Promising Phase 3 Results With New Oral MS Drug Ponesimod

October 03, 2019

A new oral drug for relapsing remitting multiple sclerosis — ponesimod (Actelion Pharmaceuticals) — has shown promising results in a phase 3 trial vs the active comparator, teriflunomide (Aubagio, Genzyme/Sanofi).

Ponesimod showed significant reductions in relapse rate, new active lesions, and fatigue-related symptoms vs teriflunomide in the OPTIMUM trial, presented at the recent 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019.

"Ponesimod showed a reassuring and benign safety profile and should be a valuable addition to the armamentarium for relapsing remitting MS," lead investigator Ludwig Kappos, MD, University Hospital Basel, Switzerland, concluded.

Ponesimod is in the same class of drugs as fingolimod, sphingosine-1-phosphate (S1P) receptor modulators, but whereas fingolimod targets several different S1P receptors, ponesimod is selective for the S1P1 receptor, the key S1P receptor involved in lymphocyte trafficking, Kappos explained.  

He described ponesimod as "a selective S1P1 receptor modulator with rapidly revisable pharmacokinetic profile and low drug interaction potential."

He pointed out that ponesimod had a short half-life (being eliminated within a week of stopping treatment), and has no active metabolites, which allows rapid reversibility — important in certain clinical situations such as infections, vaccinations, and drug sequencing. Its use is also associated with functional preservation of specific T-cell and B-cell subsets, which allows continued immune surveillance despite reduced circulating lymphocyte levels, he added.  

Asked how the side-effect profile compared with fingolimod, Kappos replied that it was difficult to compare across trials but "the overall profile appears more positive regarding cardiac side effects vs fingolimod. Specifically addressing S1P1 may not show immediate consequences but the cleaner pharmacological approach may help us to understand which receptors we need to modulate over the long term."

One Receptor

Commenting for Medscape Medical News, Finn Sellebjerg, MD, PhD, Danish Multiple Sclerosis Center, University of Copenhagen, Denmark, and cochair of the ECTRIMS session at which the OPTIMUM trial was presented, said: "This trial confirms that S1P1 modulators are efficacious in MS. Maybe that is not surprising, but it is comforting to see that when the activity is restricted to one receptor targeted by the other S1P compounds then you still have good efficacy."

"It is known that the S1P1 receptor mediates the lymphocyte effects. Fingolimod targets four different S1P receptors. Siponimod targets two of them and here we have a drug that just targets one of these receptors," Sellebjerg noted. "The question is whether you need any of the other receptors to be targeted as well as the S1P1. This study suggests that it still has good efficacy just targeting this one receptor.

"While the safety seems reasonable, it looks quite similar to the other S1P drugs, suggesting that the efficacy and side effects appear to be mediated by the same receptor. We would have hoped to see fewer side effects with a more selective drug like this."

Sellebjerg thought it was interesting that the OPTIMUM study compared the new drug against a current first-line therapy. "The major question for me is whether it will come out as a new first-line therapy when it becomes marketed or if it will be a second-line therapy. Fingolimod is second-line in Europe (which is different from the US). It would be interesting to see something that may have a higher efficacy as a first-line drug."


In the OPTIMUM trial, 1133 patients with relapsing-remitting MS were randomly assigned to receive either ponesimod 20 mg or teriflunomide 14 mg once daily for 108 weeks (2 years, 1 month). Ponesimod was gradually up-titrated over 14 days starting with a 2 mg once-daily dose to mitigate potential effects on heart rate associated with S1P-receptor modulators.

Patients had an average of 7 years' disease duration at baseline, and 40% had received prior disease-modifying treatment. Mean baseline Expanded Disability Status Scale score was 2.6 and mean disease duration 7.6 years. Mean pre-study 12-month relapse rate was 1.3, and 43% of patients had one or more gadolinium-enhancing T1 lesions on baseline MRI.

The primary endpoint of the study — annualized relapse rate over 108 weeks — was significantly reduced by 30% with ponesimod vs teriflunomide (0.202 vs 0.290; rate ratio 0.695, P = .0003).

The OPTIMUM study is the first study to include a validated disease-specific fatigue measure, the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS), as a prespecified secondary endpoint, Kappos noted.

This showed a significant reduction in fatigue symptoms with ponesimod vs teriflunomide (mean FSIQ-RMS score -3.57; P = .0019)

Combined active lesions (new Gd+T1 plus new or enlarging T2 lesions) were reduced by 56% with ponesimod (1.4 vs 3.16; P < .0001).

When looking at disability, 12-week and 24-week confirmed disability risk estimates were 17% and 16% lower, respectively, for ponesimod compared with teriflunomide, but these differences did not reach statistical significance.

In terms of safety, the proportion of patients experiencing at least one treatment emergent adverse event or serious adverse event was similar in the two groups. 

Adverse events leading to premature discontinuation occurred in 8% of ponesimod patients vs 6% of those who received teriflunomide. Most common adverse events of interest in the ponesimod group were hepatobiliary/liver enzyme abnormalities (seen in 22% of patients), hypertension (10%), and pulmonary events (8%). Effects on heart rhythm or hypotension occurred in 2% of ponesimod patients.

The OPTIMUM trial was supported by Actelion Pharmaceuticals. Kappos has received steering committee, advisory board, and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, sanofi-aventis, Santhera, Teva, Vianex and license fees for Neurostatus-UHB products. All fees have been used for research support at the University Hospital Basel. Several coauthors of the study are employees of Actelion Pharmaceuticals. 

35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2019: Abstract 93. Presented September 11, 2019.

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