Novel Immune Regulator Shows Promise as MS Therapy in Clinical Trials

The course of multiple sclerosis (MS) can be altered by the administration of disease modifying agents; limiting factors can include toxicity and the inconvenience of having to inject medications. Investigators shared a promising candidate oral drug’s clinical trial results in a late breaking session presented at the 2014 Joint ACTRIMS-ECTRIMS Meeting, held in Boston, MA.

Discussing the phase 2 clinical trial results of RPC1063, the Cleveland Clinic’s Jeffrey Cohen, MD, identified the target immunomodulating receptor for the new compound. The sphingosine-1-phosphate receptors are targets of lipid signaling molecules, and contribute to regulation of immune function and proliferative functions. The receptor subclasses targeted by RPC1063 are expressed in the central nervous system.

The phase 2 results of the RADIANCE study, a combined phase 2-3 international clinical trial, included 258 patients with relapsing MS (RMS) randomized 1:1:1 to placebo, RPC1063 0.5 mg, or RPC1063 1.0 mg. Patients age 18-55 were included if they had an Expanded Disability Status Scale (EDSS) of 5.0 or less, had magnetic resonance imaging (MRI) confirmed brain lesions, and had documented relapse within the last 12 months, or 24 months with the presence of gadolinium (GD) enhancing lesions. Patient characteristics were similar across arms, except that the placebo patients had a slightly longer time since diagnosis than the two treatment arms.

Primary outcome measures were the presence of GD enhancing lesions on MRI, with secondary efficacy endpoints that included the number of GD endpoints at week 24, the number of cumulative new or enlarging T2 lesions, and the annualized relapse rate (ARR). Cohen highlighted the high rate of study compliance and completion, with over 96% of participants completing phase 2 trials across all arms.

For the primary endpoint, the number of GD enhancing lesions in the treatment group from weeks 12 to 24 was 11.1 for the placebo arm, versus 1.5 each for the two treatment groups. The first secondary endpoint, mean number of GD lesions at week 24, yielded 3.2 for the placebo group versus 0.3 for the RPC1063 0.5 mg group (91% fewer than placebo), while the RPC1063 1 mg group had a mean of 0.2 lesions (94% fewer than placebo). The secondary endpoint of new or enlarging T2 lesions from weeks 12 to 24 showed 9 in the placebo arm, versus 1.4 in the RPC1063 0.5 mg group and 0.8 in the RPC1063 1 mg group (84% and 91% less than placebo, respectively). All of these endpoints were highly statistically significant (p<0.0001).

The secondary endpoint of ARR was 0.5 for those on placebo, 0.35 for the 0.5 mg arm (31% decrease vs. placebo, p=0.271), and 0.24 for the 1 mg arm (53% less than placebo, p=0.053). Looking at pharmacodynamics of RPC1063 in study subjects, absolute lymphocyte counts were reduced by approximately 50% and 60% versus placebo for the 0.5 mg and 1 mg treatment arms, respectively.

The safety profile for RPC1063 as reported in the phase 2 results was favorable: there were 3 serious treatment-associated adverse events (TEAEs), but none were assessed as being related to the study medications. Three study subjects had elevated liver enzymes isolated to alanine aminotransferase (ALT) between 3 and 5 times the upper limit of normal, and without clinical manifestations. These ALT elevations were transient and treatment was continued. The cardiac safety profile was also favorable, with no serious cardiac TEAEs.

Cohen emphasized the striking improvement of MRI-detected MS disease activity in study subjects and also highlighted the favorable risk-benefit profile seen to date. RPC1063 has transitioned to phase 3 clinical trials as the RADIANCE study continues; a second phase 3 trial pitting RPC1063 against interferon beta-1a, dubbed SUNBEAM, is also planned.