Clinical Trial Overview | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-trials.html
`
`Important Safety Information
`TECFIDERA Warnings and Precautions include: Anaphylaxis and Angioedema, Progressive Multifocal
`Leukoencephalopathy, Lymphopenia, Liver Injury, and Flushing.
`
`EXPAND
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`TECFIDERA Clinical Trials
`THE DEFINE* TRIAL
`
`The DEFINE trial included patients who were new to MS treatment and patients who were
`MS treatment-experienced1
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`Biogen Exhibit 2190
`Mylan v. Biogen
`IPR 2018-01403
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`Clinical Trial Overview | Tecfidera® (dimethyl fumarate)
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`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-trials.html
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`Clinical Trial Overview | Tecfidera® (dimethyl fumarate)
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`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-trials.html
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`Endpoints  2
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`Primary
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`Additional
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`Proportion of patients
`relapsed (PPR)
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`Annualized relapse rate (ARR)
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`Time to confirmed disability progression
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`Number of new or newly enlarging T2 hyperintense lesions
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`Number of Gd+ lesions
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`Number of new T1 hypointense lesions
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`Key inclusion criteria  2
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`Experienced at least 1 relapse over the year preceding the trial
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`OR
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`Had a brain magnetic resonance imaging (MRI) scan demonstrating at least 1 gadolinium-
`enhancing (Gd+) lesion within 6 weeks of randomization
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`An Expanded Disability Status Scale (EDSS) score ranging from 0 to 5
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`AND
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`Key exclusion criteria  1
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`Interferon-beta or glatiramer acetate within 3 months of randomization
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`An infusion disease-modifying therapy (DMT) within 6 months of randomization
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`Primary progressive multiple sclerosis or secondary progressive multiple sclerosis
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`Any major disease that would preclude participation in a clinical trial
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`Evaluations  2
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`Clinical Tn'al Overview | Tecfidera® (dimethyl fumarate)
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`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-u'ials.html
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`Neurological evaluations
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`Performed at baseline, every 3 months, and at time of suspected relapse
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`MRI evaluations
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`Performed in 44% of patients at baseline, month 6, and years 1 and 2
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`69% of patients treated with TECFIDERA BID completed 96 weeks of treatment
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`(compared to 65% of patients taking placebo)2
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`THE CONFIRMi TRIAL
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`The CONFIRM trial included patients who were new to MS treatment and patients who
`were MS treatment—experienced3
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`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-trials.html
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`Clinical Trial Overview | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-trials.html
`
`Endpoints  2
`
`Primary
`
`Additional
`
`Annualized Relapse Rate
`(ARR)
`
`Proportion of patients relapsed (PPR)
`
`Time to confirmed disability progression
`
`Number of new or newly enlarging T2 hyperintense lesions
`
`Number of Gd+ lesions
`
`Number of new T1 hypointense lesions
`
`Key inclusion criteria  2
`
`Experienced at least 1 relapse over the year preceding the trial
`
`OR
`
`Had a brain magnetic resonance imaging (MRI) scan demonstrating at least 1 gadolinium-
`enhancing (Gd+) lesion within 6 weeks of randomization
`
`An Expanded Disability Status Scale (EDSS) score ranging from 0 to 5
`
`AND
`
`Key exclusion criteria  3
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`Interferon-beta or glatiramer acetate within 3 months of randomization
`
`An infusion disease-modifying therapy (DMT) within 6 months of randomization
`
`Primary progressive multiple sclerosis or secondary progressive multiple sclerosis
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`Any major disease that would preclude participation in a clinical trial
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`Evaluations  2
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`Clinical Tn'al Overview | Tecfidera® (dimethyl finnarate)
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`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-u'ials.html
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`Neurological evaluations
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`Performed at baseline, every 3 months, and at time of suspected relapse
`
`MRI evaluations
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`Performed in 48% of patients at baseline, month 6, and years 1 and 2
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`70% of patients treated with TECFIDERA BID completed 96 weeks of treatment
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`(compared to 64% of patients taking placebo)2
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`;@ see how TECFIDERA significantly reduced key measures of disease activity“)
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`Indication
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`Tecfidera‘D (dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple
`sclerosis.
`
`Important Safety Information
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`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
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`or at any time during treatment. Patients experiencing signs and symptoms of anaphylaxis and
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`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
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`TECFIDERA. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that
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`typically only occurs in patients who are immunocompromised, and that usually leads to death or
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`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 (<0.8x109IL)
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`persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the
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`majority of cases occurred in patients with lymphocyte counts <0.5x109/L. The symptoms associated
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`with PML are diverse, progress over days to weeks, and include progressive weakness on one side of
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`the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and
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`orientation leading to confusion and personality changes. At the first sign or symptom suggestive of
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`PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. MRI findings may be
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`apparent before clinical signs or symptoms.
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`Clinical Trial Overview | Tecfidera® (dimethyl fumarate)
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`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-trials.html
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`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 <0.5x10 /L. TECFIDERA has not been
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`studied in patients with pre-existing low lymphocyte counts.
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`There was no increased incidence of serious infections observed in patients with lymphocyte counts
`<0.8x10 /L or 0.5x10 /L in controlled trials, although one patient in an extension study developed PML
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`in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x10 /L for 3.5 years). In
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`controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5x10 /L for
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`at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 /L with
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`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 <0.5x10 /L persist for more than six months and
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`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.
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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.
`
`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.
`
`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%).
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`A transient increase in mean eosinophil counts was seen during the first two months.
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`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.
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`Clinical Trial Overview | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/efficacy/clinical-trials.html
`
`Please see full Prescribing Information and Patient Information for additional Important Safety
`Information.
`
`*Determination of Efficacy and Safety of Oral Fumarate in Relapsing-Remit ing MS.
`1
`Study also randomized patients (n=416) to a 240 mg TID arm. TID dosing resulted in no additional benefit over 240 mg BID.
`†
`Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.
`‡
`3
`Study also randomized patients (n=345) to a 240 mg TID arm. TID dosing resulted in no additional benefit over 240 mg.
`§
`Disease activity: any change in relapse frequency, MRI activity, and/or disability progression.
`||
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`2
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`2
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`References: 1. Gold R, Kappos L, Arnold DL, et al. N Engl J Med. 2012;367:1098-1107. Erratum in: N Engl J Med. 2012;367:2362. 2. TECFIDERA Prescribing Information,
`Biogen, Cambridge, MA. 3. Fox RJ, Miller DH, Phillips JT, et al. N Engl J Med. 2012;367:1087-1097. Erratum in: N Engl J Med. 2012;367:1673.
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`© 2019 Biogen. All Rights Reserved. 02/19
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