Contributions
Abstract: P716
Type: Poster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Delayed-release dimethyl fumarate (DMF) has demonstrated a favourable benefit-risk profile in pts with relapsing-remitting multiple sclerosis (RRMS). The DMF label recommends considering treatment interruption in pts with absolute lymphocyte counts (ALCs) < 0.5 x 109/L persisting ≥6 mos. Over 190,000 pts have been treated with DMF worldwide, representing 218,988 pt-years of exposure as of 31 December 2015.
Objectives: Provide practical considerations for management of DMF-treated RRMS pts by reporting long-term ALC profiles in RRMS pts treated with DMF for up to 9 yrs, as well as lymphocyte subset profiles in a subset of pts.
Methods: We conducted an integrated analysis of the Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) DMF studies. The total safety population comprised 2513 pts and 8293 pt-years. ALCs were assessed at wks 4, 8, 12, and at least every 12 wks subsequently. Lymphocyte subsets were analyzed by flow cytometry in a subset of pts with available data.
Results: A total of 2470 pts with any post-baseline ALC were included in the analysis. Mean ALCs decreased by approximately 30% during the first yr of treatment, then plateaued, remaining above lower limit of normal (LLN; 0.91 x 109/L). Among pts treated for ≥6 mos (N=2098), 2.5% (n=53) experienced ALCs < 0.5 x 109/L persisting ≥6 mos; 10.9% (229/2098) of pts experienced moderate lymphopenia (ALCs ≥0.5 x 109/L to < 0.8 x 109/L) persisting ≥6 mos. All ALCs remained consistently ≥LLN in 84% of pts during the first 6 mos and 76% of patients during the first yr; of these patients, 0.3% and 0.1%, respectively, subsequently developed ALCs < 0.5 x 109/L persisting ≥6 mos at any time. Of those 2050 with consistent ALC ≥0.8 x 109/L for the first yr of treatment, 2 (0.098%) developed < 0.5 x 109/L persisting ≥6 mos. The incidence of infections and malignancies in pts with prolonged lymphopenia will be presented. Preliminary lymphocyte subset analyses suggest that T-cells were preferentially reduced relative to B-cells and NK cells; CD8+ T-cell counts were preferentially reduced relative to CD4+ T-cell counts. Decreases in ALCs were associated with corresponding decreases in CD4+ and CD8+ counts.
Conclusions: Based on up to 9 yrs of experience in patients treated with DMF, lymphocyte monitoring provides an effective means for early identification of pts at risk for subsequently developing prolonged lymphopenia. The overall benefit-risk of DMF remains favourable.
Disclosure:
Supported by: Biogen.
Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen and Novartis; research grant funding from Novartis.
Andrew Chan: personal compensation for activities with Allmirall Hermal, Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, Sanofi Aventis, and Teva Neuroscience; research support from Biogen, Genzyme, and Novartis.
Ralf Gold: 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.
J. Theodore Phillips: consulting fees from Acorda, Biogen, Genentech, Genzyme, Merck Serono, Sanofi, and Xenoport.
Krzysztof Selmaj: compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; compensation for speaking from Biogen.
Ray Zhang: Employee of and holds stock/stock options in Biogen.
Ih Chang: Employee of and holds stock/stock options in Biogen.
Claudia Prada: Employee of and holds stock/stock options in Biogen.
Soma Ray: Employee of and holds stock/stock options in Biogen.
Devangi Mehta: Employee of and holds stock/stock options in Biogen.
Catherine Taylor: Employee of and holds stock/stock options in Biogen.
Jing Marantz: Employee of and holds stock/stock options in Biogen.
Abstract: P716
Type: Poster
Abstract Category: Therapy - disease modifying - Risk management for disease modifying treatments
Background: Delayed-release dimethyl fumarate (DMF) has demonstrated a favourable benefit-risk profile in pts with relapsing-remitting multiple sclerosis (RRMS). The DMF label recommends considering treatment interruption in pts with absolute lymphocyte counts (ALCs) < 0.5 x 109/L persisting ≥6 mos. Over 190,000 pts have been treated with DMF worldwide, representing 218,988 pt-years of exposure as of 31 December 2015.
Objectives: Provide practical considerations for management of DMF-treated RRMS pts by reporting long-term ALC profiles in RRMS pts treated with DMF for up to 9 yrs, as well as lymphocyte subset profiles in a subset of pts.
Methods: We conducted an integrated analysis of the Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) DMF studies. The total safety population comprised 2513 pts and 8293 pt-years. ALCs were assessed at wks 4, 8, 12, and at least every 12 wks subsequently. Lymphocyte subsets were analyzed by flow cytometry in a subset of pts with available data.
Results: A total of 2470 pts with any post-baseline ALC were included in the analysis. Mean ALCs decreased by approximately 30% during the first yr of treatment, then plateaued, remaining above lower limit of normal (LLN; 0.91 x 109/L). Among pts treated for ≥6 mos (N=2098), 2.5% (n=53) experienced ALCs < 0.5 x 109/L persisting ≥6 mos; 10.9% (229/2098) of pts experienced moderate lymphopenia (ALCs ≥0.5 x 109/L to < 0.8 x 109/L) persisting ≥6 mos. All ALCs remained consistently ≥LLN in 84% of pts during the first 6 mos and 76% of patients during the first yr; of these patients, 0.3% and 0.1%, respectively, subsequently developed ALCs < 0.5 x 109/L persisting ≥6 mos at any time. Of those 2050 with consistent ALC ≥0.8 x 109/L for the first yr of treatment, 2 (0.098%) developed < 0.5 x 109/L persisting ≥6 mos. The incidence of infections and malignancies in pts with prolonged lymphopenia will be presented. Preliminary lymphocyte subset analyses suggest that T-cells were preferentially reduced relative to B-cells and NK cells; CD8+ T-cell counts were preferentially reduced relative to CD4+ T-cell counts. Decreases in ALCs were associated with corresponding decreases in CD4+ and CD8+ counts.
Conclusions: Based on up to 9 yrs of experience in patients treated with DMF, lymphocyte monitoring provides an effective means for early identification of pts at risk for subsequently developing prolonged lymphopenia. The overall benefit-risk of DMF remains favourable.
Disclosure:
Supported by: Biogen.
Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Biogen and Novartis; research grant funding from Novartis.
Andrew Chan: personal compensation for activities with Allmirall Hermal, Bayer Schering, Biogen, Genzyme, Merck Serono, Novartis, Sanofi Aventis, and Teva Neuroscience; research support from Biogen, Genzyme, and Novartis.
Ralf Gold: 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.
J. Theodore Phillips: consulting fees from Acorda, Biogen, Genentech, Genzyme, Merck Serono, Sanofi, and Xenoport.
Krzysztof Selmaj: compensation for consulting services from Genzyme, Novartis, Ono, Roche, Synthon, and Teva; compensation for speaking from Biogen.
Ray Zhang: Employee of and holds stock/stock options in Biogen.
Ih Chang: Employee of and holds stock/stock options in Biogen.
Claudia Prada: Employee of and holds stock/stock options in Biogen.
Soma Ray: Employee of and holds stock/stock options in Biogen.
Devangi Mehta: Employee of and holds stock/stock options in Biogen.
Catherine Taylor: Employee of and holds stock/stock options in Biogen.
Jing Marantz: Employee of and holds stock/stock options in Biogen.