Obi Time Will Tell: Increasing Evidence for Obinutuzumab in Treatment Refractory SLE

B-cell depleting therapies in systemic lupus erythematosus (SLE) have a checkered history with 2 large phase 3 clinical trials of rituximab failing to meet their primary endpoints (EXPLORER and LUNAR).^1,2 However, real-world data established the role of rituximab in treatment refractory lupus. The immunogenicity of a chimeric antibody does, however, remain an issue and secondary inefficacy with infusion reactions and anti-drug antibodies occurs in 14% of SLE patients on repeated retreatment with rituximab.³ Obinutuzumab is a humanised type-2 anti-CD20 antibody which may in part overcome these issues. It is currently licenced for use in lymphoma and is under investigation in trials for renal (REGENCY) and non-renal SLE (ALLEGORY), having shown promising results in the phase 2 NOBILITY trial.⁴

Mechanistic differences in how obinutuzumab brings about B-cell depletion and its humanized composition are cause for excitement regarding its future role in treatment resistant SLE. In vitro work on obinutuzumab has shown superior B-cell cytotoxicity in samples from rheumatoid arthritis and SLE patients.⁵ A recent case series from our group provides real-world data on its application in rituximab resistant SLE patients.⁶ Here we collected clinical and serological data from 9 patients treated with obinutuzumab before, and 6 months following, 2 infusions of 1000mg obinutuzumab and 100mg methylprednisolone.

We found significant improvements in the SLEDAI-2K and BILAG-2004 scores at 6 months. Median SLEDAI-2K fell from 12 to 6 (p=0.014) and median numeric BILAG-2004 fell from 21 to 2 (p=0.009).⁶ We noted statistically significant improvements in complement C3 and dsDNA titres and numeric, but not statistically significant, improvements in complement C4 levels.⁶ Four out of 9 patients were found to be in Lupus Low Disease Activity State (LLDAS) following obinutuzumab.⁶

These findings provide an advanced look at the potential future role of obinutuzumab in the management of SLE. The cohort of patients recruited to this study were treatment resistant enough to require rituximab and had all shown evidence of secondary treatment failure. Ordinarily, this would leave them with very few therapeutic options. Those options available are often accompanied by significant treatment toxicity. Evidence of a potential effective therapy here is therefore very exciting and correlates well with previous trial data.

In a broader context, rituximab, obinutuzumab, anifrolumab, and belimumab now comprise the expanding biologic armoury for SLE. Rituximab remains a good option and provides effective disease control for many people. As a generic medication, its global reach substantially surpasses other biologics, particularly in resource-poor environments. Obinutuzumab will likely provide an alternative humanised B-cell depleting option. The role of belimumab is already established and further expanding as results from the BLISS-LN trial continue to emerge.⁷ Finally Anifrolumab provides a mechanistically distinct option for those with refractory disease or non-B-cell driven pathology, something previously observed in cutaneous disease.⁸

Firm evidence for the role of obinutuzumab in SLE will be provided when the ALLEGORY and REGENCY trials come to fruition. However, the initial signs are positive, and our case series has demonstrated impressive treatment efficacy even in one of our most resistant cohorts of patients.

References:

1. Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;

2. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase ii/iii systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum [Internet]. 2010 Jan [cited 2020 Sep 1];62(1):222–33. Available from: http://doi.wiley.com/10.1002/art.27233

3. Md Yusof MY, Shaw D, El-Sherbiny YM, Dunn E, Rawstron AC, Emery P, et al. Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus. Ann Rheum Dis [Internet]. 2017 Nov 1 [cited 2020 Sep 2];76(11):1829–36. Available from: http://ard.bmj.com/

4. Furie RA, Aroca G, Cascino MD, Garg JP, Rovin BH, Alvarez A, et al. B-cell depletion with obinutuzumab for the treatment of proliferative lupus nephritis: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis [Internet]. 2021 Oct 6 [cited 2021 Nov 30];0:1–8. Available from: https://ard.bmj.com/content/early/2021/10/06/annrheumdis-2021-220920

5. Reddy V, Klein C, Isenberg DA, Glennie MJ, Cambridge G, Cragg MS, et al. Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology (Oxford) [Internet]. 2017 Jul 1 [cited 2021 Nov 24];56(7):1227–37. Available from: https://pubmed.ncbi.nlm.nih.gov/28407142/

6. Jack Arnold A, Dass S, Twigg S, Jones CH, Rhodes B, Hewins P, et al. Efficacy and safety of obinutuzumab in systemic lupus erythematosus patients with secondary non-response to rituximab. Rheumatology [Internet]. 2022 Mar 10 [cited 2022 Mar 29]; Available from: https://academic.oup.com/rheumatology/advance-article/doi/10.1093/rheumatology/keac150/6546315

7. Furie R, Rovin BH, Houssiau F, Malvar A, Teng YKO, Contreras G, et al. Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis. N Engl J Med [Internet]. 2020 Sep 17 [cited 2022 Mar 7];383(12):1117–28. Available from: https://pubmed.ncbi.nlm.nih.gov/32937045/

8. Vital EM, Wittmann M, Edward S, Md Yusof MY, MacIver H, Pease CT, et al. Brief report: Responses to rituximab suggest B cell-independent inflammation in cutaneous systemic lupus erythematosus. Arthritis Rheumatol [Internet]. 2015 Jun 1 [cited 2021 Jul 7];67(6):1586–91. Available from: https://pubmed.ncbi.nlm.nih.gov/25707733/