In 2 post hoc subgroup analyses of newly diagnosed patients,
TECFIDERA Demonstrated Efficacy at 2 Years That
Was Sustained at 6 Years1-4

See pivotal trial data for context
Post hoc subgroup analysis of DEFINE/CONFIRM

Gold, et al 2015 Study Design: A 2-year, integrated post hoc subgroup analysis, including the intent-to-treat population of DEFINE and CONFIRM, assessed the efficacy and safety of TECFIDERA in 678 patients newly diagnosed with RMS within 1 year prior to the study who had not been previously treated with a disease-modifying therapy. Data were collected from the primary and additional efficacy endpoints and incidence of AEs in the two pivotal phase 3 trials, DEFINE and CONFIRM.

Limitations: Post hoc analysis results should be interpreted with caution. Study was not designed in advance to analyze endpoints in the subgroup of newly diagnosed patients.

TECFIDERA demonstrated a reduction in ARR at 2 years vs placebo1*

ARR at 2 years
ARR at 2 years

Adapted with permission from SAGE Publications, Inc.

TECFIDERA reduced the risk of relapse at 2 years vs placebo

*ARR was calculated using a negative binomial regression model adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40 years), study, region, and number of relapses in the 1 year prior to DEFINE/CONFIRM study entry.

TECFIDERA delayed 12-week confirmed disability progression at 2 years
vs placebo†

Disability progression at 2 years
Disability progression at 2 years

Adapted with permission from SAGE Publications, Inc.

93% of newly diagnosed patients taking TECFIDERA remained free of disability progression at 2 years compared with 77% taking placebo

†Estimated proportion of patients with disability progression at week 96 was derived using Kaplan-Meier analysis. HR, 95% CI, and P value were based on a stratified Cox proportional hazards model with study as the stratifying variable, adjusted for baseline EDSS score (as a continuous variable), baseline age (<40 vs ≥40), and region.

Safety

  • Incidence of AEs is consistent with that of the overall integrated population in DEFINE/CONFIRM
  • Most common AEs (incidence ≥10% and ≥3% more than placebo) for TECFIDERA: flushing, nasopharyngitis, headache, diarrhea, nausea, and abdominal pain
  • Incidence of AEs leading to discontinuation of treatment in this subgroup was 5% and 12% in the placebo and TECFIDERA groups, respectively, compared with 12% and 14% in the overall safety population

ARR=annualized relapse rate; DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS4; CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis5; AEs=adverse events; CI=confidence interval; EDSS=Expanded Disability Status Scale; HR=hazard ratio.

Interim subgroup analysis of ENDORSE extension study

Gold, et al 2016 Study Design: A post hoc, subgroup, multicenter, parallel-group, randomized, dose-comparison analysis of the 6-year interim integrated data from the extension study, ENDORSE, as well as the two pivotal, phase 3 clinical trials, DEFINE and CONFIRM, assessed the long-term efficacy of TECFIDERA in a subset of 229 newly diagnosed patients with RMS with 6-year minimum follow-up. Patients were considered newly diagnosed with RMS according to the McDonald criteria within 1 year prior to entry into DEFINE and CONFIRM, and were either treatment naive or previously treated with corticosteroids. Enrollment in ENDORSE was at week 96, the last visit of the parent trial and the baseline visit for the extension. 144 newly diagnosed patients received continuous TECFIDERA treatment in DEFINE/CONFIRM and ENDORSE. 85 newly diagnosed patients received placebo for 2 years in DEFINE/CONFIRM, followed by 4 years of TECFIDERA in ENDORSE. The primary objective of ENDORSE was to evaluate the long-term safety of TECFIDERA in RMS.

Limitations: ENDORSE is an open-label extension study. This is a post hoc analysis in which efficacy was a secondary objective. The newly diagnosed subgroup was limited by the small sample size. There may be bias due to the disproportionate discontinuation of patients experiencing AEs or suboptimal efficacy during the extension period, or because not all patients who completed the DEFINE or CONFIRM trials chose to enroll in ENDORSE. These are interim data of an ongoing study. Results are subject to change until study is completed.

TECFIDERA demonstrated a sustained reduction in ARR at 6 years2*†

ARR at 6 years
ARR at 6 years

*Continuous treatment refers to patients who were treated with TECFIDERA in DEFINE/CONFIRM and continued on TECFIDERA in ENDORSE. †Delayed treatment refers to patients who were treated with placebo in DEFINE/CONFIRM and were treated with TECFIDERA in ENDORSE.

Continuous TECFIDERA treatment reduced 24-week confirmed disability progression vs delayed TECFIDERA over 6 years‡

Disability progression at 6 years
Disability progression at 6 years

Adapted with permission from Springer Nature: Neurol Ther. Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing-Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies, Gold et al, 2016.

84% of newly diagnosed patients receiving continuous TECFIDERA treatment remained free of disability progression at 6 years vs 76% with delayed treatment

‡Confirmed progression of disability is defined as >1.0-point increase on EDSS from a baseline EDSS score >1.0 confirmed for 24 weeks or >1.5-point increase on EDSS from a baseline EDSS score of 0 confirmed for 24 weeks. Patients were censored if they withdrew from the study or switched to alternative MS medication without progression.

Safety

  • Incidence of AEs is consistent with that of the overall safety population in ENDORSE
  • In the ENDORSE overall safety population, most common AEs were MS relapse and nasopharyngitis in patients receiving continuous TECFIDERA treatment, while flushing and GI events were more common in patients receiving delayed TECFIDERA treatment
  • Most common AEs (incidence ≥10%) for patients receiving continuous TECFIDERA: MS relapse, nasopharyngitis, upper respiratory tract infection, urinary tract infection, flushing, headache, diarrhea, back pain, pain in extremity, and fatigue

ARR=annualized relapse rate; DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS4; CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis5; ENDORSE=A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in Subjects With Relapsing-Remitting Multiple Sclerosis6; RMS=relapsing multiple sclerosis; AEs=adverse events; PBO=placebo; TEC=TECFIDERA; CI=confidence interval; HR=hazard ratio; EDSS=Expanded Disability Status Scale.

References: 1. Gold R, et al. Mult Scler. 2015;21(1):57-66. 2. Gold R, et al. Neurol Ther. 2016;5(1):45-57. 3. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 4. Gold R, et al. N Engl J Med. 2012;367(12):1098-1107. Erratum in: N Engl J Med. 2012;367(24):2362. 5. Fox RJ, et al. N Engl J Med. 2012;367(12):1087-1097. Erratum in: N Engl J Med. 2012;367(17):1673. 6. BG00012 Monotherapy Safety and Efficacy Extension Study in Multiple Sclerosis (MS) (ENDORSE). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT00835770. Accessed April 22, 2019.

INDICATION

TECFIDERA® (dimethyl fumarate) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Important Safety Information

TECFIDERA® (dimethyl fumarate) 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.

INDICATION

TECFIDERA® (dimethyl fumarate) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

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