Explore the efficacy of DMTs in RRMS

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.

A retrospective, observational, propensity score matching, comparative effectiveness analysis of data from the German NeuroTransData (NTD) registry.¹ Study design and limitations

TECFIDERA: Real-World Effectiveness Compared
To Other DMTs¹

Pivotal Trial Results^2-4

In the 2-year DEFINE and CONFIRM pivotal trials, TECFIDERA demonstrated a 53% and 44% relative reduction in annualized relapse rate (ARR) vs placebo, respectively (0.172 vs 0.364; P<0.0001), (0.224 vs 0.401; P<0.0001).

DEFINE*

(n=410 for TECFIDERA; n=408 for placebo)

CONFIRM^†

(n=359 for TECFIDERA; n=363 for placebo)

TECFIDERA efficacy compared to other DMTs across clinical measures of relapse¹

Primary Outcome: Time to First Relapse (TTFR) for TECFIDERA vs Comparator DMTs

Treatment comparison groups included interferons, Copaxone^® (glatiramer acetate), Aubagio^® (teriflunomide), or Gilenya^® (fingolimod)

Graph shows TECFIDERA TTFR results vs interferons, Copaxone, Aubagio, and Gilenya

Selected Important Safety Information

Secondary Outcome: ARR for TECFIDERA
vs Comparator DMTs

Graph shows TECFIDERA ARR results compared to interferons, Copaxone, Aubagio, and Gilenya

^‡

Pairwise data are not shown but can be found in the manuscript of the Braune study.

Discontinuation information¹

•

AEs and patient decision for nonmedical reasons were the main reasons for discontinuation in the TECFIDERA, interferons, Copaxone, Aubagio, and Gilenya populations

Time to Discontinuation (TTD):

•

TTD was found to be similar between TECFIDERA and interferons, Copaxone, and Aubagio

•

Patients treated with Gilenya had a longer TTD compared to patients treated with TECFIDERA

Explore the clinical
profile of TECFIDERA

STUDY DESIGN:

A retrospective, observational, propensity score matching (PSM)^§, comparative effectiveness analysis of data from the German NeuroTransData (NTD) MS registry, a network of 78 neurologists in 153 offices throughout Germany.

•

The study population included patients with RRMS aged ≥18 years with a valid EDSS assessment and/or relapse after index therapy initiation

−	For comparisons with interferons, Copaxone, and Aubagio, patients were treatment naive or could have received prior treatment with any of these 3 therapies, other than the therapy being compared
−	For comparisons with the overall (all-comer) Gilenya population, patients were either treatment naive or had switched from pretreatment with interferons, Copaxone, or Aubagio, with a treatment gap of up to 6 months
−	For comparisons with the Gilenya EU label subgroup, patients were previously treated with interferons, Copaxone, or Aubagio and had an on-therapy relapse within the last 12 months, indicating treatment failure on prior therapy, with a treatment gap of up to 6 months

•

Patients treated with TECFIDERA were matched in a pairwise fashion with patients in groups treated with interferons (n=439), Copaxone (n=535), Aubagio (n=388), the overall (ie, all-comer) Gilenya population (n=457), and the Gilenya EU label population (n=99)

•

1:1 propensity score matching was used to match measured baseline characteristics of TECFIDERA populations to each comparator population^||

−	Primary outcome: Time to first relapse (TTFR)
−	Secondary outcomes: Annualized relapse rate (ARR); proportion of relapse-free patients at 12 and 24 months; time to index therapy discontinuation and reasons for discontinuation
−	Non-pairwise censoring was the primary analysis method for all major outcome measurements. However, pairwise censoring was performed as a predefined sensitivity analysis^‡

STUDY LIMITATIONS:

•

Results should be interpreted with caution given the observational and retrospective nature of this study, and no formal sample size was precalculated

•

Results may not be entirely representative of the general population since the investigation included only patients from the German NTD registry, a national database

•

Propensity score matching is only based on measured confounders and cannot account for unmeasured confounders, hence there may be hidden biases

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

^‡

Pairwise data are not shown but can be found in the manuscript of the Braune study.

^§

PSM is a method that reduces the impact of confounding and selection/indication biases and balances the distributions of covariates across treatment groups, approximating a randomized study design.

^||

Covariates in this study included age, gender, disease duration, treatment history (number of prior DMTs), baseline EDSS score, and total number of relapses in the past 12 and 24 months.

CI=confidence interval; DMTs=disease-modifying therapies; EDSS=Expanded Disability Status Scale.

Copaxone, Augabio, and Gilenya are registered trademarks of Teva Neuroscience, Inc., Genzyme Corporation, and Novartis AG, respectively.

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.

References 1. Braune S, et al. J Neurol.
2018;265(12):2980-2992. 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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