Actelion‘s ponesimod, an investigational oral treatment, is superior to Sanofi‘s Aubagio (teriflunomide) in lessening the frequency of relapses and easing fatigue symptoms in adults with active, relapsing multiple sclerosis (MS), results of the OPTIMUM trial show.
These data will lay the ground for submissions in the United States and Europe seeking approval of ponesimod as a new therapy for relapsing MS, Janssen, Actelion’s owner, announced.
The findings were presented by Ludwig Kappos, MD, chair of the department of neurology at the University Hospital of Basel, Switzerland, at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held Sept. 11-13 in Stockholm.
Kappos’ oral presentation was titled: “Efficacy and safety of ponesimod compared to teriflunomide in patients with relapsing multiple sclerosis: results of the randomized, active-controlled, double-blind, parallel-group phase 3 OPTIMUM study.”
Ponesimod (formerly called ACT-128800) is an experimental treatment under development by Actelion (owned by Janssen, a subsidiary of Johnson & Johnson) for the treatment of MS.
Ponesimod is an oral modulator of the sphingosine-1-phosphate receptor 1 (S1P1), promoting the trapping of lymphocytes (a type of white blood cells, including immune T cells and B cells) inside lymph nodes, therefore lowering the numbers of “immune cells available for inflammatory attacks in the [brain and spinal cord],” Kappos said.
Key features of ponesimod include the fact it is rapidly eliminated from the body (within one week after stopping treatment), it does not form active metabolites (subproducts), has a low potential for drug interactions, and its “effects on the immune system are quickly reversible,” Kappos said.
Despite reducing the numbers of T and B cells in the bloodstream, ponesimod does not directly destroy them. This ability helps preserve part of the patient’s immune defenses.
The OPTIMUM Phase 3 study (NCT02425644) was a global, 2-year, head-to-head trial comparing the efficacy and safety of ponesimod versus Aubagio, an approved first-line oral MS medication, in adults with relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS) ages 18–55.
The trial ran at 162 sites in 28 countries, and was the first to directly compare two oral compounds for the treatment of relapsing MS.
Patients enrolled had an EDSS score of 0–5.5 (meaning no disability to disability severe enough to preclude full daily activities), and recent clinical or MRI (magnetic resonance imaging) signs of active disease (present within two years before enrollment).
In all, 1,133 patients were randomized to receive either once-daily 20 mg tablets of ponesimod (567 patients), or once-daily 14 mg tablets of Aubagio (566 patients), for two years (108 weeks).
For ponesimod recipients, a gradual up-titration regimen starting with 2 mg once daily was implemented to limit potential heart effects linked with S1P modulators.
According to Kappos, the study population represented a typical relapsing MS population — mean age 36.7 years, mean EDSS score of 2.6, and mean disease duration of 7.6 years — and similar characteristics between the ponesimod and Aubagio groups.
More than half of the patients were recruited from the European Union and the United Kingdom, with only a few (approximately 5%) coming from North America.
Patient withdrawal was identical between groups — 83.1% of the patients receiving ponesimod and 83.6% of those receiving Aubagio completed the 2-year trial.
The trial met its primary efficacy outcome, showing that, compared to Aubagio, ponesimod was significantly better at reducing annualized relapse rates (ARR). The ARR in the ponesimod group was 0.202, compared to 0.290 in the Aubagio group, representing a 30.5% reduction compared to Aubagio.
“There is a significant reduction of confirmed relapses up to the end of the study [week 108] by about 30%,” Kappos said.
Additional relapse analyses agreed with the primary findings, favoring ponesimod over Aubagio, and confirming the robustness of ponesimod’s effect, Kappos noted.
Fatigue-related symptoms were a secondary endpoint. Results showed that ponesimod outperformed Aubagio in relieving fatigue, as reported by patients through an MS-specific tool — the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis.
“Fatigue was at a stable level with ponesimod, and worsened somewhat in the [Aubagio] group” over time, Kappos said.
MRI outcomes (another secondary endpoint of the trial) also supported the efficacy of ponesimod. Results showed that two years of treatment with ponesimod resulted in a 56% reduction in the number of new active, inflammatory brain lesions, compared with Aubagio.
Regarding confirmed disability accumulation at 12 and 24 weeks (defined as increases in EDSS score relative to baseline), results showed a trend for ponesimod to reduce the risk of confirmed disability progression compared with Aubagio, but the data was not statistically significant.
As for ponesimod’s safety, its “safety profile was overall very reassuring and benign,” Kappos said.
Treatment-related adverse events — 88.8% with ponesimod, and 88.2% with Aubagio — and serious adverse events (8.7% with ponesimod, and 8.1% with Aubagio) were virtually identical.
The most common side effects were nasopharyngitis (common cold), headache, upper respiratory tract infections, and an increase in alanine aminotransferase (ALT; a marker of liver damage).
In ponesimod-treated patients, there was a higher overall frequency of liver test abnormalities (reported in 22.7% of the patients versus 12.2% in the Aubagio group), namely high levels of ALT. According to Kappos, these alterations were free of symptoms and usually resolving.
A closer look at specific side effects expected for S1P receptor modulators revealed that heart-related side effects in ponesimod users were successfully minimized by the dose-escalation period, and did not result in any significant reactions nor were a reason for treatment discontinuation, Kappos noted.
In a Janssen press release about the trial results, Kappos said: “This is the first large controlled head-to-head study comparing two oral compounds for the treatment of relapsing MS.”
“We saw superiority of the investigational agent ponesimod when compared to teriflunomide across the primary and most secondary endpoints. These data, in conjunction with the observed safety profile, underline the potential of ponesimod as a new treatment option for MS,” he concluded.
According to Janssen, data from the OPTIMUM trial will serve as the basis for regulatory submissions to the U.S. Food and Drug Administration and European Medicines Agency seeking approval of ponesimod as a treatment for relapsing forms of MS.