Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus

Abstract

Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus. Compared with vehicle-treated animals, ozanimod and RP-101075 reduced proteinuria over the duration of the study and serum blood urea nitrogen at termination. Additionally, ozanimod and RP-101075 reduced kidney disease in a dose-dependent manner, as measured by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits, and tubular atrophy. Further exploration into gene expression changes in the kidney demonstrate that RP-101075 also significantly reduced expression of fibrotic and immune-related genes in the kidneys. Of note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of interferon alpha in lupus patients, and reduced all B and T cell subsets in the spleen. Given the efficacy demonstrated by ozanimod and its metabolite RP-101075 in the NZBWF1 preclinical animal model, ozanimod may warrant clinical evaluation as a potential treatment for systemic lupus erythematosus.

Amiselimod (MT-1303), a Novel Sphingosine 1-Phosphate Receptor-1 Modulator, Potently Inhibits the Progression of Lupus Nephritis in Two Murine SLE Models

“…Administration of MT-1303 suppressed the increase in the number of plasma cells in the spleen of both strains, but the increase in anti-dsDNA antibody levels in the blood was suppressed only in MRL mice. However, these results are consistent with those observed with other S1P 1 receptor modulators in MRL/lpr and NZBWF1 mice [19][20][21][22]. A multicenter, open-label phase Ib trial in patients with SLE has been conducted to evaluate the safety, pharmacodynamics, and exploratory efficacy of MT-1303, with 17 subjects administered with a low or high dose of MT-1303 for 24 weeks (ClinicalTrials.gov NCT02307643).…”

“…Therefore, S1P 1 receptor modulators are expected to have therapeutic potential against SLE by inhibiting infiltration of autoreactive T cells into sites of inflammation and by affecting autoantibody production. In fact, studies have reported that S1P 1 receptor modulators are efficacious in reducing proteinuria and improving kidney histology in MRL/lpr, NZBWF1, and BXSB mouse models of SLE [19][20][21][22][23].…”

Sphingolipids and Diagnosis, Prognosis, and Organ Damage in Systemic Lupus Erythematosus

“…Ozanimod (RPC1063), a modulator of S1P receptors 1 and 5, was evaluated in the lupus mouse model NZBWF1 as a potential treatment of lupus nephritis (106). The lupus-prone mice showed dose dependent improvement in lupus nephritis pathology when treated with ozanimod (0.3, 1.0, 3.0 mg/kg).…”

An update on sphingosine-1-phosphate receptor 1 modulators

“…125–127 Displaying a similar mechanism of action based on S1P receptor internalization, followed by its degradation, ozanimod has proven to reduce inflammation in preliminary EAE animal experiments through reduction of cytokine production as well as significant depletion of circulating B lymphocytes, CD4 + CCR7 + T lymphocytes, and CD8 + CCR7 + lymphocytes. 126 When compared to fingolimod, siponimod, and ponesimod, ozanimod is superior in receptor specificity and reduction of adverse effects; its 10,000-fold greater agonism on S1P 1 than on S1P 3 contributes to ozanimod’s small margin of cardiac side effects.…”

“…129,130 The rejection occurred due to insufficient data regarding the metabolite, known as RP-101075, which accounts for 90% of ozanimod’s efficacy due to similar agonism on S1P 1 . 125,129,130 After this setback, Celgene publicly announced another NDA for ozanimod in the first quarter of 2019. 131 …”