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Abstract
Objective To assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA).
Methods This phase II, placebo-controlled, double-blind, dose-ranging study randomised patients with RA and inadequate DMARD response to VX-509 100 mg (n=11), 200 mg (n=10) or 300 mg (n=10) or placebo (n=12) once daily for 12 weeks. Outcome measures included American College of Rheumatology score (ACR20; improvement of ≥20%) and disease activity score (DAS28) using C reactive protein (CRP), and the RA MRI scoring (RAMRIS) system.
Results ACR20 response at week 12 was 63.6%, 60.0% and 60.0% in the VX-509 100-mg, 200-mg and 300-mg groups, respectively, compared with 25.0% in the placebo group. DAS28-CRP scores decreased in a dose-dependent manner with increasing VX-509 doses. Decreases in RAMRIS synovitis scores were significantly different from placebo for all VX-509 doses (p<0.01) and for RAMRIS osteitis scores (p<0.01) for VX-509 300 mg. Treatment was generally well tolerated.
Conclusions VX-509 plus a DMARD reduced the signs and symptoms of RA in patients with an inadequate response to a DMARD alone. MRI responses were detected at week 12. Treatment was generally well tolerated.
Trial registration number NCT01754935; results.
- Rheumatoid Arthritis
- Magnetic Resonance Imaging
- DMARDs (biologic)
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Introduction
The Janus kinase (JAK) pathway is critical in cell growth, survival, development and differentiation of immune cells,1 with JAK3 mainly expressed by haematopoietic cells1–3 and only associating with the common γ-chain receptor subunit. Cytokines signalling through the common γ-chain receptor subunit includes interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15 and IL-21, which are key to lymphocyte activation, proliferation and differentiation. Therefore, inhibition of their signalling by targeting JAK3 is a rational approach to the treatment of rheumatoid arthritis (RA).1 ,2 ,4
MRI allows sensitive detection and monitoring of inflammation and damage in RA, and changes in joint inflammation predict subsequent joint damage.5–7 The RA MRI scoring (RAMRIS) system is used to assess synovitis, bone marrow oedema (osteitis),7 erosion and joint space narrowing of the wrist and finger joints.8 A recent report from an MRI substudy of the GO-BEFORE trial, a large study of the anti-inflammatory drug golimumab, demonstrated that clinical trials of treatment for RA could be shortened by using the MRI erosion change score at 12 and 24 weeks and that fewer patients would be needed to demonstrate significant differences between the treatment arms.9
VX-509 (decernotinib; Vertex Pharmaceuticals Incorporated, Boston, Massachusetts, USA) is a novel, oral selective JAK3 inhibitor. A 12-week, placebo-controlled, phase IIa study previously demonstrated that twice-daily VX-509 50, 100 or 150 mg as monotherapy improved signs and symptoms of RA in patients with insufficient response to disease-modifying antirheumatic drugs (DMARDs). Safety signals included infections and increased liver transaminase and lipid levels.10 In a second, 24-week, placebo-controlled, phase IIb study,11 VX-509 (100, 150 or 200 mg per day or 100 mg twice daily) administered in combination with methotrexate alleviated the signs and symptoms of RA in patients who had an inadequate response to methotrexate. The findings related to safety and tolerability were consistent with those observed in the previous study.
This study evaluated early effects on joint structures as assessed by MRI of single daily doses of VX-509 in combination with stable DMARDs in adults with active RA and inadequate response to DMARD therapy.
Methods
Study design
A phase IIb, randomised, dose-ranging, double-blind, placebo-controlled, multicenter study (NCT01754935) enrolled patients with moderate-to-severe RA who were seropositive for rheumatoid factor or anti-cyclic citrullinated peptide antibody, or who demonstrated erosive disease by conventional radiography, with inadequate DMARD response. Patients received once-daily VX-509 100 mg, 200 mg, 300 mg or placebo for 12 weeks.
The study was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. The institutional review board/ethics committee of each site approved the protocol. Patients provided written informed consent.
Patients
Eligible patients were adults aged 18–65 years with RA receiving stable DMARD doses, with swollen joint count of ≥6 of 66 assessed joints, tender joint count of ≥8 of 68 assessed joints, clinical synovitis grade ≥2 of the wrist or of 2 metacarpophalangeal joints and C reactive protein (CRP) level ≥1.2×upper limit of normal (ULN) or Westergren erythrocyte sedimentation rate (ESR) ≥1.2×ULN. Key exclusion criteria included other inflammatory rheumatologic arthritic disorders, history of tuberculosis, active infection requiring antimicrobial treatment and high risk of developing infection.
Outcomes
Primary efficacy outcomes were evaluated at week 12 and consisted of the proportion of patients achieving an American College of Rheumatology (ACR) criteria of ≥20% improvement in disease severity (ACR20), mean change from baseline in disease activity score for 28 joints (composite of four components; DAS28) using CRP and mean change from baseline in RAMRIS scores. Secondary efficacy outcomes included the proportion of patients achieving ACR50 and ACR70 response and mean change from baseline in DAS28-ESR at week 12.
The hand with the highest number of clinically swollen joints at baseline was selected for MRI. The minimum required for inclusion was grade ≥2 clinical synovitis either in the wrist or in two metacarpophalangeal joints. The selection of the hand was based on clinical examination only; there was no screening MRI performed before the baseline MRI. The same hand was examined by MRI at 12 weeks post baseline. MRI sets were scored by two experienced readers, blinded to patient identity, treatment arm and chronological order of the images. The wrist, 2nd–5th metacarpophalangeal and 2nd–5th proximal interphalangeal joints were examined by MRI for synovitis (0–3 per area), osteitis (0–10 per bone) and erosion (0–10 per bone) according to the OMERACT RAMRIS.12 Each reader reviewed 100% of the subject cases. A comparison of the two readers' assessments was performed, and cases were allocated for a consensus read by the two primary readers, if the reader discordance regarding change in a score between the two time points was above a predefined threshold. These thresholds for consensus review were predefined in the Read Monitoring Plan specifically for each finding (bone erosion, osteitis, synovitis and joint space narrowing) and each anatomical area (wrist, metacarpophalangeal (MCP) and proximal interphalangeal joint (PIP) joints).
Safety measures included the nature, incidence and severity of adverse events (AEs), physical examinations, vital signs, laboratory tests and ECGs.
Statistical analysis
Patients were analysed according to their treatment group. The safety population comprised all patients who received ≥1 dose of study medication. The intent-to-treat (ITT) population included all randomised patients who received ≥1 dose of study medication. In addition, five patients who consented to synovial biopsies were to be assigned rather than randomised to the VX-509 200-mg once-daily group. The modified ITT (mITT) population included these five patients. To ensure that data for these five patients were captured, all efficacy analyses were conducted in the mITT population.
The ACR response rates were analysed using non-responder imputation, whereby patients were considered non-responders for any assessment following discontinuation from the study or for missing any assessment. The Miettinen and Nurminen method was used to compare response rates between each VX-509 dose group and the placebo group, with p values and 95% CIs provided. Mean change from baseline in DAS28-CRP, DAS28-ESR and RAMRIS scores was analysed using a mixed-effects model for repeated measures that included the change from baseline in outcome scores as the dependent variable; treatment, visit and treatment-by-visit interaction as fixed effects; and patient as a random effect, with adjustments for the continuous baseline outcome score, region and use (yes/no) of prior tumour necrosis factor inhibitor therapy.
The planned sample size was approximately 40 patients. Assuming that the true ACR20 rates at week 12 are 25%, 38%, 60% and 65% for the four treatment groups, respectively (placebo, 100, 200 and 300 mg VX-509 once daily), the study had approximately 25% power to demonstrate a significant difference between placebo and the 300 mg (highest) VX-509 dose.
Full study details are available for clinical study protocol VX12-509-103 in the online supplementary material.
Supplemental material
Results
The study was conducted at 17 sites in the USA, Lithuania and Estonia. Thirty-eight patients were randomised, and five patients consented to participate in the synovial biopsy group; all received ≥1 dose of study drug (see baseline demographics in table 1). Thus, the safety and mITT populations each comprised 43 patients, with 39 (90.7%) completing study treatment (see online supplementary figure S1).
Baseline demographics and disease characteristics (modified intent-to-treat population; n=43)
Supplementary figure
At week 12, a greater percentage of VX-509 patients achieved ACR20, ACR50 and ACR70 response versus placebo patients (figure 1A). The difference between the 300-mg and placebo groups for ACR50 was significant (p<0.05).
Response at week 12; (A) response rates for ACR20, ACR50 and ACR70 based on ACR scores (modified intent-to-treat population; n=43); (B) LS mean change from baseline in DAS28-CRP and in DAS28-ESR at week 12 (modified intent-to-treat population; n=43); (C) LS mean change from baseline in RAMRIS score for synovitis, osteitis, erosion and joint space narrowing at week 12 (modified intent-to-treat population; n=43). *p<0.05 vs placebo; **p<0.01 vs placebo. ACR, American College of Rheumatology; ACR20 (ACR50, ACR70), ≥20% (50%, 70%) improvement in disease severity according to the American College of Rheumatology criteria using C reactive protein; DAS28-CRP, disease activity score 28 using C reactive protein; DAS28-ESR, disease activity score 28 using erythrocyte sedimentation rate; LS, least squares; RAMRIS, Rheumatoid Arthritis MRI scoring system.
Mean scores at baseline and week 12 for DAS28-CRP, DAS28-ESR and RAMRIS scores for synovitis, osteitis, erosion and joint space narrowing are listed in table 2. Patients on VX-509 experienced dose-dependent reductions in the least squares (LS) mean change from baseline in DAS28-CRP and DAS28-ESR scores at week 12 (figure 1B). Patients on VX-509 200 mg and 300 mg experienced significantly greater reductions from baseline in LS mean DAS28-CRP scores versus placebo (p<0.05). Reductions in DAS28-ESR for the VX-509 200-mg and 300-mg groups were significantly greater versus placebo (p<0.05).
Efficacy assessment summary (modified intent-to-treat population; n=43)
Reductions in LS mean changes from baseline in RAMRIS scores for synovitis and osteitis were dose dependent for patients on VX-509 (figure 1C) and were significantly different from placebo for all VX-509 doses (p<0.01) for synovitis, and for osteitis in the VX-509 300-mg. Mean RAMRIS score for erosions changed minimally in all groups, and no significant differences between groups were observed. While mean changes in RAMRIS scores for joint space narrowing improved numerically with increased doses of VX-509, differences were not significantly different from placebo.
No new safety concerns arose from treatment with VX-509 in this study. Sixty-seven AEs occurred in 30 patients, all mild to moderate in severity. The most common AEs in VX-509 patients included diarrhoea, gastro-oesophageal reflux disease and sinus congestion. No AEs led to death. Two patients experienced serious AEs (1 in the 100-mg group had a partial seizure; 1 in the 200-mg group had a small intestinal obstruction); both events resolved. Two patients experienced AEs that led to discontinuation of study drug; one receiving VX-509 300 mg had hyperthyroidism and another receiving VX-509 300 mg had stomatitis, pharyngitis, dry mouth, swollen face and conjunctivitis. AEs are summarised in online supplementary table S1.
Supplementary table
Incidence of adverse events (safety population; n=43)
No clinically significant trends in vital signs and ECGs and no shifts to clinically significant abnormal ECGs were reported. Dose-related increases in total cholesterol were noted in patients treated with VX-509 as of study week 2 and continued to increase during weeks 6 and 12. These increases were more apparent in low-density than high-density lipoprotein. Triglycerides also increased in a dose-dependent manner in the VX-509 treatment groups. Patients treated with VX-509 experienced mild but consistent dose-dependent increases in alanine aminotransferase, aspartate aminotransferase and creatine kinase. The increases in cholesterol and liver enzymes in patients receiving VX-509 in this study were similar to those observed in prior studies.10 ,11
Discussion
In this study, treatment with the oral selective JAK3 inhibitor VX-509 in combination with a stable DMARD dose for 12 weeks was associated with significant improvements in the signs and symptoms of RA in patients who had inadequate response to DMARD therapy. Dose-dependent responses were observed for DAS28-CRP and DAS28-ESR scores, ACR response and RAMRIS scores for synovitis and osteitis. No new safety concerns developed, and treatment was generally well tolerated, with an AE profile similar to that previously seen for this agent.10 ,11 These findings complement those of phase II studies that demonstrated the efficacy and safety of VX-509 as monotherapy10 and in combination with methotrexate in patients with RA.11
The significant improvements from baseline in RAMRIS scores for synovitis with VX-509 200 and 300 mg and for osteitis with VX-509 300 mg provide objective documentation of the effect of VX-509 on inflammation in the synovium and bone. The LS mean changes from baseline in RAMRIS scores in synovitis and osteitis, respectively, were −7.5 (observed mean, −5.2) and −7.2 (observed mean, −3.2). In previous studies of biological drugs in methotrexate inadequate responders for up to 4 months of treatment, mean improvements in synovitis ranged from −0.31 to −2.0 and mean improvements in osteitis ranged from −1.4 to −5.1.13–17 Early reduction of synovitis and osteitis has been shown to predict reduced radiographic structural progression.5 In agreement with this, the present study showed numerical improvement in MRI scores for joint space narrowing with all three VX-509 doses compared with placebo.
This study has limitations, including the small patient population, and the relatively short duration of the study being only 12 weeks. However, while the sample size was small, statistically significant differences were observed between patients treated with VX-509 and those receiving placebo, indicating a positive response to treatment. The short duration of the study limits any conclusions that can be made on the safety of longer term use.
In conclusion, this study showed that VX-509 in combination with a DMARD was effective for improving synovitis and osteitis as assessed by MRI in patients with RA who had an inadequate response to a DMARD. Treatment was generally safe and well tolerated, and no new safety signals emerged.
Acknowledgments
Medical writing and editorial support were provided by Edwin Thrower, PhD, and Dena McWain. They are the employees of Infusion Communications, Haddam, CT, which received funding from Vertex Pharmaceuticals Incorporated.
References
Footnotes
Handling editor Tore K Kvien
Contributors MO and MG participated in designing the study. MG was a study investigator and collected/assembled data. FY and NK prepared the manuscript. All authors participated in data analysis and interpretation, and all provided critical review and revisions to the manuscript. All authors granted final approval of the manuscript.
Funding This study was sponsored by Vertex Pharmaceuticals Incorporated.
Competing interests MG has received consultancy fees from Eli Lilly, Pfizer and Vertex Pharmaceuticals Incorporated, and study grants from Sanofi and Regeneron Pharmaceuticals. FY and NK are employees of Vertex Pharmaceuticals Incorporated. MO has received consultancy/speaker fees and/or research support form Abbott/Abbvie, BMS, Boehringer-Ingelheim, Celgene, Centocor, Eli Lilly, GlaxoSmithKline, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB and Wyeth.
Patient consent Obtained
Ethics approval University of the Witwatersrand, Johannesburg, Human Research Ethics Committee, South Africa: 121002. Pharma-ethics, South Africa: 20121127. Administrative Panel on Human Subjects in Medical Research, Stanford University, California, USA: 350 (Panel: 3). Human Subjects Committee, The University of Kansas Medical Center, Kansas, USA: 13571. New England Institutional Review Board, Massachusetts, USA: 12-322. Lithuanian Bioethics Committee, Lithuania: P-12-84. The Committee on Biomedical Research Ethics for the Region North Jutland, Denmark: N-2012-003439-41. Western Institutional Review Board, Washington, USA: 1138506. Medische Ethische Toetsingscommissie University Medical Center, The Netherlands: NL42286.041.12. Tallinn Medical Research Ethics Committee, Estonia: 2956. University of California San Diego, California, USA: 130843.
Provenance and peer review Not commissioned; externally peer reviewed.