L. Peterson

Head-to-head comparison of certolizumab pegol versus adalimumab in rheumatoid arthritis: 2-year efficacy and safety results from the randomised EXXELERATE study

BACKGROUND To date, head-to-head trials comparing the efficacy and safety of biological disease-modifying antirheumatic drugs within the same class, including TNF inhibitors, in patients with active rheumatoid arthritis despite methotrexate therapy are lacking. We aimed to compare the efficacy and safety of two different TNF inhibitors and to assess the efficacy and safety of switching to the other TNF inhibitor without a washout period after insufficient primary response to the first TNF inhibitor at week 12. METHODS In this 104-week, randomised, single-blind (double-blind until week 12 and investigator blind thereafter), parallel-group, head-to-head superiority study (EXXELERATE), eligible patients from 151 centres worldwide were aged 18 years or older with a diagnosis of rheumatoid arthritis at screening, as defined by the 2010 ACR/EULAR criteria, and had prognostic factors for severe disease progression, including a positive rheumatoid factor, or anti-cyclic citrullinated peptide antibody result, or both. Participants were randomly assigned (1:1) via an interactive voice and web response system with no stratification to receive certolizumab pegol plus methotrexate or adalimumab plus methotrexate. All study staff were kept masked throughout the study and participants were masked until week 12. At week 12, patients were classified as responders (by either achieving low disease activity [LDA] according to Disease Activity Score 28-erythrocyte sedimentation rate [DAS28-ESR] ≤3·2 or DAS28-ESR reduction ≥1·2 from baseline) or as non-responders. Non-responders to the first TNF inhibitor to which they were randomised were switched to the other TNF inhibitor with no washout period. Primary endpoints were the percentage of patients achieving a 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 12 and LDA at week 104 (week 12 non-responders were considered LDA non-responders). This study is registered with ClinicalTrials.gov, number NCT01500278. FINDINGS Between Dec 14, 2011, and Nov 11, 2013, 1488 patients were screened of whom 915 were randomly assigned; 457 to certolizumab pegol plus methotrexate and 458 to adalimumab plus methotrexate. No statistically significant difference was observed in ACR20 response at week 12 (314 [69%] of 454 patients and 324 [71%] of 454 patients; odds ratio [OR] 0·90 [95% CI 0·67-1·20]; p=0·467) or DAS28-ESR LDA at week 104 (161 [35%] of 454 patients and 152 [33%] of 454 patients; OR 1·09 [0·82-1·45]; p=0·532) between certolizumab pegol plus methotrexate and adalimumab plus methotrexate, respectively. At week 12, 65 non-responders to certolizumab pegol were switched to adalimumab and 57 non-responders to adalimumab were switched to certolizumab pegol; 33 (58%) of 57 patients switching to certolizumab pegol and 40 (62%) of 65 patients switching to adalimumab responded 12 weeks later by achieving LDA or a DAS28-ESR reduction 1·2 or greater. 389 [75%] of 516 patients who received certolizumab pegol plus methotrexate and 386 [74%] of 523 patients who received adalimumab plus methotrexate reported treatment-emergent adverse events. Three deaths (1%) occurred in each group. No serious infection events were reported in the 70-day period after treatment switch. INTERPRETATION These results show that certolizumab pegol plus methotrexate is not superior to adalimumab plus methotrexate. The data also show the clinical benefit and safety of switching to a second TNF inhibitor without a washout period after primary failure to a first TNF inhibitor. FUNDING UCB Pharma.

Effect of certolizumab pegol over 96 weeks in patients with psoriatic arthritis with and without prior antitumour necrosis factor exposure.

Objective Previous reports of RAPID-PsA (NCT01087788) demonstrated efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with psoriatic arthritis (PsA), including patients with prior antitumour necrosis factor (TNF) therapy. We report efficacy and safety data from a 96-week data cut of RAPID-PsA. Methods RAPID-PsA was placebo-controlled to week 24, dose-blind to week 48 and open-label to week 216. We present efficacy data including American College of Rheumatology (ACR)/Psoriasis Area and Severity Index (PASI) responses, HAQ-DI, pain, minimal disease activity (MDA), modified total Sharp score (mTSS) and ACR responses in patients with/without prior anti-TNF exposure, in addition to safety data. Results Of 409 patients randomised, 273 received CZP from week 0. 54 (19.8%) CZP patients had prior anti-TNF exposure. Of patients randomised to CZP, 91% completed week 24, 87% week 48 and 80% week 96. ACR responses were maintained to week 96: 60% of patients achieved ACR20 at week 24, and 64% at week 96. Improvements were observed with both CZP dose regimens. ACR20 responses were similar in patients with (week 24: 59%; week 96: 63%) and without (week 24: 60%; week 96: 64%) prior anti-TNF exposure. Placebo patients switching to CZP displayed rapid clinical improvements, maintained to week 96. In patients with ≥3% baseline skin involvement (60.8% week 0 CZP patients), PASI responses were maintained to week 96. No progression of structural damage was observed over the 96-week period. In the Safety Set (n=393), adverse events occurred in 345 patients (87.8%) and serious adverse events in 67 (17.0%), including 6 fatal events. Conclusions CZP efficacy was maintained to week 96 with both dose regimens and in patients with/without prior anti-TNF exposure. The safety profile was in line with that previously reported from RAPID-PsA, with no new safety signals observed with increased exposure. Trial registration number NCT01087788.

Sustained efficacy, safety and patient-reported outcomes of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from RAPID-axSpA

Abstract Objective The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.

Dual neutralization of both interleukin 17A and interleukin 17F with bimekizumab in patients with psoriasis: Results from BE ABLE 1, a 12-week randomized, double-blinded, placebo-controlled phase 2b trial

Background Neutralizing interleukin (IL) 17F in addition to IL‐17A might provide a more complete and specific approach to inhibiting inflammation. Objective Assess the efficacy and safety of bimekizumab, a monoclonal antibody that potently and selectively neutralizes IL‐17A and IL‐17F, in patients with moderate‐to‐severe plaque psoriasis. Methods Double‐blinded, placebo‐controlled phase 2b study (NCT02905006). Patients (randomized 1:1:1:1:1:1) received subcutaneous bimekizumab every 4 weeks at doses of 64 mg, 160 mg, 160 mg with 320 mg loading dose, 320 mg, 480 mg, or placebo. Primary endpoint was ≥90% reduction in Psoriasis Area Severity Index (PASI90) at week 12. Results There was a significant (P < .0001) dose‐dependent response for PASI90 (week 12); more patients achieved PASI90 in the bimekizumab groups (46.2%‐79.1%) than patients in the placebo group (0%; P < .0001 all doses). Across all doses, there were significant improvements from baseline for all secondary endpoints (PASI90 week 8, PASI75 week 12, PASI100 week 12, and Investigators Global Assessment clear or almost clear weeks 8 and 12; P ≤ .0003) compared with placebo. More bimekizumab‐treated patients than placebo‐treated patients achieved PASI100 (week 12) (27.9%‐60.0% vs 0%; P ≤ .0002 all doses). Treatment‐emergent adverse events were reported by 126 of 208 (61%) bimekizumab‐treated patients and 15 of 42 (36%) placebo‐treated patients. Limitations No active comparator. Conclusion Dual neutralization of IL‐17A and IL‐17F with bimekizumab provided rapid and substantial clinical improvements in patients with psoriasis, with no unexpected or dose‐related safety findings.

Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks from 2 phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2)

Background Certolizumab pegol, the only Fc‐free, PEGylated anti–tumor necrosis factor biologic, demonstrated clinically meaningful improvements suggestive of a positive risk‐benefit balance in phase 2 studies in adults with moderate‐to‐severe chronic plaque psoriasis. Objective Assess certolizumab efficacy and safety versus placebo in phase 3 studies. Methods Patients with moderate‐to‐severe chronic plaque psoriasis were randomized 2:2:1 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks. At week 16, certolizumab‐treated patients achieving a 50% reduction in Psoriasis Area and Severity Index continued treatment through week 48. Coprimary endpoints were week 16 responder rates, defined as a 75% reduction in Psoriasis Area and Severity Index and Physicians Global Assessment 0/1 (clear/almost clear) and ≥2‐point improvement. Safety was assessed by treatment‐emergent adverse events. Results Week‐16 endpoints were significantly greater for both doses of certolizumab versus placebo, and the responses were maintained through week 48. For most measures, improvement was numerically greater for certolizumab 400 mg. No unexpected safety signals were identified. Limitation There was no active comparator. Conclusion Treatment with either certolizumab 400 mg or 200 mg every 2 weeks was associated with significant and clinically meaningful improvements in moderate‐to‐severe psoriasis. The 400‐mg dose could provide additional clinical benefit. The safety profile was consistent with the therapeutic class.

Comparative usability study for a certolizumab pegol autoinjection device in patients with rheumatoid arthritis

ABSTRACT Objectives: To compare the usability of a new certolizumab pegol (CZP) autoinjector with the adalimumab, etanercept, and golimumab devices in patients with rheumatoid arthritis. Methods: Two identical studies were performed in 2013 and 2016; patients performed a simulated self-injection with the CZP autoinjector and the most up-to-date device versions at the time in a randomized, consecutive sequence. The primary end point was the ranking of the four autoinjectors in order of preference. Device usability and intuitiveness were assessed across a range of secondary and exploratory end points. Results: The 2013 and 2016 study populations included 76 patients each; a significant majority (2013: 67%; 2016: 59%) ranked the CZP autoinjector as their most preferred device (p < 0.001). Most patients agreed that the CZP autoinjector was easier to use, start, and manipulate, and were more willing to use it than the comparator devices (p < 0.001 for all pairwise comparisons with CZP). Likert score differences also favored the CZP autoinjector regarding how easy it was to determine injection completion. The CZP autoinjector was associated with a low rate of use error. Conclusions: In both studies, the CZP autoinjector was the preferred choice compared to the alternative devices and was associated with a high level of patient satisfaction.

Certolizumab pegol for the treatment of chronic plaque psoriasis: Results through 48 weeks of a phase 3, multicenter, randomized, double-blind, etanercept- and placebo-controlled study (CIMPACT)

Background Phase 2 psoriasis studies with the Fc‐free, PEGylated, anti–tumor necrosis factor biologic certolizumab pegol demonstrated meaningful clinical activity. Objective Assess safety and efficacy of certolizumab in adults with moderate‐to‐severe chronic plaque psoriasis. Methods Patients were randomized 3:3:1:3 to certolizumab 400 mg, certolizumab 200 mg, or placebo every 2 weeks for 16 weeks or etanercept 50 mg twice weekly for 12 weeks. Certolizumab‐treated patients achieving a ≥75% reduction in Psoriasis Area and Severity Index (PASI) at week 16 from baseline PASI were rerandomized to certolizumab or placebo for 32 weeks. The primary endpoint was responder rate (≥75% reduction in PASI from baseline PASI) versus placebo (primary analysis) and etanercept (secondary analysis) at week 12; secondary endpoints included responder rates on various measures versus placebo at weeks 12, 16, and 48. Safety was assessed by treatment‐emergent adverse events. Results All endpoints were significantly greater for certolizumab versus placebo with the greatest response seen with 400 mg. Certolizumab 400 mg was superior to and 200 mg was noninferior to etanercept. Adverse events were consistent with the anti–tumor necrosis factor class of drugs. Limitations Etanercept was administered by unblinded study staff or self‐administered, but efficacy assessments were performed by a blinded assessor. Conclusion Both certolizumab regimens improved psoriasis symptoms, with a greater response seen with the higher dose. No new safety signals were observed.

4-year results from the RAPID-PsA phase 3 randomised placebo-controlled trial of certolizumab pegol in psoriatic arthritis

Objective To report the efficacy, patient-reported, radiographic and safety outcomes of 4 years’ certolizumab pegol (CZP) treatment in patients with psoriatic arthritis (PsA). Methods RAPID-PsA (NCT01087788) was double-blind and placebo-controlled to Week 24, dose-blind to Week 48 and open-label (OL) to Week 216. Patients were randomised 1:1:1 to either placebo or CZP 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W) (following 400 mg at Weeks 0/2/4). Patients randomised to CZP continued their assigned dose in the OL period. Patients randomised to placebo were re-randomised to CZP 200 mg Q2W or 400 mg Q4W (post-loading dose) at Week 16 (early escape) or after the double-blind phase. We present observed and imputed data; missing values were imputed using non-responder imputation (NRI) for categorical and last observation carried forward (LOCF) for continuous measures. Results 409 patients were randomised; 20% (54/273) of Week 0 patients randomised to CZP had prior anti-tumour necrosis factor (TNF) exposure; 67% (183/273) completed 216 weeks. By Week 48, 60.4% of patients achieved Disease Activity Index for Psoriatic Arthritis low disease activity or remission, which was maintained; 66.3% achieved these outcomes at Week 216 (NRI). At Weeks 48 and 216, 39.2% of patients achieved minimal disease activity (NRI). 75% reduction in Psoriasis Area and Severity Index responses were 65% and 52% at Weeks 48 and 216 (NRI). Total resolution rates for enthesitis, dactylitis and nail psoriasis, at 4 years, were 71%, 81% and 65%, respectively (LOCF). Structural damage progression was low over 4 years’ treatment. No new safety signals were identified after Week 96. Conclusions CZP efficacy in treating PsA was maintained over 4 years, in patients both with and without prior anti-TNF exposure, with no new safety signals identified.

SAT0375 Certolizumab Pegol for The Treatment of Axial Spondyloarthritis: 4-Year Outcomes from The Rapid-AXSPA Trial

Background The RAPID-axSpA trial (NCT01087762) investigated the efficacy and safety of certolizumab pegol (CZP) for the treatment of patients (pts) with axial spondyloarthritis (axSpA), including ankylosing spondylitis (AS; also termed radiographic-axSpA) and non-radiographic (nr)-axSpA pts. Previous reports have shown CZP to be safe and efficacious over 96 weeks (wks) of treatment.1 Objectives To report 4-year efficacy and safety data from the RAPID-axSpA trial. Methods RAPID-axSpA was double-blind and placebo (PBO)-controlled to Wk24, dose-blind to Wk48 and open-label (OL) to Wk204. Pts fulfilled ASAS criteria and had active axSpA with positive sacroiliac joint MRI and/or raised CRP (>7.9mg/L). Pts originally randomized to CZP (200mg Q2W or 400mg Q4W) continued on their assigned dose in the OL period. Outcomes assessed included: ASAS responses, ASDAS, BASDAI, BASFI, BASMI-linear and enthesitis. Efficacy data are presented for pts originally randomized to CZP (combined doses) as observed case and with imputation: NRI for categorical and LOCF for continuous measures. The safety set consisted of all pts treated with ≥1 dose of CZP to Wk204. Results 325 pts were randomized, of whom 218 received CZP from Wk0. Of CZP-randomized pts, 93% completed to Wk24, 88% to Wk48 and 65% to Week 204 (AS: 67%; nr-axSpA: 63%). In the OL period, 9.2% of pts withdrew due to an adverse event (AE) and 1.4% due to lack of efficacy. The proportion of pts achieving ASAS20/40 and partial remission (PR) responses at Wk24 was maintained over 4 years (to Wk204) in pts remaining in the study (Table). Efficacy, expressed as ASDAS ID rates (LOCF: Wk24: 30.3%; Wk204: 32.1%), mean ASDAS score (baseline: 3.84; LOCF: Wk24: 2.07; Wk204: 1.98), and all other outcomes reported, was maintained to Wk204. Similar improvements were seen in AS and nr-axSpA pts (Figure/Table) and in both CZP dose regimens (data not shown). Function (BASFI) was also improved in both subpopulations, with nr-axSpA pts having a particularly low mean score by Wk204 (Table). Pts in the safety set (N=315) had a total CZP exposure of 981 patient-years (PY), with an AE rate (ER) per 100 PY of 292.9. No new safety signals were identified from Wk96 to Wk204, and no deaths were reported over 4 years. Conclusions CZP efficacy was maintained in axSpA pts over 4 years with no new safety signals. Treatment responses to CZP were similar in AS and nr-axSpA pts. References Sieper J. Arthritis Rheum 2015;67:668–77 Acknowledgement The authors acknowledge Costello Medical Consulting, funded by UCB Pharma, for writing and editorial assistance. Disclosure of Interest D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Celgene, Daiichi, Eli-Lilly, Galapagos, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis and UCB Pharma, Employee of: Director of Imaging Rheumatology bv, M. Dougados Grant/research support from: UCB Pharma, Abbvie, Pfizer, Lilly, Merck and Novartis, Consultant for: UCB Pharma, Abbvie, Pfizer, Lilly, Merck and Novartis, R. Landewé Grant/research support from: Abbott, Amgen, Centocor, Novartis, Pfizer, Roche, Schering-Plough, UCB Pharma and Wyeth, Consultant for: Abbott, Ablynx, Amgen, Astra-Zeneca, Bristol Myers Squibb, Centocor, Glaxo-Smith-Kline, Novartis, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma and Wyeth, Speakers bureau: Abbott, Amgen, Bristol Myers Squibb, Centocor, Merck, Pfizer, Roche, Schering-Plough, UCB Pharma and Wyeth, J. Sieper Consultant for: Abbott, Merck, Pfizer, UCB Pharma, Novartis, Lilly and Janssen, Speakers bureau: Abbott, Merck, Pfizer, UCB Pharma, Novartis, Lilly and Janssen, W. Maksymowych Grant/research support from: Abbott, Amgen, Bristol Myers Squibb, Eli-Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi and UCB Pharma, Consultant for: Abbott, Amgen, Bristol Myers Squibb, Eli-Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi and UCB Pharma, Speakers bureau: Abbott, Amgen, Bristol Myers Squibb, Eli-Lilly, Janssen, Merck, Pfizer, Synarc, Sanofi and UCB Pharma, M. Rudwaleit Consultant for: Abbott, BMS, Janssen, MSD, Pfizer, Roche and UCB Pharma, F. van den Bosch Consultant for: Abbvie, Bristol Myers-Squibb, Celgene, Janssen, Merck, Novartis, Pfizer, UCB Pharma, Speakers bureau: Abbvie, Bristol Myers-Squibb, Celgene, Janssen, Merck, Novartis, Pfizer, UCB Pharma, J. Braun Grant/research support from: Abbott, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche and UCB Pharma, Consultant for: Abbott, Bristol Myers Squibb, Celgene, Celltrion, Chugai, Johnson & Johnson, MSD, Novartis, Pfizer, Roche and UCB Pharma, P. Mease Grant/research support from: AbbVie, Amgen, BiogenIdec, BMS, Celgene, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant for: AbbVie, Amgen, BiogenIdec, BMS, Celgene, Covagen, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Amgen, BiogenIdec, BMS, Celgene, Crescendo, Genentech, Janssen, Lilly, Pfizer and UCB Pharma, O. Davies Shareholder of: UCB Pharma, Employee of: UCB Pharma, B. Hoepken Employee of: UCB Pharma, L. Peterson Employee of: UCB Pharma, A. Deodhar Grant/research support from: AbbVie, Amgen, Eli Lilly, GSK, Janssen, Novartis, Pfizer, UCB Pharma, Consultant for: AbbVie, Amgen, Boehringer Ingelheim, Janssen, Novartis, Pfizer, UCB Pharma

PGA×BSA: A Measure of Psoriasis Severity Tested in Patients with Active Psoriatic Arthritis and Treated with Certolizumab Pegol

Objective. The product of physician’s global assessment and body surface area (PGA×BSA) to assess psoriasis severity has previously been investigated in patients with psoriasis, with the aim of assessing PGA×BSA as an alternative to the time-consuming Psoriasis Area and Severity Index (PASI). Here, we investigate PGA×BSA as an alternative to PASI in patients with psoriatic arthritis (PsA). Methods. Analyses used data from the double-blind, placebo-controlled, RAPID-PsA trial (NCT01087788) that investigated the efficacy of certolizumab pegol (CZP) in patients with PsA. Outcomes assessed whether the PGA×BSA and PASI results were comparable, and whether these outcomes correlated with one another or with the Dermatology Life Quality Index (DLQI). Results. For CZP-treated patients, both PGA×BSA and PASI demonstrated similar sensitivities to treatment between baseline and Week 24, with mean improvements of 77.4% and 69.0%, respectively. Similar improvements were also seen with placebo (PGA×BSA: 3.2%, PASI: 6.1%). Achievement of 75% response criterion in PGA×BSA and PASI was attained by similar proportions of patients with CZP (PGA×BSA75: 59.0%, PASI75: 61.4%) and placebo (PGA × BSA75: 15.1%, PASI75: 15.1%). Cross tabulations showed high concordance between achievement of response outcomes in PGA×BSA and PASI (79.6–95.2%). Spearman correlations revealed strong correlations between PGA×BSA and PASI at baseline (r = 0.78; n = 225) and percentage improvement to Week 24 (r = 0.85; n = 186). Both outcomes were only moderately correlated with DLQI (r = 0.41–0.50; n = 179–249). Conclusion. PGA×BSA is sensitive to changes in skin manifestations in patients with PsA treated with CZP. Further, PGA×BSA correlates strongly with PASI, and achievement of 75% improvement was similar for PGA×BSA and PASI.