#2341 WS016, a novel potassium binder: safety, tolerability and pharmacodynamics in first-in-human phase 1 healthy volunteer study
Authors: Zhang Faming , Song Aiyun , Fu Min , Zhou Youcheng , Hu Minglong 
Published: May 2024

Abstract

Background and Aims
Hyperkalemia is a common and potentially serious medical condition in patients with chronic kidney disease and is associated with high rates of mortality. Partiromer and Lokelma are available recently, however, edema is the common adverse event resulted from the exceed sodium exchanged by Lokelma and constipation, hypomagnesemia are frequently found using Partiromer because of the basic structure of them. WS016 is a highly selective, non-absorbed, cation-exchange polymer binder with the potential characteristics of no edema and hypomagnesemia. The objective of the trials was to assess the safety/tolerability and pharmacodynamics (PD) profiles of WS016.

Method
This is a randomized, double-blind, placebo-controlled phase 1 clinical trial. 40 healthy volunteers were randomized (6:2 randomization within a cohort) into five different cohorts administered with 6 g, 12 g, 24 g, 36 g, 48 g WS016 orally once daily for only one dose during the single dose ascending (SAD) stage and 24 healthy volunteers were randomized (6:2 randomization within a cohort) into three different cohorts administered with 12 g, 36 g, 48 g orally once daily for consecutive seven days during the multiple dose ascending(MAD) stage. Adverse events (AE) were collected, and physical examination, laboratory tests were done at baseline and different visits according to the protocol. Urinary potassium and fecal potassium were collected, tested and calculated per 24 hour. Serum potassium was evaluated alone with the timing after administration of WS016 in different cohort.

Results
Data of subjects from different placebo cohorts were pooled together for analysis in SAD and MAD stage. 40 healthy volunteers, including 6 in different WS016 cohorts and 10 in placebo cohort completed the SAD trial. 9, 5, 6, 7, 12 grade 1 AEs were reported from 12-48 g WS016 cohorts, respectively; 11 AEs were reported from placebo cohort and 1 is grade 2 AE. Totally, 5 cases with hypertriglyceridemia, 4 cases with prolonger activated partial thromboplastin time (APTT), 4 cases with decreased blood fibrinogen, 3 cases with sinus bradycardia were reported from WS016 cohort and 2 cases with hypertriglyceridemia, 1case with prolonged APTT, 1 case with decreased fibrinogen were reported from placebo cohort.
24 healthy volunteers, 6 from different WS016 cohorts and 6 from placebo cohort completed the MAD trial. 12, 10, 12 AEs were reported from 12 g, 24 g, 48 g cohort, respectively and 6 AEs were from placebo cohort. Only 1 AE as hypertriglyceridemia from 24 g cohort is grade 2, while others are grade 1. 5 cases with sinus bradycardia, 4 cases with hypertriglyceridemia, 3 cases with hyperuricacidemia, 3 cases with hypotension, 3 cases with prolonged APTT were reported from all WS016 cohort totally and 1 cases with hyperuricacidemia,1 cases with hypotension, 1 cases with prolonged APTT were reported from placebo cohort.
There is no AE related to gastrointestinal tract and no side effects on the other electrolytes such as magnesium, calcium, sodium and phosphorus, reported from both SAD and MAD.
It was found that fecal potassium excretion increased and urinary potassium decreased on D2 in SAD (Fig. 1) and on D7 in MAD (Fig. 2) compared to baseline. The serum potassium decreased quickly at about 1-2 hour after first administration of WS016 both in SAD and MAD (Figs 1 and 2) and the mean serum potassium of placebo cohort is higher than that in other WS016 cohorts during MAD (Fig. 2).

Conclusion
WS016 was generally well-tolerated following single doses and multiple doses. The AEs like constipation, hypomagnesemia commonly found in Patiromer and edema commonly found in Lokelma were not reported in WS016 cohorts. In accordance to the results from pre-clinical studies, the clinical pharmacodynamics characteristics was the increased fecal potassium along with the decreased urinary potassium, meanwhile the serum potassium decreased, especially during the first 4 hours after administration of WS016 although in the normal range among the healthy volunteers.