TECFIDERA Efficacy Compared to Other DMTs Across Clinical Measures of Relapse1

See pivotal trial
data for context

Braune, et al 2018 Study Design and Methodology:

  • 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
  • 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†
  • Propensity scores were calculated using multiple logistic regression with the treatment cohort as the dependent variable and the following confounders at index therapy initiation as independent variables: age, sex, disease duration (from first clinical symptom to start of index therapy), treatment history (number of previous therapies), baseline EDSS score and total number of relapses in the past 12 and 24 months (based on actual follow-up period before index therapy initiation) 
  • Non-pairwise censoring was the primary analysis method for all major outcome measurements. However, pairwise censoring was performed as a predefined sensitivity analysis‡

Study Population:

  • 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 pretreatemend 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

Outcome Measurements:

  • Primary: Time to first relapse (TTFR)
  • Secondary: ARR, proportion of relapse-free patients at 12 months and 24 months, time to index therapy discontinuation and reasons for discontinuation

Limitations:

  • Results should be interpreted with caution because of the observational and retrospective nature of this study and because no formal sample size was precalculated
  • Results may not be entirely representative of the general RRMS population, because the investigation included only patients from the German NTD registry, a national database
  • PSM is based only on measured confounders and cannot account for unmeasured confounders; hence, there may be hidden biases

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

Relapse rate based on TTFR was
lower in the TECFIDERA population vs
the interferons, Copaxone, and
Aubagio populations, and similar to
Gilenya populations

ARR for TECFIDERA vs Comparator DMTs

TECFIDERA had a lower ARR
vs the interferons, Copaxone,
and Aubagio populations, and a
similar ARR to Gilenya

*PSM is a method that helps reduce the impact of confounding and selection/indication biases to better balance the distributions of covariates across treatment groups, approximating a randomized study design.

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

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

§All relapse results from the non-pairwise censored analysis were confirmed by the pairwise censoring relapse results.

TECFIDERA vs Gilenya: Similar Results in Time to First Relapse

Results of the analysis comparing TECFIDERA to Gilenya showed no evidence of a difference in time to first relapse (TTFR) in the all-comer population. TTFR was also similar in patients meeting the EU label criteria for Gilenya and who had failed prior therapy with interferons, Copaxone, or Aubagio with an on-therapy relapse in the last 12 months and a treatment gap of up to 6 months.

TTFR: TECFIDERA vs Gilenya,
All-Comer Population

Adapted with permission of the authors.

  • 84% of patients receiving TECFIDERA were relapse-free at 12 months vs 81% receiving Gilenya
  • 74% of patients receiving TECFIDERA were relapse-free at 24 months vs 73% receiving Gilenya

TECFIDERA vs Gilenya,
EU Label Population

Adapted with permission of the authors.

  • 74% of patients receiving TECFIDERA were relapse-free at 12 months vs 73% receiving Gilenya
  • 57% of patients receiving TECFIDERA were relapse-free at 24 months vs 63% receiving Gilenya

Reasons for discontinuation of therapy

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

Time to discontinuation

  • Time to discontinuation (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

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

Please see full Prescribing Information.

RRMS=relapsing-remitting multiple sclerosis; EDSS=Expanded Disability Status Scale; DMTs=disease-modifying therapies; EU=European Union;
ARR=annualized relapse rate.

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

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