BOSTON – The novel oral sphingosine 1-phosphate 1 receptor modulator RPC1063 safely and effectively reduced the cumulative number of total gadolinium-enhancing lesions in relapsing multiple sclerosis patients in phase II of the randomized, double-blind, placebo-controlled RADIANCE study.

At weeks 12-24 after treatment initiation, 87 patients who received 0.5 mg of RPC1063 and 83 patients who received a 1-mg dose experienced a highly significant 86% reduction in the number of gadolinium-enhancing (GdE) lesions on brain MRI, compared with 88 patients who received placebo (cumulative number of total lesions, 1.5 for both RPC1063 doses vs. 11.1 with placebo), Dr. Amit Bar-Or of the Montreal Neurological Institute and Hospital at McGill University reported at the joint meeting of the European and Americas committees on Treatment and Research in Multiple Sclerosis.

RPC1063 patients also fared significantly better on all secondary endpoints. For example, the mean number of GdE lesions at week 24 was reduced by 91% and 94% in patients who received 0.5 and 1 mg of RPC1063, respectively, compared with the number of lesions in those who received placebo (mean of 0.3 and 0.2 lesions, respectively, vs. 3.2 lesions). In addition, the cumulative number of new or enlarging T2 lesions from weeks 12-24 was reduced by 84% and 91% in the groups, respectively (suggesting a dose response), compared with the number in those who received placebo (cumulative number, 0.8 and 0.5 vs. 9.0).

The annualized relapse rate was 0.35 and 0.24 in the 0.5- and 1-mg dose groups, compared with 0.5 in the placebo group, representing 31% and 53% decreases, respectively. Although the study was not powered to detect an effect on the annualized relapse rate, this finding also hinted at a dose-response.

Immunomodulation through the sphingosine 1-phosphate receptor family is a validated therapeutic approach for the treatment of relapsing MS – the approved oral drug fingolimod (Gilenya) is a sphingosine 1-phosphate receptor modulator with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5 – but RPC1063 has been tested previously only in healthy volunteers. The phase II results of the combined phase II/III RADIANCE trial suggest it is safe and effective in patients with MS, Dr. Bar-Or said.

Study subjects were adults aged 18-55 years (mean of 39 years) with MS as diagnosed by the revised McDonald criteria who exhibited a relapsing clinical course consistent with relapsing disease. The patients had a history of brain MRI lesions consistent with MS, a baseline Expanded Disability Status Scale (EDSS) score between 0 and 5.0 points, and either one documented relapse within the last year, or at least one documented relapse in the past 2 years plus at least one GdE lesion.

All patients underwent a 30-day screening period prior to randomization, followed by a 7-day titration period to either 0.5 mg or 1 mg of active treatment or placebo for 24 weeks. During a blinded safety extension phase, all those who received placebo were randomized to receive 0.5 or 1 mg of RPC1036.

The completion rate was similarly high across all three groups (97.7%, 98.8%, and 96.6%, respectively).

Patients in the 0.5-mg and 1-mg groups experienced approximately 50% and 60% reductions in absolute lymphocyte count at week 24, compared with placebo.

Treatment-emergent adverse events (TEAEs) during the first 24 weeks of the study occurred in 64%, 57%, and 59% of patients in the 0.5-mg, 1-mg, and placebo groups, respectively. The most common TEAEs were nasopharyngitis, headache, and urinary tract infection. Only three serious TEAEs occurred: optic neuritis, somatoform autonomic dysfunction, and uterine cervical squamous metaplasia. All were in the 0.5-mg treatment group but were deemed unrelated to RPC1063.

“There were no notable cardiac, pulmonary, ophthalmologic, infectious, or malignancy-related TEAEs. Three TEAEs of liver enzyme abnormalities greater than or equal to three times the upper limit of normal were documented, but all of these occurred with no signs or symptoms associated,” said Dr. Bar-Or, noting that two occurred in the 0.5-mg group, one occurred in the 1-mg treatment group, and all resolved with continued treatment.

The exclusion criteria of the trial nearly matched those of the label contraindications for fingolimod without “any overt attempt of extending the exclusion,” Dr. Bar-Or said during a press conference. He noted that the RADIANCE trial’s week-long titration process also helped to mitigate any potential adverse events.

Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity, with good overall tolerability and safety – including with respect to cardiac and hepatic safety results. The findings suggest a favorable risk-benefit profile in patients with relapsing MS, and they support the ongoing phase III portion of the RADIANCE trial, as well as a second phase III trial – SUNBEAM – which will compare RPC1063 and interferon beta-1a in relapsing MS, he concluded.

The trial was funded by Receptos. Dr. Bar-Or reported receiving financial support from Biogen Idec, DioGenix, Genentech, GlaxoSmithKline, Guthy-Jackson Charitable Foundation, MedImmune, Merck Serono, Novartis, Ono Pharmaceuticals, Receptos, Roche, Sanofi-Aventis, and Teva Neuroscience.

Phase II RADIANCE study results demonstrate efficacy of RPC1036 in MS