The development of oral disease modifying therapies (DMTs) for multiple sclerosis (MS) had significant impact on MS management for both patients and clinicians, but only recently have data matured sufficiently to allow analysis of long-term efficacy and safety.
A series of posters presented at the CMSC 2020 virtual meeting provided some insight into those durability issues, including long term immune cell changes, cognitive function over five years, and the utility of disability subscale measures.
Yang Maro-Draayer, MD, PhD, of the Autoimmunity Center of Excellence, Multiple Sclerosis Center, University of Michigan, Ann Arbor, and colleagues searched for changes in immune cell profiles of relapsing MS patients treated with fingolimod in the FLUENT Study.
In their poster, they sought to characterize “immune cell changes in relation to patient outcomes,” comparing patients who were fingolimod naive (cohort 1) to those who were taking fingolimod for at least 2 years (cohort 2).
The trial was a “12-month, prospective, multicenter, nonrandomized phase IV study in adults with relapsing MS receiving fingolimod 0.5 mg/day… The primary outcome was change from baseline in immune cell subsets. Secondary outcomes included anti-John Cunningham virus (JCV) antibody status, neurofilament light-chain (NfL) concentrations, Patient-Determined Disease Steps (PDDS) and incidence of adverse events (AEs).”
Among the findings:
- The 163 fingolimod naive patients (cohort 1) had higher baseline proportions of CD4+ T cells, CD8+ T cells, and B cells than the 217 cohort 2 patients.
- Compared to baseline, at 12 months, immune subsets were “substantially reduced” in cohort 1 “with naive and central memory T cells affected more than effector memory T cells and regulatory B cells.”
- There were fewer pronounced changes in those subsets among cohort 2 patients.
- 54% of cohort 1 patients and 64% of cohort 2 patients were anti-JCV positive at baseline, which was unchanged at 12 months.
“Mean (standard deviation) NfL concentration in Cohort 1 was 12.16 (11.05) pgmL at baseline and 8.57 (5.32) at month 12; Nfl concentrations in Cohort 2 were similar at baseline (9.59 [7.55]) and month 12 (9.78 [8.88]),” they wrote. “Baseline PDDS scores were low (Cohort 1, 1.7; Cohort 2, 1.8) and unchanged at month 12. Respective rates of treatment-emergent AEs (54.6% versus 44.2%) and AEs leading to treatment discontinuation (12.3% versus 5.5%) were higher in Cohort 1 than Cohort 2; rates of serious AEs (5.5% versus 5.5%) were similar between cohorts.”
The take-home? Treatment with fingolimod is associated with “temporal changes in immune cell profiles and biomarkers.”
A team of researchers from Turkey, led by Serkan Ozakhas, MD, of the Department of Neurology, Dokuz Eylul University, Izmir, and colleagues looked into cognitive function in MS patients treated for five years with DMTs. A previously published study from these investigators reported that the prevalence of cognitive impairment in a sample of 487 patients with relapsing-remitting MS (RRMS) was 53.7%.
In their CMSC 2020 poster, they assessed cognitive function in 756 patients treated with DMTs for five years.
The breakdown of therapies was:
- Interferon beta (1b or 1a, SC) (n=342).
- Glatiramer acetate (GA) (n=188).
- Fingolimod (n=226).
They noted that fingolimod patients were older than patients in the other two groups, and that difference was significant (P <0.05).
The researchers used the expanded disability status scale (EDSS) to assess physical disability, and for cognitive assessment they used the Brief International Cognitive Assessment for MS (BICAMS), “which included the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-II (CVLT-II) and the Brief Visuospatial Memory Test-Revised (BVMT- R),” they wrote. Starting at baseline, they performed annual assessments through year five.
The treatment retention rate at five years was significantly better (P<0.05) with fingolimod at 85% versus 79% for GA and 78.9% for interferon beta.
“Cognition improved in some patient (fingolimod: 11.2%, interferons: 9.6%, GA: 8%, P>0.05). More than 80% of patients remained stable or improved. The most significant improvement was observed in SDMT, and it was significantly higher than CVLT-II, and BVMT-R (30.7%, 18.6%, 17%, respectively, P=0.02),” they wrote.
The authors concluded that there was no decrease in cognitive function related to 5 years of DMT therapy, and there was no “relationship with the type of medication. Furthermore, SDMT seems to be the best predictor for cognitive change in time.”
Finally, Gary Cutter, MD, of the School of Public Health at the University of Alabama, Birmingham and colleagues sought to determine if use of subscales of the EDSS could tease out subtle differences between fingolimod and siponimod in patients with RRMS and secondary progressive MS (SPMS).
First, “PROC FACTOR procedure was used to determine best fit of baseline EDSS data to the following subscales: Motor Integration (MI: ambulation, cerebellar and pyramidal functions) and Collateral (C: bowel and bladder, brainstem, cerebral, sensory and visual functions).”
Treatment effect size in FREEDOMS (425 fingolimod/ 418 placebo) “at 24 months were −0.14, P=0.002 (EDSS); −0.18, P=0.002 (MI); −0.07, P=0.081 (C). Significant effects (P<0.05) were seen on MI from M6; effects on C were mostly nonsignificant. In EXPAND (n=1645: siponimod, n=1099; placebo, n=546), overall treatment effects were detected over 27M for EDSS (P=0.020), MI (p=0.014) and C (P=0.021). Significant ES were seen on MI (all P<0.01) at M9 (−0.28), 15 (−0.34) and 18 (−0.34), and on C at M18 (−0.24, P<0.05) and 27 (−0.54, P<0.001).”
Cutter et al concluded that treating RRMS patients with fingolimod mainly impacted the MI subscale; meanwhile, the SPMS patients treated with siponimod demonstrated an effect in both MI and C, with the MI effect appearing earlier, but the “largest [effect size] was seen later on C.”
Assessing long-term outcomes of patients on DMT therapy did not reveal any safety signals.
Note that five years of DMT therapy appeared to slow cognitive impairment in most patients.
Peggy Peck, Editor-in-Chief, BreakingMED™
Mae-Draayer reported consultant fees and contracted research fees from Acorda, Bayer, Biogen, Celgene, EMD Serono, Genentech, Teva Chugai, Novartis, Sanofi-Genzyme, NIAID Autoimmune Center of Excellence, and NIH NINDS.
Ozakbas had no disclosures.
Cutter disclosed protocol review committee work for Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, CSL Behring, Galmed Pharmaceuticals, Hisun Pharmaceuticals, Horizon Pharmaceuticals, Merck, Merck/Pfizer, Neurim, and NHLBI. He served on data safety monitoring board for Ophazyme, Opko Biologics, Reata Pharmaceuticals, Receptos/Celgene, Sanofi-Aventis, Teva Pharmaceuticals, and Vivus. He also received consulting fees from Biogen, Click Therapeutics, Genentech, Genzyme, Gilgamesh Pharmaceuticals, GW Pharmaceuticals, Klein-Buendel Incorporated, MedDay, MedImmune, Osmotica Pharmaceuticals, Perception Neurosciences, Recursion Pharmaceuticals, Roche, Somahlution, TG Therapeutics (consulting fee). Novartis and is president of Pythagoras, Inc. He also receives a salary from the University of Alabama.
Cat ID: 36
Topic ID: 82,36,730,36,764,192,925,763