Safety of Repeated Open-Label Treatment Courses of Intravenous Ofatumumab, a Human Anti-CD20 Monoclonal Antibody, in Rheumatoid Arthritis:Results from Three Clinical Trials

OBJECTIVES:To investigate the safety of ofatumumab retreatment in rheumatoid arthritis. METHODS:Patients with active rheumatoid arthritis participating in two phase III trials (OFA110635 and OFA110634) and a phase II extension trial (OFA111752) received individualised open-label ofatumumab retreatment (700 mg X 2 intravenous infusions two weeks apart) ≥24 weeks following the first course and ≥16 weeks following further courses. Retreatment required evidence of clinical response followed by disease relapse. These studies were prematurely terminated by the sponsor to refocus development on subcutaneous delivery. Due to differences in study designs and populations, data are summarised separately for each study. RESULTS:483 patients (243, 148 and 92 in OFA110635, OFA110634 and OFA111752 respectively) received up to 7 treatment courses of intravenous ofatumumab; cumulative duration of exposure was 463, 182 and 175 patient-years, respectively. Mean time between courses was 17-47 weeks. Ofatumumab induced a profound depletion of peripheral B-lymphocytes. Retreated patients derived benefit based on improvement in DAS28. Adverse events were reported for 93% (226/243), 91% (134/148) and 76% (70/92), serious adverse events for 18% (44/243), 20% (30/148) and 12% (11/92) and serious infections for 3% (8/243), 5% (7/148) and 1% (1/92) of patients in OFA110635, OFA110634 and OFA111752, respectively. The most common adverse events were infusion-related reactions during the first infusion of the first course (48-79%); serious infusion-related reactions were rare (<1% [1/243], 5% [8/148], and 1% [1/92] of patients). Two deaths occurred (fulminant hepatitis B virus infection and interstitial lung disease). CONCLUSIONS:Ofatumumab was generally well tolerated with no evidence of increased safety risks with multiple retreatments. Serious infections were uncommon and did not increase over time. TRIAL REGISTRATION:ClinicalTrials.gov 110635 ClinicalTrials.gov 110634 ClinicalTrials.gov 111752

The effect of 24-week belimumab treatment withdrawal followed by treatment restart in patients with SLE: an open-label, non-randomised 52-week study

Abstract Background Treatment goals for patients with systemic lupus erythematosus (SLE) include minimising disease activity and reducing the risk of flares. Although belimumab is effective at reducing disease activity and risk of severe flares, it was previously unknown what the clinical effects were upon treatment discontinuation. The objective of this study was to assess the impact of temporary withdrawal of intravenous (IV) belimumab in patients with SLE. Methods This multicentre, open-label, non-randomised, 52-week study (GSK Study BEL116027; NCT02119156) recruited patients with SLE and stable low disease activity, of whom those on belimumab 10 mg/kg IV plus standard therapy either discontinued belimumab for 24 weeks and then restarted belimumab 10 mg/kg IV every 4 weeks (q4w) for 28 weeks (treatment holiday [TH] group), or continued on belimumab 10 mg/kg IV plus standard therapy q4w for 52 weeks (treatment continuation [TC] group). The primary endpoint was median time to first Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) Flare Index flare. Secondary and other endpoints included rate of any flare, time to severe flare, time to renal flare and rebound (SELENA-SLEDAI score exceeding parent study baseline). Data on rebound phenomenon in patients with any disease level of SLE who had permanently withdrawn from further belimumab treatment (long-term discontinuation group [LTD]) were also assessed. Safety was assessed. Results The primary endpoint was not evaluable in the TH (n = 12) and TC (n = 29) groups as fewer than half of patients flared. Unadjusted flare rates per patient-year were 1.0 during treatment discontinuation and 0.3 during treatment restart (0.6 overall) in the TH group and 0.6 in the TC group; there were no severe or renal flares. No TH patients rebounded; 2 (6.9%) TC patients rebounded; 2 (5.1%) patients in the LTD group rebounded. There were no new safety signals. Conclusions Twenty-four-week belimumab discontinuation did not appear to increase the risk of flares or rebound in patients with low SLE disease activity; flare rates were low in both groups. Further studies may help to fully determine the effect of belimumab discontinuation. Trial registration ClinicalTrials.gov, NCT02119156 . Registered on April 21, 2014

Investigating sirukumab for rheumatoid arthritis: 2-year results from the phase III SIRROUND-D study

ObjectivesThe phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group SIRROUND-D study evaluated long-term efficacy and safety of the interleukin (IL)-6 inhibitor, sirukumab, in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drugs (DMARDs).MethodsPatients were randomised 1:1:1 to sirukumab 100  mg every 2 weeks (q2w), 50  mg every 4 weeks or placebo q2w subcutaneously. Patients initially randomised to placebo were rerandomised at Weeks 18, 40 or 52 to one of the sirukumab groups until Week 104.ResultsOf 1670 randomised patients, 1402 were included in the full analysis set and 1269 in the radiographic analysis set at Week 104. American College of Rheumatology scores, Disease Activity Score based on C-reactive protein, Clinical Disease Activity Index and clinically meaningful improvements in patient-reported outcomes were sustained at Week 104 among patients initially randomised to sirukumab. Placebo patients subsequently rerandomised to sirukumab showed clinical improvements at Week 104 that were comparable to results among patients initially randomised to sirukumab. Radiographic progression from Week 52 to Week 104 was comparable between all groups whether initially randomised to sirukumab or subsequently rerandomised to sirukumab from placebo. No new safety signals were identified in the extended exposure period compared with the initial 52 weeks of treatment.ConclusionsSirukumab treatment resulted in sustained reductions in clinical signs and symptoms and minimal progression in radiographic damage over 2 years among patients with RA refractory to DMARDs. The safety profile of sirukumab was as expected for an anti-IL-6 agent, with no new signals reported

Study Designs, Demographic and Baseline Characteristics.

<p>Study Designs, Demographic and Baseline Characteristics.</p

Daphne arisanensis Hayata

原著和名: アリサンコセウノキ科名: ジンチョウゲ科 = Thymelaeaceae採集地: 台湾 玉山山麓 (台湾省 玉山山麓)採集日: 1968/3/5採集者: 萩庭丈壽整理番号: JH048935国立科学博物館整理番号: TNS-VS-99893

Time to Retreatment in Weeks by Ofatumumab Treatment Course in Each Study.

<p>Time to Retreatment in Weeks by Ofatumumab Treatment Course in Each Study.</p

Median CD19+ B-cell Counts by Ofatumumab Treatment Course.

<p>Line plots show median B-cell CD19+ (GI/L) counts by week for each treatment course in OFA110635 (panel A) and OFA110634 (panel B). The data for OFA111752 were incomplete and have not been plotted. Inf. A, infusion A, was the first infusion of each treatment course; LLN, lower limit of normal = 0.11 GI/L; Trt, treatment.</p

Flow Diagram of Patient Disposition in Each Study.

<p>The diagram shows the numbers of patients who were enrolled/randomized, received at least one infusion of ofatumumab, completed/discontinued, and included in analysis populations in each of the three studies. DB, double-blind treatment period; OL, open-label treatment period; FU, safety follow-up.</p

Phase 3, long-term, open-label extension period of safety and efficacy of belimumab in patients with systemic lupus erythematosus in China, for up to 6 years

Objectives To evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) in China. Methods In this phase 3, open-label extension period, eligible completers of study BEL113750 (NCT01345253) received intravenous belimumab 10 mg/kg monthly for 7.5 mg/day, the number of patients with a dose reduction to <= 7.5 mg/day increased over time (year 1, week 24: 30/333 (9.0%); year 5, week 48: 36/67 (53.7%)). Conclusions Favourable safety profile and disease control appeared to be maintained in patients with SLE in China for <= 6 years, consistent with previous belimumab studies