Session Information
Session Type: Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with extensive phenotypic heterogeneity due to the underlying molecular diversity of dysregulated pathways. Patients with SLE receive glucocorticoids as part of standard-of-care treatment but can develop resistance over time, making steroid resistance an important unmet need. Furthermore, side effects make long-term use undesirable. Toll-like receptor (TLR)7 and TLR8, endosomal receptors that play a key role in innate immunity, are expressed in immune cells, where they recognize single-stranded RNA and initiate downstream signaling via the nuclear factor kappa B (NFκB) and interferon regulatory factor pathways. NFκB signaling activation via TLR7 and TLR8 pathways could be a driving factor in steroid resistance. We evaluated the steroid-sparing potential of afimetoran, an equipotent, dual TLR7 and TLR8 antagonist, currently in clinical development for SLE and cutaneous lupus erythematosus.
Methods: NZB/W mice with moderate disease (proteinuria, 60–100 mg/dL) were treated therapeutically once daily with vehicle or selected doses of afimetoran and/or prednisolone. Survival, kidney injury, splenomegaly, age-associated B cells (ABCs), serum auto-antibody titers (anti-double-stranded DNA antibodies, anti-nuclear antibodies), and interleukin-12p40 (IL-12p40) were assessed in all treatment groups. To assess the impact of afimetoran on TLR7 activation–mediated steroid resistance in vitro, C57 wild-type (WT) mouse bone marrow cells (BMCs) were challenged with the TLR7 agonist gardiquimod and treated with prednisolone alone or in combination with afimetoran. B-cell and plasmacytoid dendritic cell (pDC) apoptosis was evaluated by annexin V staining using flow cytometry in C57 WT BMCs treated in vitro and NZB/W BMCs from mice dosed orally.
Results: Afimetoran alone and in combination with prednisolone improved survival in the NZB/W mouse model. Significant, dose-dependent suppression of kidney injury markers such as proteinuria, neutrophil gelatinase-associated lipocalin (NGAL), or tissue inhibitor of metalloproteinases 1 (TIMP1) was observed. Splenomegaly was improved, particularly when afimetoran was combined with prednisolone; suppression of ABCs was also improved with this combination. Significant, dose-dependent suppression of plasma IL-12p40 and serum auto-antibody titers was also observed, demonstrating the potential of afimetoran in this mouse model of SLE. An improved steroid response was seen with afimetoran in vitro in gardiquimod-stimulated C57BL/6 mouse BMCs, which showed a significant increase in prednisolone-induced apoptosis of pDCs and B cells compared with baseline control or prednisolone alone. A similar trend was seen in vivo for BMCs collected from NZB/W mice dosed with combinations of afimetoran and prednisolone.
Conclusion: Afimetoran, alone or in combination with low-dose (1mg/kg) prednisolone, showed robust efficacy in NZB/W mice with moderate disease. Bone marrow pDCs and B cells showed afimetoran-induced reversal of resistance to prednisolone-induced apoptosis. These data confirm that afimetoran has the clinical potential to be steroid sparing.
To cite this abstract in AMA style:
Dudhgaonkar S, Chopra P, Rudra A, Subramani S, Palachandra S, Bhatt N, Pabbala V, Ranade S, Prasad Ega D, Dyckman A, Zhao Q. Steroid-sparing Effects of Afimetoran (BMS-986256), an Equipotent Toll-like Receptor (TLR)7 and TLR8 Antagonist, in a Lupus Mouse Model [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/steroid-sparing-effects-of-afimetoran-bms-986256-an-equipotent-toll-like-receptor-tlr7-and-tlr8-antagonist-in-a-lupus-mouse-model/. Accessed .« Back to ACR Convergence 2023
ACR Meeting Abstracts - https://acrabstracts.org/abstract/steroid-sparing-effects-of-afimetoran-bms-986256-an-equipotent-toll-like-receptor-tlr7-and-tlr8-antagonist-in-a-lupus-mouse-model/