Background

Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in the US and EU for the treatment of relapsing forms of multiple sclerosis (RMS).

Objectives

To characterize the long-term safety and efficacy of ozanimod in participants with RMS in an ongoing open-label extension (OLE) trial.

Methods

Participants with RMS who completed a phase 1, 2, or 3 ozanimod clinical trial were eligible to enroll in DAYBREAK (NCT02576717), where they received ozanimod 0.92 mg/d (equivalent to ozanimod HCl 1 mg). The primary objective was to evaluate safety in the overall population; treatment-emergent adverse events (TEAE) were monitored. Efficacy was evaluated with annualized relapse rate (ARR), calculated via negative binomial regression and pooled for all parent-trial treatment groups. Number of new/enlarging T2 and gadolinium-enhancing (GdE) MRI brain lesions were reported for the subset of participants who entered the OLE from an active-controlled phase 3 trial.

Results

In total, 2639 participants completed the parent trials; this interim analysis (data cut 20 December 2019) included 2494 participants with mean (range) ozanimod exposure of 35.4 (0.03–50.2) months in the OLE. Adjusted ARR in the OLE was 0.112 (95% confidence interval, 0.093‒0.135). At months 24 and 36, 79% and 75% of participants, respectively, were relapse free in the OLE. Three- and 6-month confirmed disability progression was observed in 10.8% and 8.6% of participants in the OLE, respectively. Mean number of new/enlarging T2 lesions per scan at 24 months was similar, regardless of parent-trial treatment group (range, 1.57–1.90), as were mean number of GdE lesions at month 24 (range, 0.2 ‒0.4). In the OLE, 2039 participants (81.8%) had any TEAE, 236 (9.5%) had a serious TEAE (SAE), and 56 (2.2%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent-trial treatment group. The most common TEAEs were nasopharyngitis (17.9%), headache (14%), upper respiratory tract infection (9.9%), and lymphopenia (9.6%). TEAEs were generally similar to parent trial observations. There were no serious opportunistic infections. Exposure-adjusted incidence rates of TEAEs and SAEs have decreased over time.

Conclusions

In DAYBREAK, ozanimod was associated with low ARR and low new/enlarging T2 and GdE lesion counts over time. Most participants were relapse free and did not experience disability progression. Ozanimod was generally well tolerated and no new safety concerns emerged with long-term use.

Background

Ozanimod is a potent, orally bioavailable, sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. Ozanimod was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis.

Nonclinical reproductive safety assessments with S1P modulators in rats and rabbits have shown embryo-fetal toxicity, including embryo-fetal deaths and visceral malformations. The S1P receptor is known to be involved in vascular formation during embryogenesis. In the clinical development program for ozanimod, female participants of childbearing potential are required to use effective contraception while receiving and up to 3 months after discontinuing ozanimod and to discontinue ozanimod if pregnancy is confirmed.

Objectives

To review the pregnancy outcomes data in the ozanimod clinical development program in relapsing multiple sclerosis.

Methods

Pregnancy outcomes were assessed in cases reported from all multiple sclerosis studies in the ozanimod clinical development program and diagnosed by December 31, 2019. Pregnancy outcomes through June 15, 2020 are reported.

Results

Forty-two pregnancies were reported among 1868 female ozanimod-treated participants with multiple sclerosis. Outcomes include 26 live births, including 20 normal and 3 premature but normal infants, 1 report each of neonatal icterus, late intrauterine growth retardation with subsequent normal progress over the first year, and duplex kidney (common variant in 1.8% of births). There were 6 early spontaneous abortions (of which 1 was a loss of a twin), 9 elective terminations, 1 pregnancy ongoing, and 1 subject refused consent to follow-up. The incidence of spontaneous abortion in clinical trial participants exposed to ozanimod (6/43, 14%) is at the lower end of the expected rate of early pregnancy loss in the general population (12% to 22%; García-Enguídanos et al 2002).

Conclusions

While there has been limited clinical experience with ozanimod during pregnancy, and pregnancy should be avoided while taking and for 3 months after stopping ozanimod, to date there has been no signal of an increased risk of fetal abnormalities or other adverse pregnancy outcomes seen with exposure in early pregnancy.

Background

Ozanimod is a potent, orally bioavailable, sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. Ozanimod was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis.

Nonclinical reproductive safety assessments with S1P modulators in rats and rabbits have shown embryo-fetal toxicity, including embryo-fetal deaths and visceral malformations. The S1P receptor is known to be involved in vascular formation during embryogenesis. In the clinical development program for ozanimod, female participants of childbearing potential are required to use effective contraception while receiving and up to 3 months after discontinuing ozanimod and to discontinue ozanimod if pregnancy is confirmed.

Objectives

To review the pregnancy outcomes data in the ozanimod clinical development program in relapsing multiple sclerosis.

Methods

Pregnancy outcomes were assessed in cases reported from all multiple sclerosis studies in the ozanimod clinical development program and diagnosed by December 31, 2019. Pregnancy outcomes through June 15, 2020 are reported.

Results

Forty-two pregnancies were reported among 1868 female ozanimod-treated participants with multiple sclerosis. Outcomes include 26 live births, including 20 normal and 3 premature but normal infants, 1 report each of neonatal icterus, late intrauterine growth retardation with subsequent normal progress over the first year, and duplex kidney (common variant in 1.8% of births). There were 6 early spontaneous abortions (of which 1 was a loss of a twin), 9 elective terminations, 1 pregnancy ongoing, and 1 subject refused consent to follow-up. The incidence of spontaneous abortion in clinical trial participants exposed to ozanimod (6/43, 14%) is at the lower end of the expected rate of early pregnancy loss in the general population (12% to 22%; García-Enguídanos et al 2002).

Conclusions

While there has been limited clinical experience with ozanimod during pregnancy, and pregnancy should be avoided while taking and for 3 months after stopping ozanimod, to date there has been no signal of an increased risk of fetal abnormalities or other adverse pregnancy outcomes seen with exposure in early pregnancy.