New data suggest halving the FDA-approved 0.5-mg dose of fingolimod (Gilenya, Novartis) is not as effective as either the higher dose or glatiramer acetate in the treatment of relapsing-remitting multiple sclerosis (RRMS).
Investigators compared two doses of fingolimod — 0.5 mg, the current approved dose, and 0.25 mg — to each other and to 20 mg of glatiramer acetate and found 0.5 mg of fingolimod was superior to both in reducing the annualized relapse rate and brain lesion activity.
Treatment with a 0.25-mg dose of fingolimod, however, did not significantly reduce the annualized relapse rate compared with glatiramer acetate. Nevertheless, this lower dose of fingolimod did significantly reduce the number of new or enlarging T2 or gadolinium-enhancing lesions, compared with glatiramer acetate. Rates of adverse events appeared to be similar between both doses of fingolimod and glatiramer acetate.
“My interpretation of the data is that 0.25 mg fingolimod might have had certain fewer side effects, but not sufficiently different to warrant an indicated use of this dose. Moreover, the 0.25-mg dose was not as effective as 0.5 mg fingolimod with respect to glatiramer acetate,” study investigator Bruce A.C. Cree, MD, PhD, George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California, San Francisco, told Medscape Medical News.
The results suggest that the approved dose of fingolimod for the treatment of adults with RRMS is the optimal dose, Cree added. The TRANSFORMS and FREEDOMS clinical trials showed that the 1.25-mg dose was associated with more side effects and was no more effective than the 0.5-mg dose.
“Therefore, for treatment of adult patients with relapsing MS, the 0.5-mg dose of fingolimod is the correct dose, and further studies of other fingolimod doses are not needed,” said Cree.
“The most interesting result was the demonstration of superiority of fingolimod over 20 mg daily glatiramer acetate,” Cree told Medscape Medical News. “Several other MS medications, such as preparations of interferon beta, sought to demonstrate superiority over glatiramer acetate but did not succeed.”
Results of the MS Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) were published online August 24 in JAMA Neurology.
Commenting on the findings for Medscape Medical News, Lily Jung Henson, MD, CEO of Piedmont Henry Hospital in Stockbridge, Georgia, said the study confirms the understanding of the efficacy of both drugs in modifying MS.
Although she noted that the study’s 1-year follow-up period was relatively short, the patients were similar to those enrolled in the original trials that examined the drugs’ efficacies.
“We know that new or enlarging lesions occur more often than clinical relapses do, so the fact that the number of lesions is reduced, but not the annualized relapse rate, suggests that the response from 0.25 mg of fingolimod is just not as robust as the 0.5-mg dose,” Henson said.
Overall, the study “suggests that neurologists should not be halving the dose of fingolimod in the belief that they may be reducing the risks associated with using the drug, as the efficacy is also decreased.”
Fingolimod was the first oral medication approved for the treatment of patients with RRMS. The clinical trials that demonstrated the drug’s efficacy in lowering the annualized relapse rate examined doses of 5 mg, 1.25 mg, and 0.5 mg.
The results suggested that a dose lower than 0.5 mg also might be effective and have fewer associated adverse events. The US Food and Drug Administration (FDA) recommended that a lower dose be investigated, and researchers identified 0.25 mg as the lowest dose likely to be effective.
Cree and colleagues conducted the ASSESS study in response to the FDA’s recommendation. The phase 3b trial took place at 127 sites in North and South America. After a screening phase, the investigators randomly assigned participants in approximately equal groups to receive 0.5 mg/day of fingolimod, 0.25 mg/day of fingolimod, or 20 mg/day of glatiramer acetate.
Eligible participants were between ages 18 and 65 years, had RRMS, and had had at least one documented relapse during the previous year or two documented relapses during the previous 2 years. Participants’ Expanded Disability Status Scale (EDSS) scores were between 0 and 6.0, inclusive, and participants had not had a relapse within 30 days of being randomly assigned into a cohort.
The researchers’ goal was to demonstrate the superiority of at least one dose of fingolimod to glatiramer acetate for reducing annualized relapse rate. The trial’s secondary end points included the number of new or enlarging T2 lesions, the number of gadolinium-enhancing T1 lesions, the change from baseline in patients’ satisfaction with treatment (as measured by the Treatment Satisfaction Questionnaire for Medication), and safety and tolerability.
The researchers screened 1461 patients and included 1064 in their study. Participants’ mean age was 39.6 years. About 74% of the population were women, 74% were white, and 47% were treatment-naïve. Approximately 81% of participants completed the study.
Demographic and disease characteristics were similar between all three treatment groups. The dropout rate was higher in the glatiramer acetate group (25.7%) than in the fingolimod 0.5-mg group (14.8%) or the fingolimod 0.25-mg group (15.9%).
The 0.5-mg dose of fingolimod reduced annualized relapse rate by 40.7%, compared with glatiramer acetate. Annualized relapse rate was 0.15 for 0.5 mg fingolimod and 0.26 for glatiramer acetate.
The 0.25-mg dose of fingolimod reduced annualized relapse rate, compared with glatiramer acetate, but the difference was not statistically significant.
Annualized relapse rate was 0.22 for 0.25 mg fingolimod. Both fingolimod groups had longer time to first relapse, greater reduction in risk of confirmed relapse, and a higher proportion of participants who were relapse-free at month 12, compared with the glatiramer acetate group.
Both doses of fingolimod significantly reduced the number of new or enlarging T2 lesions, compared with glatiramer acetate. The reduction was 54% for the 0.5-mg dose and 42% for the 0.25-mg dose.
Both doses of fingolimod also reduced the number of gadolinium-enhancing T1 lesions by 56% at month 12. Although treatment satisfaction improved in all three groups, compared with baseline, improvement was twice as high in the fingolimod groups as it was in the glatiramer acetate group.
The rate of adverse events was similar between groups (90.4% in the 0.5 mg fingolimod group; 88.3% in the 0.25 mg fingolimod group; and 87.3% in the glatiramer acetate group). Among patients who received fingolimod, the most common adverse events were headache, fatigue, and urinary tract infection.
The most common adverse events among patients who received glatiramer acetate were urinary tract infection and injection-site erythema. The rate of serious adverse events was slightly higher in the 0.25 mg fingolimod group (8.7%) than in the 0.5 mg fingolimod group (7.2%) or the glatiramer acetate group (6.2%). Serious adverse events included MS relapse and basal cell carcinoma. No patients died.
The efficacy of the 0.25-mg dose of fingolimod with respect to new T2 lesions and annualized relapse rate was between those of glatiramer acetate and 0.5 mg fingolimod. “MRI measures of disease activity, especially gadolinium-enhancing lesions, are more sensitive to anti-inflammatory treatment effects and therefore are more readily influenced than clinical relapses,” said Cree.
Rates of certain treatment-related adverse events, including lymphopenia and increased alanine aminotransferase) were slightly lower with the 0.25-mg dose of fingolimod, and this result is consistent with the drug’s pharmacological effects.
The study was funded by Novartis Pharma, the manufacturer of fingolimod. Cree reported receiving personal fees from Akili Interactive Labs, Alexion Pharmaceuticals, Atara Biotherapeutics, Biogen, EMD Serono, Novartis, and TG Therapeutics that were unrelated to this investigation. Henson was involved with the phase 3 study of fingolimod, but has no current relevant disclosures.
JAMA Neurology. Published online August 24, 2020. Full text