Efficacy & Clinical Trials | Tecfidera® (dimethyl fumarate)
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`https://www.tecfiderahcp.com/en_us/home/efficacy/confirm-trial.html
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`Important Safety Information
`TECFIDERA Warnings and Precautions include: Anaphylaxis and Angioedema, Progressive Multifocal
`Leukoencephalopathy, Lymphopenia, Liver Injury, and Flushing.
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`EXPAND
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`CONFIRM* Trial Efficacy
`SIGNIFICANTLY REDUCED RISK AND FREQUENCY OF
`RELAPSES1
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`Biogen Exhibit 2192
`Mylan v. Biogen
`IPR 2018-01403
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`Page 1 of 4
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`Efficacy & Clinical Trials | Tecfidera® (dimethyl fumarate)
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`https://www.tecfiderahcp.com/en_us/home/eflicacylconfirm—t1ial.hunl
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`V
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`SIGNIFICANTLY REDUCED ALL MEASURES OF MRI ACTIVITY1
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`
`
`O
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`O
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`0
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`Mean number at Gd+
`lesions at 2 years
`mm” 2 0_ lemon: 0 5, 9,“ mm
`TFFFIDFRA rl—IA7_ Dlalubr‘ n-lu
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`Mean number of new or
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`newly enlarging 1'2 lesions
`over 2 years
`Placeno m TEEF DERA 51.941000]
`TECF DEW "'11:? placebo "-W-
`
`Mean number of new T1
`lesions over 2 years
`Hm‘ehn7 c TFCFITIFRA -l n, m :cnl
`TECFIDERA '1: m Placebo —.=l.ll
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`DELAYED DISABILITY PROGRESSION1
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`%
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`
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`REUTWE RISK
`REDUCTION.
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`The reduction in the proportion with disability progression
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`was not statistically significant‘
`Placebo 17%; TECFIDERA 13%; P=0_25
`TECFIDERA n=359; Placebo n=363
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`Defining Disability Progression: At least a 1-point increase from
`baseline EDSS of 21.0, OR at least a 15-point increase for patients with
`baseline EDSS of 0 sustained for 12 weeks.1
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`a see the safety profile of TECFIDERA >
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`Efficacy & Clinical Trials | Tecfidera® (dimethyl fumarate)
`
`https://www.tecfiderahcp.com/en_us/home/efficacy/confirm-trial.html
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`Indication
`Tecfidera (dimethyl fumarate) is indicated for the treatment of patients with relapsing forms of multiple
`®
`sclerosis.
`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.
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`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 (<0.8x10 /L)
`9
`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 <0.5x10 /L. The symptoms associated
`9
`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.
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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
`9
`9
`9
`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
`9
`at least six months. In these patients, the majority of lymphocyte counts remained <0.5x10 /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.
`9
`Consider treatment interruption if lymphocyte counts <0.5x10 /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.
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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
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`Efficacy & Clinical Trials | Tecfidera® (dimethyl fumarate)
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`https://www.tecfiderahcp.com/en_us/home/efficacy/confirm-trial.html
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`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.
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`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.
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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%), 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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`Please see full Prescribing Information and Patient Information for additional Important Safety
`Information.
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`*Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.
`2
`Relapses were defined as new or recurrent neurologic symptoms not associated wi h fever or infection that lasted for at least 24 hours and were accompanied by new
`†
`objective neurologic findings.
`2
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`References: 1. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 2. 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. 3. 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.
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`© 2019 Biogen. All Rights Reserved. 02/19
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