Effects generally greater among relapsing than non-relapsing patients in EXPAND trial

The effects of siponimod (Mayzent) in secondary progressive multiple sclerosis (SPMS) were detected earlier in walking, coordination, and motor function than in other areas of disability, an analysis of EXPAND trial data showed.

Two new Expanded Disability Status Scale (EDSS) subscales — Motor Integration (walking and cerebellar/pyramidal integration) and Collateral (bowel and bladder, brainstem, cerebral, sensory and visual functions) — were derived from EXPAND data using factor analysis, said Gary Cutter, PhD, of the University of Alabama at Birmingham School of Public Health, and co-authors.

In patients with SPMS, effects of siponimod on EDSS disability manifested earlier in the Motor Integration subscale than in the Collateral subscale, they reported. Their analysis was presented as part the American Academy of Neurology (AAN) 2020 Science Highlights that featured research scheduled for presentation at the cancelled AAN annual meeting.

“EDSS assesses eight functional outcomes,” Cutter said. “Sustained disability may be associated with greater worsening in some functional systems than in others.”

Measuring disability in MS, and in MS drug trials in particular, can be complex, noted Florian Thomas, MD, PhD, of Hackensack Meridian School of Medicine at Seton Hall University in Hackensack, New Jersey, who was not involved with the study.

“EDSS is a composite score of disability in MS, originally developed in 1955,” Thomas said. “Scores are based on assessment of eight functional systems such as bowel/bladder, speech/swallow, cognition, vision, motor, sensation, coordination, and ambulation.

“This analysis of the siponimod trial shows that a newly-developed EDSS subscale — dubbed Motor Integration and consisting just of the functional systems ambulation, coordination, and motor function — was best suited to show drug benefit on retarding disease progression,” he added.

In the phase III EXPAND trial, siponimod 2 mg/day reduced confirmed overall EDSS score disability progression up to 36 months in patients with SPMS. The study showed 26% of patients treated with siponimod versus 32% in the placebo group had 3-month confirmed disability progression (relative risk reduction 21%; HR 0.79, 95% CI 0.65-0.95). Based on EXPAND data, the FDA approved siponimod in 2019 for clinically isolated syndrome, relapsing remitting MS, and SPMS.

The new analysis considered more detailed information from the two developed EDSS subscales using data from 1,645 EXPAND participants (siponimod, n=1099; placebo, n=546). The researchers assigned each of the eight EDSS functions to either the Motor Integration or Collateral subscale. Each was used only once based on the highest loading factor, where factor loading can be interpreted a similar manner to standard regression coefficients.

“We re-analyzed the functional systems scores using factor analysis, which tries to explain the variability seen in the data by taking linear combinations of the full scale scores for one score, then reuses the full scale score to create another score that is independent of the first,” Cutter explained. “It keeps going until a sufficient amount of the variability has been explained; usually this is one with one, two, or three factors, if the data can be reduced to simpler scores.”

The overall variance for Motor Integration and Collateral subscales was 55.2% and 44.8%, respectively. With the subscales in place, the researchers assessed change from baseline up to 36 months, calculating effect sizes (ES) every 3 months using mean treatment differences.

They conducted analyses for the overall EXPAND population and for subgroups of patients with and without relapses during 24 months before enrollment, and of patients with and without gadolinium-enhancing (Gd+) lesions at baseline.

Treatment effects were detected over 36 months for EDSS (P=0.020) and both subscales (Motor Integration: P = 0.014; Collateral: P = 0.021). Effect sizes favoring siponimod were observed from 6 months onwards.

At 9 months, the Motor Integration subscale showed effect sizes in all patients (ES 0.12; P=0.007), and also in subgroups with recent relapse (ES 0.25; P = 0.009) and without enhancing lesions (ES 0.13; P = 0.012). By 12 months, Motor Integration subscale effects were also seen in those with enhancing lesions (ES 0.22; P = 0.041).

At 15 months, the Collateral subscale showed ES for those with recent relapse (ES 0.19; P < 0.05) By month 27, Collateral subscale effects were seen for those with (ES 0.43; P < 0.05) and without enhancing lesions (ES 0.29; P < 0.05).

The findings are consistent with earlier EDSS subscale analyses of fingolimod data and “confirm the efficacy of siponimod on disability progression in patients with SPMS,” the researchers noted.

“Irrespective of the presence of inflammatory disease, treatment effects on disability favored siponimod over placebo,” they added. “They were generally larger among relapsing than non-relapsing patients, and among those with, than those without, baseline Gd+ lesion activity.”

“Factor analysis may help to define EDSS subscales with more clinical utility than subscales defined by other methods,” Cutter noted. “Subscales are likely to be easier for clinicians to administer routinely than the whole EDSS assessment.”

  1. Effects of siponimod (Mayzent) in secondary progressive multiple sclerosis (SPMS) were detected earlier in walking, coordination, and motor function than in other areas of disability, an analysis of EXPAND trial data showed.

  2. Findings are based on factor analysis of EXPAND trial data prepared for the American Academy of Neurology meeting. Be aware that they have not been peer-reviewed.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was funded by Novartis.

Cutter has received personal compensation from AMO Pharma, Argenix, Atara Bio-therapeutics, Axon, Biogen, BioLineRx, Bio-therapeutics, Brainstorm Cell Therapeutics, Charleston Laboratories, Inc., Click Therapeutics, Genentech, Genzyme, GW Pharma, Horizon Pharmaceuticals, Klein Buendel Inc., MedDay, MedImmune, Merck, Merck/Pfizer, Neurim, Novartis OPKO Biologics, Orphazyme, Pythagoras, Inc, Reata Pharmaceuticals, Receptos/ Celgene, Sanofi- Aventis, Roche, SciFluor, Somahlution, Teva Pharma-ceuticals, TG Therapeutics, and UTHealth Houston Teva Neuroscience.

Thomas serves on speakers’ bureaus for Genentech, Novartis, and Sanofi, and is a consultant for Greenwich Biosciences, Pharnext, and Acceleron.

Cat ID: 131

Topic ID: 82,131,730,131,36,192,167