Systemic Lupus Erythematosus is a rare chronic autoimmune disease in which the immune system mistakenly attacks healthy tissues in the body leading to tissue damage and inflammation. Resulting kidney injury occurring in up to 60% of SLE patients is known as lupus nephritis. We are currently developing ramatroban (KAR101) as a dual receptor antagonist of the PGD2/DP2 and TxA2/TP receptors for the treatment of lupus nephritis.
Pierucci et al report use of a selective TP receptor antagonist in a randomized, double-blind, crossover study of 10 patients with lupus nephritis. 48-hour continuous infusion with a TP receptor antagonist significantly increased glomerular filtration rate (GFR) (indicated by a 24% increase in inulin clearance on average) and sodium excretion compared to placebo. Therefore, TP receptor antagonism exerts a beneficial hemodynamic effect, thereby improving kidney function in lupus nephritis.
(Pierucci et al, NEJM, 1989, doi: 10.1056/NEJM198902163200703)
A lower number of circulating basophils in the blood (basopenia) is associated with SLE severity and active lupus nephritis. This is attributed to migration of basophils from the blood to secondary lymphoid organs. PGD2/DP2 promotes type 2 allergic inflammation and basophil recruitment to secondary lymph organs, thereby aggravating autoantibody generation and kidney injury.
Scarring of the kidneys (interstitial fibrosis) is associated with worse renal outcomes in lupus nephritis patients. PGD2/DP2 promotes allergic type 2 inflammation characterized by activation of Th2 immune cells which contributes to progression of renal fibrosis (scarring). Progression of fibrosis in a model of unilateral ureteral obstruction was blocked with a DP2 receptor antagonist.
(Ito et al, JASN, 2012, doi: 10.1681/ASN.2012020126
Ramatroban has been used for the treatment of allergic rhinitis in Japan for over 20 years, and therefore, has an excellent safety profile. Given the potential efficacy of ramatroban in reducing inflammation, autoantibody generation, disease progression, and fibrosis, we are looking to conduct phase 2 clinical trials of ramatroban in patients with lupus nephritis.