OPTIMUM

Ponesimod

OPTIMUM was the first phase III trial to compare two oral MS therapies directly, showing superior relapse and MRI control with ponesimod versus teriflunomide.

Phase: Phase III
Population: Relapsing multiple sclerosis (RMS)
Controlled period: Jun 4, 2015 — May 16, 2019

What was compared

Randomized 1:1Double-blindDouble-dummyOral active comparator

Intervention

Ponesimod

20 mg orally once daily after 14-day up-titration

n=567

Comparator

Teriflunomide

14 mg orally once daily

n=566

1,133 randomized participants108 weeks controlled phase

Primary endpoint

Prespecified outcome

Annualized relapse rate

108 weeks

Outcome figure

Primary endpoint results

Intervention Comparator or reference

Annualized relapse rate

Relapses per participant-year

108 weeks

Ponesimod

0.202

Teriflunomide

0.290

30.5% relative rate reduction with ponesimod (P<0.001).

Selected secondary outcomes

Combined unique active MRI lesions

56% lower with ponesimod (1.405 versus 3.164 per year; P<0.001).

Confirmed disability accumulation

12- and 24-week disability outcomes did not differ significantly.

Who was studied

Key inclusion criteria

RMS diagnosis based on McDonald criteria 2010
Recent clinical attack or gadolinium-enhancing MRI activity
Ambulatory, with EDSS no higher than 5.5

Key exclusion criteria

Clinically important cardiovascular, pulmonary, immune, hepatic, or ophthalmic conditions
Pregnancy or breastfeeding
MRI contraindication or another condition creating unacceptable study risk

Participants at baseline

Characteristic	Ponesimod 20 mgN=567	Teriflunomide 14 mgN=566
Age, years — mean ± SD	36.7 ± 8.74	36.8 ± 8.74
Female sex — n (%)	363 (64.0%)	372 (65.7%)
Time since MS symptom onset, years — mean ± SD	7.63 ± 6.78	7.65 ± 6.78
EDSS — mean ± SD	2.57 ± 1.17	2.56 ± 1.23
Relapses in the previous year — mean ± SD	1.2 ± 0.61	1.3 ± 0.65
DMT use within 2 years before randomization — n (%)	213 (38%)	211 (37%)

SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy.

Source: Kappos et al., JAMA Neurology 2021, Table 1

Safety signal

Overall treatment-emergent and serious adverse-event rates were similar between groups.
ALT elevation occurred in 19.5% with ponesimod versus 9.4% with teriflunomide; dyspnea occurred in 5.3% versus 1.2%.
Adverse-event discontinuation was more frequent with ponesimod: 8.7% versus 6.0%.

Why it mattered

OPTIMUM compared two oral treatments directly, showing ponesimod’s advantage over teriflunomide for relapses, fatigue symptoms, and MRI activity. It offered evidence for choosing between oral mechanisms, while neither confirmed-disability endpoint established superiority.

Important limitation

Superiority was demonstrated for relapse, fatigue, and MRI outcomes—not for confirmed disability accumulation during the controlled period.