Contributions
Abstract: P743
Type: Poster
Abstract Category: Therapy - disease modifying - 28 Long-term treatment monitoring
Background: Delayed-release dimethyl fumarate (DMF) has demonstrated a favourable benefit-risk profile in patients (pts) with relapsing-remitting multiple sclerosis (RRMS). There has been no increased incidence of infection observed with DMF, aside from rare cases of PML. The DMF label recommends considering treatment interruption for pts with absolute lymphocyte count (ALC) < 0.5x109/L for ≥6 months to minimize risk of developing sustained severe, prolonged lymphopenia.
Objectives: Examine the dynamics and clinical implications of on-DMF ALC decline and post-DMF ALC reconstitution in pts with RRMS treated with DMF.
Methods: We conducted an integrated analysis of the Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) DMF studies. Data starting from the first exposure to DMF were analyzed. ALCs were assessed at wks 4, 8, 12, and at least every 12 wks thereafter, or every 4 wks in pts that discontinued DMF. Pts were categorised by on-treatment ALCs.
Results: The total analysed population comprised 2513 pts and 9702 pt-years (yrs) of DMF exposure as of 1 October 2016. Among the 2470 pts with any on-treatment ALC, mean ALC decreased by ~30% during the first yr of treatment and then stabilized above the lower limit of normal (LLN; 0.91×109/L). The incidence of serious infection (4%) and serious herpes zoster (< 1%) was low; no increased incidence was observed regardless of ALC or T-cell subset count. One opportunistic infection occurred (fatal case of PML). Of 53 (2.1%) pts who developed severe, prolonged lymphopenia (< 0.5x109/L for ≥6 mos), the majority (44/53, 83%) did so within 3 yrs of initiating DMF. Of these, 34 pts continued treatment for median (range) 72 (16, 97) mos before discontinuing DMF, and ALCs were followed for ≥6 mos after discontinuation. The proportion of pts with ALC ≥0.8x109/L and ≥0.91x109/L after 6 mos of discontinuation was 41% (14/34) and 24% (8/34). In the 6 mos after DMF discontinuation, unadjusted ARR was 0.384 vs 0.496 at 6 mos on placebo in DEFINE/CONFIRM.
Conclusions: Lymphocyte decline is well characterized in RRMS pts treated with DMF for up to 10 yrs. No increased incidence of serious or opportunistic infection was observed. ALCs generally increased after DMF discontinuation following severe lymphopenia. Other analyses are ongoing to characterize lymphocyte reconstitution in pts with a shorter duration of lymphopenia. Monitoring ALC is an effective way to identify pts at risk for prolonged lymphopenia.
Supported by Biogen
Disclosure:
Supported by: this study was supported by Biogen (Cambridge, MA, USA). Editorial support was provided by Excel Scientific Solutions (Horsham, UK): funding was provided by Biogen.
Fox, Robert J: consulting fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; advisory boards for Biogen and Novartis; research grant funding from Novartis;
Chan, Andrew: compensation for activities with Almirall Hermal, Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience; research support from Biogen, Genzyme, and Novartis;
Gold, Ralf: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders;
Phillips, J.Theodore: consulting fees from Acorda, Biogen, Genentech, Genzyme, Merck Serono, Roche, and Sanofi-Aventis;
Yang, Lili: employee of and holds stock/stock options in Biogen
Liu, Shifang: employee of and holds stock/stock options in Biogen
Chalkias, Spyros: employee of and holds stock/stock options in Biogen
Mehta, Devangi: employee of and holds stock/stock options in Biogen
Taylor, Catherine: employee of and holds stock/stock options in Biogen
Abstract: P743
Type: Poster
Abstract Category: Therapy - disease modifying - 28 Long-term treatment monitoring
Background: Delayed-release dimethyl fumarate (DMF) has demonstrated a favourable benefit-risk profile in patients (pts) with relapsing-remitting multiple sclerosis (RRMS). There has been no increased incidence of infection observed with DMF, aside from rare cases of PML. The DMF label recommends considering treatment interruption for pts with absolute lymphocyte count (ALC) < 0.5x109/L for ≥6 months to minimize risk of developing sustained severe, prolonged lymphopenia.
Objectives: Examine the dynamics and clinical implications of on-DMF ALC decline and post-DMF ALC reconstitution in pts with RRMS treated with DMF.
Methods: We conducted an integrated analysis of the Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) DMF studies. Data starting from the first exposure to DMF were analyzed. ALCs were assessed at wks 4, 8, 12, and at least every 12 wks thereafter, or every 4 wks in pts that discontinued DMF. Pts were categorised by on-treatment ALCs.
Results: The total analysed population comprised 2513 pts and 9702 pt-years (yrs) of DMF exposure as of 1 October 2016. Among the 2470 pts with any on-treatment ALC, mean ALC decreased by ~30% during the first yr of treatment and then stabilized above the lower limit of normal (LLN; 0.91×109/L). The incidence of serious infection (4%) and serious herpes zoster (< 1%) was low; no increased incidence was observed regardless of ALC or T-cell subset count. One opportunistic infection occurred (fatal case of PML). Of 53 (2.1%) pts who developed severe, prolonged lymphopenia (< 0.5x109/L for ≥6 mos), the majority (44/53, 83%) did so within 3 yrs of initiating DMF. Of these, 34 pts continued treatment for median (range) 72 (16, 97) mos before discontinuing DMF, and ALCs were followed for ≥6 mos after discontinuation. The proportion of pts with ALC ≥0.8x109/L and ≥0.91x109/L after 6 mos of discontinuation was 41% (14/34) and 24% (8/34). In the 6 mos after DMF discontinuation, unadjusted ARR was 0.384 vs 0.496 at 6 mos on placebo in DEFINE/CONFIRM.
Conclusions: Lymphocyte decline is well characterized in RRMS pts treated with DMF for up to 10 yrs. No increased incidence of serious or opportunistic infection was observed. ALCs generally increased after DMF discontinuation following severe lymphopenia. Other analyses are ongoing to characterize lymphocyte reconstitution in pts with a shorter duration of lymphopenia. Monitoring ALC is an effective way to identify pts at risk for prolonged lymphopenia.
Supported by Biogen
Disclosure:
Supported by: this study was supported by Biogen (Cambridge, MA, USA). Editorial support was provided by Excel Scientific Solutions (Horsham, UK): funding was provided by Biogen.
Fox, Robert J: consulting fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; advisory boards for Biogen and Novartis; research grant funding from Novartis;
Chan, Andrew: compensation for activities with Almirall Hermal, Bayer HealthCare, Biogen, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva Neuroscience; research support from Biogen, Genzyme, and Novartis;
Gold, Ralf: honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders;
Phillips, J.Theodore: consulting fees from Acorda, Biogen, Genentech, Genzyme, Merck Serono, Roche, and Sanofi-Aventis;
Yang, Lili: employee of and holds stock/stock options in Biogen
Liu, Shifang: employee of and holds stock/stock options in Biogen
Chalkias, Spyros: employee of and holds stock/stock options in Biogen
Mehta, Devangi: employee of and holds stock/stock options in Biogen
Taylor, Catherine: employee of and holds stock/stock options in Biogen