completed the 32-week dosing time

point. Interim Analyses 2 and 3 were to be conducted after at least 15 and 20 patients, respectively, had completed the 12-week treatment period. The study was approved by a national or regional Ethics Committee in each country, and performed in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice guidelines, including all applicable patient privacy requirements and ethical principles outlined in the Declaration of Helsinki, 2008,19,20 with written, informed consent obtained from each patient before study procedures were performed. Patients Eligible patients were 18–75 years of age, had a clinical diagnosis of SLE according to American College of Rheumatology classification criteria,21,22 had clinically-active SLE (defined as a Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score 8 during the 35-day screening period), were serologically active and had unequivocally positive anti-nuclear antibody (ANA) or antidouble-stranded DNA (anti-dsDNA) antibody test results from two independent time points. Patients were excluded if they had a history of kidney disease, central nervous system disease, major organ transplant, alcohol or substance abuse, hepatitis B and/or C infection, human immunodeficiency virus infection, cancer within the last 5 years (except for adequately treated cancers of the skin or carcinoma in situ of the uterine cervix), or latent or active exposure to Mycobacterium tuberculosis. Additional reasons for exclusion included management of acute or chronic infections within 60 days of study entry, a current or chronic history of liver disease, known hepatic or biliary abnormalities, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2 upper limit of normal (ULN); alkaline phosphatase and bilirubin > 1.5 ULN, acute/ chronic infection or clinical evidence of significant unstable/uncontrolled acute or chronic diseases not due to SLE (additional criteria provided in Supplementary Material). Outcomes and assessments Pharmacodynamics

The primary endpoint for Interim Analysis 1 was the percentage inhibition of IFN transcriptional biomarker expression by GSK2586184 following 2 weeks of treatment. Quantitative polymerase chain Lupus


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reaction (qPCR) was used to assess 48 genes: 12 control genes, four cell markers (CD19, CLEC4, FCGR1A, DEFA3) and 32 IFN transcriptional biomarkers; 27 of the 32 genes were clustered in seven panels based on previously defined IFN gene signatures. Overlap of genes across certain panels was included to determine if set clusters of genes were regulated together. The five remaining genes were analysed separately (Table 1). Gene panel 7 comprised transcription factors associated with up-regulation of IFN genes that were not thought to be transcriptionally regulated themselves, and so were considered negative controls. Responses were calculated as mean inhibition compared with baseline for each individual gene within each panel for log2 values; mean inhibition was calculated across all genes within a panel for each patient and the treatment group average was determined. Patients were characterized as high or low expressors of IFN transcriptional biomarkers (according to baseline gene expression) across the seven gene panels evaluated (relative to expression levels obtained in healthy volunteers) (see Supplementary Methods). Exploratory endpoints included changes in serum neopterin and b2-microglobulin levels (assessed by enzyme-linked immunoassay (BRAHMS Germany Catalog #14-HD99.1ELISA) and nephelometry (Binding Site kit LK043T), respectively) expressed as mean ( standard deviation (SD)) absolute values (nmol/L serum). Table 1

Efficacy

The primary endpoint for Interim Analysis 2 and 3, and the final analysis was SELENA-SLEDAI score over time, assessed using a modified version of the SLEDAI.23 Assessments were planned at screening and prior to dosing on Day 0, at bi-weekly visits over Weeks 2–12 and at follow-up (Week 16). SLE responder index (SRI), SLEDAI-2 K and SLEDAI-2 K Responder Index 50 (S2K RI-50) assessments over time were secondary endpoints (additional details provided in Supplementary Material). Patient-reported health outcomes

Three patient-reported outcome questionnaires (Short Form-36 Health Survey (SF-36), Brief Fatigue Inventory (BFI) and Brief Pain Inventory (BPI)) were used to evaluate health outcomes (see Supplementary Material). Safety

The number and severity of adverse events (AEs) was a primary endpoint. Infections were recorded as AEs of special interest. Change from baseline in clinical chemistry and haematology parameters, blood pressure, heart rate and body temperature was also assessed as a primary endpoint. Pharmacokinetics (PK)

Whole blood was collected for PK analysis prior to treatment administration at each bi-weekly study

IFN transcriptional biomarker panels.*

Panel 1

Panel 2

Panel 3

Panel 4

Panel 5

Panel 6

Panel 7

OAS1 OAS2 OAS3 MX1 EPSTI1 RTP4

IFI44L MX1 OAS1 IFI44 RTP4 EPSTI1 IFIT3

IFIT1 IFI44L IFIT3 IFI44 LY6E MX2 IFI6 CXCL10 IFIH1 MX1

IFNAR2 IL1RN GBP1 SOCS3 USP18 CXCL10

IFI44L EPSTI1 RSAD2 GBP1 ISG15 OAS2 MX1 IFI44 OAS3 OAS1

LY6E OAS1 OAS2 IFIT1 IFI44 ISG15 MX1

IRF1 IRF3 IRF5 IRF7 IRF9

*A total of 48 genes were assessed: 12 control genes (including the housekeeping genes HPRT1, b actin, GAPDH, RPL13A and b2 microglobulin); four cellular markers (CD19, CLEC4, FCGR1A, DEFA3) and 32 IFN-related genes. Twenty-seven genes were then clustered into seven panels; the five that did not cluster into one of the panels (SPATS2L, FPR2, ISG20, SIGLEC1 and GBP2) were analysed separately. CD19, cluster of differentiation 19; CLEC4, C-type lectin domain family; CXCL10, C-X-C motif chemokine 10; EPSTI1, epithelial stromal interaction 1; FCGR1A, Fc gamma receptor I-a; FPR2, formyl peptide receptor 2; GAPDH, Glyceraldehyde 3-phosphate dehydrogenase; GBP, IFN-induced guanylate-binding protein; HPRT1, hypoxanthine phosphoribosyltransferase 1; IFI44, IFN-induced protein 44; IFI44L, IFN-induced protein 44-like; IFI6, IFN alpha-inducible protein 6; IFIH1, IFN-induced with helicase C domain 1; IFIT, IFN-induced protein with tetratricopeptide repeats; IFN, interferon; IFNAR2, IFN-alpha/beta receptor beta chain; IL1RN, interleukin-1 receptor antagonist; IRF, IFN regulatory factor; ISG15, IFN-induced 17 kDa protein; ISG20, IFN-stimulated exonuclease gene 20 kDa; LY6E, lymphocyte antigen 6 complex, locus E; MX, IFN-induced GTP-binding protein; OAS oligoadenylate synthetase; RPL13A, ribosomal protein L13a; RSAD2, radical S-adenosyl methionine domain containing 2; RTP4, receptor transporter protein 4; SIGLEC1, sialic acid-binding immunoglobulin-type lectin; SOCS3, suppressor of cytokine signalling 3; SPATS2L, spermatogenesis associated, serine-rich 2-like protein; USP18, ubiquitin specific peptidase 18. Lupus


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visit. Drug exposure was estimated according to area under the concentration–time curve (AUC0- ). Apparent clearance (CL/F) and apparent volume of distribution (V/F) were also measured. No statistical analysis of PK data was performed. Post hoc analyses

In order to compare the results to previous literature,4 an ad hoc analysis was conducted using mRNA intensity (i.e. back-transformed log2 values). Additional post hoc exploratory analyses were also permitted to allow further investigation of safety data (see Supplementary Material). Sample size and statistical analyses The study design permitted initiation of recruitment with a range of GSK2586184 doses and placebo. Interim analyses were planned to ensure continuing recruitment in only treatment groups meeting pharmacodynamic and safety criteria (Interim Analysis 1), and clinical efficacy and safety recruitment progression criteria (Interim Analyses 2 and 3). Sample size re-estimation at each Interim Analysis was permitted to adjust for imbalances in baseline expression of IFN transcriptional biomarkers. Interim Analysis 1 was scheduled when at least five patients in each treatment group had completed 2 weeks of treatment. GSK2586184 treatment groups dosed over 2 weeks with 40% mean reduction in the IFN transcriptional biomarker signature and no decrease in renal function were to continue in the study. Statistical analyses to detect a relationship between IFN transcriptional biomarker expression and dose would have > 90% power (alpha ¼ 0.05; determined through 10,000 simulations), assuming 0, 20, 40, 60 and 70% inhibition (on log2 scale) for placebo, GSK2586184 50 mg, 100 mg, 200 mg and 400 mg, respectively, with a between-patient SD of 10%4 and assuming a maximum effect model.

Results Patients Study recruitment was terminated at Interim Analysis 1, following recruitment of 50 patients to the intent-to-treat (ITT) population, because of futility (the predicted 40% mean reduction in the IFN transcriptional signature biomarker at 2 weeks was not observed). The most common reasons for withdrawal were study termination (n ¼ 16) and AEs (n ¼ 7) (Figure 1).

Study participants showed baseline characteristics typical of an SLE population including: female sex (all patients), 21–63 years of age, a positive ANA titre and mean SELENA-SLEDAI scores of 9.8–12.0 across treatment groups (Table 2). Most patients were receiving steroids (90%) and hydroxychloroquine (54%) as lupus medications (Table 3, Supplementary Table 1). Pharmacodynamics IFN transcriptional biomarker analysis

Of the patients with available baseline IFN transcriptional biomarker expression data, 84–92% (n ¼ 42–46) were high expressors (> 2 SD from healthy volunteers) across the seven gene panels (including the patients who went on to develop liver events and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)), and approximately 4–16% (n ¼ 2–8) were low expressors. At Week 2, GSK2586184 had no notable or consistent effects on gene expression in any panels assessed, using either log2 values (data for panel 6 (representative of gene panels 1–6) and panel 7 (negative control) are shown in Figures 2a and b) or, as an ad hoc analysis, back-transformed log2 values. However, although no dose–response was observed, by Week 6 the 400 mg dose showed a mean (range) inhibition in back-transformed log2 values as follows: Panel 1: 35.4% (51.9, 87.5%); Panel 2: 33.0% (68.0, 88.4%); Panel 3: 27.3% (60.5, 81.4%); Panel 5: 33.8% (65.2, 88.3%); Panel 6: 38.4% (50.3, 92.3%) (Table 4; summary by Week presented in Supplementary Table 2). In comparison, Panel 7 (the negative control panel) showed a mean (range) inhibition of 8.0% (29.8, 26.6%), and Panel 4 (consisting of genes previously shown to be inhibited in preclinical experiments involving GSK2586184 (GSK, data on file)) had a mean (range) inhibition of 4.1% (40.8, 48.7%). No differences in gene expression were observed in the subgroup analysis (by expressor status at baseline) at Interim Analysis 1, and there were no consistent effects observed when single genes or cellular markers were assessed using log2 values. As the criteria for the primary endpoint of a 40% mean inhibition in IFN transcriptional signature biomarker following 2 weeks of GSK2586184 treatment was not met at Interim Analysis 1, study futility was declared and recruitment was halted. Serum neopterin and 2-microglobulin

There were no apparent differences in serum neopterin or b2-microglobulin levels between the active Lupus


1424 Final data, n=30* (or up to a maximum of 50 per treatment group) with 12 weeks exposure

Subjects with active SLE and SELENA-SLEDAI score ≥8

Interim analysis 1 RECRUITMENT HALTED

Interim analysis 2

Interim analysis 3 (if required)

Subjects who had been randomised (n=50)

GSK2586184 50 mg BID (n=9) • Completed (n=4) • Withdrew (n=5)




– Adverse event (n=1) – Study terminated (n=4)

– Adverse event (n=1) – Study terminated (n=4)

– Adverse event (n=4) – Protocol deviation (n=1) – Withdrew consent (n=1)

– Adverse event (n=1) – Investigator discretion (n=1) – Study terminated (n=3) – Withdrew consent (n=1)

Placebo (n=11) • Completed (n=5) • Withdrew (n=6) – Lost to follow-up (n=1) – Study terminated (n=5)

Figure 1 Study population flow. *If indicated by sample size selection at the interim analyses. BID: twice daily; SELENA-SLEDAI: Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index; SLE: systemic lupus erythematosus.

treatment groups and placebo over the 12-week treatment period (Figures 2c and d). Efficacy SELENA-SLEDAI score

SELENA-SLEDAI scores were available for the full ITT population at baseline (n ¼ 50). However, due to study termination, only 18 patients completed 12 weeks of GSK2586184 dosing and four patients completed 12 weeks of placebo. Statistical analyses were not performed because of the limited data. For patients with available data, the mean change (range) in score at Week 12 was 3.6 (8.0–0) for placebo and 6.2 to 3.0 (17–4) for GSK2586184 50–400 mg, with no clear dose–response evident. SRI response rate over time

Data on the SRI response rate were not available for all patients over the course of the study (see Supplementary Material). At Week 12, none of the five patients receiving placebo were considered responders, but a small number of the 18 patients in the GSK2586184 treatment groups were considered Lupus

to be responders (GSK2586184 50 mg, n ¼ 1/4; GSK2586184 100 mg, n ¼ 1/5; GSK2586184 200 mg, n ¼ 1/4; GSK2586184 400 mg, n ¼ 2/5). SLEDAI-2 K and S2K RI-50 scores were not determined, as technical difficulties during data collection meant the data were not interpretable. Patient-reported health outcomes For the physical component of the SF-36 score at Week 12, the placebo-treated group (n ¼ 7) exhibited a mean (SD) change from baseline of 2.30 (11.50), compared with 2.47 [9.91]–9.13 [10.53] for GSK2586184 50–400 mg. A change in BFI score of 0.46 was observed for placebo at Week 12 versus baseline, compared with 2.73 to 1.65 across the GSK2586184 treatment groups. For the pain severity component of the BPI score, a change of 0.071 was observed with placebo at Week 12, compared with 2.14 to 1.18 in the active treatment groups. For the pain interference component of the BPI score, a change of 0.71 was observed for placebo, compared with 2.51 to 1.45 across the GSK2586184 treatment groups.


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Table 2 Patient demographics and baseline characteristics.*

Age, years Mean (SD) Female, n (%) BMI, kg/m2 Mean (SD) Ethnicity, n (%) American Indian or Alaskan Native Asian (Central/South Asian) Asian (East Asian) White Mixed race SELENA-SLEDAI score Mean (SD) SLE disease duration, days Anti-dsDNA antibody (IU/ml), n Mean (SD) Positive ANA titre Total, n 1:80 1:160 1:320 1:640 1:1280

Placebo (n ¼ 11)

GSK2586184 50 mg (n ¼ 9)

GSK2586184 100 mg (n ¼ 10)

GSK2586184 200 mg (n ¼ 10)

GSK2586184 400 mg (n ¼ 10)

36.9 (10.14) 11 (100)

38.0 (12.55) 9 (100)

43.1 (11.23) 10 (100)

37.3 (7.15) 10 (100)

47.5 (10.99) 10 (100)

23.11 (5.22)

29.31 (6.26)

26.18 (4.23)

25.09 (3.46)

25.39 (5.23)

4 (36) 0 0 7 (64) 0

2 (22) 1 (11) 0 6 (67) 0

2 (20) 0 0 6 (60) 2 (20)

3 (30) 0 0 7 (70) 0

1 (10) 0 1 (10) 8 (80) 0

9.8 (1.66) 2232 (2727)

9.9 (2.85) 2364 (2020)

11.1 (3.54) 1985 (1419)

12.0 (5.60) 2113 (2078)

10.6 (3.53) 3144 (3546)

71.0 (88.22)

154.9 (94.79)

97.4 (99.34)

41.4 (48.26)

84.7 (93.04)

11 0 5 2 1 3

9 2 2 1 1 3

10 2 1 4 0 3

10 3 0 2 3 2

10 3 2 2 2 1

*Based on patients assessed at Interim Analysis 1. ANA: anti-nuclear antibody; BMI: body mass index; CI: confidence interval; SD: standard deviation; SELENA-SLEDAI: Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index; SLE: systemic lupus erythematosus.

Table 3 Lupus medications at baseline Patients receiving medications at baseline, n (%)

Medications Steroids (methylprednisolone, prednisolone, prednisone) Methylprednisolone Prednisolone Prednisone Hydroxychloroquine Azathioprine Chloroquine Methotrexate

Placebo (n ¼ 11)

GSK2586184 50 mg (n ¼ 9)

GSK2586184 100 mg (n ¼ 10)

GSK2586184 200 mg (n ¼ 10)

GSK2586184 400 mg (n ¼ 10)

Total (n ¼ 50)

10 (91)

6 (67)

10 (100)

10 (100)

9 (90)

45 (90)

4 (36) 1 (9) 5 (45) 5 (45) 4 (36) 2 (18) 1 (9)

3 (33) 0 (0) 3 (33) 4 (44) 2 (22) 1 (11) 3 (33)

4 (40) 0 (0) 6 (60) 8 (80) 0 (0) 1 (10) 2 (20)

5 2 2 6 4 2 1

19 (38) 4 (8) 22 (44) 27 (54) 12 (24) 8 (16) 8 (16)

Safety AEs occurred in 64% of patients (n ¼ 7) in the placebo group and 60–89% of patients (n ¼ 6–8) in the GSK2586184 treatment groups, with no evidence of a dose–relationship. The most common AE was urinary tract infection (placebo: n ¼ 3; GSK2586184 treatment groups, n ¼ 4; Table 5). Serious AEs (SAEs) were reported in eight patients (Table 5). Liver-related SAEs were reported in six of these eight patients, 9–42 days

3 1 6 4 2 2 1

(30) (10) (60) (40) (20) (20) (10)

(50) (20) (20) (60) (40) (20) (10)

following initiation of GSK2586184; in two patients the symptoms were consistent with DRESS syndrome. A 61-year-old female patient receiving GSK2586184 400 mg BID, hydroxychloroquine, paracetamol and prednisone experienced DRESS syndrome. After 9 days of study drug, treatment was interrupted for 5 days due to fever and a suspected infection (amoxicillin/clavulanate was prescribed). Within an hour of re-exposure to GSK2586184, the patient experienced a tingling Lupus


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(b) 20 15 10 5 0 ●● ■● –5 –10 –15 Baseline

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Inhibition in IFN transcripts (%)

Inhibition in IFN transcripts (%)

(a)

12

6 4 2 0 ●●■● –2 –4 –6 –8 –10 Baseline

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Change from baseline β2-microglobulin (nmol/L)

Change from baseline neopterin (nmol/L)

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(d)

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6

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GSK2586184 100 mg BID

GSK2586184 200 mg BID ● ● ● GSK2586184 400 mg BID

● ● ● Placebo BID

100 80 60 40 ■ 20 ●● ● 0 ●●■● –20 –40 –60 –80 –100 Baseline 2

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4

Visit (week) ● ● ● GSK2586184 50 mg BID

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GSK2586184 100 mg BID


25 20 15 ■ 10 ● 5 ● ● 0 ●●■● –5 –10 –15 Baseline 2

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Visit (week)


(c)

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Visit (week) ● ● ● GSK2586184 50 mg BID

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Visit (week)

GSK2586184 100 mg BID



● ● ● GSK2586184 50 mg BID ■■■

GSK2586184 100 mg BID



Figure 2 Change from baseline in (a) IFN transcriptional biomarker expression (gene panel 6, log2 data); (b) IFN transcriptional biomarker expression (gene panel 7, log2 data); (c) serum neopterin levels; and (d) b2 microglobulin levels over time. BID: twice daily; IFN: interferon.

Table 4 Summary of percentage inhibition from baseline for each gene panel of IFN transcriptional biomarkers for GSK2586184 400 mg and placebo at Week 6 (ad hoc analysis of back-transformed log2 data) 95% CI Treatment Panel 1 400 mg BID Placebo Panel 2 400 mg BID Placebo Panel 3 400 mg BID Placebo Panel 4 400 mg BID Placebo Panel 5 400 mg BID Placebo Panel 6 400 mg BID Placebo Panel 7 400 mg BID Placebo

n

Mean

Lower

Upper

SD

Median

Min

Max

9 8

35.42 53.54

5.0 188.8

75.8 81.7

52.63 161.86

43.3 10.7

51.86 446.03

87.52 47.63

9 8

33.01 61.68

12.6 221.8

78.6 98.4

59.42 191.54

46.0 11.9

67.96 529.30

88.40 51.68

9 8

27.27 39.62

11.3 154.0

65.8 74.8

50.22 136.87

36.6 9.4

60.53 374.46

81.44 47.82

9 8

4.05 9.82

15.9 49.4

24.0 29.7

26.06 47.34

2.7 5.8

40.80 113.02

48.70 50.77

9 8

33.84 62.50

9.5 217.0

77.1 92.0

56.40 184.89

41.1 7.3

65.15 513.78

88.30 48.83

9 8

38.42 60.23

2.0 199.6

78.9 79.2

52.65 166.79

45.3 3.9

50.33 466.74

92.31 42.54

9 8

8.00 5.16

7.2 22.3

23.2 12.0

19.90 20.55

14.4 4.5

29.75 29.55

26.57 27.59

Baseline defined as Day 1 (pre-dose); percentage inhibition is the percentage reduction from baseline. Log2 normalized data were back-transformed prior to the calculation of the percentage inhibition. BID: twice daily; CI: confidence interval; IFN: interferon. Lupus


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Table 5 Summary of adverse events and serious adverse events.* Preferred term Adverse events, n (%) Any event Urinary tract infection Nasopharyngitis Upper respiratory tract infection Lymphopenia Headache Vaginal infection Leukopenia Serious adverse events, n (%) Any event Drug-induced liver injury Hypertransaminasaemia Liver injury Liver function test abnormal Transaminases increased Upper abdominal pain Pyrexia Urinary tract infection Blighted ovum Drug reaction with eosinophilia and systemic symptoms

Placebo (n ¼ 11)

GSK2586184 50 mg (n ¼ 9)

GSK2586184 100 mg (n ¼ 10)

GSK2586184 200 mg (n ¼ 10)

GSK2586184 400 mg (n ¼ 10)

7 (64) 3 (27) 0 0 0 1 (9) 0 0

8 (89) 1 (11) 2 (22) 0 0 0 0 0

7 1 1 1

7 (70) 0 0 0 3 (30)y 0 2 (20) 2 (20)z

6 (60) 2 (20) 0 2 (20) 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0

1 (11) 0 0 0 1 (11) 0 0 0 0 0 0

2 (20) 0 0 0 0 1 (10) 0 0 1 (10) 0 0

(70) (10) (10) (10) 0 2 (20) 0 0

4 1 1 1

(40) (10) (10) (10) 0 0 1 (10) 1 (10) 0 1 (10) 0

1 (10) 0 0 0 0 0 0 0 0 0 1 (10)

*Adverse events occurring in > 1 patient; adverse events or serious adverse events could occur more than once in a single patient; ytwo Grade 1 and one Grade 4 in severity; zboth Grade 1 in severity.

and cold sensation, headache, nausea, stomach pain, vomiting, diarrhoea and fever. The patient became hypotensive, and developed generalized rash and raised liver transaminases the following day (AST levels, 41 ULN; ALT levels, 18 ULN), although bilirubin levels were normal. The patient was treated with high-dose corticosteroids. AST and ALT levels resolved 18 days after onset, and the patient recovered from DRESS syndrome 45 days later. A 28-year-old female patient receiving GSK2586184 200 mg BID, omeprazole, ethinylestradiol/gestodene, hydroxychloroquine, and prednisone developed fever, epigastric pain, oedema and liver function test (LFT) abnormalities meeting Hy’s Law criterion.24 After 10 days of study drug, treatment was interrupted for 4 days due to suspected laryngitis/bacterial pharyngitis (amoxicillin/clavulanate was prescribed). Within 5–6 hours of re-initiating GSK2586184 treatment, the patient developed symptoms consistent with DRESS syndrome (although a formal diagnosis was not made), with elevated AST (8 ULN) and ALT (7.5 ULN) levels. Treatment was discontinued and the patient received high-dose steroids. Two days later, bilirubin levels were 2.17 ULN. ALT and AST levels peaked at Week 2, followed by resolution of symptoms and normalization of liver enzyme levels 22 days after onset.

Four other patients receiving GSK2586184 50 mg (n ¼ 1), GSK2586184 100 mg (n ¼ 1) and GSK2586184 200 mg (n ¼ 2) experienced LFT abnormalities with ALT levels of 4.7–10 ULN. In each of the four cases, symptoms resolved upon treatment discontinuation. For all six patients with liver-related SAEs, no dose–response relationship was observed, and human leukocyte antigen (HLA) typing revealed no association between HLA type and the ALT elevations in these patients (data not shown). Investigations of viral load and serological evaluation for a panel of the herpes viruses (including cytomegalovirus, Epstein-Barr virus, varicella zoster virus, herpes simplex virus type 1 and 2, and human herpes virus type 6 and 7) were performed and the results suggested a lack of reactivation of herpes viruses in these patients. One patient receiving GSK2586184 200 mg developed Grade 4 lymphopaenia and met the protocol-specified haematology criterion for treatment interruption after 15 days of treatment. Lymphocyte count returned to baseline levels 3 days post-treatment discontinuation and the patient subsequently re-initiated study medication, completing the 12-week treatment period. Infections (as an AE of special interest) were primarily Grade 1/2 except for one Grade 3 event (nasopharyngitis) in a patient receiving Lupus


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GSK2586184 50 mg with no dose–relationship observed (Supplementary Table 3). No deaths were reported during the study. A dose-related increase in mean values for serum creatinine levels was observed with GSK2586184 over the study. All serum creatinine values remained within the normal range and returned to baseline levels following treatment cessation (Supplementary Material and Supplementary Table 4). Cholesterol levels were also elevated with GSK2586184; the mean (SD) change from baseline at Week 12 was 0.12 (0.33)–0.60 (0.53) mmol/L for GSK2586184 50–400 mg compared with a change of 0.18 (0.35) mmol/L for placebo. High-density lipoprotein (HDL) levels appeared to increase dosedependently with GSK2586184, but there were no apparent differences between the placebo and active treatment groups for low-density lipoprotein (LDL) and triglyceride levels. There were no clinically-significant changes in platelet counts, vital signs or clinical chemistry parameters during the study. PK The geometric means for CL/F and V/F were consistent across the treatment groups (52.24–59.24 L/h and 174.22–226.01 L, respectively). AUC0- increased in an approximately dose-proportional manner for GSK2586184 50–400 mg (Supplementary Table 5).

Discussion Evidence suggests that modulation of the JAKSTAT pathway may diminish IFN-mediated effects in patients with SLE.7,8 This study in patients with SLE therefore aimed to evaluate the effect of GSK2586184 on expression of IFN-mediated transcriptional biomarkers and cell markers. The significant decrease in IFN-induced gene expression following GSK2586184 administration in healthy volunteers exposed to an in vivo IFNa challenge (GSK, data on file) was not observed in patients with SLE following 2 weeks of treatment with GSK2586184 in this study. An ad hoc analysis using back-transformed log2 values showed that at Week 6, up to 38% mean inhibition was detectable in five different panels containing genes involved in IFN-mediated signalling, following administration of the 400 mg dose. However, only nine patients provided data at Week 6 and the results were variable. Although most patients had high baseline values for IFN gene expression, consistent with an active SLE population, the reason Lupus

for the minimal effect of GSK2586184 at Week 2 (in both the log2 and back-transformed log2 data analyses) is not clear. The differing circumstances of the enhanced levels of IFN gene expression (an acute in vivo IFN challenge in healthy volunteers compared with chronic overproduction of IFN in patients with SLE) may have contributed to disparity in the results. beta 2-microglobulin levels are elevated in cases of active lupus, and correlate positively with SLEDAI scores.25 Although the present study demonstrated a trend towards a decrease in b2microglobulin levels with active treatment, this was not reflected in serum neopterin levels. These results are inconsistent with a prior study of GSK2586184 in healthy volunteers, where GSK2586184 was shown to inhibit IFNa-induced increase in neopterin and b2-microglobulin levels (GSK, data on file). SRI response rates at Week 12 showed a numerical imbalance, with higher SRI response rates in the GSK2586184 treatment groups compared with placebo. However, no conclusions may be drawn and caution should be applied to the interpretation of these data due to the small number of patients in each group, who participated until Week 12 (n ¼ 22). Although there was a greater change from baseline in BFI and BPI scores with active treatments compared with placebo, there are no published data relating to the minimum clinically important difference in SLE. Further, the small number of patients in each treatment group limits interpretation of these data. As the futility determination was not based on safety data, the protocol permitted consenting patients to complete the scheduled 12 weeks of dosing. However, safety data emerging at the time of Interim Analysis 1 (including elevated liver enzymes in six patients, as previously described26) led to immediate cessation of dosing in all patients. One confirmed case of DRESS met the RegiSCAR’s criterion with a final score of 8,27 and a second patient experienced onset of DRESS-like symptoms with elevated ALT and bilirubin levels (meeting Hy’s Law criterion).24 The temporal association of the SAEs with re-initiation following treatment interruption of 4–5 days, in these two patients, was consistent with a hypersensitivity reaction to GSK2586184. The normalization of LFT abnormalities within 2–4 weeks following treatment discontinuation in the four other patients suggested that no permanent liver injury had occurred. Although LFT abnormalities have been reported with other JAK inhibitors (e.g. tofacitinib) in patients with RA,13,28 there have been no previous reports of DRESS following exposure to other JAK inhibitors. There were also no cases of


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DRESS or serious liver-related AEs when GSK2586184 was assessed in patients with psoriasis.18 It is unknown whether SLE or receiving concomitant medications predisposed patients in the present study to the described reactions, or what mechanisms are involved. Five of the six patients experiencing elevated liver enzymes and/or DRESS were receiving hydroxychloroquine or chloroquine. There have been reports describing chloroquine hypersensitivity syndrome and hydroxychloroquine-induced DRESS syndrome,29,30 but the relationship between these medications and the SAEs described here remains unclear. Reactivation of viruses of the herpes family has been reported to occur at the onset of DRESS.31 However, this was not observed in the six patients with liver SAEs. Similarly, no relationship between HLA type and ALT elevations was observed. Reversible, clinically insignificant elevations of serum creatinine concentrations occurred with GSK2586184 treatment. This is thought to be related to inhibition of renal transporters, consistent with observations in healthy subjects (GSK, data on file) and studies of other JAK1 inhibitors in RA.32,33 Overall, GSK2586184 appeared to have no adverse renal effects, consistent with observations in healthy volunteers (GSK, data on file). The increases in HDL were consistent with studies of pan-JAK inhibitors in RA.13,32,33 However, the increase in LDL in RA studies, attributed to IL-6 inhibition,34 was not observed in this study. The small study sample size at the time of termination was adequate for the primary IFN transcriptional biomarker endpoint. However, the small sample size limited interpretation of patient-related health outcomes and clinical efficacy parameters such as SELENA-SLEDAI and SRI and no firm conclusions could be drawn from these data. Nevertheless, the PK results were generally consistent with data from studies in healthy volunteers (GSK, data on file). and patients with psoriasis,18 with similar values for apparent clearance and volume of distribution of GSK2586184. The present study was terminated early following recruitment of only 50 subjects, because of the declaration of futility at Interim Analysis 1 based on protocol-defined pharmacodynamic criteria. The analysis of b2-microglobulin and the ad hoc analysis of mean inhibition of IFN gene expression at Week 6 (using back-transformed log2 values) suggest biological activity of GSK2586184 over placebo. However, the results cannot be viewed as evidence of clinical efficacy and remain equivocal due to the small number of subjects in each treatment group, especially at Week 12. The most

significant clinical data in the study related to elevated liver enzymes in six subjects receiving GSK2586184 (including one confirmed and one suspected case of DRESS). Taken together, these data indicate that the risk-benefit of treatment with this experimental JAK-1 inhibitor does not support further clinical development for treatment of lupus.

Acknowledgements Editorial assistance in the preparation of the manuscript (provided by Moira Hudson and Natasha Thomas, PhD, of Fishawack Indicia Ltd) was funded by GSK.

Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The work presented here, including the content of the study, data analysis and interpretation, was supported by GSK. JP, ML, KH, MD, LC, LS and SZ are employees of GSK and hold stocks/shares in GSK. LK was employed by GSK during JAK115919 study conduct and reporting and as of 1 June 2015, is employed by ViiV Healthcare but holds stocks/shares in GSK. LC was employed by GSK during JAK115919 study conduct and reporting and as of 2 March 2015, is employed by PAREXEL International but holds stocks/shares in GSK. EH received lecture fees from GSK and Roche. RFvV has received grants from AbbVie, Bristol-Myers Squibb, GSK, Pfizer, Roche and UCB, and fees from AbbVie, Biotest, Bristol-Myers Squibb, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB and Vertex. DM, DS-S and GL declare no conflict of interest. MB is an employee of Pfizer.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study (115919) was funded by GSK.

References 1 Laurence A, Pesu M, Silvennoinen O, O’Shea J. JAK kinases in health and disease: An update. Open Rheumatol J 2012; 6: 232–244. Lupus


1430 2 Sohn SJ, Barrett K, Van Abbema A, et al. A restricted role for TYK2 catalytic activity in human cytokine responses revealed by novel TYK2-selective inhibitors. J Immunol 2013; 191: 2205–2216. 3 Niewold TB, Clark DN, Salloum R, Poole BD. Interferon alpha in systemic lupus erythematosus. J Biomed Biotechnol 2010; 948364. 4 Yao Y, Richman L, Higgs BW, et al. Neutralization of interferonalpha/beta-inducible genes and downstream effect in a phase I trial of an anti-interferon-alpha monoclonal antibody in systemic lupus erythematosus. Arthritis Rheum 2009; 60: 1785–1796. 5 Yao Y, Richman L, Morehouse C, et al. Type I interferon: Potential therapeutic target for psoriasis? PLoS One 2008; 3: e2737. 6 Baechler EC, Batliwalla FM, Karypis G, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci 2003; 100: 2610–2615. 7 Beadling C, Guschin D, Witthuhn BA, et al. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. EMBO J 1994; 13: 5605–5615. 8 Silvennoinen O, Ihle JN, Schlessinger J, Levy DE. Interferoninduced nuclear signalling by Jak protein tyrosine kinases. Nature 1993; 366: 583–585. 9 Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol 2012; 83: 1136–1145. 10 Van Rompaey L, Galien R, van der Aar EM, et al. Preclinical characterization of GLPG0634, a selective inhibitor of JAK1, for the treatment of inflammatory diseases. J Immunol 2013; 191: 3568–3577. 11 Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebocontrolled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799–807. 12 Kontzias A, Laurence A, Gadina M, O’Shea JJ. Kinase inhibitors in the treatment of immune-mediated disease. F1000 Med Rep 2012; 4: 5. 13 XELJANZ; Highlights of prescribing information. Available at: http://labeling.pfizer.com/ShowLabeling.aspx?id=959 (2012, accessed September 2015). 14 Neubauer H, Cumano A, Mu¨ller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93: 397–409. 15 Grisouard J, Hao-Shen H, Dirnhofer S, Wagner KU, Skoda RC. Selective deletion of Jak2 in adult mouse hematopoietic cells leads to lethal anemia and thrombocytopenia. Haematologica 2014; 99: e52–e54. 16 Haan C, Rolvering C, Raulf F, et al. Jak1 has a dominant role over Jak3 in signal transduction through gammac-containing cytokine receptors. Chem Biol 2011; 18: 314–323. 17 GlaxoSmithKline. GSK2586184 investigator’s brochure. GlaxoSmithKline document number 2011N131059_01. 2013. 18 Ludbrook VJ, Hicks KJ, Hanrott KE, et al. Investigation of selective JAK1 inhibitor GSK2586184 for the treatment of psoriasis in a randomized placebo-controlled Phase 2 a study. Br J Dermatol, Epub ahead of print 2016. DOI: 10.1111/bjd.14399. 19 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline: Guideline for good clinical practice E6(1). Available at: http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/ E6_R1_Guideline.pdf (1996, accessed September 2015). 20 World Medical Association. WMA Declaration of Helsinki: Ethical principles for medical research involving human subjects.

Lupus

21 22 23 24

25 26

27

28

29 30 31 32

33 34

Available at: http://www.wma.net/en/30publications/10policies/ b3/17c.pdf (2008, accessed September 2015). Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–1277. Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J Med 2005; 353: 2550–2558. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for Industry. Drug-induced liver injury: Premarketing clinical evaluation. Available at: http://www.fda.gov/downloads/Drugs/.../Guidances/ UCM174090.pdf (2009, accessed September 2015). Skare TL, Ferri K, Santos MA. Systemic lupus erythematosus activity and beta two microglobulin levels. Sao Paulo Med J 2014; 132: 239–242. van Vollenhoven R, Layton M, Kahl L, et al. Severe, unexpected drug reactions and reversible liver function abnormalities in subjects with systemic lupus erythematosus treated with the highly selective JAK-1 inhibitor GSK2586184. Lupus 2015; 24: 648–649. Kardaun SH, Sidoroff A, Valeyrie-Allanore L, et al. Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: Does a DRESS syndrome really exist? Br J Dermatol 2007; 156: 609–611. US Food and Drug Administration. FDA background materials for new drug application 203214: tofacitinib for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had inadequate response to one or more disease modifying anti-rheumatic drugs. Available at: http://www.fda. gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/ ArthritisAdvisoryCommittee/UCM302960 (2012, accessed September 2015). Kanny G, Renaudin J-M, Lecompte T, Moneret-Vautrin DA. Chloroquine hypersensitivity syndrome. Eur J Intern Med 2002; 13: 75–76. Volpe A, Marchetta A, Caramaschi P, Biasi D, Bambara L, Arcaro G. Hydroxychloroquine-induced DRESS syndrome. Clin Rheum 2008; 27: 537–539. Picard D, Janela B, Descamps V, et al. Drug reaction with eosinophilia and systemic symptoms (DRESS): A multiorgan antiviral T cell response. Sci Transl Med 2010; 2: 46ra62. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009; 60: 1895–1905. Riese RJ, Krishnaswami S, Kremer J. Inhibition of JAK kinases in patients with rheumatoid arthritis: Scientific rationale and clinical outcomes. Best Pract Res Clin Rheumatol 2010; 24: 513–526. McInnes IB, Thompson L, Giles JT, et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann Rheum Dis 2015; 74: 694–702.