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

CONTRAINDICATIONS

TECFIDERA® (dimethyl fumarate) is contraindicated in patients with known hypersensitivity to dimethyl fumarate or any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema.

WARNINGS AND PRECAUTIONS

Anaphylaxis and Angioedema

  • TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema

Progressive Multifocal Leukoencephalopathy (PML)

  • 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 for 4 years while enrolled in a clinical trial
  • PML has occurred in the postmarketing setting in the presence of lymphopenia (<0.9 x 109/L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts <0.8 x 109/L persisting for more than 6 months
  • At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical 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
  • Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Monitoring with MRI for signs consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present

Herpes Zoster and Other Serious Opportunistic Infections

  • Serious cases of herpes zoster have occurred with TECFIDERA, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on TECFIDERA for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered
  • Other serious opportunistic infections have occurred with TECFIDERA, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment
  • Consider withholding TECFIDERA treatment in patients with herpes zoster or other serious infections until the infection has resolved

Lymphopenia

  • TECFIDERA may decrease lymphocyte counts. In the MS placebo-controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. The incidence of infections and serious infections was similar in patients treated with TECFIDERA or placebo. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8 x 109/L or ≤0.5 x 109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5 x 109/L for 3.5 years)
  • In controlled and uncontrolled clinical trials with TECFIDERA, 2% of patients experienced lymphocyte counts <0.5 x 109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5 x 109/L with continued therapy. TECFIDERA has not been studied in patients with preexisting low lymphocyte counts
  • Obtain a CBC, including lymphocyte count, before initiating treatment with TECFIDERA, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts less than 0.5 x 109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if TECFIDERA is discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients with serious infections until resolution

Liver Injury

  • 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

Flushing

  • TECFIDERA may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). Forty percent 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 (up to 325mg) 30 minutes prior to dosing may reduce the incidence or severity of flushing

ADVERSE REACTIONS

  • The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea
  • Gastrointestinal adverse reactions: TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA
  • Hepatic transaminases: An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels < 3 times the upper limit of normal (ULN) during controlled trials. There were no elevations in transaminases ≥ 3 times the ULN with concomitant elevations in total bilirubin > 2 times the ULN. Discontinuations due to elevated hepatic transaminases were < 1% and were similar in patients treated with TECFIDERA or placebo
  • Eosinophilia adverse reactions: A transient increase in mean eosinophil counts was seen during the first two months

PREGNANCY

  • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TECFIDERA during pregnancy. Encourage patients to enroll by calling 1-866-810-1462 or visiting www.tecfiderapregnancyregistry.com

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