The phase III OPTIMUM (Oral Ponesimod Versus Teriflunomide In Relapsing Multiple Sclerosis) study shows that ponesimod is superior to teriflunomide in reducing annualized relapse rate (ARR), fatigue, MRI activity, and brain volume loss in relapsing multiple sclerosis (RMS).

“Although oral disease-modifying therapies [DMTs] such as teriflunomide, fingolimod, dimethyl fumarate and siponimod represent significant progress in MS treatment, there is still an unmet need for effective, safe and convenient treatments that can be used early in the disease course. Yet head-to-head comparative trials to inform choices among the numerous oral treatments are still lacking,” wrote the researchers. [Lancet Neurol 2014;13:247-256; N Engl J Med 2010;362:387-401; N Engl J Med 2012;367:1098-1107; Lancet Neurol 2020;19:336-347] “OPTIMUM, to our knowledge, is the first phase III global superiority study comparing efficacy and safety of two oral DMTs in RMS.”

In OPTIMUM, 1,133 adult patients aged 18–55 years (median age, 37 years) with RMS were randomized to receive 20 mg of ponesimod (n=567), an orally active, highly selective modulator of the sphingosine-1-phosphate receptor 1 (S1P1), or 14 mg of teriflunomide (n=566) once daily, for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg to mitigate first-dose cardiac effects of S1P1 modulators and a follow-up period of 30 days. [JAMA Neurol 2021;doi:10.1001/jamaneurol.2021.0405]

In total, 242 confirmed relapses were reported in the ponesimod arm vs 344 in the teriflunomide arm. Ponesimod reduced the primary endpoint of ARR by 30.5 percent vs teriflunomide (mean ARR, 0.202 vs 0.290; rate ratio, 0.695; 99 percent confidence limits, 0.536 to 0.902; p<0.001).

Superiority vs teriflunomide was also shown in the analysis of two key secondary outcomes: reduction of combined unique active lesions, an established MRI measure of focal inflammatory disease activity (−56 percent), and improvement of MS-associated fatigue, as measured by Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis weekly symptom score (mean difference, −3.57). [J Neurol 2005;252(Suppl 5):v46-v53]

“Despite the well-known negative implications on quality of life and the high socioeconomic burden associated with fatigue, no previous phase III study in MS has addressed fatigue prospectively as a key outcome,” highlighted the researchers. [Neurophysiol Clin 2017;47:139-171]

Overall, the proportion of patients who experienced ≥1 treatment-emergent adverse event (TEAE) was similar between the ponesimod and teriflunomide groups (88.8 percent vs 88.2 percent). The most common TEAEs (≥10 percent in either group) were increased alanine aminotransferase level (19.5 percent vs 9.4 percent), nasopharyngitis (19.3 percent vs 16.8 percent), headache (11.5 percent vs 12.7 percent), upper respiratory tract infection (10.6 percent vs 10.4 percent), and alopecia (3.2 percent vs 12.7 percent).

Treatment discontinuation rates were similar in the two treatment groups. “More patients in the teriflunomide group discontinued treatment because of efficacy, consistent with the greater benefit of ponesimod observed across multiple efficacy endpoints. Discontinuations attributable to adverse events or tolerability were more frequent in the ponesimod group,” noted the researchers.

Dalam analisis eksplorasi yang direncanakan sebelumnya dari perubahan volume otak setelah 2 tahun penelitian, pasien yang menggunakan ponesimod ditemukan memiliki lebih sedikit kehilangan volume otak dibandingkan mereka yang menerima teriflunomide (perbedaan, 0,34 persen). “Manfaat Ponesimod dalam hal kelelahan dan kehilangan volume otak, yang ditunjukkan melawan obat dengan efek yang mapan pada kehilangan volume otak, menunjukkan bahwa manfaat ponesimod tidak terbatas untuk menekan kekambuhan dan lesi fokal dalam patogenesis MS, tetapi meluas ke pencegahan akumulasi kerusakan jaringan, ”para peneliti menyimpulkan.