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Gilenya

 

Third case of PML reported to Novartis(19/08/15)

Novartis has been notified of a third case of progressive multifocal leukoencephalopathy (PML) in a patient with relapsing multiple sclerosis (MS) treated with Gilenya.

According to a notice on the company's Gilenya Information Center web page, the diagnosis of PML was based on suggestive clinical symptoms, magnetic resonance imaging findings, and tests for JC virus. The patient did not have prior exposure to Tysabri, treatment, which is already associated with increased PML risk.

The patient reportedly has a history of colorectal cancer treated with chemotherapy and radiation treatment, as well as Crohn's disease.

Novartis says it is currently in "active discussions with external advisors to review details of this case and the role of various risk factors contributing to the development of PML."

Earlier this month, the US Food and Drug Administration (FDA) warned that a case of definite PML and a case of probable PML have been seen in patients taking Gilenya for relapsing MS, as reported by Medscape Medical News. Neither of these patients had previously received Tysabri treatment.

"Patient safety is of paramount importance for Novartis and we recently updated the Gilenya prescribing information, in collaboration with health authorities, to increase vigilance for PML," Novartis said in a statement.

The FDA has been notified of the third case.

Patients taking Gilenya are being urged to contact their healthcare professionals immediately if they experience symptoms such as new or worsening weakness; increased trouble using their arms or legs; or changes in thinking, eyesight, strength, or balance. Healthcare professionals should stop treatment and perform a diagnostic evaluation if PML is suspected.

Novartis said that with more than 125,000 patients having been treated with Gilenya and 240,000 patient years of exposure in both clinical trials and postmarketing setting, they continue to "stand behind the positive benefit-risk profile" of the drug in relapsing MS.

Source: Medscape Multispeciality Copyright © 1994-2015 by WebMD LLC (19/08/15)

FDA issues PML warning for MS patients taking Gilenya(05/08/15)

Following reports of progressive multifocal leukoencephalopathy among patients taking Gilenya for multiple sclerosis, the FDA has issued a warning of possible infection for those prescribed the immunosuppressant drug.

Gilenya (fingolimod, Novartis) is an immunomodulator used to treat patients with relapsing forms of multiple sclerosis (MS). In 2013, a patient was reported to have developed progressive multifocal leukoencephalopathy (PML) after taking the drug; however, no conclusive link could be made due to previous treatment with multiple courses of IV corticosteroids and another immunosuppressant drug known to cause the infection.

Recently, the FDA was notified by Novartis of two more PML cases, one probable and one confirmed. The patient with probable PML was asymptomatic, but was diagnosed based on MRI results and the detection of JC virus in cerebrospinal fluid. The other patient was diagnosed based on clinical symptoms, MRI and virus detection.

The FDA recommends patients taking fingolimod and are experiencing symptoms to contact a health care professional immediately, and those prescribing the drug to stop treatment if PML is suspected. In addition, information about the two recent cases is being added to the drug label.

Source: Healio © 2015 (05/08/15)

Study finds lesions may compromise heart rate in Gilenya patients(20/07/15)

In a recent study published in the Journal PLOS One, a team of researchers found that the autonomic cardiovascular dysfunction in MS patients with delayed heart rate re-acceleration upon Gilenya-initiation suggest MS-related central autonomic lesions may compromise heart rate re-acceleration.

Gilenya causes the heart rate to slow even in healthy people and may also cause prolonged or more prominent heart rate slowing in some MS patients. Results from phase III clinical trials showed Gilenya caused bradycardia and serious cardiovascular adverse events, including atrioventricular blocks.

The European Medicines Agency (EMA) recommends that upon Gilenya initiation, patients should have their heart rate monitored for at least six hours or if it is at the lowest value six hours following the first dose, extended monitoring for at least two more hours and until the heart rate increases again.

It remains unclear why some patients with MS have prolonged heart rate slowing, or why some develop atrioventricular blocks or bradycardia.

In their study, Central Autonomic Dysfunction Delays Recovery Of Fingolimod (Gilenya) Induced Heart Rate Slowing, Ralf A. Linker from the Department of Neurology, University of Erlangen-Nuremberg, Erlangen in Germany and colleagues hypothesised that autonomic dysfunction, such as the sympathetic-parasympathetic imbalance and Gilenya-induced bradycardia are due to pathophysiology of the central control and adjustment of cardiovascular autonomic modulation.

Based on this assumption, the team of researchers examined whether standard autonomic cardiovascular testing is able to indicate central autonomic cardiovascular dysfunction prior to initiation of Gilenya in MS patients who need more than six hours after Gilenya-initiation to re-increase their heart rate.

The researchers recorded electrocardiographic RR-intervals (RRIs) and blood-pressure (BP) at rest, upon standing-up, during metronomic deep-breathing before Gilenya-initiation in a population of 21 patients with relapsing-remitting MS, and in 20 healthy controls.

The results revealed that upon Gilenya-initiation, seven patients had prolonged heart rate slowing. Prior to the initiation of Gilenya, the seven patients were found to have a higher resting BP and also a higher BP increase during handgrip-exercise in comparison with the other participants. The results also showed that the patients did not reduce parasympathetic heart rate parameters upon standing-up. After Valsalva-strain-release exercise the researchers found that the patients parasympathetic heart rate slowing in response to BP-overshoot was four times higher than in the other participants.

The researchers indicate the need for further studies comparing cardiovascular autonomic modulation of MS patients on Gilenya and patients on other disease modifying treatment which might be helpful to further strengthen this study findings.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (20/07/15)

Tags: MS, multiple sclerosis, Gilenya, Autonomic Dysfunction, immunotherapy, relapsing-remitting multiple sclerosis, RRMS, European Medicines Agency, EMA

Gilenya ‘found to have long-term positive effects’(30/06/15)

A new study published in the Journal of Neurology, Neurosurgery and Psychiatry has found long-term Gilenya therapy can maintain a low disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). The study, Long-Term (up to 4.5 years) Treatment With Fingolimod (Gilenya) In Multiple Sclerosis: Results From The Extension Of The Randomised TRANSFORMS Study, was conducted by an international team of researchers.

Gilenya is an immunomodulating drug and an effective therapy for RRMS. The safety, tolerability and efficacy of two oral doses (0.5 or 1.25 mg once daily) were assessed in the 12-month, randomised, double-blind phase three clinical trial called TRANSFORMS (NCT00340834) in relapsing remitting MS (RRMS) patients in comparison to treatment with interferon (IFN) beta-1a. The study revealed Gilenya at both doses significantly improved clinical and magnetic resonance imaging (MRI) outcomes with patients experiencing a reduction in the frequency of relapses in comparison to IFN beta-1a treatment.

Researchers conducted an extension study (up to 4.5 years) of the TRANSFORMS trial in which RRMS patients previously receiving Gilenya continued the same treatment and those under IFN beta-1a therapy received either 0.5 or 1.25 mg of the drug. The team analysed the patient’s annualised relapse rate, disability progression and MRI measures. In total, 1027 RRMS patients entered this extension study and only 772 completed it.

Researchers found the annualised relapse rate was significantly lower in patients under continuous Gilenya treatment than in patients who switched over from IFN beta-1a. Nevertheless, patients who switched from IFN to Gilenya exhibited a 50 per cent reduction in annualised relapse rate and a reduced MRI disease activity. Among the patients who switched therapies, there was an increase of around 50 per cent in the proportion of patients with no evidence of disease activity in the first year after Gilenya treatment. After 4.5 years of Gilenya therapy, both disability progression and MRI outcomes were not significantly different between the groups.

The research team concluded that switching from IFN beta-1a to Gilenya improved treatment efficacy, and that Gilenya therapy has a continuous long-term effect in maintaining a low disease activity in RRMS patients.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (30/06/15)

Tags: ms, multiple sclerosis, Gilenya, relapsing-remitting multiple sclerosis, RRMS, IFN beta-1a, research

Researchers suggest short transition period between RRMS therapies(18/06/15)

A team led by researchers at the University Hospital Basel in Switzerland say they have found a short period of eight to 12 weeks is the optimal timing to be considered when patients with relapsing-remitting multiple sclerosis (RRMS) are switched from Tysabri (natalizumab) to Gilenya (fingolimod) therapy.

The study was recently published in the journal Neurology.

In this study, researchers conducted a randomised, multicentre, double-blind, placebo-controlled trial (TOFINGO) to determine the optimal timing for initiating Tysabri after discontinuing Gilenya in 142 RRMS patients. The goal was to maintain disease control and avoid potentially harmful additive effects on immune surveillance. The team tested the intervals of eight, 12 and 16 weeks between the last Tysabri infusion and the first Gilenya treatment over 32 weeks. Brain MRI recurrence and clinical disease activity were evaluated.

Researchers found in total, 78.9% (112) of the patients completed the study. The number of active MRI lesions was found to increase according with the duration of the interval between the two therapies. More patients were found to be relapse-free in the eight-week (88%) and 12-week (91%) periods in comparison to the 16-week period (84%). Of the cohort, 68% of the patients experienced mild or moderate adverse events with no major differences between the groups. No unusually severe relapses or opportunistic infections were reported.

The team concluded that patients with RRMS switching from Tysabri to Gilenya therapy should undergo a short period of eight to 12 weeks between therapies, as this time interval is associated with less MRI disease activity than longer periods. The authors suggest that additional studies should be performed to determine whether an interval shorter than eight weeks would further improve disease control with reasonable risks.

Source: Multiple Sclerosis News Today © BioNews Services 2015 (18/06/15)

New insights into MS treatment(18/05/15)

Data from two Novartis phase III clinical trials show that adding brain shrinkage (brain volume loss) to an existing tool to assess multiple sclerosis activity (m-Rio) will give a more precise prediction of the likelihood of future disability progression.

A pooled analysis from the two-year Freedoms and Freedoms II trials also further confirm the high efficacy of Fingolimod in previously treated patients with highly-active relapsing MS. In the trials, patients on Fingolimod achieved no evidence of disease activity (Neda) across four key measures: relapses, MRI lesions, brain shrinkage and disability progression. Achieving Neda is especially critical for highly-active RMS patients, who are likely to lose more physical and cognitive functions over time despite being treated.

The Fingolimod clinical trial data was presented at the 67th American Academy of Neurology annual meeting in Washington, DC. Developed by Novartis, Fingolimod is the only oral disease-modifying therapy to impact the course of relapsing MS with high efficacy across four key measures of disease activity: relapses, MRI lesions, brain shrinkage (brain volume loss) and disability progression.

“Accurate assessment of disease activity is key to guide treatment decisions in relapsing MS. These data on Fingolimod and new methods of assessing the impact of MS have the potential to give physicians a more comprehensive picture of an individual’s disease and allow patients to better understand their MS,” said Dr Ludwig F. Damian, consultant neurologist.

“Novartis is committed to innovation beyond the research and development of new treatments to help physicians and patients improve how MS is managed,” said Dr Nikolaos Tripodis, Novartis Healthcare Philippines president and managing director.

Source: INQUIRER.net © Copyright 1997-2015 INQUIRER.net (18/05/15)

Peripheral blood T cell dynamics predict relapse in MS patients on Fingolimod(29/04/15)

Abstract

Background

Fingolimod efficiently reduces multiple sclerosis (MS) relapse by inhibiting lymphocyte egress from lymph nodes through down-modulation of sphingosine 1-phosphate (S1P) receptors. We aimed to clarify the alterations in peripheral blood T cell subsets associated with MS relapse on fingolimod.

Methods/Principal Findings

Blood samples successively collected from 23 relapsing-remitting MS patients before and during fingolimod therapy (0.5 mg/day) for 12 months and 18 healthy controls (HCs) were analysed for T cell subsets by flow cytometry. In MS patients, the percentages of central memory T (CCR7+CD45RO+) cells (TCM) and naïve T (CCR7+CD45RO-) cells decreased significantly, while those of effector memory T (CCR7-CD45RA-) and suppressor precursor T (CD28-) cells increased in both CD4+T and CD8+T cells from 2 weeks to 12 months during fingolimod therapy. The percentages of regulatory T (CD4+CD25highCD127low) cells in CD4+T cells and CCR7-CD45RA+T cells in CD8+T cells also increased significantly. Eight relapsed patients demonstrated greater percentages of CD4+TCM than 15 non-relapsed patients at 3 and 6 months (p=0.0051 and p=0.0088, respectively). The IL17-, IL9-, and IL4-producing CD4+T cell percentages were significantly higher at pre-treatment in MS patients compared with HCs (p<0.01 for all), while the IL17-producing CD4+T cell percentages tended to show a transient increase at 2 weeks of fingolimod therapy (pcorr=0.0834).

Conclusions

The CD4+TCM percentages at 2 weeks to 12 months during fingolimod therapy are related to relapse.

Full Article

Source: PLOS One (29/04/15)

Patient taking Gilenya contracts PML(10/03/15)

A woman in a Gilenya after-market study says the company didn’t notify all participants about a new case of progressive multifocal leukoencephalopathy (PML).

Novartis executives have confirmed a multiple sclerosis patient has developed the brain infection after taking their drug Gilenya for more than four years.

PML is a reactivation of the John Cunningham virus (JCV). JCV lives in the bodies of more than 75 percent of people in the United States. Most people’s immune systems are strong enough to keep the virus at bay.

The Switzerland-based pharmaceutical company posted a notice on their website announcing the development. The website notice said the patient is doing well. It said the patient had been taking Gilenya for an extended period when he or she contracted PML.

A company spokesman said Novartis officials were not available to comment on the case.

In late October, a patient in Europe died from PML after taking Tecfidera for more than four years. Biogen Idec Inc. manufactures that MS drug.

In 2013, the Food and Drug Administration (FDA) sent out an alert after a patient in Europe developed PML after taking Gilenya for eight months.

In their web posting, Novartis officials noted Gilenya has a “positive benefit-risk profile” in relapsing-remitting MS patients based on experience with 114,000 people who have taken the drug.

One woman who is part of a current Gilenya after-market extension study said she learned about the most recent PML case after Novartis contacted another person in the study. The woman then found the announcement on the company’s website.

The woman in the extension study, who has MS, said she was well aware of the remote possibility of contracting PML while taking Gilenya, so she wasn’t surprised by the announcement. She claimed Novartis did not contact everyone in her study group or update their informed consent documentation.

“I’m not upset, but I am disappointed,” the woman said.

People with weakened immune systems are at greater risk. That group includes people with AIDS, cancer patients taking chemotherapy drugs, transplant patients on anti-rejection drugs, and people taking immune-suppressing drugs for autoimmune conditions.

Source: Healthline Copyright © 2005 - 2015 Healthline Networks, Inc (10/03/15)

Gilenya may be best in MS patients failing initial treatment(11/02/15)

Switching multiple sclerosis patients with disease activity despite treatment with a first-line injectable to oral fingolimod (Gilenya) was associated with fewer relapses than switching them to another standard injectable, researchers have found.

In a study, patients on either interferons or glatiramer acetate (Copaxone) who were switched to fingolimod had a significantly lower mean annualized relapse rate than those who changed to another injectable immunomodulator, according to Tomas Kalincik, MD, PhD, of Royal Melbourne Hospital in Australia, and colleagues.

Patients in the study, reported online in JAMA Neurology, were switching medications following clinical relapse or disability progression while on the initial treatment.

In an accompanying editorial, Olaf Stuve, MD, PhD, of the University of Texas, and Diego Centonze, MD, PhD, of To Vergata University and Hospital in Rome, said the study adds to growing evidence that switching to newer agents like natalizumab (Tysabri) or fingolimod may be more effective.

Although it was an observational study, it assessed high-quality data and used appropriate propensity score matching to control for potential confounding factors, they wrote.

They noted, however, that the study's median follow-up of 13.1 months may be "too short to draw definite conclusions on the relapse rate."

Kalincik and colleagues conducted their matched retrospective analysis of data that was collected prospectively from MSBase, which collects data on MS patients in routine clinical care, from July 1996 to April 2014.

Patients with relapsing-remitting MS had been on a beta-interferon drug or glatiramer acetate for at least 6 months before making the change to another injectable (beta-interferon or glatiramer acetate) or to fingolimod because of clinical disease activity. They were then observed on the new medication for at least 3 months. Some of the patients initially taking a beta-interferon drug were switched to a different beta-interferon.

Overall, 379 patients in the injectable group were matched to 148 patients in the fingolimod group. Median follow-up was 13.1 months.

Kalincik and colleagues found that those switched to fingolimod not only had a lower mean annualized relapse rate but also a lower risk of first on-treatment relapse than those switched to another injectable immunomodulator.

Those changed to the oral drug also had a lower risk of disability progression and a higher rate of disability regression (HR 2.0, 95% CI 1.2-3.3, P=0.005), they reported.

They also had a lower rate of treatment discontinuation at 2 years.

The researchers noted that sensitivity analyses replicated in full the relapse and disability outcomes seen in the primary analysis. They did not, however, replicate the finding that switching to fingolimod improved treatment persistence, suggesting that this finding be interpreted with caution.

Kalincik and colleagues concluded that in the absence of randomized clinical trials, use of high-quality observational data provides an important tool for comparisons of drug effectiveness in a real-world setting.

In their editorial, Stuve and Centonze agreed that the quality of observational data in their study can provide "crucial information to support decision making relevant for MS management in real-world practice."

They said the results provide the first evidence that "switching to fingolimod is superior to switching to a second injectable immunomodulator with respect to disability outcomes, likely owing to the more efficient prevention of relapses associated with an incomplete recovery."

The results are in line with studies such as TRANSFORMS, one of the clinical trials leading up to fingolimod's approval, which found patients with active disease activity despite immunomodulatory therapy "may still have optimal disease control after switching to fingolimod."

In addition to the limitation of a short follow-up time, the study was also limited by lack of data on interferon-neutralizing antibodies, and because patients who were switched from one interferon preparation to another may not have served as true controls: "Most MS experts would not likely recommend this strategy because the agents are biochemically almost identical, and their mechanisms of action identical," they noted. The study, which was funded by fingolimod's manufacturer, also did not examine switches to natalizumab or newer oral agents.

Still, they concluded that evidence has accumulated that "escalating to the more effective medications natalizumab or fingolimod should be an early consideration for most patients with breakthrough disease. Switching to another injectable immunomodulator may still be considered in certain cases only."

The study was supported by Novartis, MSBase Foundation, Multiple Sclerosis Research Australia, National Health and Medical Research Council, and the Center for Research Excellence.

MSBase Foundation receives support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, and Sanofi.

The researchers disclosed financial relationships with Biogen Idec, Novartis, Genzyme, Merck Serono, Teva, Bayer Schering, Sanofi, Lundbeck, Bayer, Biologix, GSK, Roche, and bioCSL.

The editorialists disclosed financial relationships with Teva, Opexa, Merck Serono, Genzyme, Bayer Schering, Biogen Idec, Novartis, Almirall, GW Pharmaceuticals, Roche, and Mitsubishi.

Source: MedPage Today © 2015 MedPage Today, LLC (11/02/15)

MS drug Gilenya may increase risk of lymphopenia(05/01/15)

Studies in Sweden and Germany indicate that underweight women with multiple sclerosis who take the MS drug Gilenya (fingolimod) seem to be at increased risk for lymphopenia. The drug also poses a risk for patients who have low lymphocyte levels before they start drug treatment.

Lymphopenia (also known as lymphocytopenia) is a condition in which a person has a deficiency (penia) of lymphocytes, which are a subset of white blood cells (leukocytes). Lymphocytes, which can be T cells, B cells, or natural killer cells, play a crucial role in supporting immune system function.

It’s been known that fingolimod can lower the level of circulating lymphocytes. In fact, among the serious side effects reported by the Food and Drug Administration (FDA) and the drug’s manufacturer, Novartis Pharma Stein AG, is infections.

Risk of infections is increased because the drug lowers lymphocyte levels. The two newly reported studies cast new light on some of the factors associated with this risk.

In the German study, 418 individuals with relapsing-remitting multiple sclerosis were enrolled in an open label study in which they took 0.5 mg of fingolimod daily. Blood samples were collected on four separate occasions: immediately before treatment and at months 1, 4, and 6. In the Swedish study, data from 438 patients were used to validate the findings.

Here are some of the findings:

- Women who had a body mass index (BMI) less than 18.5 kg/m2 had a 26 percent increased risk for developing lymphopenia (counts at or lower than 0.2 x 109/L associated with drug use. This effect was not seen in men with this BMI.

- Individuals whose starting lymphocyte levels were less than 1.6 x 109/L had a 46 percent increased risk of lymphopenia while using the drug.

- Use of glatiramer acetate (Copaxone) before use of Gilenya seemed to help protect against the development of lymphopenia, although the researchers were uncertain about the immunologic effect of this drug.

Prior research (phase III trials) has indicated that the decline in lymphocyte counts among MS patients who take fingolimod is not associated with meal timing or the use of other medications, such as corticosteroids.

The findings of the two new studies provide doctors with additional information to consider when Gilenya is on the treatment table, such as monitoring of female patients who are underweight and/or individuals who have low baseline lymphocyte counts. Other serious side effects that may develop with use of Gilenya include slow heart rate (bradycardia), which can occur when starting treatment; macular edema, which typically appears after three to four months of treatment; liver problems; and shortness of breath.

SOURCES
Food and Drug Administration
Warnke C et al. Initial lymphocyte count and low BMI may affect fingolimod-induced lymphopenia. Neurology 2014. DOI:10.1212/WNL.0000000000001049

Source: Emaxhealth (05/01/15)

Novartis provides update on fingolimod Phase 3 trial in primary progressive MS (01/12/14)

Novartis announced today that the Phase III INFORMS study in primary progressive multiple sclerosis (PPMS) did not show a significant difference between fingolimod and placebo on a combination of disability measures. The safety results were consistent with the well-characterized safety profile of fingolimod in relapsing MS (RMS).

PPMS is a disorder of the central nervous system (CNS) which affects approximately 10% of the 2.3 million patients diagnosed with MS worldwide. PPMS is a distinct disease form, different from relapsing MS in terms of its basic disease process, near-absence of acute relapses and fewer active MRI lesions. The severe irreversible damage to the CNS in PPMS is thought to be caused by different pathways leading to loss of nerve cells and a more rapid, continuous loss of function over time which profoundly impacts patients' lives. Additionally, the disease is typically diagnosed later than other types of MS, when significant damage to the CNS has already occurred. Despite considerable research and academic focus, there are currently no approved treatments that have been shown to change the course of this debilitating disease and management focuses mainly on the treatment of symptoms.

"We understand this news is very disappointing for those affected by PPMS and involved in its management. While PPMS is a focus of the MS community, relatively little is known about the disease so finding effective treatments remains a challenge. We will actively work with the MS community to review and analyze the INFORMS results to help increase the understanding of this devastating disease," said Vasant Narasimhan, Global Head of Development at Novartis Pharmaceuticals. "Gilenya (fingolimod) revolutionized the treatment of relapsing MS as the first oral disease-modifying therapy. We remain strongly committed to continuing to research new treatment options for patients with MS and other neurological conditions."

The INFORMS study was based on the knowledge that fingolimod enters the central nervous system (CNS) and can interact with damage-causing cells residing in the CNS. It was hypothesized that this central effect, which is well understood in relapsing forms of MS, would also be relevant in PPMS. As opposed to the consistently strong efficacy seen in relapsing MS, the results of the INFORMS study seem to suggest that PPMS and relapsing forms of MS have different underlying mechanisms.

Fingolimod, marketed as Gilenya®, is approved in the US for first-line treatment of relapsing forms of MS in adults. In the EU, Gilenya is indicated for adult patients with highly active relapsing-remitting MS (RRMS) defined as either high disease activity despite treatment with at least one disease-modifying therapy (DMT), or rapidly evolving severe RRMS. Gilenya is the only DMT to impact the course of relapsing MS with high efficacy across four key measures of disease activity: relapses, MRI lesions, brain shrinkage (brain volume loss) and disability progression. The likelihood of achieving 'no evidence of disease activity' (NEDA) across four key measures is more than four-times greater in relapsing MS patients treated with Gilenya compared to placebo. The safety profile of Gilenya in RMS is well understood and based on substantial evidence from three major clinical trials and extensive real-world experience in more than 100,000 patients, with the total patient exposure now at approximately 172,500 patient years.

About INFORMS

The INFORMS study is a double-blind, randomized, multi-center, placebo-controlled parallel group study, comparing the efficacy and safety of fingolimod (0.5 mg) versus placebo in people with primary progressive multiple sclerosis (PPMS)[16]. The INFORMS study is the largest clinical trial ever conducted in PPMS. Nine-hundred and seventy (970) people aged 25-69 years with PPMS were enrolled in INFORMS from 148 sites, across 18 countries, including Australia, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, Turkey, UK and the US. Patients were treated for at least three years.

The primary endpoint was to evaluate the effect of fingolimod versus placebo on reducing the risk of three-month sustained disability progression based on a composite measure of Expanded Disability Status Scale (EDSS), assessment of upper limb function (9-Hole Peg Test, HPT), and walking speed (25-foot Timed Walk Test, TWT).

About Gilenya (fingolimod)

In relapsing MS, the loss of physical and cognitive function is driven by two types of damage that result in the loss of neurons and brain tissue - distinct inflammatory lesions (referred to as focal damage), and more widespread inflammatory neurodegenerative processes (referred to as diffuse damage). Focal damage results in the loss of brain tissue and can clinically present as relapses. Diffuse damage starts early in the disease, often goes unnoticed and is also associated with loss of brain tissue and accumulated loss of function.

Gilenya (fingolimod) targets both focal and diffuse central nervous system (CNS) damage that drive loss of function in relapsing MS. It prevents cells that cause focal inflammation from reaching the brain (referred to as 'peripheral' action), but also enters the CNS and reduces the diffuse damage by preventing the activation of harmful cells residing in the CNS (referred to as 'central action'). It is important to address both focal and diffuse damage in relapsing MS to effectively impact disease activity and help preserve an individual's physical (e.g. walking) and cognitive (e.g. memory) function.

Phase III studies with fingolimod are currently being conducted in two rare diseases, pediatric MS and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), where there is a high unmet need.

About Novartis in Multiple Sclerosis

Novartis is committed to the research and development of innovative and targeted treatment options for people suffering from different types of MS.

The Novartis MS portfolio includes Gilenya (fingolimod, oral DMT) and Extavia® (interferon beta-1b for subcutaneous injection) for the treatment of relapsing MS. In addition to the current clinical development program with Gilenya, Novartis is investigating BAF312 (siponimod), a second generation, selective S1P1 and 5 receptor modulator, in the largest Phase III trial in secondary progressive MS (SPMS). The IL-17 pathway is also being explored as a novel therapeutic target in MS.

Source: Novaratis 01/12/14

SMC first to introduce oral Gilenya® as a first line treatment option for people with a severe form of MS(14/10/14)

SMC first to introduce oral Gilenya® as a first line treatment option for people with a severe form of MS

• Scottish people with a severe form of relapsing remitting multiple sclerosis are first in UK to get access to once daily pill fingolimod as a first line treatment option1
• Once daily pill fingolimod reduces the risk of relapses by 67% compared to placebo2

Today, the Scottish Medicines Consortium (SMC) has accepted once daily pill fingolimod (Gilenya®) as a first line option for people with a severe form of relapsing remitting MS, which has been shown to reduce the risk of relapses by 67% compared to placebo.1,2 This is the first time that an oral treatment has been made available as a first line treatment option for people with this severe form of MS - known as rapidly evolving severe relapsing remitting MS (RES RRMS).1

The SMC heard from patient groups that MS is an incurable progressive disease with devastating effects on those with the condition and their families.1 Symptoms can include intense pain, mobility problems, severe depression, fatigue, incontinence and loss of vision.1 MS affects over 100,000 people in the UK, with rates highest in Scotland.3,4

85% of people with MS are diagnosed with the relapsing remitting form - when symptoms flare up aggressively - known as relapses.5 There are different types of RRMS, including highly active and RES RRMS.6 In September 2012, the SMC agreed to reimburse fingolimod for people with highly active RRMS who are failing on first line interferon injections.7 Today’s decision means that fingolimod is now also reimbursed for RES RRMS – when a person has two or more disabling relapses in one year with associated MRI changes.1 The SMC’s decision to broaden access to fingolimod means this is the first time that people with this more severe form of RRMS will have the choice of a once daily pill as a first line treatment option.1

Prior to today’s decision, only one SMC approved treatment was available for people with RES RRMS – a hospital-based infusion called natalizumab required every 28 days.1 Fingolimod is a once daily pill that can be taken at home after the first dose, avoiding the need to travel to hospital every month. It has been shown to reduce relapses by 67% compared to placebo in those with RES RRMS (ARR 0.24 for fingolimod and 0.74 for placebo).2 The analysis was conducted in a subgroup of patients from the original phase III FREEDOMS trial.

Scottish patients with RES RRMS will have access to once daily pill fingolimod as a first line treatment option before those in the rest of the country. This is because the SMC process allows manufacturers to submit new data at any time. NICE is set to review fingolimod alongside a range of other MS treatments in 2015. This means that people with this severe form of RRMS north of the border will have an increased choice of first line treatments before their southern counterparts.

Today’s announcement follows a series of recent decisions by the European Commission and NHS England to extend the use of fingolimod to a wider group of people, just three years after its original licence was granted in March 2011.

To date, more than 100,000 people worldwide have been treated with fingolimod in clinical trials and in the post-marketing setting.8 Fingolimod has been approved in 80 countries.8

References 1. SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya®). October 2014
2. Devonshire V, Havrdová E, Radue EW et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol. 2012; 11:420-28
3. The Scottish Parliament. Briefing for the Public Petitions Committee. http://www.scottish.parliament.uk/ResearchBriefingsAndFactsheets/Petitions%20briefings%20S3/PB10-1353.pdf Last accessed 10 October 2014.
4. MS Society. What is MS? http://www.mssociety.org.uk/about_ms/what_is_ms/index.html Last accessed 10 Oct 2014
5. MS Society. http://www.mssociety.org.uk/what-is-ms/types-of-ms/relapsing-remitting-rrms Last accessed 10 October 2014
6. MS Trust. http://www.mstrust.org.uk/atoz/types.jsp Last accessed 10 October 2014
7. SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya®). SMC No. (763/12). 12 March 2012
8. Gilenya World Watch. http://www.gilenya-world-watch.com/English.html Last accessed 10 October 2014
9. European Commission. Community register of medicinal products for human use. Gilenya. http://ec.europa.eu/health/documents/community-register/html/h677.html Last accessed 10 October 2014.
10. NHS England commissioning guideline for Gilenya. June 2014

Source: Novartis (14/10/14)

MS drug Gilenya in new therapeutic indication: Added benefit not proven(13//10/14)

The immunosuppressive drug fingolimod (trade name: Gilenya) was approved for an expanded therapeutic indication in May 2014: It is now also available for adults with highly active relapsing remitting multiple sclerosis (RRMS) who had received other pretreatment than interferon beta (IFN-β). In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether the drug offers an added benefit over the appropriate comparator therapy in this patient group.

According to the findings, such an added benefit is not proven: For some of the patients, the drug manufacturer presented no data. For other patients, the available study data either showed no differences between the treatment groups, or the data were not evaluable.

G-BA specifies appropriate comparator therapy

The Federal Joint Committee (G-BA) distinguishes between two patient groups for the assessment: In patients with highly active RRMS despite full previous treatment (no interferon beta), fingolimod was to be compared with glatiramer acetate or interferon beta. In patients with incomplete previous treatment, the G-BA distinguishes between two cases for the appropriate comparator therapy: In patients who had received glatiramer acetate, this medication was to be optimized and continued. In patients who had received a different drug, treatment was to be changed to interferon beta or glatiramer acetate.

Only data of few study participants relevant for the assessment

One relevant study was available for the early benefit assessment, an approval study on fingolimod (TRANSFORMS), which compared treatment with fingolimod versus treatment with IFN-β1a in adults with RRMS. However, the disease was rated as "highly active" in only nearly half of the 866 participants. Only 263 of these 402 patients had received full previous treatment. Only 42 participants, i. e. a little less than five percent of the total study population, had not been treated with interferon beta (17 patients in the fingolimod arm, 25 in the interferon beta arm). However, only these patients correspond to the subpopulation relevant for this benefit assessment, because it is only this subpopulation that fingolimod had received expanded approval for. The informative value of the results was considerably limited because only data of few participants were evaluable.

Differences between treatment arms not statistically significant

No deaths occurred during the total study duration of 12 weeks. There were differences between the fingolimod and the interferon beta group with regard to relapses and disability progression, but these were not statistically significant.

No evaluable data were available for the patient group for which fingolimod was newly approved regarding other aspects of the outcome "morbidity", e.g. fatigue or activities of daily living, and for the outcome "health-related quality of life". One of the reasons for this is that different proportions of patients were not considered in the analysis.

There were group differences in side effects (serious adverse events and treatment discontinuation due to adverse events), which again were not statistically significant.

Dossier without relevant study on patients with incomplete treatment

In its dossier, the manufacturer presented no relevant study for patients who had not received full previous treatment.

In summary, an added benefit of fingolimod is therefore not proven for patients with highly active relapsing remitting multiple sclerosis (RRMS) who had received a different pretreatment than interferon beta.

Discrepancy between approval and study population

In 2011, fingolimod had been approved for two therapeutic indications: for rapidly progressive severe RRMS and for highly active RRMS that had been pretreated with interferon beta. For these two patient groups, IQWiG had published a dossier assessment according to AMNOG in January 2012.

In this first assessment the problem had already occurred that participants with different types of RRMS had been included in the relevant study, and that the authorities had then limited the approval to specific, relatively small patient groups. Since the first approval and assessment, the manufacturer apparently conducted no further studies for the expansion of approval.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G-BA then decides on the extent of the added benefit, thus completing the early benefit assessment.

Source: Medical Xpress © Medical Xpress 2011-2014, Science X network (13//10/14)

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