Ozanimod (formerly RPC1063) is an investigational, oral, selective sphingosine 1-phosphate (S1PR1) and 5 (S1PR5) receptor modulator now in advanced Phase 3 testing as a potential treatment for relapsing-remitting multiple sclerosis (RRMS). It is also in development for ulcerative colitis and Crohn’s disease.
How ozanimod works
In MS, inflammation caused by the body’s immune system can result in damage to the myelin sheath. The myelin sheath is essential to protecting and insulating nerve fibers in the central nervous system (CNS).
S1PR1 receptor modulators interfere with S1P signaling. They block immune cells (lymphocytes) from exiting the lymph nodes, and entering tissues such as the CNS. This keeps the immune cells, such as T- and B-cells trapped inside the node. The result is a reduction of circulating immune cells, leading to anti-inflammatory activity because the drug stops the migration of certain immune cells to the actual sites of inflammation.
Researchers believe that selective binding with S1PR5 receptors activates specific cells within the brain and spinal cord, which have the potential to enhance remyelination and prevent synaptic defects. Ultimately, neurological damage may be prevented.
Studies involving ozanimod
In September 2016, Celgene, the company developing ozanimod, announced positive results from its Phase 2 RADIANCE study (NCT01628393). Findings demonstrated that ozanimod was effective in reducing total brain lesions, as determined by magnetic resonance imaging (MRI) scans, after 24 weeks of treatment. Results of a nearly two-year safety and efficacy extension study further emphasized the potential of ozanimod to treat RRMS.
Common side effects reported in treated patients were mostly minor infections (nasopharyngitis, respiratory tract and urinary tract infections ) and headache, with no reports of new safety or tolerability issues.
This trial (NCT02047734) evaluated the efficacy, safety, and tolerability of two oral doses of ozanimod (0.5 mg and 1 mg) against weekly intramuscular interferon beta-1a (Avonex) and placebo in approximately 1,200 RRMS patients over 24 months of treatment.
Both ozanimod doses met the study’s primary endpoint of reducing annualized relapse rates. Key secondary goals regarding the number of new or enlarging T2 MRI lesions and the number of gadolinium-enhancing MRI lesions after the 24-month treatment period were also met. (Gadolinium is a large molecule that only crosses the blood-brain barrier when inflammation exists. In an MRI, gadolinium is used as a contrast material to highlight new and active areas of inflammation.)
Another Phase 3 trial called SUNBEAM (NCT02294058) finished in December 2016, and topline data were released in February 2017. The randomized, double-blind study compared the safety and effectiveness of oral ozanimod (0.5 mg and 1 mg doses) with Avonex in 1,346 RRMS patients.
Results showed that treatment with ozanimod — at either dose — produced both statistically significant and clinically meaningful improvements in treated patients in the trial’s primary goal of lower annualized relapse rates, compared to those given Avonex. Ozanimod-treated patients also showed significant and meaningful improvements in the trial’s secondary objectives: fewer gadolinium-enhancing MRI lesions and new or enlarging T2 MRI lesions at month 12, and again at month 24.
A pre-specified analysis of time to onset of disability progression was also conducted, in an agreement with the FDA under the protocol assessment, using pooled results from both the SUNBEAM and RADIANCE Phase 3 trials. A very low rate of disability progression in all three treatment groups was observed — ozanimod and Avonex — meaning ozanimod was not significantly superior to Avonex. But the Phase 3 trials did show that ozanimod, at both 0.5 mg and 1 mg, significantly reduced brain atrophy compared to Avonex.
A new Phase 3 (NCT02576717) open-label extension study is now recruiting RRMS patients who participated in earlier ozanimod trials, an estimated 2,350 people, to further evaluate the treatment’s safety and efficacy. This trial is currently expected to run through mid-2020.
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