FIRST AND ONLY
DISEASE-MODIFYING
THERAPY PROVEN
SUPERIOR IN ARR
TRIALS vs AVONEX®,
COPAXONE®,
AND
PLACEBO IN ADULT
RRMS PATIENTS1-4

�I�m concerned about having another relapse and I want an effective oral therapy.� -A quote from an adult RRMS patient who prefers an oral DMT

Not an actual patient.

�I�m concerned about having another relapse and I want an effective oral therapy.� -A quote from an adult RRMS patient who prefers an oral DMT

RELY ON GILENYA

PROVEN EFFICACY

RELY ON GILENYA

PROVEN EFFICACY

2-YEAR STUDY
vs PLACEBO

See study

1-YEAR STUDY
vs AVONEX

See study

1-YEAR STUDY
vs COPAXONE

See study

2-Year
STUDY vs
PLACEBO

1-Year
STUDY vs
AVONEX

1-Year
STUDY vs
COPAXONE

SIGNIFICANTLY LOWER ARR IN ADULT PATIENTS WITH RRMS
TREATED WITH GILENYA vs PLACEBO1,2

SIGNIFICANTLY LOWER
ARR IN ADULT PATIENTS
WITH RRMS
TREATED WITH
GILENYA vs PLACEBO1,2

FREEDOMS was a 2-year, placebo-controlled study in adult patients with RRMS. At baseline, patients had ≥1 relapse during the prior year or ≥2 relapses during the prior 2 years, were 18 to 55 years of age, and had an EDSS score of 0.0 to 5.5 (median baseline score was 2.0).

Chart showing main takeaways from adult RRMS treatment study: GILENYA patients (0.5 mg pill) had a lower annualized relapse rate than placebo patients.

More adults were relapse-free

70% free of relapses with GILENYA 0.5 mg (n=425) vs 46% with placebo (n=418); (P<0.001)

SECONDARY END POINTS

DISABILITY PROGRESSION*

30
%

(18% vs 24%)

reduction in risk

with GILENYA vs

placebo (HR, 0.70;

95% CI, 0.52-0.96;

P

=0.02)

Derived from HR.

Gd+ T1 LESIONS

82
%

(0.2 vs 1.1)

fewer Gd+ T1 lesions

on average for GILENYA

(n=425) vs placebo

(n=418);

 P

<0.001

NEW OR NEWLY ENLARGING T2 LESIONS

74
%

(2.5 vs 9.8)

fewer T2 lesions

on average for GILENYA

(n=425) vs placebo

(n=418);

 P

<0.001

MRI evaluations were performed at screening and at 2 years for the total population.

*Confirmed at 24 months, where 3-month confirmed disability progression was defined as an increase of 1 point in the EDSS score from baseline (or half of a point increase if the baseline EDSS score was equal to 5.5) sustained for 3 months.

See full FREEDOMS study design below

SIGNIFICANTLY LOWER ARR
IN ADULT PATIENTS WITH
RRMS TREATED WITH
GILENYA vs AVONEX1,3

TRANSFORMS was a 1-year, active-controlled study vs Avonex (interferon beta-1a) injection in adult patients with RRMS. At baseline, patients had ≥1 relapse during the prior year or ≥2 relapses during the prior 2 years, were 18 to 55 years of age, and had an EDSS score of 0.0 to 5.5 (median baseline score was 2.0).

Chart showing main takeaways from adult RRMS treatment study: GILENYA patients (0.5 mg pill) had a lower annualized relapse rate than Avonex patients.

More adults were relapse-free

83% free of relapses with GILENYA 0.5 mg (n=429) vs 70% with Avonex (n=431); (P<0.001)

Secondary end point information about disability progression*, Gd + T1 lesions, and new or newly enlarging T2 lesions. *Confirmed at 12 months, where 3-month confirmed disability progression was defined as an increase of 1 point in the EDSS score from baseline (or half of a point increase if the baseline EDSS score was equal to 5.5) sustained for 3 months.

MRI evaluations were performed at screening and at 1 year for the total population.

*Confirmed at 12 months, where 3-month confirmed disability progression was defined as an increase of 1 point in the EDSS score from baseline (or half of a point increase if the baseline EDSS score was equal to 5.5) sustained for 3 months.

See full TRANSFORMS study design below

SIGNIFICANTLY LOWER
ARR IN ADULT PATIENTS
WITH
RRMS TREATED WITH
GILENYA vs COPAXONE4

ASSESS

ASSESS was a 1-year, active-controlled, randomized, double-blind, phase IIIb study vs Copaxone (glatiramer acetate injection) 20 mg in adult patients with RRMS. At baseline, patients had ≥1 relapse during the prior year or ≥2 relapses during the prior 2 years, were 18 to 65 years of age, and had an EDSS score of 0.0 to 6.0 (median baseline score was 2.5).

Chart showing main takeaways from adult RRMS treatment study: GILENYA patients (0.5 mg pill) had a lower annualized relapse rate than Copaxone patients.

First and only DMT proven superior in ARR vs both Avonex and Copaxone in adult patients with RRMS

See full ASSESS study design below

RELATIVE ARR
REDUCTIONS IN ADULT
PATIENTS WITH RRMS
ACROSS
SUBGROUPS BY AGE2,3,5

In pooled results of the GILENYA arms of FREEDOMS and TRANSFORMS, GILENYA demonstrated a consistent and/or significant reduction in ARR vs comparator in subgroups defined by age.*

  • Both studies were randomized, double-blind, parallel, placebo- or active-controlled, and designed to demonstrate the efficacy and safety of GILENYA using number of relapses as the primary end point for each study
Chart showing main takeaways from adult RRMS treatment study for patients under 40 years of age and patients over 40 years of age.

LIMITATIONS

Relative reduction percentages observed from a pooled, post hoc analysis of clinical trial data are shown. The figures above present effects in various subgroups, each of which is formed based on a baseline characteristic. The P values that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be overinterpreted.

*Patients in FREEDOMS and TRANSFORMS were between 18 and 55 years of age and included patients with baseline EDSS 0.0 to 5.5.

See full FREEDOMS and TRANSFORMS study designs below

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STUDY DESIGNS

1,2

  • A 2-year, randomized, double-blind, placebo-controlled phase Ill study of 1,272 adults with RRMS

  • Patients were randomly assigned to receive GILENYA at a once-daily dose of 0.5 mg (n=425) or 1.25 mg (n=429) or matching placebo once daily (n=418) for 2 years

  • Patient baseline characteristics

    • Between 18 and 55 years of age

    • A diagnosis of RRMS with at least 1 documented relapse during the previous year or at least 2 documented relapses during the previous 2 years

    • A score of 0.0 to 5.5 on the EDSS. Median score at baseline was 2.0

  • Primary end point: ARR

  • Key secondary end point: time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5) sustained for 3 months*

  • Additional secondary end points included number of Gd+ T1 lesions and number of new or newly enlarged lesions on T2-weighted MRI scans

  • The FDA-approved dose of GILENYA is 0.5 mg orally once daily. Doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefits

  • 81.2% (345/425) of patients assigned to GILENYA 0.5 mg completed the study on GILENYA 0.5 mg at 2 years while 18.8% (80/425) discontinued GILENYA

*The analysis of a key secondary end point includes the same intent-to-treat population as the primary end point(s), as well as logistic regression adjusting for certain baseline characteristics of the sample.

1,3

  • A 1-year, randomized, double-blind, double-dummy, active-controlled (IFNβ-1a IM), phase Ill study of 1,292 adults with RRMS

  • Patients were randomly assigned to receive GILENYA at a once-daily dose of 0.5 mg (n=431) or 1.25 mg (n=426) or IFNβ-1a IM injection at a weekly dose of 30 μg (n=435) for 1 year

  • Patient baseline characteristics

    • Between 18 and 55 years of age

    • A diagnosis of RRMS with at least 1 documented relapse during the previous year or at least 2 documented relapses during the previous 2 years

    • A score of 0.0 to 5.5 on the EDSS. Median score at baseline was 2.0

    • Previous therapy with either any type of interferon-beta or glatiramer acetate was not a criterion for exclusion

  • Primary end point: the primary objective was to demonstrate that GILENYA was superior to Avonex in terms of ARR in patients with RRMS treated for up to 12 months

  • Two key secondary end points: number of new or newly enlarged hyperintense lesions on T2-weighted MRI scans at 1 year and the time to 3-month confirmed disability progression as measured by at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5) sustained for 3 months*

  • The FDA-approved dose of GILENYA is 0.5 mg orally once daily. Doses higher than 0.5 mg are associated with a greater incidence of adverse reactions without additional benefits

  • 89.7% (385/429) of patients who received GILENYA 0.5 mg completed the study on GILENYA 0.5 mg at 1 year while 10.3% (44/429) discontinued GILENYA

*The analysis of a key secondary end point includes the same intent-to-treat population as the primary end point(s), as well as logistic regression adjusting for certain baseline characteristics of the sample.

ASSESS 4

A 1-year, randomized, dose-blind, rater-blind, active-controlled (glatiramer acetate injection) SQ phase lllb study in adults with RRMS. Patients randomly assigned to receive once-daily GILENYA 0.25 mg and 0.5 mg vs once-daily subcutaneous injections of Copaxone 20 mg. At baseline, patients with RRMS between 18 and 65 years of age (median 39) had ≥1 documented relapse during the previous year or ≥2 documented relapses during the previous 2 years, and had a score of 0.0 to 6.0 on the EDSS (median score at baseline was 2.5). The primary end point was ARR.

ARR=annualized relapse rate; CI=confidence interval; EDSS=Expanded Disability Status Scale; Gd+=gadolinium-enhancing; HR=hazard ratio; IFN=interferon; IM=intramuscular; MRI=magnetic resonance imaging; MS=multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis; SQ=subcutaneous.

Avonex is a registered trademark of Biogen.

Copaxone is a registered trademark of Teva Pharmaceutical Industries Ltd.

References: 1. Gilenya [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; December 2019. 2. Kappos L, Radue E-W, O'Connor P, et al; for FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. 3. Cohen JA, Barkhof F, Comi G, et al; for TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010.362(5):402-415. 4. Data on file. Data Analysis Report: Study CFTY720D2312. Novartis Pharmaceuticals Corp; July 2015. 5. Data on file. Summary of Clinical Efficacy in Multiple Sclerosis. Novartis Pharmaceuticals Corp; November 2009.

References: 1. Gilenya [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; December 2019. 2. Kappos L, Radue E-W, O'Connor P, et al; for FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401. 3. Cohen JA, Barkhof F, Comi G, et al; for TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010.362(5):402-415. 4. Data on file. Data Analysis Report: Study CFTY720D2312. Novartis Pharmaceuticals Corp; July 2015. 5. Data on file. Summary of Clinical Efficacy in Multiple Sclerosis. Novartis Pharmaceuticals Corp; November 2009.

Indication and Important Safety
Information

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Important Safety Information

Contraindications

  • Patients who in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure (HF) requiring hospitalization or Class III/IV HF

  • History or presence of Mobitz Type II second-degree or third-degree atrioventricular (AV) block or sick sinus syndrome, unless patient has a functioning pacemaker

Indication

GILENYA is a sphingosine 1-phosphate receptor modulator 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 patients 10 years of age and older.

Bradyarrhythmia and Atrioventricular (AV) Block: Monitor patients during GILENYA initiation because of a risk of bradyarrhythmia and AV block. Prior to dosing and at the end of the observation period, obtain an electrocardiogram (ECG) in all patients (10 years of age and older). Monitor all patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure (BP) measurement.

Continue monitoring until the abnormality resolves if any of the following is present after 6 hours: (1) The heart rate (HR) 6 hours postdose is <45 bpm in adults, <55 bpm in pediatric patients 12 years of age and older, or <60 bpm in pediatric patients 10 or 11 years of age. (2) The HR 6 hours postdose is at the lowest value postdose suggesting that the maximum pharmacodynamic effect on the heart may not have occurred. (3) The ECG 6 hours postdose shows new onset second degree or higher atrioventricular (AV) block.

Begin continuous ECG monitoring in patients with symptomatic bradycardia until resolution. If pharmacological intervention is required, continue ECG monitoring overnight in a medical facility, and repeat 6-hour monitoring after the second dose. Some patients may experience a second decrease in HR within 24 hours after the first dose.

Patients with pre-existing ischemic heart disease, history of MI or cardiac arrest, CHF, cerebrovascular disease, uncontrolled hypertension, history of symptomatic bradycardia or recurrent syncope, severe untreated sleep apnea, AV block, sinoatrial heart block, or on concomitant drugs that slow HR or AV conduction should be evaluated by a physician and, if treated with GILENYA, monitored overnight with continuous ECG in a medical facility after first dose due to higher risk of symptomatic bradycardia or heart block. Patients with or at risk for QT prolongation or on concomitant QT-prolonging drugs with a known risk of torsades de pointes should also be monitored overnight with continuous ECG.

Repeat first-dose monitoring if GILENYA is interrupted ≥1 day within first 2 weeks or >7 days during weeks 3 and 4, or >14 days after the first month of treatment because effects on HR and AV conduction may occur upon reinitiation. First-dose monitoring is also recommended when the dose is increased in pediatric patients switching from 0.25 mg to 0.5 mg.

Infections: GILENYA may increase risk of infections. Life threatening and fatal infections have occurred in association with GILENYA. A recent CBC should be available before initiating GILENYA. Consider suspending GILENYA if a patient develops a serious infection. Monitor for signs and symptoms of infection during treatment and up to 2 months after discontinuation. Do not start GILENYA in patients with active acute or chronic infections until infection is resolved. Two patients receiving a higher than recommended dose of GILENYA (1.25 mg) in conjunction with high-dose corticosteroid therapy died of herpetic infections. In the postmarketing setting with GILENYA, serious infections, some fatal, have been reported with opportunistic pathogens, including viruses (eg, John Cunningham virus [JCV], herpes simplex viruses 1 and 2, varicella zoster virus [VZV]), fungi (eg, cryptococci), bacteria (eg, atypical mycobacteria), and Kaposi's sarcoma. Patients with signs and symptoms consistent with any of these infections should undergo prompt diagnostic evaluation and treatment. Concomitant use with antineoplastic, immunosuppressive, or immune-modulating therapies are expected to increase the risk of additive immunosuppression. When switching to GILENYA from these types of therapies, consider their duration of effect and mode of action to avoid this risk.

Before initiating GILENYA, patients should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients is recommended prior to starting treatment. GILENYA initiation should be postponed for 1 month after vaccination. It is recommended that pediatric patients, if possible, complete all immunizations in accordance with current immunization guidelines prior to initiating GILENYA.

Human papilloma virus (HPV) infections, including papilloma, dysplasia, warts, and HPV-related cancer, have been reported with GILENYA in the postmarketing setting. Vaccination against HPV should be considered prior to treatment initiation, taking into account vaccination recommendations. Cancer screening, including Papanicolaou (Pap) test, is recommended as per standard of care for patients using an immunosuppressive therapy.

Progressive Multifocal Leukoencephalopathy (PML): Cases of PML occurred in patients with MS who received GILENYA in the postmarketing setting. 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 usually leads to severe disability or death. PML has occurred in patients who had not been treated previously with natalizumab, which has a known association with PML, and who were not taking concomitant immunosuppressive or immunomodulatory medications.

Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, visual disturbances, and changes in thinking, memory, and orientation, leading to confusion and personality changes.

MRI findings may be apparent before clinical signs or symptoms. PML, diagnosed based on MRI findings and detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, has been reported in patients treated with MS medications associated with PML, including GILENYA. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful. Any suspicious findings should lead to further investigation to allow for an early diagnosis of PML. Lower PML-related morbidity and mortality have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or differences in disease in these patients.

At the first sign or symptom suggestive of PML, withhold GILENYA and perform an appropriate diagnostic evaluation.

Macular Edema: Fingolimod increases the risk of macular edema, with or without visual symptoms. Perform an exam of the fundus, including the macula, before starting GILENYA, and 3 to 4 months after initiation. Monitor visual acuity at baseline, during routine patient evaluations, and if a patient reports visual disturbances while on GILENYA. Patients with diabetes mellitus or history of uveitis are at increased risk and should have regular ophthalmologic evaluations.

Liver Injury: Clinically significant liver injury has occurred in patients treated with GILENYA in the postmarketing setting. Signs and symptoms of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as 10 days after the first dose and also have been reported after prolonged use. Cases of acute liver failure requiring liver transplant have been reported.

Elevation of liver enzymes (ALT, AST, and GGT) 3- and 5-fold the upper limit of normal and greater has occurred with GILENYA. The majority occurred within 6 to 9 months and returned to normal within 2 months after discontinuing GILENYA. Recurrence of liver transaminase elevations occurred with rechallenge in some patients.

Prior to starting treatment with GILENYA (within 6 months), obtain serum transaminases (ALT and AST) and total bilirubin levels, and periodically until 2 months after GILENYA discontinuation. Patients should be monitored for signs and symptoms of any hepatic injury. Treatment with GILENYA should be interrupted if the patient is found to have an ALT greater than 3 times the reference range with serum total bilirubin greater than 2 times the reference range. Patients with severe hepatic impairment should be closely monitored, as their risk of adverse reactions is greater.

Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported with GILENYA. Symptoms reported include sudden onset of severe headache, altered mental status, visual disturbances, and seizure. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, GILENYA should be discontinued.

Respiratory Effects: Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and diffusion lung capacity for carbon monoxide (DLCO) were observed in GILENYA patients as early as 1 month after initiation. Changes in FEV1 appear to be reversible after discontinuing GILENYA; however, there is insufficient information to determine reversibility of DLCO. Obtain spirometry and DLCO when clinically indicated.

Fetal Risk: GILENYA may cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Because it takes approximately 2 months to eliminate GILENYA from the body, advise females of reproductive potential to use effective contraception to avoid pregnancy during and for 2 months after stopping GILENYA treatment. A registry for women who become pregnant during GILENYA treatment is available. Contact the GILENYA Pregnancy Registry by calling 1-877-598-7237, sending an e-mail to gpr@quintiles.com, or visiting gilenyapregnancyregistry.com.

Severe Increase in Disability After Stopping GILENYA: Severe increase in disability accompanied by multiple new lesions on MRI has been reported following discontinuation of GILENYA in the postmarketing setting. Most of these reported cases did not return to the functional status they had before stopping GILENYA. The increase in disability generally occurred within 12 weeks after stopping GILENYA, but was reported up to 24 weeks after GILENYA discontinuation.

The possibility of severe increase in disability should be considered in patients who discontinue GILENYA, including those who are pregnant or planning for pregnancy. Monitor patients for development of severe increase in disability following discontinuation of GILENYA and begin appropriate treatment as needed.

Tumefactive Multiple Sclerosis: MS relapses with tumefactive demyelinating lesions on imaging have been observed during GILENYA therapy and after discontinuation in the postmarketing setting. Most reported cases occurred within the first 9 months after initiation, but may occur at any point during treatment. Cases have also been reported within the first 4 months after discontinuation of GILENYA. Tumefactive MS should be considered when a severe MS relapse occurs during treatment, especially during initiation, or after discontinuation, prompting imaging evaluation and initiation of appropriate treatment.

Increased Blood Pressure (BP): Monitor BP during treatment with GILENYA. An average increase of 3 mm Hg in systolic and 2 mm Hg in diastolic BP was observed in clinical trials versus placebo.

Malignancies: The risk of basal cell carcinoma (BCC) and melanoma is increased in patients treated with GILENYA. Melanoma, squamous cell carcinoma, and Merkel cell carcinoma have been reported with GILENYA in the postmarketing setting. Monitor and evaluate suspicious skin lesions.

Cases of lymphoma, including both T-cell and B-cell types and CNS lymphoma, have occurred in patients receiving GILENYA. The reporting rate of non-Hodgkin lymphoma with GILENYA is greater than that expected in the general population. Cutaneous T-cell lymphoma (including mycosis fungoides) has also been reported in the postmarketing setting.

Immune System Effects Following Discontinuation: Fingolimod remains in the blood and has pharmacodynamic effects, including decreased lymphocyte counts for up to 2 months following the last dose. Lymphocyte counts generally return to normal range within 1 to 2 months of stopping therapy. Initiating other drugs during this period warrants the same considerations needed for concomitant administration.

Hypersensitivity Reactions: Hypersensitivity reactions including rash, urticaria, and angioedema have been reported with GILENYA.

Drug Interactions: Closely monitor patients receiving systemic ketoconazole. The use of live attenuated vaccines should be avoided during, and for 2 months after stopping GILENYA.

Common Adverse Reactions: The most common adverse reactions with GILENYA 0.5 mg (incidence ≥10% and >placebo) were headache, liver transaminase elevations, diarrhea, nausea, cough, influenza, sinusitis, abdominal pain, back pain, and pain in extremity.

Seizure: Cases of seizures, including status epilepticus, have been reported with the use of GILENYA in clinical trials and in the postmarketing setting in adults. In adult clinical trials, the rate of seizures was 0.9% in GILENYA-treated patients and 0.3% in placebo-treated patients.

Pediatric Patients 10 Years of Age and Older: In the pediatric study, the safety profile in pediatric patients receiving GILENYA 0.25 mg or 0.5 mg daily was similar to that seen in adult patients. Cases of seizures were reported in 5.6% of GILENYA-treated patients and 0.9% of interferon beta-1a-treated patients.

Indication

GILENYA is a sphingosine 1-phosphate receptor modulator 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 patients 10 years of age and older.

Click here for full Prescribing Information.