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22-10-2020 | Rheumatology | News | Article

Support for further investigation of otilimab in rheumatoid arthritis

Author: Claire Barnard

medwireNews: Otilimab, a human monoclonal antibody that inhibits granulocyte–macrophage colony-stimulating factor (GM-CSF), may warrant further investigation for the treatment of rheumatoid arthritis (RA), indicate findings from two phase 2 trials published in The Lancet Rheumatology.

GM-CSF “is a key driver in a broad range of immune-mediated conditions,” and results from preclinical studies and early clinical trials suggest that “[t]argeting GM-CSF is […] a promising therapeutic strategy in rheumatoid arthritis,” say the authors of the first study.

Mark Genovese (Stanford University, Palo Alto, California, USA) and co-investigators therefore carried out a phase 2a mechanistic trial to evaluate the effect of otilimab on the GM-CSF–chemokine (C-C motif) ligand 17 (CCL17) signaling pathway and synovial inflammation.

In all, 39 patients with active RA despite previous DMARD treatment were randomly assigned to receive otilimab (n=28) or placebo (n=11) alongside stable methotrexate. Otilimab was given subcutaneously at a dose of 180 mg once weekly for 5 weeks, followed by once every 2 weeks for an additional 5 weeks.

Genovese and team report that average serum concentrations of otilimab–GM-CSF complex – indicating target engagement – increased weekly to a maximum of 138.4 ng/L at week 4 but subsequently decreased during fortnightly dosing, suggesting “that full target engagement was not achieved with this dosing regimen.”

They found that treatment with otilimab, but not placebo, led to a reduction in average CCL17 levels from baseline to week 1, which was maintained until week 8 but increased toward baseline levels at week 12, leading them to propose “that CCL17 shows promise as a pharmacodynamic biomarker for otilimab in future studies.”

The investigators say that the RA magnetic resonance imaging (MRI) scoring system (RAMRIS) and RA MRI quantitative score (RAMRIQ) imaging measures of synovitis “showed a reduction” from baseline to the 12-week follow-up. Participants in the otilimab group experienced a least-squares mean (LSM) decrease in RAMRIS synovitis score of 1.3 points, compared with a 0.8-point increase for those in the placebo group; the LSM reductions in RAMRIQ synovitis score were 1417.0 μL and 912.3 μL, respectively.

Although these findings “showed some evidence for improved synovitis” in spite of “suboptimal exposure,” Genovese and colleagues note that there were no significant between-group differences in the magnitude of reduction in RAMRIS synovitis, osteitis, and bone erosion, or in RAMRIQ synovitis and erosion damage scores.

The second trial was a phase 2b dose-ranging study involving 222 patients with moderate-to-severe RA who were randomly assigned to receive otilimab 22.5 mg, 45 mg, 90 mg, 135 mg, or 180 mg once weekly for 5 weeks, followed by once every 2 weeks until week 50, or to receive placebo. All participants received stable methotrexate throughout the trial.

The investigators report that rates of remission (DAS28-CRP <2.6 points) at week 24 – the primary study endpoint – were “consistently higher” among participants treated with otilimab versus placebo, but there were no significant between-group differences. The difference in remission rate relative to placebo ranged from 2.7% to 16.2% in the otilimab groups, with the greatest difference seen with the 90 mg dose.

Paul Tak (University of Amsterdam, the Netherlands) and colleagues note that participants who did not have a good or moderate EULAR response at week 12 or who had a DAS28-CRP score above 3.2 points at week 24 were switched to otilimab 180 mg. They say that a “substantial number” of patients switched to the 180 mg dose (49% of 175 at week 12 and 69% of 83 at week 24), and therefore other efficacy endpoints were analyzed at the 12-week follow-up.

At this time, ACR20 response rates were significantly higher among patients treated with any dose of otilimab versus placebo (35–51 vs 11%), and ACR50 response rates were significantly higher among patients treated with otilimab 45 mg or 135 mg than those given placebo (27 and 30 vs 8%, respectively). Participants in the majority of otilimab dose groups also reported significantly greater improvements in pain and physical function than those in the placebo arm.

A total of 14–24% of patients in the otilimab groups and 5% of those in the placebo arm experienced treatment-related adverse events (AEs); the most common AEs occurring in more than 5% of participants were nasopharyngitis (8–24 vs 3%), upper respiratory tract infection (3–8 vs 8%), anemia (0–14 vs 0%), and alanine aminotransferase increase (0–8 vs 0%).

“The results of this study build on the existing data and support a positive benefit:risk profile of treatment with otilimab in active rheumatoid arthritis and provide a basis for further clinical development,” conclude Tak et al.

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Lancet Rheumatol 2020; doi:10.1016/S2665-9913(20)30224-1
Lancet Rheumatol 2020; doi:10.1016/S2665-9913(20)30229-0