Crown - Thesis Publication, Amirmasoud Nikahd 2016

Author’s contact information: amir.m.nikahd@gmail.com
Thesis supervisor contact information: Peivand.Pirouzi@crownacademy.ca
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 )

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).

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

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

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.

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