RPC1063 is an orally available, potent, selective sphingosine-1-phosphate 1 receptor ( S1P1R ) agonist, which has been shown to decrease inflammation in animal models of colitis.
Stimulation of S1P1R results in pharmacologic activities likely to improve pathological processes in ulcerative colitis and is associated with decrease in heart rate ( HR ) on initial dosing, with diminished effect on HR and tachyphylaxis on repeat dosing.
Fingolimod, a non-selective S1PR agonist, has demonstrated prolongation of QTc. S1P3R is expressed on mouse heart conduction tissue and may be responsible for this QTc prolongation.
A single-centre, double-blind, randomized, placebo-and positive-controlled, parallel-group, nested crossover for positive control, TQT study of RPC1063 has enrolled 124 healthy male and female subjects, aged 18–45.
The patients were randomized in a 1:1 ratio to RPC1063 ( 0.25 to 2 mg dose titration regimen [ DT ] ) or placebo. Moxifloxacin 400 mg served as a positive control.
QT assessments were performed at baseline, day 10 ( 1 mg ) and day 14 ( 2 mg ), and days 2 and 17 ( Moxifloxacin ).
24-hour continuous ECG monitoring was also performed for cardiac adverse event monitoring and heart rate at baseline, day 1, and at dose increases on days 5, 8 and 11.
Safety assessments included adverse effects, vital signs, laboratory, electrocardiogram, telemetry, and physical exam.
The PK of RPC1063 and its metabolites in plasma was evaluated using a validated LC-MS/MS assay and a non-compartmental method.
The upper 95% 1-sided confidence limit for QTc change from baseline was always below 10 msec at both 1 mg and 2 mg doses, meeting pre-specified criteria to rule out a relevant QT effect of RPC1063. Assay sensitivity was demonstrated with QTc change from baseline more than 5 ms following Moxifloxacin treatment.
Dose titration was well tolerated, attenuated first dose effects, and minimized decreases in heart rate throughout titration period.
Generally, RPC1063 treatment was well tolerated. Adverse reactions, including cardiac adverse effects, were similar in RPC1063 and control groups, and similar to those seen previously with RPC1063.
Most common adverse effects were administration site reaction, headache, orthostatic hypotension, dizziness, musculoskeletal chest pain and constipation.
No severe adverse reactions occurred in the study.
Two active metabolites that retain the S1P1R potency and selectivity of the parent were measurable at concentrations sufficient to derive pharmacokinetics ( PK ) parameters. The pharmacokinetics of the metabolites was similar to that of RPC1063, characterized by a late Tmax ( 6–8hrs ), an elimination half-life of 19–22 hours, and low inter-subject variability.
In conclusion, the study has confirmed the absence of a relevant effect of RPC1063 on QTc prolongation. Overall, the emerging favourable cardiac, safety, and PK profiles of RPC1063 support its development in ulcerative colitis and multiple sclerosis. ( Xagena )
Source: European Crohn's and Colitis Organisation ( ECCO ) Meeting, 2014