OP0034 Efficacy and Safety of Mavrilimumab, A Fully Human Gm–CSFR-Alpha Monoclonal Antibody in Patients with Rheumatoid Arthritis: Primary Results from the Earth Explorer 1 Study

Abstract

BackgroundOf patients with RA, ∼40% of do not achieve a minimal acceptable improvement (ACR20) despite modern biologic therapy.1,2,3 Granulocyte-macrophage colony-stimulating factor (GM–CSF) is implicated in RA pathogenesis via myeloid and granulocyte cell lineage activation. In a 12-week Phase IIa study, mavrilimumab, a first-in-class inhibitor of the GM–CSF receptor-α demonstrated a sustained effect via this novel therapeutic pathway in RA.4ObjectivesTo evaluate the efficacy and safety of mavrilimumab in patients with moderate to severe, adult-onset RA in a 24-week, Phase IIb study.MethodsPatients (18–80 yrs; inadequate response to ≥1 DMARDs; DAS28–CRP ≥3.2; ≥4 SJC) receiving MTX were randomized to receive 1 of 3 SC mavrilimumab dosages (150, 100, 30 mg every other week [eow]) or placebo (PBO) plus MTX (7.5–25.0 mg/week). Co-primary endpoints were change in DAS28–CRP (Day 1 to Week 12) and ACR20 response rate (Week 24). Safety and tolerability were measured through assessment of AEs and pulmonary parameters. Results were analyzed using the modified ITT population.Results326 patients from Europe, South America, and South Africa (mean [SD] age, 51.8 [11.1] yrs; female, 86.5%; mean [SD] DAS28–CRP, 5.8 [0.9]; RF+/anti-CCP+, 81.9%) received mavrilimumab 150, 100 or 30 mg eow or PBO (N=79, 85, 81 and 81, respectively). At Week 12, a statistically significant difference in DAS28–CRP change from baseline (p<0.001) was observed for all dosages of mavrilimumab vs. PBO. At Week 24, a significantly greater percentage of all mavrilimumab-treated patients also met the ACR20 co-primary endpoint vs. PBO (table). A dosage response was observed across several secondary endpoints, with separation from PBO evident as early as Week 1 and first dose. The most common treatment-emergent AEs were headache (7.6%, 4.7%, 6.2%, 2.5%), nasopharyngitis (7.6%, 3.5%, 4.9%, 7.4%) and bronchitis (5.1%, 1.2%, 3.7%, 7.4%) for mavrilimumab 150, 100, 30 mg eow or PBO, respectively. There was no increase in pulmonary AEs for mavrilimumab vs. PBO (6.3%, 3.5%, 6.2% vs. 9.9%). No serious infections were observed in the 100 and 150 mg eow groups. Two cases of pneumonia were observed (one each in mavrilimumab 30 mg eow and PBO groups). There were no deaths or anaphylaxis, and no apparent dosage relationship for AEs. >90% of patients entered a long-term, open-label extension study.ConclusionsThis Phase IIb study demonstrated the potential benefit of inhibiting macrophage activity via the GM–CSF receptor-α pathway on RA disease activity. The study met both co-primary endpoints with a clear dosage response. Mavrilimumb was well-tolerated over the 24-week study period.ReferencesWeinblatt ME, et al. N Engl J Med 1999;340:253–9.Lipsky PE, et al. N Engl J Med 2000;343:1594–602.Weinblatt ME, et al. Arthritis Rheum 2003;48:35–45,Burmester GR, et al. Ann Rheum Dis 2013;72:1445–52.AcknowledgementsFunded: MedImmune. Editorial assistance: N Panagiotaki, QXV Communications, UK†Joint senior authors.Disclosure of InterestG. Burmester Grant/research support from: AbbVie, P...

Phase 1b randomized, double-blind study of namilumab, an anti-granulocyte macrophage colony-stimulating factor monoclonal antibody, in mild-to-moderate rheumatoid arthritis

“…The analysis showed that patients receiving namilumab (150 and 300 mg) had greater improvements from baseline in DAS28-CRP, TJCs, and SJCs compared with patients who received placebo. These improved efficacy outcomes with namilumab were reported as early as week 2, as has been reported for mavrilimumab [26–29]. Considering the size of our study, it was an appropriate approach to analyze the DAS28-CRP profile (AUC) in the 150 and 300 mg namilumab combined group versus placebo.…”

Spotlight on mavrilimumab for the treatment of rheumatoid arthritis: evidence to date

“…Although the study was not powered to demonstrate statistical significance between mavrilimumab and golimumab, in sDMARD-IR subgroup, 24-week ACR20, ACR50, and ACR70 response rates seem to be apparently lower in the mavrilimumab-treated patients compared with golimumab (53.8%, 35.9%, and 10.3% vs 69.4%, 44.4%, and 27.8%, respectively) 62. However, the authors argued that the dose adopted in this study might be suboptimal as compared to the one (150 mg eow) predicted as most effective by the previously described exposure–response relationship simulation58 and subsequently confirmed by the results of EARTH EXPLORER 1 study 61. This argument is reasonable because ACR20, ACR50, and ACR70 response rates in the 150 mg group of EARTH EXPLORER 1 study seem to be higher (73.4%, 40.5%, and 13.9%, respectively) compared with the 100 mg group of EARTH EXPLORER 2 study (53.8%, 35.9%, and 10.3%, respectively) and comparable with the golimumab group of EARTH EXPLORER 2 study (69.4%, 44.4%, and 27.8%, respectively).…”

“…The most common TEAEs reported were headache, nasopharyngitis, and upper respiratory tract infections 61,62,68. In the first study, two cases of pneumonia were observed (one in the mavrilimumab 30 mg eow group and one in the placebo group),61 whereas in the second study, one pneumocystis pneumonia and one lung disorder were observed in the golimumab group 68. During the open-label long-term extension of both phase IIb studies, the most common TEAEs were bronchitis (4.8%), respiratory tract infection (2%), cholelithiasis (1%), cough (0.8%), and neutropenia (0.8%) 65…”

Biologicals in rheumatoid arthritis: current and future

“… 53 54 Moreover, the results of the phase IIb trial met the primary end points (DAS28 and ACR20) with a clear dose–response effect with excellent tolerability. 55 Another compound is MOR103, a fully human mAb directed towards GM-CSF. This alternative approach was tested in a phase Ib/IIa study with promising results, including imaging data.…”