Jeffrey Hartung

Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND Modulation of sphingosine 1-phosphate (S1P) receptors in a non-selective manner decreases disease activity in patients with multiple sclerosis but has potential safety concerns. We assessed the safety and efficacy of the oral selective S1P receptor modulator ozanimod in patients with relapsing multiple sclerosis. METHODS RADIANCE is a combined phase 2/3 trial. Patients with relapsing multiple sclerosis were recruited from 55 academic and private multiple sclerosis clinics in 13 countries across Europe and the USA. Eligible participants were aged 18-55 years, had an Expanded Disability Status Scale (EDSS) score of 0-5·0, and had either one or more relapses in the previous 12 months, or one or more relapses in the past 24 months and one or more gadolinium-enhancing lesions on MRI in the previous 12 months before screening. Participants were assigned by a computer-generated randomisation sequence in a 1:1:1 ratio to ozanimod (0·5 mg or 1 mg) or matching placebo once daily for 24 weeks by an independent, unmasked, statistical team. Trial participants, study site personnel, MRI assessors, steering committee members, and the study statistician were masked to treatment assignment. To attenuate first-dose cardiac effects, ozanimod was up-titrated from 0·25 mg to 0·5 mg or 1 mg over 8 days. The primary endpoint was the cumulative number of total gadolinium-enhancing MRI lesions measured by an independent MRI analysis centre at weeks 12-24 after treatment initiation. Analysis was by intention to treat. Here, we report results from the 24-week phase 2 trial. This trial is registered with ClinicalTrials.gov, number NCT01628393. The 2-year phase 3 trial is ongoing. FINDINGS The first patient was randomised on Oct 18, 2012, and the final visit of the last randomised patient was on May 11, 2014. The intention-to-treat and safety population consisted of 258 participants, 88 were assigned placebo, 87 ozanimod 0·5 mg, and 83 ozanimod 1 mg; 252 (98%) patients completed the assigned treatment. The mean cumulative number of gadolinium-enhancing lesions at weeks 12-24 was 11·1 (SD 29·9) with placebo compared with 1·5 (3·7) with ozanimod 0·5 mg (odds ratio 0·16, 95% CI 0·08-0·30; p<0·0001) and 1·5 (3·4) with ozanimod 1 mg (odds ratio 0·11, 95% CI 0·06-0·21; p<0·0001). Three serious adverse events unrelated to treatment were reported in patients assigned ozanimod 0·5 mg: optic neuritis, somatoform autonomic dysfunction, and cervical squamous metaplasia (HPV-related). No serious infectious or cardiac adverse events were reported, and no cases of macular oedema arose. The most common adverse events in the ozanimod 0·5 mg and 1 mg groups compared with placebo were nasopharyngitis (11 and five vs 12), headache (five and three vs eight), and urinary-tract infections (six and two vs two). The maximum reduction in mean heart rate by Holter monitoring during the first 6 h in ozanimod-treated participants was less than 2 beats per min (bpm) compared with baseline, with no patient having a minimum hourly heart rate less than 45 bpm. Electrocardiograms and 24-h Holter monitoring showed no increased incidence of atrioventricular block or sinus pause with ozanimod. INTERPRETATION Ozanimod significantly reduced MRI lesion activity in participants with relapsing multiple sclerosis, with a favourable safety profile over a period of 24 weeks. These findings warrant phase 3 trials, which are ongoing. FUNDING Receptos, Inc.

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator

The sphingosine‐1‐phosphate 1 receptor (S1P1R) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P1R and S1P5R receptors in clinical development for the treatment of chronic immune‐mediated, inflammatory diseases. This first‐in‐human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose‐escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose‐limiting toxicities. The most common ozanimod‐related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady‐state volume of distribution (73–101 L/kg), moderate oral clearance (204–227 L/h), and an elimination half‐life of approximately 17 to 21 hours. Ozanimod produced a robust dose‐dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose‐dependent negative chronotropic effect was observed following the first dose, with the dose‐escalation regimen attenuating the first‐dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once‐daily regimens under clinical investigation.

Cardiac Safety of Ozanimod, a Novel Sphingosine‐1‐Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study

Ozanimod is a novel, selective, oral sphingosine‐1‐phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double‐blind, placebo‐controlled, positive‐controlled, parallel‐group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time‐matched, placebo‐corrected, baseline‐adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2‐sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10‐millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimods evolving favorable cardiac safety profile.

Effects of High- and Low-Fat Meals on the Pharmacokinetics of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator

Ozanimod (RPC1063) is an oral selective modulator of the sphingosine‐1‐phosphate 1 and 5 receptors under development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease. The effects of high‐fat and low‐fat meals on the pharmacokinetics (PK) of a single oral dose of ozanimod were evaluated in 24 healthy volunteers in a randomized, open‐label crossover trial. Each subject received a 1‐mg dose of ozanimod hydrochloride under 3 meal conditions (fasted, high‐fat, and low‐fat), each separated by 7 days. Mean plasma concentration–time profiles for ozanimod and its active metabolites (RP101988 [major], RP101075 [minor]) were similar under all 3 conditions. Moreover, all PK parameters for ozanimod, RP101988, and RP101075 were similar under the 3 meal conditions. The 90% confidence intervals (CIs) for the ratios of geometric least‐squares mean (fed/fasted) were within the equivalence limits of 0.80 to 1.25 for area under the concentration–time curve from time 0 to infinity (AUC0–∞) and maximum plasma concentration (Cmax) for ozanimod, RP101988, and RP101075, except for the high‐fat effect on RP101075 Cmax (90%CI, 0.76–0.88). Given this lack of a food effect on the exposure of ozanimod and its active metabolites, ozanimod can be taken without regard to meals.