oxadiazoles and Atrioventricular-Block

Ozanimod is a sphingosine-1-phosphate (S1P) modulator that inhibits lymphocyte trafficking from lymph nodes to the circulation. It is approved by the US Food and Drug Administration (FDA) for the treatment of relapsing multiple sclerosis and most recently for the management of moderate-severe ulcerative colitis (UC).. Here we review the status of drugs approved for moderate-severe UC, the unmet needs in the management of UC, proposed mechanisms of action of S1P modulators, clinical data regarding ozanimod in UC, and emerging S1P modulators being evaluated in inflammatory bowel disease.. Ozanimod is superior to placebo in inducing and maintaining clinical and endoscopic remission in UC. Adverse events include transient asymptomatic bradycardia, first-degree atrioventricular blocks, transient asymptomatic hepatotoxicity, macular edema in patients with preexisting risk factors, and increased risk of nasopharyngitis. Ozanimod is contraindicated in patients with clinically significant cardiovascular diseases, type II second-, or third-degree atrioventricular blocks, and females of childbearing age who do not use contraception. Ozanimod is the first S1P modulator to be approved for UC, offering a new therapeutic class option for patients. It has the advantages of being convenient with a once-daily oral administration, non-immunogenic, and overall safe when used in patients without contraindications.

Topics: Adult; Atrioventricular Block; Colitis, Ulcerative; Female; Humans; Indans; Oxadiazoles

Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular interferon beta-1a in participants with relapsing multiple sclerosis.. SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18-55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0-5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, number NCT02294058 and EudraCT, number 2014-002320-27.. Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or interferon beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the interferon beta-1a group). Adjusted ARRs were 0·35 (0·28-0·44) for interferon beta-1a, 0·18 (95% CI 0·14-0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41-0·66] vs interferon beta-1a; p<0·0001), and 0·24 (0·19-0·31) for ozanimod 0·5 mg (RR 0·69 [0·55-0·86] vs interferon beta-1a; p=0·0013). Few ozanimod-treated participants discontinued treatment because of adverse events (13 [2·9%] who received ozanimod 1·0 mg; seven [1·5%] who received ozanimod 0·5 mg; and 16 [3·6%] who received interferon beta-1a). No first-dose, clinically significant bradycardia or second-degree or third-degree atrioventricular block was reported. The incidence of serious adverse events was low and similar across treatment groups (13 [2·9%] participants who received ozanimod 1·0 mg; 16 [3·5%] who received ozanimod 0·5 mg; and 11 [2·5%] who received interferon beta-1a). No serious opportunistic infections occurred in ozanimod-treated participants.. In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than interferon beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis.. Celgene International II.

Topics: Adult; Atrioventricular Block; Bradycardia; Brain; Cognition Disorders; Disease Progression; Female; Gray Matter; Humans; Immunosuppressive Agents; Indans; Interferon beta-1a; Magnetic Resonance Imaging; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Neuroimaging; Organ Size; Oxadiazoles; Quality of Life; Severity of Illness Index; Sphingosine-1-Phosphate Receptors

The tolerability, pharmacokinetics, and pharmacodynamics of single (SD) and repeat (RD) doses of GSK2018682, a selective S1P1 receptor modulator, were evaluated in healthy volunteers. The bioavailability (BA) of different formulations and effects of food were also evaluated. SD of up to 24 mg and RD of up to 6 mg/day for 28 days were reasonably tolerated, despite higher incidences of gastrointestinal and cardiovascular adverse events compared to placebo. There was a linear relationship between dose and systemic exposure with a dose-independent half-life (t1/2 ) between 44.9 and 63.3 hours. GSK2018682 induced acute, transient and non-symptomatic decreases in heart rate and blood pressure. Dose-dependent reduction in absolute lymphocyte count (ALC), and all tested subsets, was observed to various degrees, up to a nadir of over 70% reduction from baseline. There was no difference in major pharmacokinetic parameters among three formulations of GSK2018682 and between fasted and fed subjects. However, there was a reduction in the extent of bradycardia following dosing in the fed state. Additionally, exercise induced robust increase in heart rate in subjects who had bradycardia following RD of GSK2018682 up to 6 mg, suggesting possible physiological methods of reducing the extent of S1P mediated bradycardia and subsequent AV-block.

Topics: Administration, Oral; Adolescent; Adult; Area Under Curve; Atrioventricular Block; Australia; Biological Availability; Bradycardia; Cross-Over Studies; Drug Compounding; Female; Food-Drug Interactions; Half-Life; Healthy Volunteers; Heart Rate; Humans; Indoles; Linear Models; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Oxadiazoles; Receptors, Lysosphingolipid; Single-Blind Method; Sphingosine-1-Phosphate Receptors; Young Adult