Effectiveness and safety of levilimab in combination with methotrexate in treatment of patients with active rheumatoid arthritis resistant to methotrexate monotherapy (double-blinded randomized placebo controlled phase III clinical study SOLAR)

Levilimab is anti-interleukin-6 receptor (IL6R) monoclonal antibody. The article presents data obtained during 24 weeks of the SOLAR phase III study.
Objective: to confirm efficacy and safety of levilimab in combination with methotrexate (MTX) in patients with methotrexate resistant active rheumatoid arthritis (RA).
Patients and methods. 154 adult patients, aged ≥18 years with the diagnosis of RA (ACR/EULAR 2010) and confirmed disease activity at screening despite treatment with MTX for at least 12 weeks (in a stable dose 15-25 mg/week). Patients were randomized 2:1 in levilimab (162 mg once a week, subcutaneously) + MTX (n=102) or placebo + MTX (n=52) group.
The hypothesis of superiority of levilimab over placebo was tested for two co-primary efficacy endpoints: proportion of subjects who achieved ACR20 at week 12 and proportion of subjects who achieved low disease activity (LDA) of RA (DAS28-CRP <3.2) at week 24. Safety was assessed through monitoring of adverse events (AEs).
Results and discussion. Seventy (68.6%) subjects who received levilimab and 20 (38.5%) who received placebo achieved ACR20 response at week 12. Fifty three (52%) subjects who received levilimab and 3 (5,8%) subjects who received placebo achieved LDA at week 24. The most common adverse events (reported in ≥5% of subjects) in levilimab and placebo arms, respectively were (by decreasing frequency): blood c holesterol increase (24% vs 12%), alanine aminotransferase elevation (11% vs 8%), lymphocyte count decrease (9% vs 8%), blood total bilirubin increase (11% vs 0%), blood triglycerides increase (10% vs 2%), aspartate aminotransferase elevation (7% vs 4%), positive interferon-gamma release assay (IGRA) with M.tuberculosis antigen blood test (5% vs 6%), absolute neutrophil count decrease (8% vs 0%). No deaths were occurred.
Conclusion. The study confirmed superior efficacy of levilimab + MTX over placebo + MTX in subjects with MTX resistant active RA. Levilimab showed favorable safety profile and low immunogenicity. No new important safety risks were detected.

1. Nasonov EL, Olyunin YuA, Lila AM. Rheumatoid arthritis: problems of remission and resistance to therapy. Nauchno-prakticheskaya revmatologiya. 2018;56(3):263-71. (In Russ.).

2. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010 Sep; 69(9):1580-8. doi: 10.1136/ard.2010.138461.

3. Almutairi KB, Nossent JC, Preen DB, et al. The Prevalence of Rheumatoid Arthritis: A Systematic Review of Populationbased Studies. J Rheumatol. 2021 May;48(5): 669-76. doi: 10.3899/jrheum.200367. Epub 2020 Oct 15.

4. Nagy G, Roodenrijs NMT, Welsing PM, et al. EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis. 2021 Jan;80(1):31-5. doi: 10.1136/annrheumdis2020-217344. Epub 2020 Oct 1.

5. Mazurov VI, Zotkin EG, Gaidukova IZ, et al. Efficacy and safety of levilimab in combination with methotrexate in patients with rheumatoid arthritis: results of the Phase II AURORA study. Nauchno-prakticheskaya revmatologiya. 2021;59(2):141-51. (In Russ.).

6. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010 Sep; 62(9):2569-81. doi: 10.1002/art.27584.

7. Hochberg MC, Chang RW, Dwosh I, et al. The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum. 1992 May;35(5):498-502. doi: 10.1002/art.1780350502.

8. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995 Jun;38(6):727-35. doi: 10.1002/art.1780380602.

9. Anderson J, Caplan L, Yazdany J, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken). 2012 May; 64(5):640-7. doi: 10.1002/acr.21649.

10. Van Gestel AM, Prevoo ML, van 't Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996 Jan;39(1):34-40. doi: 10.1002/art.1780390105.

11. Van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol. 1999 Mar;26(3):743-5.

12. Dougados M, Kissel K, Conaghan PG, et al. Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study. Ann Rheum Dis. 2014 May;73(5):803-9. doi: 10.1136/annrheumdis2013-204761. Epub 2014 Jan 28.

13. EMA/CHMP/606295/2013 RoActemra Assessment report. 2014. https://www.ema.europa.eu/en/documents/variation-report/roactemra-h-c-955-x-0030-epar-assessmentreport-variation_en.pdf.

14. Genovese MC, Fleischmann R, Kivitz AJ, et al. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis Rheumatol. 2015 Jun;67(6):1424-37. doi: 10.1002/art.39093.

15. Kivitz A, Olech E, Borofsky M, et al. Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014 Nov;66(11):1653-61. doi: 10.1002/acr.22384.