OPTIMUM Phase 3 Trial for Multiple Sclerosis Nearing Completion

A phase 3 multi-center, randomized, double-blind, parallel group, active-controlled superiority study assessing oral ponesimod versus teriflunomide (Aubagio) in relapsing multiple sclerosis (MS) (OPTIMUM) is nearing its estimated primary completion date of April 17, 2019.

The 1100-patient study, which kicked off in June 2015, is a comparison of the efficacy and safety of once-daily 20 mg ponesimod and 14 mg teriflunomide. The primary outcome measure is annualized relapse rate (ARR) with secondary outcome measures of time to 12-week confirmed disability accumulation (CDA), percent change in brain volume (PCBV), time to first confirmed relapse, cumulative number of combined unique active lesions (CUAL), and change from baseline to week 108 in fatigue-related symptoms.

Ponesimod is an orally active, selective sphingosine-1-phosphate receptor 1 (S1P₁) immunomodulator which prevents lymphocytes from leaving lymph nodes, thus rapidly reducing circulating blood lymphocyte counts and preventing infiltration of lymphocytes into target tissues. In a double-blind, placebo-controlled, dose-finding phase 2b study evaluating ponesimod, study author Tomas Olsson, MD, PhD, and colleagues found that ponesimod 10, 20, or 40 mg was well-tolerated and significantly reduced the number of new T1 Gd+ lesions at weeks 12-24 of the 24-week trial.

Analysis of pharmacokinetics revealed that ponesimod has a favorable safety profile that allows for maximizing its ability to inhibit circulating lymphocytes in a given dosing regimen. It can be sustained with continued dosing, and with its short half-life, is rapidly eliminated upon discontinuation.

"Our clinical development program for ponesimod in multiple sclerosis was already innovative when we decided to move into phase 3,” Guy Braunstein, MD and Head of Global Clinical Development at Actelion Ltd., said in a statement. “OPTIMUM is the first study in MS to target superiority over a commercialized oral therapy. It also includes a number of patient-oriented outcome assessments."

Actelion is also sponsoring a second phase 3 trial with ponesimod, the multicenter, randomized, double-blind, parallel-group, add-on, superiority study (POINT). An ongoing trial with an estimated completion date of March 2020, POINT compares the efficacy, safety, and tolerability of therapy with 20 mg ponesimod vs placebo, in an estimated enrollment of 600 subjects with active RMS who are treated with twice-daily dimethyl fumarate (Tecfidera).

"I have always believed that combination therapy is the future for the treatment of relapsing multiple sclerosis,” Jean-Paul Clozel, MD and Chief Executive Officer of Actelion, said in a statement. “The properties of ponesimod, supported by our preclinical knowledge and clinical results, all point towards ponesimod being ideally suited for use in combination.”

The primary outcome measure of POINT is the confirmed relapses per subject-year as compared to placebo. Secondary outcome measures include CDA, time to first confirmed relapse, CUALs per post-baseline scan, longitudinal change over time in fatigue-related symptoms as measured by the symptoms domain of the FSIQ-RMS, and longitudinal percent change from baseline over time in brain volume. Treatment adverse events (AE) and serious AEs will also be recorded.

“With POINT, the first trial in active RMS adding one oral drug to another, we will assess the clinical utility of combination therapy with ponesimod, to offer patients better control of their disease,” said Braunstein.

Details and updates to the trial, “Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM),” can be found here.