Bristol Myers Squibb Lawrenceville, NJ, United States
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Shailesh Dudhgaonkar1, Puneet Chopra2, Anjuman Rudra2, Siva Subramani2, Sourabha Palachandra2, Nikita Bhatt2, Veeresh Pabbala2, Sourabh Ranade2, Durga Siva Prasad Ega2, Alaric Dyckman3 and Qihong Zhao3, 1Bristol Myers Squibb, Bangalore, India, 2Biocon Bristol Myers Squibb Research Center, Bangalore, India, 3Bristol Myers Squibb, Lawrenceville, NJ
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.
S. Dudhgaonkar: Bristol-Myers Squibb(BMS), 3, 11; P. Chopra: Bristol-Myers Squibb(BMS), 3; A. Rudra: Bristol-Myers Squibb(BMS), 3; S. Subramani: Bristol-Myers Squibb(BMS), 3; S. Palachandra: Bristol-Myers Squibb(BMS), 3; N. Bhatt: Bristol-Myers Squibb(BMS), 3; V. Pabbala: Bristol-Myers Squibb(BMS), 3; S. Ranade: Bristol-Myers Squibb(BMS), 3; D. Prasad Ega: Bristol-Myers Squibb(BMS), 3; A. Dyckman: Bristol-Myers Squibb(BMS), 3; Q. Zhao: Bristol-Myers Squibb(BMS), 3, 11.
