Long-term safety and efficacy of sarilumab with or without background csDMARDs in rheumatoid arthritis.

OBJECTIVE: To evaluate the long-term safety and efficacy of sarilumab with/without conventional synthetic (cs)DMARDs in RA. METHODS: The analyses evaluated two open-label extensions (OLEs): EXTEND and MONARCH OLE, which included patients from six randomized trials. Patients received sarilumab 200 mg once every 2 weeks (q2w) for at least 264 weeks up to 516 weeks (EXTEND: Sarilumab Monotherapy and Sarilumab + csDMARD groups) or for 276 weeks (MONARCH OLE: Continuation and Switch groups). Primary endpoints included safety, immunogenicity and changes in laboratory parameters. Secondary endpoints included clinical signs and symptoms along with health-related quality-of-life (HRQOL) questionnaires. RESULTS: The Sarilumab Monotherapy (n = 111), Continuation (n = 165) and Switch (n = 155) groups received sarilumab monotherapy, while the Sarilumab + csDMARD group (n = 1910) received sarilumab in combination with csDMARDs. Incidence of one or more treatment-emergent adverse events was 126 (Sarilumab Monotherapy group), 169 (Sarilumab + csDMARD group), 159 (Continuation group) and 159 (Switch group) events/100 patient-years. Neutropenia was the most common adverse event. Neutropenia was not associated with an increased incidence of infections. Most neutropenia cases normalized on-treatment. Adverse events of special interests, such as malignancies, major adverse cardiovascular events, venous thromboembolism and gastrointestinal perforations, were rare. Immunogenicity was low and not associated with hypersensitivity reactions or discontinuations due to lack or loss of efficacy. Improvements in clinical signs and symptoms and HRQOL, observed during the initial blinded trials, were maintained throughout the OLE assessment period. CONCLUSIONS: Long-term sarilumab treatment with/without csDMARDs in patients with RA revealed no new safety findings. Efficacy and HRQOL were maintained or further increased over the open-label assessment period. TRIAL REGISTRATION: EXTEND, ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT01146652, NCT01146652; MONARCH OLE, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02332590, NCT02332590.

Long-term effects of interleukin-17A inhibition with secukinumab in active ankylosing spondylitis: 3-year efficacy and safety results from an extension of the Phase 3 MEASURE 1 trial.

OBJECTIVES: Secukinumab, a fully human anti-IL-17A monoclonal antibody, provided rapid and sustained improvements in signs and symptoms of ankylosing spondylitis (AS) over 2 years in the Phase 3 MEASURE 1 trial. Here, we report efficacy and safety after 3 years of treatment. METHODS: AS subjects completing 2 years of treatment every 4 weeks with subcutaneous secukinumab 150 or 75 mg (following intravenous loading or initial placebo treatment to 16/24 weeks) entered a separate 3-year extension study (NCT01863732). Assessments included ASAS20/40, ASAS5/6, BASDAI, BASDAI 50, BASFI, BASMI, SF-36 physical component summary, ASAS partial remission and ASDAS-CRP. Results were also analysed by prior anti-TNF treatment status. RESULTS: Among 290 subjects completing the core trial, 274 entered the extension study, with 260 subjects (94.9%) completing 156 weeks of treatment. ASAS20/40 response (observed) was 80.2%/61.6% in the IV→150 mg group and 75.5%/50.0% in the IV→75 mg group after 156 weeks. Sustained improvements were also seen in BASDAI, BASFI, BASMI and across all other endpoints regardless of previous exposure to anti-TNF agents. Mean secukinumab exposure was 964.3 days (137.8 weeks). Discontinuation rates were low, and secukinumab had a favourable safety profile, consistent with previous reports. Exposure-adjusted incidence rates for serious infections, Candida infections, Crohn's disease, ulcerative colitis, malignant/unspecified tumours, and adjudicated major adverse cardiac events were 1.1, 0.4, 0.5, 0.1, 0.5 and 0.7 per 100 subject-years, respectively. CONCLUSIONS: Secukinumab provided sustained efficacy in signs, symptoms and physical function in subjects with AS over 3 years. No new safety signals were observed.

Improvement of Signs and Symptoms of Nonradiographic Axial Spondyloarthritis in Patients Treated With Secukinumab: Primary Results of a Randomized, Placebo-Controlled Phase III Study.

OBJECTIVE: To report the primary (1-year) results from PREVENT, the first phase III study evaluating secukinumab in patients with active nonradiographic axial spondyloarthritis (SpA). METHODS: A total of 555 patients were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with a loading dose (loading dose [LD] group), secukinumab 150 mg without a loading dose (non-loading dose [NL] group), or placebo weekly and then every 4 weeks starting at week 4. The NL group received placebo at weeks 1, 2, and 3 to maintain blinding. Switch to open-label secukinumab or standard of care was permitted after week 20. The study had 2 independent analysis plans, per European Union and non-US (plan A; week 16) and US (plan B; week 52) regulatory requirements. The primary end point was 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society (ASAS40) criteria at week 16 (in the LD group) and at week 52 (in the NL group) in tumor necrosis factor inhibitor (TNFi)-naive patients. Safety analyses included all patients who received ≥1 dose of study treatment. RESULTS: Overall, 481 patients completed 52 weeks of treatment, including 84.3% (156 of 185) in the LD group, 89.7% (165 of 184) in the NL group, and 86.0% (160 of 186) in the placebo group. The proportion of patients who switched to open-label or standard of care between weeks 20 and 48 was 50.8% in the LD group, 47.3% in the NL group, and 64.0% in the placebo group. Both primary and all secondary end points were met at week 16. The proportion of TNFi-naive patients who met ASAS40 was significantly higher for LD at week 16 (41.5%) and NL at week 52 (39.8%) versus placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05). No new safety findings were reported. CONCLUSION: Our findings indicate that secukinumab 150 mg provides significant and sustained improvement in signs and symptoms of nonradiographic axial SpA through 52 weeks. Safety was consistent with previous reports.

A comparison of the efficacy and safety of celecoxib 200 mg and celecoxib 400 mg once daily in treating the signs and symptoms of psoriatic arthritis.

OBJECTIVE: To evaluate the efficacy of the cyclooxygenase-2 selective inhibitor celecoxib in treating patients with psoriatic arthritis (PsA) in flare. METHODS: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study compared the efficacy and safety of celecoxib 400 mg (n=201) or celecoxib 200 mg (n=213) once daily (qd) with placebo (n=194) in treating the signs and symptoms of PsA in flare. The primary efficacy measure was the number of patients responding to treatment according to the American College of Rheumatology Responders Index 20% (ACR-20) at week 12. Efficacy and safety were assessed for all randomized patients who received at least 1 dose of study medication. RESULTS: At the week-12 primary endpoint, approximately 50% of patients in each treatment group were responders according to the ACR-20 criteria, and no statistically significant treatment differences between treatment groups were observed. However, at week 2, the ACR-20 response rates for the celecoxib 400 mg (49%) and 200 mg (39%) groups were significantly higher than for the placebo group (28%) (P<0.001 and P=0.016, respectively). Within the celecoxib 400 mg group, ACR-20 response rates were similar at weeks 2, 6 (46%), and 12 (49%). In contrast, in the celecoxib 200 mg and placebo treatment groups, ACR-20 response rates increased 7 and 16%, respectively, from week 2 to week 6, and remained relatively unchanged from week 6 to week 12. There were no statistically significant differences in ACR-20 response rates between the celecoxib 400 mg and 200 mg groups at any time point. Treatment with celecoxib 200 and 400 mg qd was statistically superior to placebo treatment at weeks 2 and 6 for Patient's Assessment of Arthritis Pain. Both doses of celecoxib were well tolerated. CONCLUSIONS: Celecoxib 400 mg and 200 mg qd were efficacious and well tolerated in treating the signs and symptoms of PsA in flare after 2 weeks of treatment. However, although the clinical effects of celecoxib 400 mg and 200 mg qd were observed for 12 weeks, there was a high placebo response at these time points, and there were no differences relative to placebo treatment at week 12.

Pain management in osteoarthritis: a focus on onset of efficacy--a comparison of rofecoxib, celecoxib, acetaminophen, and nabumetone across four clinical trials.

UNLABELLED: We compared onset of efficacy (during days 1 to 6) of 2 coxibs (rofecoxib, celecoxib) with acetaminophen and nabumetone by using a prespecified approach to data from 4 similarly designed 6-week randomized osteoarthritis trials. In 2 trials, rofecoxib (12.5 mg and 25 mg once daily) was compared with celecoxib (200 mg once daily) and acetaminophen (4000 mg daily). In the other 2 trials, rofecoxib (12.5 mg) was compared with nabumetone (1000 mg once daily) and placebo. Efficacy end points included Patient Global Response to Therapy and Western Ontario and McMaster Osteoarthritis Index scores. Rofecoxib (12.5- and 25-mg doses) consistently demonstrated a faster onset of osteoarthritis (OA) efficacy than the comparator drugs during the first 6 days of therapy of OA patients experiencing "flare." Acetaminophen resulted in the slowest onset of efficacy. There was a strong correlation (0.7) between efficacy response during days 1 to 6 and that averaged over 6 weeks. Rates of discontinuation as a result of lack of efficacy were significantly lower (P < .02) for each of the coxib-treated groups compared with acetaminophen and for rofecoxib 12.5 mg (P = .01) compared with nabumetone. Rofecoxib treatment, with its faster onset of OA efficacy and lower rates of related discontinuations, might provide efficacy advantages in the treatment of OA pain. PERSPECTIVE: The efficacy of rofecoxib, celecoxib, nabumetone, and acetaminophen is established for the majority of OA patients within the first 6 days of therapy, and this predicts efficacy during the longer term. Rofecoxib provides significantly faster time to onset of efficacy and better improvement on multiple measures versus the comparators.

Long-term safety and effectiveness of tanezumab as treatment for chronic low back pain.

A noncontrolled, randomized, multicenter study (NCT00924664) evaluated long-term safety and effectiveness of tanezumab in patients with chronic low back pain following a randomized placebo- and active-controlled parent study that evaluated analgesic efficacy. Patients were randomized to tanezumab 10mg (n=321) or 20mg (n=527) administered at 8-week intervals via 3 intravenous injections followed by 4 subcutaneous injections. Effectiveness analyses included change from parent study baseline in Brief Pain Inventory Short Form, Roland Morris Disability Questionnaire, and Patient's Global Assessment of low back pain. Safety assessments included adverse event documentation, physical/neurological examinations, and laboratory tests. Mean treatment duration during the extension study was 194 and 202 days with tanezumab 10 and 20mg, respectively. Both tanezumab doses provided similar and sustained improvements in all effectiveness outcomes. The most frequently reported adverse events were arthralgia, paresthesia, and hypoesthesia. Adverse events initially described as osteonecrosis were reported in 6 patients (tanezumab 10mg, n=2; tanezumab 20mg, n=4); 9 additional patients (tanezumab 10mg, n=7; tanezumab 20mg, n=2) underwent total joint replacement (TJR). A blinded, independent adjudication committee reviewed all 6 patients with reported osteonecrosis and 4 of the 9 patients undergoing TJR. Adjudication outcomes were osteonecrosis (n=0), worsening osteoarthritis (n=5; 1 rapidly progressive), and another diagnosis or indeterminate (n=5). Tanezumab 10mg had better tolerability than tanezumab 20mg, and may represent an effective long-term treatment for chronic low back pain.