Crown - Thesis Publication, Amirmasoud Nikahd 2016

Author’s contact information: [email protected] Thesis supervisor contact information: [email protected] This is a publication of the Crown Medical Research and Pharmaceutical Sciences College of Canada, 2016. All rights reserved. www.crownacademy.ca

Recent Trends in Treatment of Multiple Sclerosis:

An Oral Medication: Gilenya

Amirmasoud Nikahd

Medical Doctor from Hamadan University of Medical Sciences, Iran

Post graduate Diploma in Clinical Research, Drug Safety and Pharmacovigilance from

Academy of Applied Pharmaceutical Sciences, Canada

2016

Advising Professor: Peivand Pirouzi, Ph.D., MBA Crown Medical Research and Pharmaceutical Sciences College of Canada

Abstract Gilenya ( Fingolimode ) is one of the newest medications for treatment of Relapsing form Multiple

Sclerosis to control the symptoms and reduce the rate of disability. Basically, one of the privileges

is that, it has been designed as oral tablet compared to previous medications which all were

injections. However, there have been some side effects and moreover, it should not be used in

immunosuppression, allergy and active infection. Several clinical trials and studies have been done

including Novartis and FREEDOM in which the efficacy and effectiveness of Gilenya have been

indicated.

Keywords: MS ( Multiple Sclerosis )

mailto:[email protected]


http://www.crownacademy.ca/


Gilenya ( Fingolimode )

Introduction

Gilenya is a new class of medication called a sphingosine 1-phosphate receptor modulator, which

is thought to act by retaining certain white blood cells (lymphocytes) in the lymph nodes, thereby

preventing those cells from crossing the blood-brain barrier into the central nervous system (CNS).

Preventing the entry of these cells into the CNS reduces inflammatory damage to nerve cells.

Indications

Gilenya was approved by the U.S. Food and Drug Administration (FDA) in 2010 for adults with

relapsing forms of MS to reduce the frequency of clinical relapses and to delay the accumulation

of physical disability.

This medication is used to treat adult patients with the relapsing and remitting form of multiple

sclerosis (MS). It is generally recommended for MS patients who have not responded well to, or

cannot tolerate one or more of the other therapies for multiple sclerosis.

GILENYA does not cure MS, but it helps to reduce the number of attacks (relapses) that occur,

reduce inflammation in the brain (brain lesions identified seen on MRI scans), and slow the build-

up of physical problems due to MS (disability progression).

This medication changes how the body’s immune system works by decreasing the ability of

lymphocytes to move freely within the body. This lowers the number of lymphocytes in the blood

and prevents them from reaching the brain and spinal cord. This may reduce the inflammation and

nerve damage that happens in MS

Contraindications





Allergy (hypersensitive) to fingolimod or to any of the other ingredients listed in this

leaflet.

Immune system is weakened (immunocompromised) due to disease

(immunodeficiency syndrome) or medicines or treatments that suppress the immune

system, such as medicines used to treat cancer or bone marrow transplantation.

Severe active infection or an active chronic infection such as hepatitis or tuberculosis.

Active cancer (except for a type of skin cancer called basal cell carcinoma).

Severe liver disease

Medicinal Ingredient The active substance of GILENYA is fingolimod.

What the nonmedicinal ingredients are:

The nonmedicinal ingredients of GILENYA hard capsules are: gelatin, magnesium stearate,

mannitol, titanium dioxide and yellow iron oxide.

Warnings,

Precautions and

Adverse Drug

Reaction

Breast feeding.

Monitoring: Before start treatment and periodically during treatment, should undergo several

tests to help monitor side-effects of GILENYA. These will include:

blood tests (to check white blood cell counts, liver function), eye examination (to monitor for

macular edema), checks of heart rhythm and blood pressure, and possibly lung function.





Slow heart rate and irregular heart beat

GILENYA causes the heart rate to slow down, especially during the first month of treatment. It

can also cause an irregular heartbeat, especially after the first dose. Irregular heartbeat usually

returns to normal in less than one day. Slow heart rate usually returns to normal within one

month. These heart rhythm disturbances may be more likely in patients with risk factors, such as

heart disease, or when certain interacting drugs are taken. In general, people more than 65 years

of age are at higher risk.

If there is an irregular or abnormal heartbeat or a history of sudden loss of consciousness (fainting),

condition may worsen temporarily with GILENYA. The same applies if there is a slow heart rate

or if taking medicines which slow the heartbeat.

If experiencing any symptoms of a possible heart rhythm disturbance, such as dizziness,

palpitations (sensation of rapid, pounding, or irregular heart beat), fainting, or seizures, at any time

during treatment with GILENYA, you should seek immediate medical attention.

Because GILENYA has side effects on the heart, requires to have an electrocardiogram

(ECG) to check the health of heart before starting GILENYA. Depending on the results of

the ECG, blood pressure checks , may need to be observed for longer, possibly overnight, in a

health care facility. The same observation process may apply if starting treatment again after a

break from GILENYA therapy.

Infections

The effects of GILENYA on body’s immune system may reduce body’s ability to fight infections

and may get infections more easily while taking GILENYA (and for up to 2 months after stop

taking it).

.

Macular edema

A problem with vision, called macular edema, can occur during treatment with GILENYA.

Macular edema can cause some of the same vision symptoms as an MS attack (optic neuritis).

Macular edema usually starts in the first 3 to 4 months after start taking GILENYA.

Other warnings

The effects of GILENYA on the body’s immune system may increase the risk of developing

lymphoma and other cancers such as skin cancer. Lymphoma and skin cancer, mostly basal cell

carcinoma, have been reported in patients treated with GILENYA.





If already have moles or open sores before starting treatment with it , should pay attention for

changes in the size, shape or color of moles or the healing of open sores (not healing within weeks)

after starting treatment.

A type of skin cancer called basal cell carcinoma (BCC) has been reported in MS patients treated

with GILENYA.

Older people (over 65 years old)

GILENYA was studied in very few MS patients over 65 years old. Treatment with GILENYA

requires extra caution in older patients due to the greater likelihood of having other medical

problems in addition to MS.

Children and adolescents (under 18 years old)

GILENYA should not be used in children and adolescents as it has not been studied in MS

patients aged under 18.

Pregnancy and breast-feeding

Contraindicated . Should avoid becoming pregnant while taking GILENYA or in the two months

after stop taking it because of the risk of harming unborn child.

.

INTERACTIONS WITH THIS

MEDICATION

Antifungal drugs (such as ketoconazole).

Antibiotics (such as erythromycin).

Drugs to treat HIV infection.

Asthma drugs.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

As with all medicines, patients treated with GILENYA may experience side effects, although not

everybody gets them.





Very common side effects (affect more than 1 in 10 patients):

Flu virus infection

Headache

Diarrhea

Back pain

Cough

Common side effects (affect between 1 and 10 in every 100 patients):

Sinusitis

Fungal infections affecting skin, nails or hair

Dizziness

Migraine

Weakness

Mild increase in blood pressure

Skin rash

Hair loss

Itchy skin

Weight loss

Blurred vision

Breathlessness

Tingling or numbness

Depression

Eye pain

Uncommon side effects (affect between 1 and 10 in every 1,000 patients):

Depressed mood

Not known:

Allergic reactions, including symptoms of rash or itchy hives, swelling of lips, tongue or

face, which are more likely to occur on the day you start GILENYA treatment.

A rare brain disorder caused by infection and called progressive multifocal

leukoencephalopathy (PML). The symptoms of PML may be similar to MS (e.g.

weakness or visual changes).

Nausea.





Clinical Trials

Company: Novartis Pharmaceuticals Corp.

Oral medication; 0.5 mg capsule taken once daily

Approved for relapsing form of MS

MSAA ( Multiple Sclerosis Association of America )

Gilenya is the first in a class of immunomodulatory drugs, called “S1P-receptor modulators.” It is

similar in structure to a naturally occurring component of cell-surface receptors on white blood

cells. Gilenya blocks potentially damaging T cells from leaving lymph nodes, lowering their

number in the blood and tissues. It may reduce damage to the central nervous system (CNS) and

enhance the repair of damaged nerves within the brain and spinal cord. Study data suggest that

Gilenya may have neuro-protective effects.

Some adverse events with Gilenya include: an initial reduction in heart rate; infrequent changes in

the conduction of electricity in the heart (atrioventricular [AV] block); macular edema (a condition

that can affect vision, caused by swelling behind the eye); and infections, including reactivation of

herpes infections. Following the death of a patient within 24 hours after taking a first dose of

Gilenya in November 2011, the FDA conducted an investigation, and in April 2012, updated the

prescribing guidelines for Gilenya.

Other deaths from cardiac causes have been reported from among the many thousands of people

in several countries who have been treated with this medication. Contraindications now include a

history or presence of cardiac conditions (such as myocardial infarction or stroke in the previous

six months, second-and third-degree atrioventricular block, or other serious cardiac rhythm

disturbances) or in patients treated with certain antiarrhythmic drugs.

The updated prescribing information recommends that all patients starting treatment should

undergo electrocardiography immediately before the first dose and at the end of the initial six-hour

observation period, along with hourly measurement of blood pressure and heart rate. Continuous

cardiac monitoring must be performed in some cases. This “First Dose Observation” is part of a

set of monitoring requirements that need to be completed when Gilenya is prescribed.





Study Information

The FREEDOMS Phase III study compared Gilenya with placebo and showed the drug to be safe

and well tolerated. Gilenya reduced the risk of confirmed disability progression by 30 to 32 percent

versus placebo, and significantly increased the proportion of patients who were disease-free over

two years. It also resulted in a 30-percent reduction of brain-volume loss as compared with placebo

at one and two years, suggesting a possible direct neuroprotective effect. A second Phase III study,

FREEDOMS II, compared Gilenya with placebo, and reported similar results.

Two deaths from herpes virus infections occurred in the FREEDOMS trials; both of these

individuals received a higher dose of fingolimod that is not FDA-approved or prescribed. No

deaths from infections were reported in those individuals treated with the FDA-approved lower

dose, which is the only dose available for MS patients.

The TRANSFORMS Phase III trial was a 12-month study of the efficacy of Gilenya as compared

to Avonex in individuals with RRMS. In summary, Gilenya was more effective in reducing the

annual relapse rate, resulted in less deterioration in the ability to independently perform daily

activities, was associated with a lower rate of brain atrophy, and showed a greater effect on

reducing MRI measures of lesion activity. No difference in progression of disability was

demonstrated in this 12-month study.

In both the FREEDOMS and TRANSFORMS studies, Gilenya significantly reduced the frequency

of severe relapses and the number of individuals who required intervention (steroids or

hospitalization), along with reducing the number of relapses with no or only partial recovery. In

the TRANSFORMS trial, Gilenya also consistently reduced the annualized relapse rate in patients

with highly active MS as compared to Avonex.

Interim data were presented in 2013 from LONGTERMS, a single-arm, open-label extension study

that began in June 2010 and will continue through June 2016. Clinical disease activity remained

low for up to five years in patients treated with Gilenya, an interim data analysis indicates. Most

patients remained relapse-free and disability remained stable for up to five years. Approximately

70 percent of patients continuing on Gilenya were relapse-free. As with many extension trials,

individuals dropping out may have caused a “selection bias” favoring long-term use.

Several analyses of Gilenya’s clinical trials have demonstrated that Gilenya has significant effects

on slowing brain atrophy in MS. In the TRANSFORMS trial, Gilenya significantly reduced brain

volume loss over one year compared with Avonex, and in the FREEDOMS trials, Gilenya reduced

brain volume loss over two years compared with placebo.

Intriguingly, in new research presented in 2013, patients on Gilenya who remained disease-free

over 48 months were shown to have less brain-volume loss over the four-year study than those

who were not disease-free. In addition, reduced brain-volume loss was associated with better

clinical outcomes at month 48. These data suggest that the effect of Gilenya on slowing brain

atrophy may have a clinical impact on preventing disability.

An Italian study confirms that the first dose of Gilenya is generally safe and well- tolerated; these

results are consistent with results from previous trials. Data were collected from 812 Italian





patients who were undergoing the required six-hour First-Dose Observation period following

administration of Gilenya. Most patients (95.2 percent) did not have any adverse events during the

six hours. Cardiovascular adverse events occurring in 18 patients were all self-limiting, and did

not require intervention.

The six-month Phase IV EPOC study also presented data in 2013. This study was designed to

evaluate: patient-reported outcomes; physician assessment of a change; as well as safety and

tolerability in patients with relapsing MS, who had also been previously treated with other DMTs

and are now receiving Gilenya. This study found that, based on the Treatment Satisfaction

Questionnaire for Medication (TSQM), people with relapsing multiple sclerosis (MS) reported

greater treatment satisfaction after starting the oral treatment Gilenya versus switching to, or

staying on, one of the injectable DMTs (one of the interferons or Copaxone).

Although Gilenya was approved for RRMS in 2010, clinical trials have continued to evaluate its

role in MS. The 36-month INFORMS trial evaluated the effect of Gilenya relative to placebo on

delaying the time to sustained disability progression in patients with PPMS. As there is presently

no FDA-approved medication for PPMS, this is an important study for the field.

The enrollment of 969 PPMS patients into the INFORMS trial was completed in 2011, and the

trial’s data analysis was completed in 2014. Novartis announced by press release in December

2014 that unfortunately, the primary outcome of the study was not met: Gilenya did not show a

significant difference from placebo on a combination of disability measures. Detailed data will be

presented at the 2015 American Academy of Neurology meeting, and it is hoped that these data

will yield further insight into the pathogenesis of PPMS.

Another ongoing Gilenya clinical trial is a Study Evaluating Safety and Efficacy of Two Doses of

Fingolimod Versus Copaxone. This 12-month trial will compare the marketed dose of Gilenya

with one-half this dose, using Copaxone as a comparison, on annual MS relapses and several MRI

measures of disease. The goal of this study, which was required by the FDA, is to assess if a lower

dose of this medication may be equally effective at preventing relapses. This study is expected to

report data in 2015

Study : FREEDOMS

On October 8, 2015, data on two Phase III clinical trials called FREEDOMS and FREEDOMS II

on Gilenya (fingolimod), a drug developed by Novartis, were presented at the 31st Congress of

the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), currently

being held in Barcelona, Spain (October 7-10). Results from the data analysis reinforced the long-

term efficacy profile of Gilenya in patients with relapsing multiple sclerosis (RMS).




http://multiplesclerosisnewstoday.com/clinical-trials/

http://multiplesclerosisnewstoday.com/gilenya-fingolimod-multiple-sclerosis/

http://multiplesclerosisnewstoday.com/gilenya-fingolimod-multiple-sclerosis/

https://www.novartis.com/

http://www.ectrims-congress.eu/2015/ectrims-2015.html#&panel1-3

http://www.ectrims-congress.eu/2015/ectrims-2015.html#&panel1-3

http://multiplesclerosisnewstoday.com/profile/


Multiple sclerosis (MS) is a disease that damages the brain through inflammation and tissue loss,

disturbing the brain’s normal functioning and preventing an effective communication between

brain regions. An average of 2.3 million people live with MS worldwide, and the disease is

considered one of the most common neurological diseases and major cause of disability in young

adults. It is believed that MS is caused by an abnormal immune response and environmental factors

such as infections, cigarette smoking and exposure to hazard chemicals. Signs and symptoms of

MS may include difficulties in movement/coordination, muscle weakness/spasms, problems with

speech/swallowing, and impairment in vision, among others. RMS patients experience attacks and

worsening of the symptoms, along with a physical and cognitive dysfunction that results from loss

of neurons/brain tissue, distinct inflammatory lesions, and widespread inflammatory

neurodegenerative processes.

There is no cure for MS, but a large number of medications are currently available on the market,

having different mechanisms of action. Among them, an oral disease-modifying drug called

Gilenya (fingolimod) is approved in the U.S. as a first-line treatment for RMS in adults. Its efficacy

was evaluated with four key measures: relapses, MRI lesions, brain shrinkage (brain volume loss)

and disability progression. Gilenya has been used to treat upwards of 125,000 patients and the

overall benefit risk profile of the drug was ranked positive. However, the long-term efficacy of

Gilenya in RMS patients is unknown.

At the ECTRIMS 2015 congress, pooled data from the FREEDOMS and FREEDOMS II core and

extension trials on Gilenya were analyzed by looking at a new evaluation criteria called ‘no

evidence of disease activity’ (NEDA-4). Basically, NEDA-4 is performed at a yearly basis and for

the Gilenya clinical trials was extended to over seven years. NEDA-4 is defined as having: no

relapses, MS-related brain shrinkage, MRI lesions, and disability progression over a certain period

of time.

Results showed that during the first year, 27.1% of the patients treated with Gilenya accomplished

NEDA-4 compared to 9.1% on placebo. Furthermore, when RMS patients switched from placebo

to Gilenya after the second year, the proportion of patients who accomplished NEDA-4 doubled

in year three from 12.7% to 27.4%. Finally, among patients on continuous Gilenya treatment,

31.2% to 44.8% achieved NEDA-4 in the years three to seven.

Based on the results, the team suggested that instead of evaluating the three standard parameters

(relapses, MRI lesions and disability progression), it is recommended that physicians and

specialists use the NEDA-4 method to anticipate brain shrinkage and long-term disability

outcomes. Also, NEDA-4 evaluation is advised during the first year as it is a good predictor of

disability and brain shrinkage over the subsequent five years.

In summary, the findings reinforced further the long-term efficacy profile of Gilenya in patients

with RMS, and highlighted the importance of NEDA-4 in assessing RMS, facilitating the

prediction of long-term consequences of disease progression in MS patients.





“MS is a chronic debilitating disease and these data are important in showing the long-term

efficacy of Gilenya, and the importance of early treatment to help improve long-term outcomes

for patients,” said Vas Narasimhan, Novartis Global Head of Development in a press release.

“Better understanding of the course of a person’s MS through assessment of NEDA-4 can help

physicians identify the optimal, effective treatment approach as early as possible for their patients.”

Efficacy and Safety of Fingolimod (FTY720) in Patients With Relapsing-remitting Multiple Sclerosis

Information source: Novartis ClinicalTrials.gov processed this data on August 23, 2015, www.clinicaltrials.gov.

Condition(s) targeted: Multiple Sclerosis

Intervention: Fingolimod (Drug); Placebo (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Novartis

Official(s) and/or principal investigator(s): Novartis Pharmaceuticals, Study Chair, Affiliation: Novartis Pharmaceuticals

Summary

This study assessed the safety, tolerability and efficacy of two doses of oral fingolimod compared

to placebo on efficacy parameters in patients with relapsing-remitting multiple sclerosis (RRMS).

Clinical Details




https://www.novartis.com/news/media-releases/long-term-efficacy-gilenya%C2%AE-reinforced-new-no-evidence-disease-activity-neda-4


Official title: 24-month Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-

group Study Comparing the Efficacy and Safety of 0.5 mg and 1.25 mg Fingolimod (FTY720)

Administered Orally Once Daily Versus Placebo in Patients With Relapsing-remitting Multiple

Sclerosis With Optional Extension Phase

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study,

Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator,

Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Aggregate Annualized Relapse Rate (ARR) Estimate up to Month 24

Secondary outcome:

Aggregate Annualized Relapse Rate (ARR) Estimate up to End of Study

Percent Change From Baseline in Brain Volume

Number of New or Newly Enlarged T2 Lesions

Number of Gadolinium-enhanced T1 Lesions

Change From Baseline in Lesion Volume at Month 24 (Core Phase)

Percentage of Participants Free of 3-month Confirmed Disability Progression at Month 24 and

End of Study

Percentage of Participants Free of 6-month Confirmed Disability Progression at Month 24 and

End of Study

Percentage of Participants Relapse-free up to Month 24

Percentage of Participants Relapse-free up to End of Study

Change From Baseline in Multiple Sclerosis Functional Composite (MSFC) Z-score

FTY720 in Patients With Primary Progressive Multiple Sclerosis





Information source: Novartis ClinicalTrials.gov processed this data on August 23, 2015

www.clinicaltrials.gov. .

Condition(s) targeted: Primary Progressive Multiple Sclerosis

Intervention: FTY720 (Drug); Placebo (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Novartis Pharmaceuticals

Official(s) and/or principal investigator(s): Novartis Pharmaceuticals, Study Director, Affiliation: Novartis Pharmaceuticals

Summary

The purpose of this study is to evaluate whether FTY720 is effective in delaying MS disability

progression compared to placebo in patients with PPMS.

Clinical Details

Official title: A Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel-group

Study Comparing the Efficacy and Safety of 0.5mg FTY720 Administered Orally Once Daily

Versus Placebo in Patients With Primary Progressive Multiple Sclerosis

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study,

Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver,

Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: To evaluate the effect of FTY720 relative to placebo on delaying the time to

sustained disability progression for patients treated for at least 36 months

Secondary outcome:

To evaluate the safety and tolerability of FTY720 compared to placebo in patients with PPMS

To evaluate the effect of FTY720 relative to placebo on conventional MRI parameters

To evaluate the effect of FTY720 relative to placebo on Patient Reported Outcomes




https://clinicaltrials.gov/show/NCT00731692


Minimum age: 25 Years. Maximum age: 65 Years. Gender(s): Both.

References

1- Data on file. Novartis Pharmaceuticals.

2- http://mymsaa.org/publications/msresearch-updates-2015/gilenya

3- http://multiplesclerosisnewstoday.com/2015/10/09/gilenya-clinical-trials-results

4-Kutzelnigg A et al. Handbook Clinical Neurology 2014; Volume 122 (3rd series): 15-58.

5- Brinkmann V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune

and the central nervous system. Br J Pharmacol 2009;158(5):1173-1182.

6- Chun J & Hartung HP. Mechanism of Action of Oral Fingolimod (FTY720) in Multiple

Sclerosis. Clin Neuropharmacol. 2010 March-April;33(2):91-101.

7- www.clinicaltrials.gov

8- http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008mg.pdf (link is

external). Accessed November 2014.

9- http://ec.europa.eu/health/documents/community-register/html/h677.htm (link is external).

Accessed November 2014.

10- Cohen JA et al.; for TRANSFORMS Study Group. Oral fingolimod or intramuscular

interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415.

11- Kappos L et al.; for FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod

in relapsing multiple sclerosis.

12- Montalban et al. Long-term efficacy of fingolimod in patients with relapsing-remitting

multiple sclerosis previously treated with interferon beta-1a or disease-modifying therapies: A

Post-hoc analysis of the TRANSFORMS 4.5 year extension study. European Neurological

Society, June 10, 2013 P539.

13- Kappos L et al. Phase 3 FREEDOMS study extension: fingolimod (FTY720) efficacy in

patients with relapsing-remitting multiple sclerosis receiving continuous or placebo-fingolimod

switched therapy for up to 4 years. Poster presented at: 28th Congress of the European

Committee for Treatment and Research in Multiple Sclerosis; October 10-13, 2012; Lyon,

France. Poster P979.

14- Chin PS et al. Early effect of fingolimod on clinical and MRI related outcomes in relapsing

multiple sclerosis. Poster presented at: 28th Congress of the European Committee for Treatment

and Research in Multiple Sclerosis; October 10-13, 2012; Lyon, France. Abstract P459.




http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008mg.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008mg.pdf

http://ec.europa.eu/health/documents/community-register/html/h677.htm

Education

Crown - Thesis Publication, Amirmasoud Nikahd 2016