Contributions
Abstract: P929
Type: Poster Sessions
Abstract Category: Therapy - Risk management for disease modifying treatments
Introduction: Delayed-release dimethyl fumarate (DMF) demonstrated favourable benefit-risk profile in patients (pts) with relapsing-remitting multiple sclerosis (RRMS). Following the occurrence of 1 case of progressive multifocal leukoencephalopathy (PML) in the ENDORSE study, the DMF label was amended in 2015 to recommend treatment interruption for pts with severe, prolonged lymphopenia (absolute lymphocyte count [ALC] < 0.5x109/L ≥6 months). As of 31 January 2018, 5 cases of PML associated with DMF use have occurred against a background exposure of >544,000 pt-years (yrs) in the clinical trial and post marketing setting.
Objectives: Examine the clinical implications of DMF-associated lymphopenia and post-treatment ALC dynamics in pts with RRMS.
Methods: An integrated analysis of the DMF Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) studies was conducted. Data from 1st DMF exposure were analysed. ALCs were assessed at weeks (wks) 4, 8, 12, and every 12 wks thereafter.
Results: As of 01 Sept 2017, the analysis population comprised 2513 pts (10454 pt-yrs). In pts followed for up to 11 yrs, severe, prolonged lymphopenia was not associated with increased incidence of serious infection (0.016 vs. 0.010 for pts with ALC always above normal) or serious herpes zoster (0 vs. 0.006 for pts with ALC always above normal). One fatal case of PML previously occurred in the setting of severe lymphopenia of ~3.5 yrs duration. Following the implementation of a stopping rule requiring pts with an ALC < 0.5x109/L for ≥6 months to discontinue DMF treatment, no additional cases of PML have been observed in this study. Aside from the 1 PML case, no other opportunistic infections were observed, regardless of ALC. In pts with mild or moderate lymphopenia while on DMF, and with an ALC < 0.91x109/L at DMF discontinuation (n=138), median time to ALC ≥0.8x109/L was 5 wks after discontinuation. Most of these pts (79%, 109/138) achieved this milestone during the follow-up period, or prior to study discontinuation.
Conclusions: These data support that DMF-associated lymphopenia is not associated with an increased incidence of serious or opportunistic infection aside from very rare PML. ALCs increased following DMF discontinuation for the majority of pts in this analysis, and did so within 2 months of discontinuation. These data may be informative for clinicians and pts when considering treatment options in the context of DMF-associated lymphopenia.
Supported by: Biogen
Disclosure: Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; advisory committees for Biogen and Novartis; research grant funding from Novartis.
Amit Bar-Or: participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Atara Biotherapeutics, Biogen, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme.
Andrew Chan: compensation for activities with Actelion, Allmirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva Neuroscience; research support from Genzyme and UCB.
Ralf Gold: honoraria/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, and TG Therapeutics.
Lili Yang: Employee of and holds stock/stock options in Biogen.
Chongshu Chen: Employee of and holds stock/stock options in Biogen.
Jerome Hanna: Employee of and holds stock/stock options in Biogen.
Devangi Mehta: Employee of and holds stock/stock options in Biogen.
Catherine Miller: Employee of and holds stock/stock options in Biogen.
Abstract: P929
Type: Poster Sessions
Abstract Category: Therapy - Risk management for disease modifying treatments
Introduction: Delayed-release dimethyl fumarate (DMF) demonstrated favourable benefit-risk profile in patients (pts) with relapsing-remitting multiple sclerosis (RRMS). Following the occurrence of 1 case of progressive multifocal leukoencephalopathy (PML) in the ENDORSE study, the DMF label was amended in 2015 to recommend treatment interruption for pts with severe, prolonged lymphopenia (absolute lymphocyte count [ALC] < 0.5x109/L ≥6 months). As of 31 January 2018, 5 cases of PML associated with DMF use have occurred against a background exposure of >544,000 pt-years (yrs) in the clinical trial and post marketing setting.
Objectives: Examine the clinical implications of DMF-associated lymphopenia and post-treatment ALC dynamics in pts with RRMS.
Methods: An integrated analysis of the DMF Phase 2b, Phase 3 (DEFINE/CONFIRM) and extension (ENDORSE) studies was conducted. Data from 1st DMF exposure were analysed. ALCs were assessed at weeks (wks) 4, 8, 12, and every 12 wks thereafter.
Results: As of 01 Sept 2017, the analysis population comprised 2513 pts (10454 pt-yrs). In pts followed for up to 11 yrs, severe, prolonged lymphopenia was not associated with increased incidence of serious infection (0.016 vs. 0.010 for pts with ALC always above normal) or serious herpes zoster (0 vs. 0.006 for pts with ALC always above normal). One fatal case of PML previously occurred in the setting of severe lymphopenia of ~3.5 yrs duration. Following the implementation of a stopping rule requiring pts with an ALC < 0.5x109/L for ≥6 months to discontinue DMF treatment, no additional cases of PML have been observed in this study. Aside from the 1 PML case, no other opportunistic infections were observed, regardless of ALC. In pts with mild or moderate lymphopenia while on DMF, and with an ALC < 0.91x109/L at DMF discontinuation (n=138), median time to ALC ≥0.8x109/L was 5 wks after discontinuation. Most of these pts (79%, 109/138) achieved this milestone during the follow-up period, or prior to study discontinuation.
Conclusions: These data support that DMF-associated lymphopenia is not associated with an increased incidence of serious or opportunistic infection aside from very rare PML. ALCs increased following DMF discontinuation for the majority of pts in this analysis, and did so within 2 months of discontinuation. These data may be informative for clinicians and pts when considering treatment options in the context of DMF-associated lymphopenia.
Supported by: Biogen
Disclosure: Robert J. Fox: consultant fees from Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; advisory committees for Biogen and Novartis; research grant funding from Novartis.
Amit Bar-Or: participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Atara Biotherapeutics, Biogen, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme.
Andrew Chan: compensation for activities with Actelion, Allmirall, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Sanofi-Aventis, and Teva Neuroscience; research support from Genzyme and UCB.
Ralf Gold: honoraria/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, and TG Therapeutics.
Lili Yang: Employee of and holds stock/stock options in Biogen.
Chongshu Chen: Employee of and holds stock/stock options in Biogen.
Jerome Hanna: Employee of and holds stock/stock options in Biogen.
Devangi Mehta: Employee of and holds stock/stock options in Biogen.
Catherine Miller: Employee of and holds stock/stock options in Biogen.