The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.
ObjectiveThis 24‐week, phase IIb, double‐blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte–macrophage colony‐stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti‐TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) (referred to as DMARD‐IR) and/or inadequate response to other anti‐TNF agents (referred to as anti‐TNF–IR).MethodsPatients with active RA and a history of DMARD‐IR (≥1 failed regimen) or DMARD‐IR (≥1 failed regimen) and anti‐TNF–IR (1–2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate. The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures. This study was not powered to formally compare the 2 treatments.ResultsAt week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, −3.5% (90% confidence interval [90% CI] −16.8, 9.8), −8.6% (90% CI −22.0, 4.8), and −9.8% (90% CI −21.1, 1.4), respectively; in the anti‐TNF–IR group, 11.1% (90% CI −7.8, 29.9), −8.7% (90% CI −28.1, 10.7), and −0.7% (90% CI −18.0, 16.7), respectively. Differences in the percentage of patients achieving a DAS28‐CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were −11.6% (90% CI −23.2, 0.0) in all patients, and −4.0% (90% CI −20.9, 12.9) in the anti‐TNF–IR group. The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups. Treatment‐emergent adverse events were reported in 51.4% of mavrilimumab‐treated patients and 42.6% of golimumab‐treated patients. No deaths were reported, and no specific safety signals were identified.ConclusionThe findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well‐tolerated in patients who had shown an inadequate response to DMARDs and/or other anti‐TNF agents.
ObjectiveMavrilimumab, a human monoclonal antibody, targets granulocyte–macrophage colony‐stimulating factor receptor α. We undertook to determine the long‐term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open‐label extension study (ClinicalTrials.gov identifier: NCT01712399).MethodsIn study 1071, patients with an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate. In study 1107, patients with an inadequate response to anti–tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate. Patients entering the open‐label extension study received 100 mg mavrilimumab every other week plus methotrexate. Long‐term safety and efficacy of mavrilimumab were assessed.ResultsA total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open‐label extension study discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient‐years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1–3.3 years). The most common treatment‐emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient‐years) and bronchitis (n = 51; 5.68 per 100 patient‐years). At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with AEs. Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <3.2, and 40.6% of patients achieved a DAS28‐CRP of <2.6.ConclusionLong‐term treatment with mavrilimumab maintained response and was well‐tolerated with no increased incidence of treatment‐emergent AEs. Safety data were comparable with those from both phase IIb qualifying studies.
BackgroundMavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, has demonstrated efficacy and safety in disease-modifying antirheumatic drug (DMARD)-inadequate responder (IR) patients (pts) with rheumatoid arthritis (RA).1ObjectivesFew head-to-head studies in tumor necrosis factor antagonist (aTNF)-IR assess alternative aTNFs vs. other agents; this Phase IIb exploratory study (NCT01715896) evaluates the efficacy and safety of mavrilimumab and golimumab in aTNF-IR and DMARD-IR pts.MethodsThis 24-week study enrolled pts with active RA (28-joint Disease Activity Score [DAS28]–C-reactive protein [CRP]/erythrocyte sedimentation rate ≥3.2); ≥4 swollen joints; inadequate response to ≥1 DMARDs and/or 1–2 aTNFs receiving concomitant methotrexate (MTX; 7.5–25.0 mg/week). Pts received subcutaneous mavrilimumab 100 mg every other week (eow), based on data from the Phase IIa study,2 or golimumab 50 mg alternating with placebo eow. Key endpoints were ACR20/50/70 responses, DAS28–CRP <3.2 and <2.6, Health Assessment Questionnaire Disability Index improvement >0.22 at Week 24 and safety/tolerability. Treatment estimates for mavrilimumab and golimumab are presented with standard errors.ResultsPts were randomized to mavrilimumab or golimumab (1:1) (Table). Data for pts receiving mavrilimumab 100 mg eow and golimumab 50 mg at Week 24 are shown for the aTNF-IR, DMARD-IR and overall strata (Table). The most common treatment-emergent adverse events (TEAEs) for mavrilimumab 100 mg and golimumab 50 mg were nasopharyngitis (5.7%, 1.5%), headache (4.3%, 2.9%), upper respiratory tract infection (4.3%, 2.9%), viral upper respiratory tract infection (4.3%, 2.9%), and hepatic enzyme increase (4.3%, 2.9%), respectively. Related serious TEAEs were pneumocystis pneumonia (n=1) and lung disorder (n=1) [both in golimumab-treated pts]. No deaths were reported and no significant pulmonary safety signals were identified.ConclusionsIn this exploratory study, mavrilimumab 100 mg eow and golimumab 50 mg demonstrated efficacy and an acceptable safety profile in DMARD-IR and aTNF-IR pts. The study was not powered to demonstrate statistical significance between mavrilimumab and golimumab. As mavrilimumab 100 mg eow has previously been shown to be suboptimal compared with 150 mg eow in DMARD-IR pts (EARTH EXPLORER 1),1 additional studies are needed to establish the benefit of a higher dose in pts with moderate to severe RA and inadequate response to aTNF agents.ReferencesBurmester G, et al. Arthritis Rheum. 2014;66:S1231Burmester G, et al. Ann Rheum Dis. 2013;72:1445–1452AcknowledgementFunded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UKJoint senior authors: D. Close and G. BurmesterDisclosure of InterestM. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, Astra Zeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche, I. McInnes Grant/research support from: Research award to University...
BackgroundMavrilimumab, a fully human monoclonal antibody, which targets granulocyte-macrophage colony-stimulating factor receptor-α, has demonstrated efficacy and an acceptable safety profile in prior 12- and 24-week studies.1,2ObjectivesThis analysis evaluated all long-term (LT) safety and efficacy, through 74 weeks of treatment, of mavrilimumab.MethodsThis open-label extension (OLE) study (NCT01712399) enrolled adult rheumatoid arthritis (RA) patients (pts) who had completed the EARTH EXPLORER 12 and 2 (NCT01715896) Phase IIb studies or were rescued as inadequate responders (from Week 12). Pts received subcutaneous mavrilimumab 100 mg every other week (eow), consistent with data from the Phase IIa study1. The primary objective was to assess the LT risk:benefit ratio of mavrilimumab via evaluation of i) Treatment emergent adverse events (TEAEs), TE serious AEs (TESAEs), and independently adjudicated pulmonary function tests (PFTs) ii) Exploratory LT efficacy endpoints (DAS28–CRP/ACR responses). AEs with onset date after start of mavrilimumab are presented. Change from baseline (BL) in modified Total Sharp Score (mTSS) was used to explore radiographic progression in EARTH EXPLORER 1 pts.ResultsAt the 74 week (includes original study) cutoff, 391 pts had been enrolled in the OLE study. Of these, 329 (84.1%) continued on treatment, 62 (15.9%) discontinued (due to withdrawal of consent, 9 [2.3%]; adverse event, 7 [1.8%]; non study-related site closure, 20 [5.1%]; other, 24 [6.1%]; lost-to-follow-up, 1 [0.3%]; death [sudden cardiac arrest, preferred term cardiopulmonary failure], 1 [0.3%]), and 239 (61.1%) were assessed for efficacy at Week 74. Between the Phase IIb and OLE studies, 440 pts received mavrilimumab, with a safety exposure of 603 pt years (yr) and median duration of 1.6 yr. Most common TEAEs (n [/100 pt yr]) were nasopharyngitis (51 [8.45]), bronchitis (36 [5.97]) and hypertension (32 [5.30]); the serious infection rate was 1.82/100 pt yr. Pulmonary events/defined PFT changes occurred in a few pts and were generally transient with no signal identified (Table). Mavrilimumab demonstrated sustained efficacy (DAS28–CRP/ACR responses) (Table). After 74 weeks of treatment, 68% of pts showed no radiographic progression (<0.5 change in mTSS vs. BL) (Table).ConclusionsMavrilimumab continues to demonstrate a sustained efficacy and safety profile in pts with active RA, over the 74 week treatment duration reported. Although mavrilimumab 100 mg eow is suboptimal compared with 150 mg eow in DMARD-IR pts,2 efficacy results are comparable with those of previous studies.1,2ReferencesBurmester G, et al. Ann Rheum Dis 2013;72:1445–1452Burmester G, et al. Arthritis Rheum 2014;66:S1231AcknowledgementFunded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UKJoint senior authors: D. Close and M. WeinblattDisclosure of InterestG. Burmester Consultant for: MedImmune, I. McInnes Grant/research support from: Research award to University of Glasgow, Consultant for: MedImmune, AstraZeneca, J. Kremer ...
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