Abstracts are up for the ASN Kidney Week 2017 Conference in New Orleans October 31 to November 5. Go here and click on the 2017 document to view all the abstracts. I found two Resverlogix abstracts.

FR-PO454 Poster Friday November 3

CKD: Risk Factors for Incidence and Progression - II 

Analysis of the Plasma Proteome Reveals Dysregulation of Molecular Pathways in Patients with Stage 4 CKD

Ewelina Kulikowski, Sylwia Wasiak, Laura Tsujikawa, Christopher Halliday, Stephanie Stotz, Dean Gilham, Ravi Jahagirdar, Kamyar Kalantar-Zadeh, RichardA. Robson, Michael Sweeney, Jan O. Johansson, Norman C. Wong.

Christchurch Clinical Studies Trust, Christchurch, New Zealand; Resverlogix Corp, Calgary, AB, Canada; University of California Irvine, School of Medicine, Orange, CA; Resverlogix Inc., San Francisco, CA.

Background: Chronic kidney disease (CKD) is associated with progressive loss of renal function. To gain insight into molecular mechanisms and biological consequences of pathway dysregulation in CKD, plasma proteome profiling of stage 4 CKD patients was performed using a novel somamer-based approach coupled to bioinformatics.

Methods: Eight subjects with stage 4 CKD not on dialysis (mean eGFR=20 ml/min/1.73m2) and eight matched control subjects (mean eGFR=78.5 ml/min/1.73m2) participated in the study. Plasma samples were collected for analysis with the SOMAscan® 1.3K platform, which detects 1305 proteins in a multiplexed, sensitive and reproducible manner. Proteomics data were analysed with Ingenuity Pathway Analysis (IPA®).

Results: SOMAscan® proteomic analysis of plasma from CKD versus control subjects identified 289 differentially expressed proteins (difference>10%, p<0.05). 191 of those proteins were upregulated by more than 50% in CKD plasma relative to controls. Many of the enriched markers correlate with CKD progression, including cystatin C, B2M, LCN2, LFABP and FGF23. Other differentially expressed proteins include cytokines and their soluble receptors, adhesion molecules, metalloproteases, complement, coagulation and fibrinolytic factors. IPA® bioinformatics of the plasma proteome confirmed an upregulation of pathways known to be activated in CKD such as the inflammatory and immune response, endothelial dysfunction, thrombosis, reninangiotensin system, calcification and oxidative stress.

Conclusions: This study provides an exhaustive list of plasma proteins that are dysregulated in stage 4 CKD. In combination with pathway analysis, this CKD plasma proteome contributes new knowledge of molecular processes that accompany CKD and potential new disease markers.

SA-PO650 Poster Saturday November 4

Pharmacokinetics, Pharmacodynamics, Pharmacogenomics

Apabetalone (RVX-208) Impacts Key Markers and Pathways Associated with CKD in Patients with Severe Renal Impairment

Ewelina Kulikowski, Sylwia Wasiak, Laura Tsujikawa, Christopher Halliday, Stephanie Stotz, Dean Gilham, Ravi Jahagirdar, Kamyar Kalantar-Zadeh, RichardA. Robson, Michael Sweeney, Jan O. Johansson, Norman C. Wong.

Christchurch Clinical Studies Trust, Christchurch, New Zealand; Resverlogix, Calgary, AB, Canada;  Resverlogix Corp, Calgary, AB, Canada;  Resverlogix Corp., San Francisco, CA;  University of California Irvine, School of Medicine, Orange, CA;  Resverlogix Inc, San Francisco, CA.

Background: Chronic kidney disease (CKD) is associated with a progressive loss of renal function and a high risk of cardiovascular disease (CVD). Apabetalone is an orally active BET protein inhibitor that decreased major adverse cardiac events (MACE) in CVD patients in phase 2 clinical trials. Thus, a phase 1, open-label, parallel group study of patients with impaired kidney function was conducted to determine the effect of apabetalone on plasma proteins associated with CVD complications in CKD.

Methods: 8 subjects with stage 4 CKD not on dialysis (mean eGFR=20 ml/min/1.73m2) and 8 matched controls (mean eGFR=78.5 ml/min/1.73m2) received a single 100 mg dose of apabetalone. Plasma was collected over 48h for PK analysis and at 12h post dose for proteomics analysis using the SOMAscan® platform (1305 proteins). Data were analysed with Ingenuity® Pathway Analysis (IPA®) to identify pathways regulated by apabetalone.

Results: PK parameters were similar in CKD patients and controls. Plasma proteomics in CKD patients showed that after 12h apabetalone altered levels of 261 proteins by 10-58% (p<0.05), versus baseline. 257/261 proteins were downregulated, consistent with inhibition of BET sensitive genes. IPA® revealed a robust effect of apabetalone on pathways involved in immunity and inflammation, acute phase response, diabetes, endothelial dysfunction, vascular calcification, fibrosis, and hypertension. Apabetalone also reduced circulating CKD and CVD markers, including IL-6, TNFα, IL-1, ICAM-1, VCAM-1, CRP, PAI-1, L-selectin, E-selectin, MMP-3, MMP-10, fibronectin and SPP1 (p<0.05).

Conclusions: In stage 4 CKD patients, apabetalone rapidly downregulates plasma markers and molecular pathways linked to renal disease and CVD complications. The long term impact of apabetalone is currently being studied in a subpopulation with impaired kidney function of the phase 3 BETonMACE CVD outcomes trial.