Stanley L Cohan1, Harold Moses2, Jonathan Calkwood3, Carlo Tornatore4, Chris LaGanke5, Kyle E Smoot6, Venkata Meka7, Macaulay Okwuokenye8, Christophe Hotermans9, Jason P Mendoza10, Monica K Mann11, Leslie A Meltzer12. 1. Providence Multiple Sclerosis Center, Providence Health & Services, 9427 SW Barnes Road, Portland, OR 97225, USA; Providence Brain and Spine Institute, Providence Health & Services, 9135 SW Barnes Road, Suite 461, Portland, OR 97225, USA. Electronic address: stanley.cohan@providence.org. 2. Vanderbilt-Ingram Cancer Center, 691 Preston Building, Nashville, TN 37232, USA. Electronic address: harold.moses@Vanderbilt.Edu. 3. Schapiro Center for Multiple Sclerosis, Minneapolis Clinic of Neurology, 4225 Golden Valley Road, Golden Valley, MN 55422, USA. Electronic address: Jcalkwood@gmail.com. 4. Department of Neurology, Medstar Georgetown University Hospital, Pasquerilla Healthcare Center (PHC), 7th Floor, 3800 Reservoir Road, N.W., Washington, D.C. 20007, USA. Electronic address: Tornatoc@gunet.georgetown.edu. 5. North Central Neurology Associates, 1809 Kress St., Cullman, AL 35058, USA. Electronic address: claganke@prn-inc.net. 6. Providence Multiple Sclerosis Center, Providence Health & Services, 9427 SW Barnes Road, Portland, OR 97225, USA; Providence Brain and Spine Institute, Providence Health & Services, 9135 SW Barnes Road, Suite 461, Portland, OR 97225, USA. Electronic address: kyle.smoot@providence.org. 7. Biogen, 225 Binney St., Cambridge, MA 02142, USA. Electronic address: vennmeka@yahoo.com. 8. Biogen, 225 Binney St., Cambridge, MA 02142, USA. Electronic address: chiefendorce@hotmail.com. 9. Biogen, 225 Binney St., Cambridge, MA 02142, USA. Electronic address: Christophe.Hotermans@Biogen.com. 10. Biogen, 225 Binney St., Cambridge, MA 02142, USA. Electronic address: Jason.Mendoza@biogen.com. 11. Biogen, 225 Binney St., Cambridge, MA 02142, USA. Electronic address: monica.mann@Biogen.com. 12. Biogen, 225 Binney St., Cambridge, MA 02142, USA. Electronic address: lmeltzer@gmail.com.
Abstract
BACKGROUND: Delayed-release dimethyl fumarate (DMF) may be a therapeutic option for patients with relapsing-remitting multiple sclerosis (RRMS) who are treated with natalizumab and require a change in therapy. However, there is limited information regarding predictors of favorable treatment outcomes in patients switching from natalizumab to DMF. Clinical practices and sequencing protocols vary. Herein, we present the clinical results, including annualized relapse rate (ARR) and risk of relapse, of a phase 4 retrospective observational study of patients with RRMS who switched from natalizumab to DMF in a community practice setting (STRATEGY). METHODS: STRATEGY was performed through a single time point medical record abstraction; no study visits or procedures were required. Key inclusion criteria included age ≥ 18 years, RRMS diagnosis (McDonald criteria, 2010 revised), ≥ 12 months of continuous treatment with natalizumab monotherapy before DMF initiation, and initiation of DMF ≥ 12 months before enrollment. Patients were eligible to enroll regardless of current DMF use. RESULTS: A total of 530 patients at 45 US sites enrolled, and 506 met the inclusion criteria and were included in the modified evaluable population for analysis. Mean (SD) age at DMF initiation was 47.0 (10.9) years, with a mean (SD) of 12.7 (7.2) years since MS diagnosis. The mean (SD) duration of natalizumab treatment was 3.4 (1.9) years, and the mean (SD) washout from natalizumab discontinuation to DMF initiation (n = 502) was 101.6 (164.0) days. Overall risk of relapse 12 months after DMF initiation was 19.6%. Overall unadjusted ARR was higher during the 12 months following initiation of DMF treatment compared with the 12 months following initiation of natalizumab treatment (rate ratio, 2.32 [95% CI, 1.69-3.18]; p < 0.0001), but was lower compared with that observed in the year before initiation of natalizumab (rate ratio, 0.51 [95% CI, 0.40-0.64]; p < 0.0001). At 1 year following initiation of DMF treatment, the relapse rate was lower for patients who did not experience a relapse during 1 year following initiation of natalizumab treatment than for those who did (rate ratio for relapse rate, 0.47 [95% CI, 0.16-1.38]; p = 0.1664). The relapse rate for patients who did not relapse during natalizumab treatment was significantly lower with a washout period of ≤ 90 days as compared with a washout period of > 90 days (rate ratio for relapse rate, 0.49 [95% CI, 0.26-0.90]; p = 0.0216). A total of 42 (8%) patients reported ≥ 1 adverse event leading to DMF discontinuation during the study; the most commonly reported events were gastrointestinal disorders (n = 21; 4%). CONCLUSIONS: Results from this multicenter retrospective observational study suggest that DMF may be an effective treatment option for patients who discontinue natalizumab in routine clinical practice. ARR was lower in patients who initiated DMF within 90 days of natalizumab discontinuation compared with patients who initiated DMF after 90 days of natalizumab discontinuation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02159573.
BACKGROUND: Delayed-release dimethyl fumarate (DMF) may be a therapeutic option for patients with relapsing-remitting multiple sclerosis (RRMS) who are treated with natalizumab and require a change in therapy. However, there is limited information regarding predictors of favorable treatment outcomes in patients switching from natalizumab to DMF. Clinical practices and sequencing protocols vary. Herein, we present the clinical results, including annualized relapse rate (ARR) and risk of relapse, of a phase 4 retrospective observational study of patients with RRMS who switched from natalizumab to DMF in a community practice setting (STRATEGY). METHODS: STRATEGY was performed through a single time point medical record abstraction; no study visits or procedures were required. Key inclusion criteria included age ≥ 18 years, RRMS diagnosis (McDonald criteria, 2010 revised), ≥ 12 months of continuous treatment with natalizumab monotherapy before DMF initiation, and initiation of DMF ≥ 12 months before enrollment. Patients were eligible to enroll regardless of current DMF use. RESULTS: A total of 530 patients at 45 US sites enrolled, and 506 met the inclusion criteria and were included in the modified evaluable population for analysis. Mean (SD) age at DMF initiation was 47.0 (10.9) years, with a mean (SD) of 12.7 (7.2) years since MS diagnosis. The mean (SD) duration of natalizumab treatment was 3.4 (1.9) years, and the mean (SD) washout from natalizumab discontinuation to DMF initiation (n = 502) was 101.6 (164.0) days. Overall risk of relapse 12 months after DMF initiation was 19.6%. Overall unadjusted ARR was higher during the 12 months following initiation of DMF treatment compared with the 12 months following initiation of natalizumab treatment (rate ratio, 2.32 [95% CI, 1.69-3.18]; p < 0.0001), but was lower compared with that observed in the year before initiation of natalizumab (rate ratio, 0.51 [95% CI, 0.40-0.64]; p < 0.0001). At 1 year following initiation of DMF treatment, the relapse rate was lower for patients who did not experience a relapse during 1 year following initiation of natalizumab treatment than for those who did (rate ratio for relapse rate, 0.47 [95% CI, 0.16-1.38]; p = 0.1664). The relapse rate for patients who did not relapse during natalizumab treatment was significantly lower with a washout period of ≤ 90 days as compared with a washout period of > 90 days (rate ratio for relapse rate, 0.49 [95% CI, 0.26-0.90]; p = 0.0216). A total of 42 (8%) patients reported ≥ 1 adverse event leading to DMF discontinuation during the study; the most commonly reported events were gastrointestinal disorders (n = 21; 4%). CONCLUSIONS: Results from this multicenter retrospective observational study suggest that DMF may be an effective treatment option for patients who discontinue natalizumab in routine clinical practice. ARR was lower in patients who initiated DMF within 90 days of natalizumab discontinuation compared with patients who initiated DMF after 90 days of natalizumab discontinuation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02159573.
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