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European League Against Rheumatism 2016
The aim of the EULAR Annual European Congress of Rheumatology, held June 8–11 in London, is to provide a forum of the highest standard for scientific (both clinical and basic), educational, and social exchange between professionals involved in rheumatology, working with patient organizations, in order to achieve progress in the clinical care of people with rheumatic and musculoskeletal diseases. This year’s Congress drew more than 14,000 attendees from more than 100 countries.
Antibodies to Infliximab in Remicade-Treated Rheumatic Patients Show Identical Reactivity Towards Biosimilar CT-P13
Results of a retrospective analysis of 250 patients and 77 controls with active rheumatoid arthritis and spondyloarthritis treated with the biologic Remicade (infliximab, Janssen Biotech) showed that when antibodies develop in response to infliximab, they also cross-react with CT-P12, a biosimilar of infliximab, potentially leading to loss of response.
Dr. Nagore, the study’s lead author, noted that while biologics, such as infliximab, have revolutionized treatment of many rheumatic diseases, immune responses to them are generated in some patients. “While most studies show there are no significant differences in clinical response between a biosimilar and the original product, some physicians and patient advocacy groups have questioned how interchangeable they really are, and whether it is safe to switch from the brand-name version to the biosimilar,” Dr. Nagore said. He also said that over the past decade, biosimilars have been introduced in the U.S. and Europe with the goal of reducing treatment costs and increasing accessibility to therapy for patients. In the U.S., Inflectra (infliximab-dyyb, Celltrion/Pfizer) is an approved infliximab biosimilar.
Patients in Dr. Nagore’s analysis had not been treated previously with the biosimilar. Assessing concentrations of anti-infliximab antibodies with his company’s assay (Promonitor-anti-IFX), he found that 50.4% of patients treated with infliximab tested positive for anti-infliximab antibodies. All of those patients also tested positive for antibody reactivity against the biosimilar. Similar findings, he noted, have been reported in infliximab-treated patients with inflammatory bowel disease.
Dr. Nagore pointed out that the presence of anti-infliximab antibodies is likely to augment drug clearance, weaken responses, and increase side effect risk. “Therefore, in patients where biological infliximab is ineffective due to the presence of circulating antibodies, switching to its biosimilar will lead to the same problems,” Dr. Nagore concluded.
Certolizumab Pegol for the Treatment of Axial Spondyloarthritis: Four-Year Outcomes From the RAPID-axSpA Trial
In the RAPID-axSpA trial, certolizumab pegol treatment efficacy was maintained over four years in patients with axial spondyloarthritis (axSpA), a chronic inflammatory disease primarily characterized by inflammation of the sacroiliac joints and spine, which causes chronic back pain, according to Dr. van der Heijde.
Patients with axSpA (also called radiographic-axSpA) and nonradiographic (nr)-axSpA were enrolled in the RAPID-axSpA trial, which is the first to include both of these populations, Dr. van der Heijde said in an interview. The inclusion of patients with (nr)-axSpA is noteworthy because some clinicians, especially in the U.S., have held the view that this population has self-limiting disease and that, for them, symptoms are likely to disappear without treatment.
Treatment with certolizumab pegol, a monoclonal antibody to tumor necrosis factor-alpha, in RAPID-axSpA was double-blind and placebo-controlled for 24 weeks, dose blind to week 48, and open label to week 24. All patients had active axSpA (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] score of 4 or more and spinal pain score of 4 or more) with positive sacroiliac joint magnetic resonance imaging and/or inflammation marked by a C-reactive protein level greater than 7.9 mg/L. Patients were originally randomized to certolizumab pegol 200 mg every two weeks or 400 mg every four weeks and were continued on their assigned dose in the open-label period. The primary objective of a 20% improvement using Assessment of SpondyloArthritis International Society criteria (ASAS20) at week 12 was met and has been previously reported.
Among the patients completing 48 weeks of treatment (65%; n = 211), the completer proportions were similar in both the axSpA (67%) and (nr)-axSpA (63%) subpopulations, Dr. van der Heijde said.
Overall, ASAS20, ASAS40, and ASAS-PR (partial remission) were achieved in 54.1%, 44.0%, and 23.4% of patients, respectively, using nonresponder imputation (missing data considered as nonresponders). In the axSpA patients, ASAS20, ASAS40, and ASAS-PR were achieved in 56.2%, 44.6%, and 21.5%, respectively. In the (nr)-axSpA patients, the rates were 51.5%, 43.3%, and 25.8%, respectively.
Mean BASDAI score reductions were similar for the axSpA (–3.4) and (nr)-axSpA (–3.6) groups, as were Bath Ankylosing Spondylitis Functional Index (BASFI) score reductions (–2.6 and –2.7, respectively). Reductions were greater for BASDAI/BASFI in patients remaining on treatment (observed cases) in both axSpA and (nr)-axSpA groups with reductions of –4.1 and –3.0, respectively.
Dr. van der Heijde commented that, among the patients remaining on treatment, responses to certolizumab pegol were maintained in very high proportions. ASAS20, ASAS40, and ASAS-PR rates were 83.7%, 68.1%, and 36.5%, respectively, and were similar in both axSpA and (nr)-axSpA groups.
The four-year safety profile for certolizumab pegol was consistent with previous reports of RAPID-axSpA results, with no new safety signals.
“For clinicians, these data show that efficacy is good after four years of treatment,” Dr. van der Heijde said. She observed that patients who left the trial had more active disease than patients who remained. “The fact that response rates were very similar in patients with radiographic and nonradiographic disease sends an important message: that (nr)-axSpA is not a self-limiting disease.”
Certolizumab Pegol for the Treatment of Psoriatic Arthritis: Four-Year Outcomes From the RAPID-PsA Trial
Maintained efficacy for certolizumab pegol 200 mg every two weeks and 400 mg every four weeks was achieved for 409 patients with psoriatic arthritis (PsA) in the RAPID-PsA trial after long-term, four-year follow-up. Continuing increases in high-threshold outcomes between week 24 and week 216 were demonstrated.
Dr. Mease noted that more than half of PsA patients have chronic, progressive, erosive disease with subsequent clinical function impairment within two years of the onset of disease, and that it is important that PsA therapies demonstrate that benefits are maintained over long periods.
RAPID-PsA, a 216-week phase 3 study, was double-blind and placebo-controlled to week 24, dose blind to week 48, and open label to week 216. Prior reports have shown that certolizumab pegol improves signs and symptoms of PsA over 96 weeks. RAPID-PsA included patients with active disease, including swollen and tender joints, and a C-reactive protein level greater than 7.9 mg/L (upper limit of normal) or an erythrocyte sedimentation rate of 28 mm/hour or greater.
Dr. Mease reported that 67% of patients assigned to certolizumab pegol completed to week 216. American College of Rheumatology (ACR) criteria responder rates and the proportion of patients achieving minimal disease activity (MDA) were sustained with both certolizumab pegol dose regimens from week 24 to week 216. Incremental ACR response improvements were observed in completers from week 24 to week 216, with increases in the high-threshold outcome measures of ACR 70% (ACR70) and MDA. Improvements were observed from week 24 to week 216 even with the most conservative measures (e.g., nonresponder imputation [NRI] and counting all noncompleters as nonresponders).
ACR20, ACR50, and ACR70 response rates were roughly equivalent for the two certolizumab pegol doses, as were MDA rates. Using NRI, dosing certolizumab pegol 400 mg every four weeks had an MDA proportion somewhat higher (40.7%) than the group of patients who received 200 mg every two weeks (37.7%) and much higher by NRI (53.1% versus 63.2%).
ACR20 rates at 216 weeks for NRI/observed cases were 54.6%/80.5%; ACR50 rates were 43.2%/63.8%; and ACR70 rates were 34.8%/51.4%.
The safety profile was in line with prior RAPID-PsA reports, with no new safety signals.
In an interview, Dr. Mease pointed to an additional RAPID-PsA trial analysis (also presented at EULAR) specifically evaluating the 20% of patients who had previously been exposed to anti–tumor necrosis factor (TNF) therapy. “Theoretically, those [patients] don’t respond as well when exposed to a drug with the same mechanism of action. So we were surprised to see that those patients had essentially an identical response to those with no anti-TNF exposure,” he said. At week 216, ACR20 rates in patients with anti-TNF exposure receiving the 200-mg or 400-mg doses of certolizumab pegol were 81.8% and 83.3%, respectively; in patients without prior anti-TNF exposure, the rates were 75.0% and 85.3%, respectively.
Dr. Mease noted that critics often level the charge of “cherry-picking” against trial reports that include results only for observed cases. “Here, we show the NRI data, as well, and it shows that responses are maintained at four years.”
The continued improvement in high-threshold outcomes observed between week 24 and week 216, he said, demonstrates that patients not achieving high-threshold outcomes at early time points may achieve them with continued treatment.
Effect of Secukinumab, an Interleukin-17A Inhibitor, on Spinal Radiographic Changes Through Two Years In Patients With Active Ankylosing Spondylitis: Results of MEASURE 1
In a first report of interleukin-17A inhibition on structural changes in ankylosing spondylitis (AS), 80% of patients receiving secukinumab over 104 weeks had no radiographic progression. Inhibition of radiographic spinal changes, which are primarily osteoproliferative in nature in active AS, is a primary therapy goal, according to Dr. Braun. The objective of the phase 3 MEASURE 1 study was to assess secukinumab effects up to 104 weeks on radiographic progression.
Patients (N = 1,371) in the secukinumab arm received a 10-mg/kg intravenous (IV) loading dose at baseline and at weeks 2 and 4, and then 150 mg or 75 mg subcutaneously every four weeks from week 8. Placebo was given on the same schedule. The placebo patients were re-randomized to secukinumab 150 mg or 75 mg subcutaneously every four weeks based on Assessment in Ankylosing Spondylitis response criteria at week 16 (nonresponders were switched at week 16; responders at week 24). Lateral radiographs of the cervical and lumbar spine performed at baseline and at week 104 were read centrally applying the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS).
Dr. Braun’s analysis included 168 patients randomized to secukinumab who had x-rays available. At baseline, 62% of this group had syndesmophytes, bony growths originating inside intervertebral joints, to which AS patients are particularly prone.
Because the researchers found no major radiographic differences between the 150-mg and 75-mg secukinumab groups, their data were pooled. Approximately 80% of patients showed no radiographic progression from baseline to week 104. New syndesmophytes were found in 5% of patients who were without syndesmophytes at baseline. In male patients and patients who had syndesmophytes or elevated C-reactive protein levels at baseline, changes were higher. Among patients with syndesmophytes at baseline, about 70% developed no new syndesmophytes.
Analysis of 168 patients who started on IV secukinumab and later received any subcutaneous secukinumab treatment showed a 0.30 average increase in mSASSS from baseline after 104 weeks. Among an additional 89 placebo-group patients who switched to subcutaneous secukinumab, the average change in mSASSS from baseline to 104 weeks was 0.54. Comparative two-year mSASSS progression in AS patients treated with a tumor necrosis factor inhibitor has been about 0.8 to 0.9, Dr. Braun said, and AS patients not treated with an active biologic drug have shown a two-year mSASSS progression of about 1.0.
This is the first trial with evidence for such an effect with a biologic or other agent in ankylosing spondylitis; however, because MEASURE 1 was an open-label trial without historical controls, confirmation in further studies is necessary, Dr. Braun said.
Bimekizumab, a Monoclonal Antibody That Inhibits Both IL-17A and IL-17F, Produces a Profound Response in Both Skin and Joints: Results of an Early-Phase, Proof-of-Concept Study in Psoriatic Arthritis
Interleukin (IL)-17 and IL-17F are key proinflammatory cytokines that are overexpressed in the skin lesions of patients with psoriasis. An early-phase study of bimekizumab, a monoclonal antibody potently and selectively inhibiting both IL-17 and IL-17F, demonstrated safety and profound responses in both skin and joints in patients with psoriatic arthritis.
In Dr. Glatt’s study, 52 psoriatic arthritis patients (mean disease duration, 6.6 years) were randomized to either one of four doses of bimekizumab (n = 38) or placebo (n = 14). All received a single loading dose of 80–560 mg bimekizumab administered at week 0; further doses of 40–320 mg bimekizumab were administered at weeks 3 and 6. Efficacy endpoints were American College of Rheumatology 20% improvement (ACR20), ACR50, mean Disease Activity Score (using C-reactive protein [CRP]) for joints, and Psoriasis Area Severity Index (PASI) scores for skin (mean, 90).
At baseline, mean CRP was 12.5 mg/L. In patients with skin involvement of 3% or more, the mean PASI score was 15.9. Dr. Glatt observed that onset of response was rapid for both skin and joints. For the top three bimekizumab doses, the ACR20 response rate (RR) was 80% at week 8, compared with 17% in the placebo group (n = 12). Dr. Glatt noted that Bayesian analysis showed a high posterior probability (greater than 90%) that the observed bimekizumab ACR20 RR at week 8 is greater than that of placebo and of that reported for anti-TNF and anti-IL-17A agents.
Increased ACR70 RRs were observed within two weeks of the first bimekizumab infusion, and maximal ACR response was achieved at week 16 (ACR70, 37%). Clinically relevant responses in disease activity measures were maintained to week 20.
Mean PASI75 and PASI100 RRs were 0% for placebo (n = 5) and 100% and 87% for bimekizumab (n = 15) at week 8. The scores are considered “really high,” Dr. Glatt said in an interview.
The majority of treatment-emergent adverse events were mild or moderate, with no severe adverse events attributed to treatment. Two cases of fungal infection (oropharyngitis and vulvovaginal candidiasis) were classified as mild.
“These proof-of-concept study findings are very good in terms of ACR, and for those patients with skin involvement, they are also very good,” she said. Maximal responses were seen as early as week 8. “Of course, we need to see similar results in the larger phase 2 and 3 studies.”
“Bayesian analysis indicated that the bimekizumab ACR20 RR is greater than that reported for current therapies including anti-IL-17A. Our results support that inhibition of both IL-17A and IL-17F could provide additional clinical benefit in IL-17-mediated diseases,” she concluded.