In patients who discontinued Copaxone® (glatiramer acetate) after suboptimal response,* TECFIDERA Improved Clinical Measures of Relapse and the Majority of Patient-Reported Outcomes1

See pivotal trial
data for context

RESPOND Study Design and Methodology:

  • Phase 4, prospective, open-label, single-arm, 12-month observational trial conducted at 63 sites in the United States

Study Population:

  • Inclusion: ≥18 years of age, received treatment with Copaxone, experienced suboptimal response* to Copaxone or discontinued treatment with Copaxone for RMS after a suboptimal response within 30 days of enrollment
  • Exclusion: Presented with major comorbid conditions as determined by the prescribing physician, history of malignancy, current serious infection, enrolled in other studies, or received previous treatment with TECFIDERA

Outcome Measurements:

  • Primary: ARR at 12 months
  • Secondary: PPR at 12 months and change in PRO scores from baseline to 12 months. Safety as assessed by adverse events (AEs) and serious adverse events (SAEs) leading to treatment discontinuation was an additional endpoint 

Limitations:

  • Results should be interpreted with caution due to the observational nature of the study and lack of a control group, lack of a randomized or serial-selection protocol since patients were self selected, and potential bias due to regression to the mean 

*Suboptimal response=perceived suboptimal efficacy, intolerance,
or poor adherence to Copaxone, as determined by the
prescribing physician.

More patients were relapse-free after 12 months of TECFIDERA
vs the prior
12 months on Copaxone

Primary Endpoint

Unadjusted ARR 12 months before
and after TECFIDERA initiation

Rate ratio (95% CI): 0.22 (0.14-0.34)

Adapted with permission from Elsevier Inc.

Secondary Endpoint

Proportion of Patients With Relapses

†Estimated PPR is based on Kaplan-Meier curve (8% of TECFIDERA patients relapsed in the 12 months after TECFIDERA initiation compared with 41% who relapsed in the 12 months before TECFIDERA initiation). 
‡Observed PPR. Over 12 months of treatment with TECFIDERA, 7% (22/318) of patients relapsed.

Mean changes in PRO scores from baseline to month 12
Measure Description Component Mean (SD) Change in Score Results
SF-36 8 multi-item domains
(36-item questionnaire)
assess physical and mental
components of MS 		Physical summary
(n=217)		 1.63 (10.46) Improved
Mental summary
(n=215)		 1.71 (9.03) Improved
MFIS-5 5 items assess how fatigue
impacts patients’ lives		 (n=226) –0.88 (3.51) Improved
TSQM-14 14 items assess patient
treatment satisfaction		 Effectiveness
(n=225)		 14.69 (24.30) Improved
Side effects
(n=222)		 8.39 (27.99) Improved
Convenience
(n=222)		 30.19 (21.81) Improved
Global
(n=219)		 19.30 (26.03) Improved
WPAI-MS 6 items assess the number of
work hours missed, impact
on productivity, and daily
activities during past 7 days		 Work impairment†
(n=108)		 –4.31 (23.61) Improved
Activity impairment
(n=218)		 –2.11 (20.86) Stable‡
BDI-7 7 items assess depression
during the past 2 weeks		 (n=226) –0.54 (2.99) Improved
PR-EDSS Assesses disease progression
as reported by the patients		 (n=222) –0.01 (1.30) Stable‡

Mean changes in PRO scores from baseline to month 12

Improved Score
Stable Score‡
Measure
Component

SF-36

8 multi-item domains (36-item questionnaire) assess physical and mental components of MS

Physical Summary

(n=217) Mean (SD) Change in Score:
1.63 (10.46)
Mental Summary (n=215) Mean (SD) Change in Score:
1.71 (9.03)

MFIS-5

5 items assess how fatigue impacts patient's lives		 (n=226) Mean (SD) Change in Score:
-0.88 (3.51)

TSQM-14

14 items assess patient treatment satisfaction

Effectiveness

(n=225)

Mean (SD) Change in Score:

14.69 (24.30)

Side Effects

(n=222) Mean (SD) Change in Score:

8.39 (27.99)

Convenience

(n=222) Mean (SD) Change in Score:

30.19 (21.81)

Global

(n=219) Mean (SD) Change in Score:

19.30 (26.03)
WPAI-MS
6 items assess the number of work hours missed, impact on productivity, and daily activities during past 7 days

Work Impairment†

(n=108) Mean (SD) Change in Score:
-4.31 (23.61)

Activity Impairment

(n=218) Mean (SD) Change in Score:
-2.11 (20.86)

BDI-7

7 items assess depression during the past 2 weeks		 (n=226) Mean (SD) Change in Score:
-0.54 (2.99)

PR-EDSS

Assesses disease progression as reported by the patients		 (n=222) Mean (SD) Change in Score:
-0.01 (1.30)

*Suboptimal response=perceived suboptimal efficacy, intolerance, or poor adherence to Copaxone, as determined by the prescribing physician. †Assessment was performed only for those patients working. ‡A PRO score was considered stable if it had little or no change in either direction. SF-36=36-item Short Form Health Survey. Higher score indicates improved functioning (range 0–100); MFIS-5=5-item Modified Fatigue Impact Scale. Lower score indicates improved functioning (range 0–20); TSQM-14=14-item Treatment Satisfaction Questionnaire for Medication. Higher score indicates satisfaction (range 0–100); WPAI-MS=Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis. Higher score indicates higher impairment and lower productivity; BDI-7=7-item Beck Depression Inventory. Lower score indicates less severe depressive symptoms (range 0–21); PR-EDSS=Patient-Reported Expanded Disability Status Scale. Mean change in PROs from baseline to 12 months was assessed using a Wilcoxon signed-rank test.

SAEs and AEs leading to discontinuation

  • Of the 328 patients included in the safety
    population, 18% (60/328) experienced ≥1
    AE leading to treatment
    discontinuation,
    and 2% (5/328) experienced ≥1 SAE
    leading to treatment discontinuation
  • Most common SAEs were cardiac
    disorders (4/328) and vascular disorders
    (3/328)
  • The AEs most commonly leading to
    treatment discontinuation were gastrointestinal (GI) disorders (10%), skin

    and subcutaneous tissue disorders (3%),
    and vascular disorders (2%)
  • The incidence of AEs leading to treatment discontinuation due to GI disorders (10%)
    was higher than those
    reported in DEFINE
    (5%) and CONFIRM (3%) trials

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

  • The TECFIDERA pregnancy registry study is now closed

Please see full Prescribing Information.

PRO=patient-reported outcome; RMS=relapsing multiple sclerosis; ARR=annualized relapse rate; PPR=proportion of patients relapsed; CI=confidence interval; DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS2; CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.3

References: 1. Kresa-Reahl K, et al. Clin Ther. 2018;40(12):2077-2087. 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. 

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