RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473

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

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

Effect of treatment on histological changes in the kidney measured at termination.

<p>Combined histology score for glomerular lesions (includes mesangial expansion, endocapillary proliferation, glomerular deposits and extracapillary proliferation) for (A) RPC1063 and (B) RP 101075. Combined histology score for tubular and interstitial lesions (includes interstitial infiltrates, tubular atrophy and interstitial fibrosis) for (C) RPC1063 and (D) RP-101075. (E) Inflammatory infiltrates in a representative (E) vehicle-treated animal and (F) RPC1063 3 mg/kg-treated animal. Calibration bars (E,F) 1 mm, 4× objective, 11×s1p magnification. Histology data presented as mean ± SEM. Baseline data collected from NZBWF1 mice sacrificed at week 23 prior to dosing initiation. *<i>p</i> <0.05, **<i>p</i> <0.01, ***<i>p</i> <0.001, ****<i>p</i> <0.0001, ns = not significant, for treatment versus vehicle-treated animals.</p

Effect of treatment on kidney function.

<p>Weekly proteinuria scores for (A) RPC1063 and (B) RP-101075 treated mice. Scores for animals that died mid-study were given a maximum score of 4.0 for the remainder of the study. Cumulative proteinuria area under the effect curve (AUEC) for (C) RPC1063, and (D) RP-101075. Serum blood urea nitrogen (BUN) at termination for (E) RPC1063 and (F) RP-101075. The normal range for mouse serum BUN levels is approximately 8–33 mg/dL (<a target="_blank">https://www.ahc.umn.edu/rar/refvalues.html</a>). Data presented as mean ± SEM. *<i>p</i> <0.05, **<i>p</i> <0.01, ***<i>p</i> <0.001, ****<i>p</i> <0.0001, ns = not significant, for treatment versus vehicle-treated animals.</p

Groups and treatment.

<p>Groups and treatment.</p

IFNAR1 expression on pDC isolated from NZBWF1 spleens.

<p>(A) Percentage of pDCs expressing IFNAR1. (B) IFNAR1 mean fluorescence intensity (MFI) on pDC as determined by flow cytometry.</p