Ozanimod reduced the annualized relapse rate and lowered the number of T2 lesions versus interferon beta-1a for RMS.
Jeffrey A. Cohen, MD
Ozanimod reduced the annualized relapse rate (ARR) by up to 38% and lowered the number of new/enlarging T2 lesions by 42% compared with interferon beta-1a (IFN) for patients with relapsing multiple sclerosis (RMS), according to 2-year findings from the phase 3 RADIANCE study presented at the 2017 MS Paris Meeting.
The ARR was 0.276 with IFN compared with 0.218 for ozanimod at the 0.5 mg dose and 0.172 with the 1.0 mg dose. This represented a 21% (P = .0167) and a 38% (P <.0001) reduction in ARR for the 0.5 mg and 1.0 mg doses compared with IFN, respectively. There were 3.183 new/enlarging T2 lesions in the IFN group compared with 2.092 (34% reduction; P = .0001) and 1.835 (42% reduction; P <.0001) for the 0.5 and 1.0 mg doses of ozanimod, respectively.
"Results on annualized relapse rate were supported by positive results on secondary measures of MRI lesion activity—new and enlarged T2 lesions and Gd-enhancing lesions over 2 years," said Jeffrey A. Cohen, MD, Mellen Center for MS Treatment and Research, Cleveland Clinic. "Brain volume, cortical gray matter volume, and thalamic volume loss were also slowed compared with IFN."
The RADIANCE trial enrolled 1313 patients to receive ozanimod at 1 mg (n = 441), 0.5 mg (n = 439), or the active control IFN at 30 mcg (n = 433). The first dose of ozanimod was escalated over a 7-day period to help mitigate potential cardiac events. Overall, of those who entered, 89.6% completed the study in the 1 mg group and 85.2% completed in the 0.5 mg group and the IFN arm.
Patients were enrolled in 21 countries and had similar baseline characteristics across each group. Overall, the mean age was 36 years and 67% were female. The baseline expanded disability status scale (EDSS) score was 2.5 and patients had a mean of 1.3 relapses in the prior year. Overall, 29% of patients had received prior disease modifying therapy (DMT) and 43% had Gd-enhancing lesions.
In addition to improvements in ARR and new/enlarging lesions, there were fewer Gd-enhancing (GdE) lesions with ozanimod at 2 years compared with IFN. In the IFN group, there were 0.373 GdE lesions compared with 0.197 for the 0.5 mg dose and 0.176 for the 1.0 mg dose of ozanimod, representing a 47% (P = .003) and a 53% (P = .0006) reduction compared with IFN.
There was a -0.940 percent reduction in normalized brain volume with IFN compared with -0.710 for the 0.5 mg dose (25% reduction vs IFN; P <.0001) and -0.690 for the 1.0 mg dose (27% reduction vs IFN; P <.0001). For cortical gray matter volume, IFN had a -1.270 percent change versus -0.550 and -0.630 for the 0.5 and 1.0 mg doses, respectively, representing a 57% and a 58% reduction (P <.0001). Thalamic volume loss was -1.880, -1.326, and -1.280 for IFN and the 0.5 mg and 1.0 mg doses of ozanimod, respectively.
Patients treated with IFN were more likely to have an adverse event (AE) of any grade (83.0%) compared with ozanimod at 0.5 mg (74.3%) or 1.0 mg (74.7%). More patients experienced a moderate or severe AE in the IFN group (53.4%) versus the 0.5 mg (38.5%) and 1.0 mg arms (39.2%). In the IFN arm, 48.9% of patients had influenza like illness, compared with 5.9% and 6.2% in the 0.5 mg and 1.0 mg groups, respectively. The rates of herpetic infections were similar across each treatment group.
The AEs of interest with ozanimod at 0.5 mg and 1.0 mg were headache (12.5% and 10.1%), alanine aminotransferase increase (6.6% and 6.0%), pharyngitis (5.5% and 3.9%), and urinary tract infection (5.0% and 4.4%). "Liver enzyme elevations tended to be mild and self-limited and resolved even with continuation of study drug," Cohen noted.
There were no signs of 2nd degree or higher atrioventricular block, and the largest mean supine heart rate reduction was just -0.6 beats per minute. Overall, serious cardiac AEs were infrequent and balanced between the treatment groups, with 2 events in the IFN group and 3 in the 0.5 mg dose. None of the patients in the 1.0 mg dose arm had a serious cardiac AE.
"The incidences of serious cardiac-related adverse events were very rare and were balanced across the 3 treatment arms," said Cohen. "It appears that the dose escalation protocol effectively mitigated cardiac effects."
In a pooled analysis of the RADIANCE study and the phase 3 SUNBEAM trial, which also explored ozanimod at 0.5 and 1.0 mg doses compared with IFN, there was not a statistically significant different between the groups for confirmed disability progression; however, there were few progression events at the time of the analysis making an effective analysis challenging, Cohen noted. Overall, ozanimod demonstrated similar improvements in ARR and MRI activity in the SUNBEAM study.
"The results of the phase 3 RADIANCE trial confirm the data observed in SUNBEAM and are consistent with the long-term phase 2 RADIANCE trial," Bruce Cree, MD, PhD, associate professor of Neurology, Multiple Sclerosis Center, University of California, San Francisco, said in a statement. "The significant effects seen with ozanimod on relapse and MRI outcomes, including brain volume loss, coupled with the safety and tolerability profile observed in the two phase 3 trials, represent an exciting advancement for a disease which needs additional oral therapies with favorable benefit-risk profiles."
Ozanimod, a novel selective receptor modulator of S1PR1 and S1PR5, is also under exploration for patients with other immune-inflammatory indications, including ulcerative colitis and Crohn's disease. For patients with MS, Celgene, the company developing ozanimod, announced plans to submit a new drug application to the FDA for patients with RMS, based on findings from the SUNBEAM and RADIANCE trials. This application is expected by the end of 2017, according to a statement from the company released earlier this year.
Cohen JA, Comi G, Selmaj KW, et al. Ozanimod vs interferon β-1a: clinical and MRI results of RADIANCE part B - A 2-year Phase 3 trial in relapsing multiple sclerosis. Presented at: 7th Joint ECTRIMS - ACTRIMS Meeting; October 25-28, 2017, Paris, France. Abstract 280.