Date: 2016-09-16
Type of information: Presentation of results at a congress
phase: 2
Announcement: presentation of results at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
Company: Celgene (USA - NJ)
Product: ozanimod
Action
mechanism: sphingosine 1-phosphate receptor (S1PR) modulator. Ozanimod is a small molecule sphingosine 1-phosphate 1 and 5 receptor modulator in development for immune-inflammatory indications including relapsing multiple sclerosis and inflammatory bowel disease. Treatment with S1P receptor modulators is believed to work by interfering with S1P signaling and blocks the response of lymphocytes to exit signals from the lymph nodes, sequestering them within the nodes. The result is thought to be a downward modulation of circulating lymphocytes and anti-inflammatory activity by inhibiting cell migration to sites of inflammation.
Disease: relapsing multiple sclerosis
Therapeutic area: Neurodegenerative diseases - Autoimmune diseases
Country:
Trial
details: The phase 2 portion of RADIANCE is a randomized, double-blind study assessing the efficacy, safety and tolerability of two orally administered doses (0.5 mg and 1 mg) of ozanimod against placebo in 258 patients with relapsing multiple sclerosis across 77 sites in 13 countries. The primary endpoint of the trial is the reduction in the cumulative number of total GdE lesions determined by MRI from week 12 to week 24 of study treatment, a standard endpoint for phase 2 trials in this indication. The secondary endpoints of the trial were: the number of GdE at week 24, the cumulative number of new or enlarging T2-hyperintense lesions at weeks 12–24, the annualized relapse rate from baseline until week 24 and safety and tolerability, as judged by the site investigator. The 2-year phase 3 portion of RADIANCE was initiated under a Special Protocol Assessment with the FDA in December 2013.
Latest
news: * On September 16, 2016, Celgene announced results from the 96-week blinded extension period (for a total of up to 120 weeks of exposure on treatment) of the RADIANCE phase 2 trial of ozanimod in patients with relapsing multiple sclerosis (RMS). The results were presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), which is being held in London from September 14-17, 2016 . As previously announced at ECTRIMS 2014, RADIANCE met its primary efficacy endpoint — reduction in the cumulative number of total gadolinium-enhancing (GdE) lesions, as determined by MRI, from week 12 to week 24. In the blinded extension period of the study, patients originally randomized to ozanimod continued their assigned dose (0.5 mg, n = 85; 1 mg, n = 81), while patients in the placebo arm were randomized to either dose of ozanimod (0.5 mg, n = 41; 1 mg, n = 42). The extension week 96 visit was completed by 224 of the patients (90 percent) who entered the extension study. * On February 18, 2016, Celgene announced 72-week results from the RADIANCE phase 2 trial of ozanimod, an investigational selective S1P 1 and 5 receptor modulator, in patients with relapsing multiple sclerosis. The results were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) in New Orleans, Louisiana. Full details of the 24-week study results were also recently published online in the Lancet Neurology. As previously announced, RADIANCE met its primary efficacy endpoint — reduction in the cumulative number of total gadolinium-enhancing (GdE) lesions, as determined by MRI, from week 12 to week 24. In the 48-week blinded extension portion of the study, patients originally randomized to ozanimod continued their assigned dose (0.5 mg, n = 85; 1 mg, n = 81), while patients in the placebo arm were randomized to either dose of ozanimod (0.5 mg, n = 41; 1 mg, n = 42). For patients who received ozanimod continuously through week 72, the mean number of GdE lesions at week 72 was 0.4 for patients on the 0.5 mg dose and 0.2 for the 1 mg dose, similar to results obtained at week 24. For placebo patients switched after week 24 to either dose of ozanimod, the mean number of GdE lesions was decreased by 90 to 95 percent compared with that at week 24. For patients who received ozanimod continuously through week 72, the proportion of patients who were free of GdE lesions at week 72 was 73 percent for the 0.5 mg dose and 88 percent for the 1 mg dose, compared with 84 percent and 89 percent, respectively, at week 24. For those who switched from placebo to ozanimod, the corresponding proportions at week 72 were 85 percent for the 0.5 mg dose and 79 percent for the 1 mg dose, respectively, compared with 59 percent and 69 percent, respectively, at week 24. The unadjusted annualized relapse rate (uARR) was decreased in both ozanimod dose groups; a larger treatment effect was observed in the 1 mg dose group. For those on ozanimod continuously through week 72, the reduction in uARR was 0.43 for the 0.5 mg dose and 0.24 for the 1 mg dose at week 24, and 0.27 and 0.15, respectively, at week 72. Comparable results were seen in the groups switched from placebo to ozanimod after week 24. Reported adverse events (AEs) were similar across ozanimod dose groups; the most commonly reported non-laboratory treatment-emergent AEs were minor infections (nasopharyngitis, upper respiratory tract and urinary tract), back pain and headache. Maximum first-dose reductions from baseline in mean hourly heart rate were less than one beat per minute. Alanine aminotransferase at least three times the upper limit of normal was reported in 3-4 percent of patients through week 72.
At extension week 96, the mean number of GdE lesions was 0.3 for patients on the 0.5 mg dose and 0.1 for the 1 mg dose, compared with 0.4 and 0.1, respectively, at week 48. The proportion of patients who were free of GdE lesions was 91 percent for the 0.5 mg dose and 89 percent for the 1 mg dose. The cumulative number of new or enlarging T2-hyperintense lesions was 1.8 for the 0.5 mg dose and 0.6 for the 1 mg dose, compared with 1.3 and 0.7, respectively, at week 48.
The effect on unadjusted annualized relapse rate (uARR) was maintained in both ozanimod dose groups with uARR of 0.30 for the 0.5 mg dose and 0.19 for the 1 mg dose at extension week 96, and 0.26 and 0.15, respectively, at week 48.
No evidence of disease activity (NEDA: no GdE or new/enlarging T2 lesions, and no relapse or increase in Expanded Disability Status Scale [EDSS]) was achieved in 44 percent and 39 percent of patients at extension week 48 and 96, respectively, on the 0.5 mg dose and 62 percent and 47 percent on the 1 mg dose.
Reported treatment-emergent adverse events (AEs) were comparable across ozanimod dose groups; the most common reported AEs during the blinded extension (weeks 24 to 96) were minor infections (nasopharyngitis, respiratory tract and urinary tract) and headache. Alanine aminotransferase at least three times the upper limit of normal was reported in 11 patients (4.4 percent) through extension week 96. Consistent with extension week 48 data, no noteworthy occurrences of cardiac, pulmonary, serious opportunistic infections, ophthalmologic, or malignancy-related TEAEs were observed. No first-dose TEAEs of bradycardia of AV block ? 2nd degree were reported from day 1 of the study or day 1 of the extension.
Celgene is currently evaluating ozanimod in two ongoing pivotal phase 3 clinical trials in RMS.
