Explore the efficacy of DMTs in RRMS

{{customText[Here are the real-world efficacy data we discussed|More about RRMS therapies in a real-world analysis|Find out about a real-world analysis of RRMS patients|How DMTs performed across clinical measures of relapse]}}

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.

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

Dear {{customText[Dr.|Mr.|Mrs.|Ms.|]}} {{accFname}} {{accLname}},

{{customText[Thank you for your interest in TECFIDERA.|Thanks for taking the time to let me share the recent findings about TECFIDERA.|Thanks for your interest in the Braune analysis about the real-world comparative efectiveness of DMTs.|Would you like to hear more about how TECFIDERA performed in a real-world analysis of DMTs?|I’d like to schedule time to talk with you about the efficacy of DMTs in RRMS treatment.]}} {{customText[As a continuation of our discussion, I would like to review some results from TECFIDERA pivotal trials as well as a real-world comparative effectiveness analysis of DMTs in RRMS.|Here is some information on TECFIDERA pivotal trials, along with results from a real-world analysis comparing the clinical efficacy of TECFIDERA to interferons, Copaxone® (glatiramer acetate), Aubagio® (teriflunomide), and Gilenya® (fingolimod).|As a follow-up to our meeting, I wanted to share some more data with you about TECFIDERA pivotal trials and the real-world effectiveness of TECFIDERA vs other DMTs.|Here’s some information that may interest you about TECFIDERA pivotal trials as well as how TECFIDERA compared to other RRMS therapies in a real-world analysis.|See below for information about TECFIDERA pivotal trials as well as a real-world comparative efficacy analysis by Braune, which analyzed the relapse efficacy of TECFIDERA vs other RRMS therapies.]}}

Pivotal Trial Results^1-3

In the 2-year DEFINE* and CONFIRM^† pivotal trials in RRMS patients, TECFIDERA demonstrated a 53% and 44% relative reduction in annualized relapse rate (ARR) vs placebo, respectively (DEFINE: 0.172 vs 0.364; P<0.0001; n=410 for TECFIDERA; n=408 for placebo. CONFIRM: 0.224 vs 0.401; P<0.0001; n=359 for TECFIDERA; n=363 for placebo).

Important Safety Information

CONTRAINDICATIONS

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

TECFIDERA Showed Improved Clinical Relapse Measures vs Most Comparator DMTs⁴

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.

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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

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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)

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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:

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

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

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

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

Important Safety Information (cont'd)

WARNING 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

Secondary Outcome: ARR for TECFIDERA
vs Comparator DMTs

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

Discontinuation Information:

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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):

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

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

Explore the clinical
profile of TECFIDERA

{{customText[I hope you’ve found this information interesting. Please reach out if you have any further questions.|I’m glad we were able to discuss pivotal trial results as well as these real-world findings comparing the relapse efficacy of TECFIDERA to other DMTs. If you would like more information, please don't hesitate to ask.|I hope this information about TECFIDERA has been relevant to your practice, and I look forward to speaking with you again soon.|Please reach out if you have any questions about this analysis, or if there’s any other information about TECFIDERA that I can provide.|I hope you have found this information about TECFIDERA interesting, and I look forward to meeting with you to discuss it in more detail.]}}

Important Safety Information (cont'd)

WARNING AND PRECAUTIONS (CONT'D)

Progressive Multifocal Leukoencephalopathy (PML)

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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

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PML has occurred in the postmarketing setting in the presence of lymphopenia (<0.8 x 10⁹/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 <0.5 x 10⁹/L

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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

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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

Lymphopenia

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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. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5 x 10⁹/L. The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with DMF or placebo, respectively. 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)

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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

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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 >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. Decisions about whether or not to restart TECFIDERA should be individualized based on clinical circumstances

Liver Injury

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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

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

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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

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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

MOST COMMON ADVERSE REACTIONS

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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%), and nausea (12% vs 9%)

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

PREGNANCY

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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
and Patient Information.

{{customText[Best,|Kind regards,|Regards,|Sincerely,|Thanks,|Thank you,]}}

Biogen Representative

DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS.²

^†

CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.³

^‡

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

^§

For comparisons with interferons, Copaxone, and Aubagio, patients were treatment naive or could have received prior treatment with any of these 3 therapies. 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.

^||

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.

^¶

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

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.

1. TECFIDERA Prescribing Information, Biogen, Cambridge, MA 2. Gold R, et al. N Engl J Med. 2012;367(12):1098-1107. Erratum in: N Engl J Med. 2012;367(24):2362. 3. Fox RJ, et al. N Engl J Med. 2012;367(12):1087-1097. Erratum in: N Engl J Med. 2012;367(17):1673. 4. Braune S, et al. J Neurol. 2018;265(12):2980-2992.

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