Ozanimod (formerly RPC1063)
Experimental Medications: New S1P Receptor Modulators
- Oral medication studied at several doses
- Being studied in RRMS
Ozanimod (RPC1063) is a selective modulator of two types of S1P receptors: S1P1 and S1P5. It is given as a once-daily pill, and was studied in a trial called RADIANCE, where this experimental medicine was compared at two different doses with placebo. A total of 258 individuals with RRMS were studied in this trial, which began with a seven-day gradual titration of ozanimod up to the full dose under investigation. (Titration refers to starting with a lower dose and gradually increasing the dose until the full dose is reached. This helps to reduce the risk of side effects when starting a new medication.) The double-blind study ran for 24 weeks, followed by a year-long safety-extension period.
At the end of the initial 24-week treatment period, patients in both groups taking ozanimod showed an 86-percent decrease in the cumulative number of gadolinium-enhanced lesions compared to the placebo group. The relapse rates also decreased in the treatment groups compared with placebo, with a 31-percent decrease in the 0.5-mg group and a 53-percent decrease in the 1-mg group.
The most common side effects reported were nasopharyngitis (inflammation of the nasal passages and upper part of the throat) and headache. However, both of these events were reported more commonly in placebo-treated individuals compared with ozanimod- treated participants. Notably, no serious cardiac events, infections, or episodes of macular edema were reported in the subjects receiving ozanimod. (Macular edema is a swelling behind the eye, which is a potential risk for individuals who take Gilenya.)49
In February 2016, the 72-week extension data of the RADIANCE trial were released. These showed a continued reduction in relapses and gadolinium-enhancing lesions for those individuals who remained on ozanimod, with all efficacy results favoring the 1-mg dose over the lower 0.5-mg dose. No new safety or tolerability issues were identified during this blinded extension phase of the trial.
This medication was then evaluated in two larger, Phase III trials that compared its efficacy against Avonex® (interferon beta-1a). The first trial, SUNBEAM, enrolled more than 1,300 people with RMS in 20 countries who were followed for at least 12 months. The second trial, RADIANCE Part B, enrolled 1,320 individuals with RMS over two years. Both studies assessed 1 mg and 0.5 mg of ozanimod compared with Avonex. Results from the two studies were announced in late October 2017 at MSParis2017, the 7th Joint ECTRIMS-ACTRIMS Meeting.
The SUNBEAM study showed a significant reduction in the annualized relapse rate (ARR) for both the 1-mg and 0.5-mg doses of ozanimod over an average of 13.6 months of treatment. Both doses of ozanimod also demonstrated a significant reduction in new or enlarging T2 lesions and gadolinium-enhanced MRI lesions over one year compared to Avonex. Further, at one year, whole-brain volume loss – which is associated with MS progression – was reduced by one-third with the 1-mg dose of ozanimod and by 12 percent with the 0.5-mg dose compared with Avonex.50
In SUNBEAM, 75 percent of patients receiving Avonex and just under 60 percent receiving ozanimod reported an adverse event related to treatment. Among individuals receiving ozanimod, the most common adverse events reported were nasopharyngitis, headache, and upper respiratory infection. The incidences of serious adverse events were 2.9 percent for patients receiving 1 mg of ozanimod, 3.5 percent for those taking 0.5 mg of ozanimod, and 2.5 percent for study participants receiving Avonex.50
The results of the two-year RADIANCE Part B study were similar to those of the one-year SUNBEAM trial. Individuals receiving ozanimod saw a significant reduction in annualized relapse rate (ARR) compared to individuals receiving Avonex. Those rates were 0.17 for people taking 1 mg of ozanimod, 0.22 for those on 0.5 mg of ozanimod, and 0.28 for individuals receiving interferon. Ozanimod-treated individuals also had a significant reduction in new or enlarging T2 lesions and gadolinium-enhanced MRI compared with those in the Avonex arm of the study. Additionally, a reduction in brain-volume loss (BVL) was seen for both ozanimod doses relative to interferon. Whole BVL was reduced by 27 percent with the 1-mg dose of ozanimod and by 25 percent in the 0.5-mg group versus Avonex.51
Eighty-three percent of study participants receiving Avonex reported an adverse event related to treatment, compared with 75 percent of patients on ozanimod 1-mg and 74 percent of those on ozanimod 0.5-mg. Most of the adverse events were mild. The most common were nasopharyngitis, headache, increased liver enzymes, flu-like symptoms, high blood pressure, pharyngitis, and urinary tract infection. Serious adverse effects were experienced by 6.5 percent of the participants taking ozanimod 1 mg, 7.1 percent of individuals on ozanimod 0.5 mg, and 6.4 percent of those receiving Avonex.51
At the outset of the studies, investigators planned (or “pre-specified”) a pooled analysis of the SUNBEAM and RADIANCE Part B studies to assess outcomes, including confirmed disability progression (CDP). In this pooled analysis, ozanimod did not reach statistical significance compared with Avonex in the time to three-month confirmed disability progression. This may, however, reflect the fact that a very low rate of disability progression was present in all three of the treatment groups, which could make statistically significant differences difficult to emerge. For example, in SUNBEAM, the number of patients with three-month confirmed disability progression by the end of the study was 13 (2.9 percent) in the ozanimod 1-mg group, 17 (3.8 percent) in the ozanimod 0.5-mg group, and 19 (4.2 percent) in the Avonex group.51
On the basis of those study results, Celgene submitted a New Drug Application (NDA) to the FDA for use of ozanimod in treating patients with relapsing forms of MS. In late February 2018, however, the FDA declined to accept the NDA, saying that the nonclinical and clinical pharmacology sections of the NDA were insufficient to allow a complete review of the application. In response to that “Refusal to File” letter from the FDA, Celgene expressed its confidence in ozanimod and said it would work with the FDA to address any outstanding items.52