Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: interim safety and efficacy results from the Phase 3 EVOLVE-MS-1 study
ECTRIMS Online Library. Then Bergh F. 279695; EP1553
Florian Then Bergh
Florian Then Bergh
Contributions
Abstract

Abstract: EP1553

Type:

Abstract Category: Therapy - Immunomodulation/Immunosuppression

F. Then Bergh1, B.A. Singer2, J. Drulovic3, I. Bidollari4, H. Chen5, R. Englishby6, J. Hanna6, B. Kandinov4, M. Lopez-Bresnahan4, R. Leigh-Pemberton4, C. Miller5, O. Mokliatchouk5, S.J. Shafer7

1Department of Neurology, University of Leipzig, Leipzig, Germany, 2The MS Center for Innovations in Care, Missouri Baptist Medical Center, St Louis, MO, United States, 3Clinic of Neurology, University of Belgrade, Belgrade, Serbia, 4Alkermes, Waltham, 5Biogen, Cambridge, MA, United States, 6Biogen, Maidenhead, United Kingdom, 7Vero Beach Neurology and Research Institute, Vero Beach, FL, United States

Introduction: Diroximel fumarate (DRF; ALKS 8700, BIIB098) is a novel oral fumarate in development for patients with relapsing-remitting multiple sclerosis (RRMS). DRF undergoes rapid, presystemic conversion to monomethyl fumarate (MMF), the same pharmacologically active metabolite as the approved drug, dimethyl fumarate (DMF). Because MMF levels are bioequivalent for DRF and DMF, it is expected the efficacy and safety profiles will be similar.
Objectives: To report interim safety, tolerability and efficacy outcomes in DRF-treated patients in EVOLVE-MS-1.
Methods: EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability and efficacy in adults with RRMS. Adverse events (AEs) and relapses were evaluated in patients who received ≥1 DRF dose; radiological outcomes were assessed in patients who also completed ≥1 post-baseline efficacy assessment.
Results: As of 30 November 2018, 888 patients were enrolled, 674 of whom had prior disease-modifying therapy use. Median DRF exposure was 84.0 (range 0.1-100.0) weeks. AEs were reported in 83.1% (738/888) of patients; most were mild (30.6%; 272/888) or moderate (44.7%; 397/888) in severity. Serious AEs occurred in 9.1%. Overall, 16.3% (145/888) discontinued the study; AEs led to discontinuation in 7.1% and GI AEs in < 1%. Mean absolute lymphocyte count (ALC) declined by 27.5% by Week 48 and then stabilized. A majority of patients (64.3%; 560/871) had ALCs always >lower limit of normal. Serious infections occurred in 4 (< 1%) patients; there were no cases of serious opportunistic infection, including PML. Adjusted annualized relapse rate was 0.15 (95% CI 0.13-0.18) overall, representing a 79.4% (95% CI 75.1-82.9; p< 0.0001) reduction from the reported rate during the 12 months before study entry (0.74 [95% CI 0.69-0.79]). Significant reductions in mean (SD) number of gadolinium-enhancing lesions were observed from baseline 1.4 (5.2) to Week 96 (0.6 [4.6]; 57.1% reduction; p=0.0064; n=310). Similar findings in newly diagnosed patients will be presented.
Conclusions: Data from this ongoing study demonstrate that DRF safety and efficacy outcomes are consistent with the known benefit-risk profile for DMF. The low rate of treatment discontinuation, specifically those due to GI events, suggest DRF is a well-tolerated treatment option for patients with RRMS. The distinct chemical structure of DRF may be contributing to the GI tolerability profile.
Support: Biogen/Alkermes
Disclosure: Florian Then Bergh receives grant support from the German Research Foundation (DFG) and Federal Ministry of Education and Research (BMBF). He has received, through his institution, grant support and travel support to attend scientific meetings from Actelion, Bayer-Schering, Biogen, Genzyme, Merck-Serono and Novartis. He has received personal honoraria for speaking or serving on advisory boards from Actelion, Bayer-Schering, Genzyme, Merck-Serono, Novartis and Roche.
Barry A. Singer received research support from AbbVie, Acorda, Alkermes, Biogen, MedImmune, Novartis, Sanofi Genzyme and Roche; speaking/consulting fees from AbbVie, Acorda, Bayer, Biogen, Celgene, Genentech, EMD Serono, Novartis, Roche, Sanofi Genzyme, Teva and TG Therapeutics.
Jelena Drulovic receives research grant support from the Ministry of Education, Science and Technological Development, Republic of Serbia (project no. 175031); personal honoraria for speaking or serving on advisory boards from Bayer Schering Pharma, Merck-Serono, TEVA, Sanofi Genzyme, Roche, Hemofarm, Pfizer and Medis; and participates as a principal investigator in clinical trials for Merck Serono, Teva, Biogen Idec, Roche, Genzyme, a Sanofi Company, Receptos, Celgene, Alkermes, MedImmune.
Ilda Bidollari is a full-time employee of and holds stock/stock options in Alkermes
Hailu Chen is a full-time employee of and holds stock/stock options in Biogen
Ronnie Englishby is a full-time employee of and holds stock/stock options in Biogen
Jerome Hanna is a full-time employee of and holds stock/stock options in Biogen
Boris Kandinov is a full-time employee of and holds stock/stock options in Alkermes
Maria Lopez-Bresnahan is a full-time employee of and holds stock/stock options in Alkermes
Richard Leigh-Pemberton is a full-time employee of and holds stock/stock options in Alkermes
Catherine Miller is a full-time employee of and holds stock/stock options in Biogen
Oksana Mokliatchouk is a full-time employee of and holds stock/stock options in Biogen
S. James Shafer receives speaker/consulting/advisory board fees from Genentech, Mallinkrodt, Biogen, Accorda, Sanofi-Genzyme and Novartis; research support from Roche, Biogen, Genentech, Novartis, Alkermes, Pfizer, Actellion, Adamas, Sanofi-Genzyme, Sunovion, Accorda, Chugai, Boehringer-Ingellheim, Lunbeck and Opexa.
Supported by: This study was funded by Biogen (Cambridge, MA, USA) and Alkermes (Waltham, MA, USA); medical writing support was provided by Excel Scientific Solutions (Southport, CT, USA) and funded by Biogen.

Abstract: EP1553

Type:

Abstract Category: Therapy - Immunomodulation/Immunosuppression

F. Then Bergh1, B.A. Singer2, J. Drulovic3, I. Bidollari4, H. Chen5, R. Englishby6, J. Hanna6, B. Kandinov4, M. Lopez-Bresnahan4, R. Leigh-Pemberton4, C. Miller5, O. Mokliatchouk5, S.J. Shafer7

1Department of Neurology, University of Leipzig, Leipzig, Germany, 2The MS Center for Innovations in Care, Missouri Baptist Medical Center, St Louis, MO, United States, 3Clinic of Neurology, University of Belgrade, Belgrade, Serbia, 4Alkermes, Waltham, 5Biogen, Cambridge, MA, United States, 6Biogen, Maidenhead, United Kingdom, 7Vero Beach Neurology and Research Institute, Vero Beach, FL, United States

Introduction: Diroximel fumarate (DRF; ALKS 8700, BIIB098) is a novel oral fumarate in development for patients with relapsing-remitting multiple sclerosis (RRMS). DRF undergoes rapid, presystemic conversion to monomethyl fumarate (MMF), the same pharmacologically active metabolite as the approved drug, dimethyl fumarate (DMF). Because MMF levels are bioequivalent for DRF and DMF, it is expected the efficacy and safety profiles will be similar.
Objectives: To report interim safety, tolerability and efficacy outcomes in DRF-treated patients in EVOLVE-MS-1.
Methods: EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability and efficacy in adults with RRMS. Adverse events (AEs) and relapses were evaluated in patients who received ≥1 DRF dose; radiological outcomes were assessed in patients who also completed ≥1 post-baseline efficacy assessment.
Results: As of 30 November 2018, 888 patients were enrolled, 674 of whom had prior disease-modifying therapy use. Median DRF exposure was 84.0 (range 0.1-100.0) weeks. AEs were reported in 83.1% (738/888) of patients; most were mild (30.6%; 272/888) or moderate (44.7%; 397/888) in severity. Serious AEs occurred in 9.1%. Overall, 16.3% (145/888) discontinued the study; AEs led to discontinuation in 7.1% and GI AEs in < 1%. Mean absolute lymphocyte count (ALC) declined by 27.5% by Week 48 and then stabilized. A majority of patients (64.3%; 560/871) had ALCs always >lower limit of normal. Serious infections occurred in 4 (< 1%) patients; there were no cases of serious opportunistic infection, including PML. Adjusted annualized relapse rate was 0.15 (95% CI 0.13-0.18) overall, representing a 79.4% (95% CI 75.1-82.9; p< 0.0001) reduction from the reported rate during the 12 months before study entry (0.74 [95% CI 0.69-0.79]). Significant reductions in mean (SD) number of gadolinium-enhancing lesions were observed from baseline 1.4 (5.2) to Week 96 (0.6 [4.6]; 57.1% reduction; p=0.0064; n=310). Similar findings in newly diagnosed patients will be presented.
Conclusions: Data from this ongoing study demonstrate that DRF safety and efficacy outcomes are consistent with the known benefit-risk profile for DMF. The low rate of treatment discontinuation, specifically those due to GI events, suggest DRF is a well-tolerated treatment option for patients with RRMS. The distinct chemical structure of DRF may be contributing to the GI tolerability profile.
Support: Biogen/Alkermes
Disclosure: Florian Then Bergh receives grant support from the German Research Foundation (DFG) and Federal Ministry of Education and Research (BMBF). He has received, through his institution, grant support and travel support to attend scientific meetings from Actelion, Bayer-Schering, Biogen, Genzyme, Merck-Serono and Novartis. He has received personal honoraria for speaking or serving on advisory boards from Actelion, Bayer-Schering, Genzyme, Merck-Serono, Novartis and Roche.
Barry A. Singer received research support from AbbVie, Acorda, Alkermes, Biogen, MedImmune, Novartis, Sanofi Genzyme and Roche; speaking/consulting fees from AbbVie, Acorda, Bayer, Biogen, Celgene, Genentech, EMD Serono, Novartis, Roche, Sanofi Genzyme, Teva and TG Therapeutics.
Jelena Drulovic receives research grant support from the Ministry of Education, Science and Technological Development, Republic of Serbia (project no. 175031); personal honoraria for speaking or serving on advisory boards from Bayer Schering Pharma, Merck-Serono, TEVA, Sanofi Genzyme, Roche, Hemofarm, Pfizer and Medis; and participates as a principal investigator in clinical trials for Merck Serono, Teva, Biogen Idec, Roche, Genzyme, a Sanofi Company, Receptos, Celgene, Alkermes, MedImmune.
Ilda Bidollari is a full-time employee of and holds stock/stock options in Alkermes
Hailu Chen is a full-time employee of and holds stock/stock options in Biogen
Ronnie Englishby is a full-time employee of and holds stock/stock options in Biogen
Jerome Hanna is a full-time employee of and holds stock/stock options in Biogen
Boris Kandinov is a full-time employee of and holds stock/stock options in Alkermes
Maria Lopez-Bresnahan is a full-time employee of and holds stock/stock options in Alkermes
Richard Leigh-Pemberton is a full-time employee of and holds stock/stock options in Alkermes
Catherine Miller is a full-time employee of and holds stock/stock options in Biogen
Oksana Mokliatchouk is a full-time employee of and holds stock/stock options in Biogen
S. James Shafer receives speaker/consulting/advisory board fees from Genentech, Mallinkrodt, Biogen, Accorda, Sanofi-Genzyme and Novartis; research support from Roche, Biogen, Genentech, Novartis, Alkermes, Pfizer, Actellion, Adamas, Sanofi-Genzyme, Sunovion, Accorda, Chugai, Boehringer-Ingellheim, Lunbeck and Opexa.
Supported by: This study was funded by Biogen (Cambridge, MA, USA) and Alkermes (Waltham, MA, USA); medical writing support was provided by Excel Scientific Solutions (Southport, CT, USA) and funded by Biogen.

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