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Indication

Tecfidera^®(dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Please see below for Important Safety Information, and see here for full Prescribing Information.

RESPOND Study: A Phase IV, open-label, single-arm, 12-month observational trial.
Study design and limitations

TECFIDERA Impacted Patient-Reported Outcomes in Patients Who Discontinued Copaxone^®(glatiramer acetate) After Suboptimal Response¹*^†


PIVOTAL TRIAL RESULTS^2-4

DEFINE^‡Results
(n=410 for TECFIDERA, n=408 for placebo)
•	Primary endpoint: PPR was 27% on TECFIDERA compared with 46% on placebo, representing a 49% relative risk reduction (P<0.0001)
•	Secondary endpoint: ARR was 0.172 on TECFIDERA compared with 0.364 on placebo, representing a 53% relative reduction (P<0.0001)

CONFIRM^§Results
(n=359 for TECFIDERA, n=363 for placebo)
•	Primary endpoint: ARR was 0.224 on TECFIDERA compared with 0.401 on placebo, representing a 44% relative reduction (P<0.0001)
•	Secondary endpoint: PPR was 29% on TECFIDERA compared with 41% on placebo, representing a 34% relative risk reduction (P=0.0020)

See here to view TECFIDERA pivotal trial study designs.

Discontinuation rates due to an adverse reaction with TECFIDERA were 14% vs 11% with placebo in 2 pivotal trials.

Suboptimal response=suboptimal efficacy, intolerance, or poor adherence to Copaxone, as determined by the prescribing physician.

Selected Important Safety Information

9 of 11 PRO components improved and 2 remained stable after 12 months of TECFIDERA treatment. See full results below:

Mean (SD) change from baseline to month 12

Mean (SD) Score:
			Improved				Stable^‖

Measure

Component

SF-36
8 multi-item domains (36-item questionnaire) assess physical and mental components of MS

		Physical summary (n=217)
		Mean (SD) Score: 1.63 (10.46)
		Mental summary (n=215)
		Mean (SD) Score: 1.71 (9.03)

MFIS-5
5 items assess how fatigue impacts patients’ lives

		(n=226)
		Mean (SD) Score: -0.88 (3.51)

TSQM-14
14 items assess patient treatment satisfaction

		Effectiveness (n=225)
		Mean (SD) Score: 14.69 (24.30)
		Side effects (n=222)
		Mean (SD) Score: 8.39 (27.99)
		Convenience (n=222)
		Mean (SD) Score: 30.19 (21.81)
		Global (n=219)
		Mean (SD) Score: 19.30 (26.03)

WPAI-MS
6 items assess the number of work hours missed, impact on productivity and daily activities during past 7 days

		Work impairment (n=108)
		Mean (SD) Score: -4.31 (23.61)
		Activity impairment (n=218)
		Mean (SD) Score: -2.11 (20.86)

BDI-7
7 items assess depression during the past 2 weeks

		(n=226)
		Mean (SD) Score: -0.54 (2.99)

PR-EDSS
Assesses disease progression as reported by the patients

		(n=222)
		Mean (SD) Score: -0.01 (1.30)

^‖	A PRO score was considered stable if it had little or no change in either direction.

PRO=patient-reported outcome; SF-36=36-item Short Form Health Survey. Higher score indicates improved functioning (range 0–100); MFIS-5=5-item Modified Fatigue Impact Scale. Lower score indicates improved functioning (range 0–20); TSQM-14=14-item Treatment Satisfaction Questionnaire for Medication. Higher score indicates higher satisfaction (range 0–100); WPAI-MS=Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis. Assessment was performed only for those patients working. Higher score indicates higher impairment and lower productivity; BDI-7=7-item Beck Depression Inventory. Lower score indicates less severe depressive symptoms (range 0–21); PR-EDSS=Patient-Reported Expanded Disability Status Scale.

Safety as assessed by AEs leading to treatment discontinuation and SAEs

•	Of the 328 patients included in the safety population, 18% (60/328) experienced ≥1 AE leading to treatment discontinuation, and 2% (5/328) experienced ≥1 SAE leading to treatment discontinuation
•	4% (14/328) of patients experienced ≥1 SAE. Most common SAEs were cardiac disorders (4/328) and vascular disorders (3/328)
•	The AEs most commonly leading to treatment discontinuation were gastrointestinal (GI) disorders (10%), skin and subcutaneous tissue disorders (3%), and vascular disorders (2%)
•	The incidence of AEs leading to treatment discontinuation due to GI disorders (10%) was higher than those reported in DEFINE (5%) and CONFIRM (3%)

Explore the demonstrated clinical profile of TECFIDERA^3,4

STUDY DESIGN:

RESPOND was a Phase IV, prospective, multicenter, open-label, single-arm, 12-month observational study conducted to evaluate clinical outcomes and patient-reported outcomes (PROs) in patients with RMS who switched from Copaxone to TECFIDERA after suboptimal response to Copaxone in real-world clinical practice. A suboptimal response was defined as suboptimal efficacy, intolerance, or poor adherence to Copaxone, as determined by the prescribing physician. 333 patients with RMS were enrolled in the study, 328 patients were used in the safety population, and 318 patients were included in the primary analysis population. Relapse data were collected from medical records, including hospitalizations due to MS relapses and MS relapses associated with intravenous or oral corticosteroid use over the 12-month study duration, to assess clinical effectiveness over the 12 months before and after TECFIDERA initiation. The primary endpoint was ARR at 12 months, and the secondary endpoints included PPR at 12 months and change in PRO scores from baseline to 12 months. Safety as assessed by AEs leading to treatment discontinuation and SAEs was an additional objective.

STUDY LIMITATIONS:

Study results should be interpreted with caution due to the observational nature of the study and lack of a control group, potential bias due to regression to the mean, and the fact that patients were self-selected for switching rather than having a randomized or serial selections protocol.

Important Safety Information

TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or any of the excipients of TECFIDERA. TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Patients experiencing signs and symptoms of anaphylaxis and angioedema (which have included difficulty breathing, urticaria, and swelling of the throat and tongue) should discontinue TECFIDERA and seek immediate medical care.

Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with TECFIDERA. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received TECFIDERA in a clinical trial. PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L) persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5x109/L. The symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.

TECFIDERA may decrease lymphocyte counts; in clinical trials there was a mean decrease of ~30% in lymphocyte counts during the first year which then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but not to baseline. Six percent of TECFIDERA patients and <1% of placebo patients had lymphocyte counts <0.5x109/L. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.

There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or ≤0.5x109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years). In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5x109/L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x109/L with continued therapy. A complete blood count including lymphocyte count should be obtained before initiating treatment, 6 months after starting, every 6 to 12 months thereafter and as clinically indicated. Consider treatment interruption if lymphocyte counts <0.5x109/L persist for more than six months and follow lymphocyte counts until lymphopenia is resolved. Consider withholding treatment in patients with serious infections until resolved. Decisions about whether or not to restart TECFIDERA should be based on clinical circumstances.

Clinically significant cases of liver injury have been reported in patients treated with TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients.

Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials.

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating TECFIDERA and during treatment, as clinically indicated. Discontinue TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected.

TECFIDERA may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). 40% of patients taking TECFIDERA reported flushing, which was mostly mild to moderate in severity. Three percent of patients discontinued TECFIDERA for flushing and <1% had serious flushing events that led to hospitalization. Taking TECFIDERA with food may reduce flushing. Alternatively, administration of non-enteric coated aspirin prior to dosing may reduce the incidence or severity of flushing.

TECFIDERA may cause gastrointestinal (GI) events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). Four percent of TECFIDERA patients and <1% of placebo patients discontinued due to GI events. The incidence of serious GI events was 1%. The most common adverse reactions associated with TECFIDERA versus placebo are flushing (40% vs 6%) and GI events: abdominal pain (18% vs 10%), diarrhea (14% vs 11%), nausea (12% vs 9%).

A transient increase in mean eosinophil counts was seen during the first two months.

TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage patients who become pregnant while taking TECFIDERA to enroll in the TECFIDERA pregnancy registry by calling 1-866-810-1462 or visiting www.TECFIDERApregnancyregistry.com.

Please see full Prescribing Information and Patient Information.

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^†

Copaxone is a registered trademark of Teva Neuroscience, Inc.

^‡

DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS.³

^§

CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.⁴

PPR=proportion of patients relapsed; ARR=annualized relapse rate; CI=confidence interval; SAE=serious adverse event; AE=adverse event.

References: 1. Kresa-Reahl K, et al. Clin Ther. 2018;40(12):2077-2087. 2. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 3. Gold R, et al. N Engl J Med. 2012;367(12):1098-1107. Erratum in: N Engl J Med. 2012;367(24):2362. 4. Fox RJ, et al. N Engl J Med. 2012;367(12):1087-1097. Erratum in: N Engl J Med. 2012;367(17):1673.

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