Ponesimod shows promise in relapsing MS

Ponesimod, a highly selective sphingosine-1-phosphate receptor 1 modulator, demonstrated superiority over teriflunomide in reducing relapse rate, fatigue, and active lesions in patients with relapsing multiple sclerosis (RMS), results of the phase III OPTIMUM* trial showed.

In this multicentre, double-blind, superiority trial, 1,133 patients aged 18–55 years (median age 37 years, 64.9 percent female) with RMS, Expanded Disability Status Scale score 0–5.5, and recent clinical or magnetic resonance imaging (MRI) were randomized 1:1 to receive once-daily doses of ponesimod (20 mg, gradually up-titrated from 2 mg over 14 days) or teriflunomide (14 mg) plus placebos for 108 weeks.

Baseline characteristics were generally similar between groups, though enhancing lesions were more common in the teriflunomide than the ponesimod group (45.4 percent vs 39.9 percent). About 35 percent of patients had highly active disease.

Ponesimod reduced annualized relapse rate (ARR; between randomization and end of follow-up) by 30.5 percent compared with teriflunomide (mean ARR; 0.202 vs 0.290; rate ratio [RR], 0.695; p<0.001). [JAMA Neurol 2021;doi:10.1001/jamaneurol.2021.0405]

Patients on ponesimod also experienced a 56 percent relative risk reduction in MRI-confirmed combined unique active lesions per year compared with those on teriflunomide at week 108 (mean 1.405 vs 3.164; RR, 0.444; p<0.001).

There was a significant reduction in fatigue-associated symptoms according to the symptom domain of the Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ–RMS) at week 108 with ponesimod vs teriflunomide (least-square [LS] means, -0.01 vs 3.56; mean difference, -3.57; p=0.002).

However, the reduction in time to 12-week and 24-week confirmed disability accumulation (CDA) did not significantly differ between the ponesimod and teriflunomide groups (10.1 percent vs 12.4 percent; hazard ratio [HR], 0.83; p=0.29 [12 weeks] and 8.1 percent vs 9.9 percent; HR, 0.84; p=0.37 [24 weeks]).

The authors suggested that the low level of disability in the study population and the low number of CDA events at 12 weeks may have reduced the likelihood of identifying a between-group difference.

At week 108, brain volume loss was significantly reduced with ponesimod vs teriflunomide (LS mean change, -0.91 percent vs -1.25 percent; mean difference, 0.34 percentage points, p_exploratory<0.001). Likelihood of achieving NEDA**-3 and NEDA-4 status at study end was more likely with those on ponesimod than teriflunomide (25.0 percent vs 16.4 percent; odds ratio [OR], 1.70; p<0.001 [NEDA-3] and 11.4 percent vs 6.5 percent; OR, 1.85; p=0.003 [NEDA-4]).

Treatment-emergent adverse events (TEAEs) occurred at a comparable rate between the ponesimod and teriflunomide groups (88.8 percent vs 88.2 percent), as did serious TEAEs (8.7 percent vs 8.1 percent).

The most common TEAEs (≥10 percent in either group) in the ponesimod vs teriflunomide groups were increased alanine aminotransferase levels (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).

There were more frequent AE-related discontinuations among ponesimod than teriflunomide recipients (8.7 percent vs 6.0 percent). Two teriflunomide recipients died, though neither death was deemed related to study drug. Discontinuations for efficacy reasons were more common in the teriflunomide than ponesimod group (4.3 percent vs 1.9 percent).

First-dose heart rate and rhythm AE of special interest (AESI) on day 1 of up-titration or treatment re-initiation occurred in 12 and two patients in the ponesimod and teriflunomide groups, respectively, though none were serious or led to treatment discontinuation. The most common AESIs in the ponesimod vs teriflunomide group were hepatobiliary disorders or liver enzyme abnormalities (22.7 percent vs 12.2 percent), hypertension (10.1 percent vs 9.0 percent), pulmonary events (8.0 percent vs 2.7 percent), and herpetic infection (4.8 percent in each group). Two ponesimod and four teriflunomide recipients experienced serious hepatobiliary disorder or liver enzyme abnormality AESIs.

A new treatment on the horizon?

“Oral disease-modifying therapy (DMT) options such as teriflunomide, fingolimod, dimethyl fumarate, and siponimod have broadened disease management options in MS. [However,] there is still an unmet need for effective, safe, and convenient treatments that can be used early in the disease course,” noted the researchers.

“OPTIMUM … showed that ponesimod is superior to teriflunomide, an approved oral DMT, on … ARR and … MRI activity and fatigue,” they said.

“Together, the effect of ponesimod on fatigue and the reduction of brain volume loss, shown against a drug with an established effect on brain volume loss, suggests that ponesimod’s benefits are not restricted to suppressing relapses and focal lesions reflecting short-term events in the pathogenesis of MS but extend to the prevention of tissue damage accumulation,” they continued.

Additionally, ponesimod is rapidly eliminated and its effects on lymphocyte levels reversible, which enables fast recovery of immune system function, the researchers pointed out.