番茄社区

STOCKHOLM -- Ponesimod, an investigational selective sphingosine-1-phosphate receptor 1 (S1P1) modulator, bested teriflunomide (Aubagio) in a head-to-head trial of adult relapsing multiple sclerosis (MS) patients, researchers for the reported here.

Compared with teriflunomide -- an approved first-line oral MS drug -- oral ponesimod reduced annual relapse rate (ARR) by 30.5% over about 2 years, according to Ludwig Kappos, MD, of University Hospital of Basel in Switzerland, and co-authors, in a presentation at the 2019 ECTRIMS Congress. At 108 weeks, ponesimod 20 mg had an ARR of 0.202, compared with an ARR for teriflunomide 14 mg of 0.290 (P=0.0003).

"This is the first head-to-head study comparing a new compound with one of the oral drugs," Kappos said in an interview with 番茄社区. Comparative studies had been conducted in the past with injectable MS drugs, he noted, but this trial aims to place ponesimod within the spectrum of the oral drugs, "which are getting to be, more and more, the standard treatment."

Ponesimod is a selective modulator of the sphingosine-1 phosphate receptor, like fingolimod (Gilenya) and siponimod (Mayzent). Binding of the drug to the receptor lowers the number of circulating lymphocytes by trapping them in the lymph nodes, reducing the number of lymphocytes that could enter the central nervous system and damage myelin.

Fingolimod, which was approved by the FDA in 2010, requires on-site patient monitoring for signs and symptoms of bradycardia for at least 6 hours after the first dose is administered. In contrast to the long half-life of fingolimod, and its pharmacological effects are rapidly reversible.

"With the new compounds after fingolimod, you still see cardiac side effects, but the difference is that you can do a dose titration scheme," said Tobias Derfuss, MD, also of the University Hospital Basel, who was not part of the OPTIMUM trial. "With the new drugs, you do an up-titration," he said; in the U.S., for example, patients who have healthy hearts don't need to be monitored for 6 hours after their first dose of siponimod.

"From the data, it would make sense that you see less cardiac side effects with ponesimod than with fingolimod at the start of the dosing," Derfuss added. "That is an advantage: the side effect profile [of ponesimod] is better."

OPTIMUM compared the efficacy and safety of ponesimod with teriflunomide in 1,133 adult patients with relapsing MS at 162 sites in 28 countries. The average age of participants was about 37; 65% were female, and 51% were from EU countries.

At baseline, the mean Expanded Disability Status Scale (EDSS) score was about 2.6 (indicating mild disability on the of 1 to 10), and the average disease duration was 7.6 years. The mean pre-study 12-month relapse rate was 1.3, and 483 patients (42.7%) had one or more gadolinium-enhancing T1 lesions on baseline MRI.

The OPTIMUM researchers randomized patients 1:1 to receive either ponesimod 20 mg or teriflunomide 14 mg once daily for 108 weeks. Ponesimod treatment started at 2 mg once daily and was titrated up for 14 days to mitigate potential cardiac effects.

In addition to meeting the study's primary endpoint of a significant reduction in ARR at 108 weeks, ponesimod reduced the number of new inflammatory lesions on MRI by 56% compared with teriflunomide (P>0.0001). At 12 and 24 weeks, the confirmed disability accumulation, measured as change in EDSS, was not significantly different between the two groups.

Ponesimod also showed effects on fatigue based on a -- the Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis -- compared with teriflunomide (mean difference -3.57, P=0.0019) at 108 weeks.

Common adverse events included hepatobiliary disorders and liver enzyme abnormalities, hypertension, and pulmonary events. Most liver enzyme increases were single transient asymptomatic episodes that resolved when treatment was discontinued.

Data from the OPTIMUM study will be used to support regulatory filings for ponesimod in the U.S. and Europe, a spokesperson for Johnson & Johnson said. Submissions to the FDA and the European Medicines Agency are expected later this year.