Amirmasoud Nikahd. Advisory Committee Researcher in Dena Clinical Research Consultants, Toronto.

Transcription

1 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 Advisory Committee Researcher in Dena Clinical Research Consultants, Toronto Abstract Gilenya ( Fingolimod ) 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 ) RRMS ( Relapsing Remitting Multiple Sclerosis ) CNS ( Central Nervous System ) - 1 -

2 Introduction Gilenya is a new class of medication called a sphingosine 1-phosphate receptor modulator, which is thought to act by retaining specific white blood cells (lymphocytes) in the lymph nodes, thus, 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 decrease the frequency of clinical relapses and to postpone physical disability. This medication is used to treat adult patients with the relapsing and remitting form of multiple sclerosis (RRMS). It is generally recommended for MS patients who have not responded well to, or cannot tolerate one or more of the other treatments for multiple sclerosis. It should be considered that 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 down the deterioration 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. -2-

3 Contraindications Allergy (hypersensitivity) to Fingolimod or to any of the other ingredients listed as non-medical ingredients. Significant suppression of Immune system (immunocompromised patients ) due to diseases ( such as advanced Diabetes, Acquired ImmunoDeficiency Syndrome) or medicines or treatments that suppress the immune system particularly long term Steroid use. Severe active infection or an active chronic infection such as hepatitis or tuberculosis. Active cancer (except for a specific type of Basal Cell Carcinoma of the skin). Acute and severe liver disease. Medicinal Ingredient The active substance of Gilenya is fingolimod. Furthermore, the non-medicinal ingredients of Gilenya hard capsules are: Manitol, Magnesium, Gelatin, magnesium salt, Titanium dioxide and yellow Iron oxide. Precautions and Adverse Drug Reactions Monitoring: Before starting the treatment and intermittently during treatment, patient should undergo several tests to help monitoring the side effects of Gilenya. These will include: 1-Blood tests (to check white blood cell counts and evaluation of liver function), 2-Eye examination (to monitor for macular edema) 3- Checks of heart rhythm 4- Blood pressure 5- Possibly lung function ( Pulmunary Function Test ) -3-

4 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 patient is taking medications which decrease the heart rate. If MS patient experiences any symptoms of a possible heart rhythm disturbance, such as dizziness, palpitations, fainting, or seizures, at any time during treatment with Gilenya, he/she should seek immediate medical attention. Because Gilenya has adverse effects on the heart, requires to have an electrocardiogram (ECG) to check the overall condition of the heart before starting medicine. Depending on the results of the ECG, blood pressure checks, it 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 Gilenya can negatively affect the immune system which can result in inability of body to fight against infections and may get infections more easily while taking Gilenya (even for up to 2 months after stop taking it).. Macular edema Macular edema, can happen during treatment with Gilenya and this condition can result in some of the same vision symptoms as an MS attack (optic neuritis). It usually starts in the first 3 to 4 months after start taking Gilenya

5 Other warnings One of the most serious but rare adverse effects of Gilenya on immune system is increase the risk of developing lymphoma and other cancers such as skin cancer. Lymphoma and skin cancer, particularly 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. Older people (over 65 years old) Gilenya was studied in very few MS patients over 65 years old. Treatment with this medication requires extra caution in older patients due to the greater chance 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 These two are one of the Contraindications of Gilenya.Patients Should avoid becoming pregnant while taking Gilenya or in the two months after stop taking it because of the risk of fetal abnormalities. DRUG INTERACTIONS Antifungal drugs (such as Ketoconazole). Antibiotics (such as Erythromycin). Drugs to treat HIV infection. Asthma medications ( Bronchodilators and Inhaled Corticosteroids )

6 SIDE EFFECTS AND WHAT TO DO ABOUT THEM As with all medicines, patients treated with Gilenya may experience adverse drug reactions which based on their prevalence are classified in very common ( more than 10 % ), common ( 1-10% ) and uncommon ( % ). 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 or worsening of the severity of Migraine Weakness Mild increase in blood pressure Skin rash Hair loss Pruritis Weight loss Orbital pain Uncommon side effects (affect between 1 and 10 in every 1,000 patients): Depressed mood Shortness of breath Blurred vision Paresthesia ( tingling and numbness ) of lower extremities Not known: Allergic reactions and hypersensitivity including symptoms of rash or itchy hives, swelling of lips, tongue or face, which are most likely to happen in the first or second day patient starts treatment with medication. A rare brain disorder caused by infection and called progressive multifocal leukoencephalopathy (PML). The symptoms of PML may be similar to MS ( particularly weakness or visual changes)

7 Clinical Trials Company: Novartis Pharmaceuticals Corp. Oral medication; 0.5 mg capsule taken once daily Approved for relapsing- remitting form of MS ( RRMS ) 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 sixhour 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. - 7

8 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 diseasefree 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 fingolimode 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 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

9 The six-month Phase IV EPOC study also presented data in 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 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 Fingolimode 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

10 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 longterm 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

11 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, 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, Parallelgroup 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

12 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, 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

13 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

14 References 1- Data on file. Novartis Pharmaceuticals Kutzelnigg A et al. Handbook Clinical Neurology 2014; Volume 122 (3rd series): Brinkmann V. FTY720 (fingolimod) in multiple sclerosis: therapeutic effects in the immune and the central nervous system. Br J Pharmacol 2009;158(5): Chun J & Hartung HP. Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis. Clin Neuropharmacol March-April;33(2): (link is external). Accessed November (link is external). Accessed November Cohen JA et al.; for TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5): 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 P 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 P 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 P