Dimethyl Fumarate Has Low Risk of Progressive Multifocal Leukoencephalopathy, Short Duration of Lymphopenia, and Long-Term Efficacy for Relapsing Multiple Sclerosis
At the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Berlin, Germany October 10-12, results were reported from an integrated analysis of data from the DEFINE (NCT00420212), CONFIRM (NCT00451451), and ENDORSE (NCT00835770) studies of dimethyl fumarate for treatment of patients with relapsing multiple sclerosis (MS).
The data analyzed represented 2,513 patients treated with DMF followed for up to 11 years (10,454 patient-years). Severe lymphopenia (ALC < 0.5x109/L for ≥ 6 months) did not correlate with increased incidence of serious infections (0.016 vs. 0.010 for patients with ALC always above normal) or serious herpes zoster (0 vs. 0.006 for pts with ALC always above normal).
During clinical trials, a single fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient who had severe lymphopenia for ~3.5 yrs duration. This fatality led to the recommendation on the label to stop treatment for 6 months in patients with severe lymphopenia. Following implementation of that rule, no additional cases of PML were observed in clinical trials.
As of January 31, 2018, 5 cases of DMF-associated PML against a background exposure of > 544,000 patients years in the clinical trial and postmarketing settings.
Another analysis of data from 33 patients obtained in retrospective medical chart review showed that among patients discontinued treatment with DMF for any reason, most (78%) achieved lymphocyte recovery within 3 months.
Results from the 5-year observational ESTEEM study (NCT02047097) evaluating real-world efficacy of DMF for treating patients with relapsing MS were also presented.
Patients with relapsing MS who were diagnosed within 3 years who had either not been treated or been treated only with a single course of interferon ß-1a (IFN) or glatiramir acetate (GA) were enrolled in the study and treated with DMF. Of the 3,075 patients, 73% were being treated with DMF at the time of interim analysis with median follow-up time of 13 months of treatment with DMF.
The unadjusted annualized relapse rate (ARR) after 2 years of treatment with DMF was significantly reduced compared to the year prior to DMF initiation (P < .0001) providing real-world evidence for the effectiveness of DMF for patients with relapsing MS treated early in the course of their disease (Table).
In long-term results of the extension trial ENDORSE (NCT00835770), patients who had been diagnosed with relapsing MS and had either not been treated or treated only with corticosteroids, began treatment with DMF or with a placebo for 2 years. Subsequently, all of these patients were treated with DMF and followed for another 7 years. Among those who remained on DMF (110 of 229; 48%), the adjusted ARR (95% CI) was 0.14 (0.10-0.18) for those who had DMF for the entire study and 0.15 (0.10-0.23) for those who had placebo and then DMF. At year 9, 93% of patients still being treated with DMF were still able to walk (Expanded Disability Status Scale 3.5 or less).
Brain MRIs from a subset of 209 patients treated with DMF were analyzed annually and 68% to 72% of these patients had no new T1 hypointense lesions each year over a period of 7 years. The adjusted mean percent brain volume loss (PBVL) was also positively affected and this benefit was maintained. After 2 years of treatment, PBVL was -0.22 (n = 134); in years 3-6, PBVL was -0.28 (n = 116), -0.37 (n = 114), -0.22 (n = 108), and -0.19 (n = 89).