Date: 2015-10-08
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Barcelona, Spain
Company: Novartis (Switzerland)
Product: Gilenya® (fingolimod)
Action
mechanism: sphingosine 1-phosphate receptor (S1PR) modulator. Gilenya®, licensed from Mitsubishi Tanabe Pharma Corporation, is the first in a new class of drugs called sphingosine 1-phosphate receptor (S1PR) modulators. In multiple sclerosis, the immune system damages the covering that protects nerve fibers in the central nervous system which includes the brain and spinal cord. Fingolimod reduces the ability of T cells to move from the lymph nodes towards the brain and spinal cord thus limiting the damage they cause in multiple sclerosis. It does this by blocking the action of a receptor on the T cells called the sphingosine-1-phosphate receptor, which is involved in regulating the movement of these cells in the body.
Disease: relapsing forms of multiple sclerosis
Therapeutic area: Autoimmune diseases - Neurodegenerative diseases
Country:
Trial details:
Latest
news: * On October 8, 2015, Novartis announced a new analysis from the phase III FREEDOMS and FREEDOMS II trials reinforcing the long-term efficacy profile of Gilenya® (fingolimod). The analysis evaluated the proportion of Gilenya patients with relapsing multiple sclerosis (RMS) achieving 'no evidence of disease activity' (NEDA-4) every year over seven years[1]. NEDA-4 is achieved when a patient has no relapses, MRI lesions, MS-related brain shrinkage and disability progression. These data were presented at the 31st Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Barcelona, Spain. This follow-up analysis of pooled data from the FREEDOMS and FREEDOMS II core and extension trials was conducted to assess NEDA-4 each year for seven years in patients with RMS. The data showed that in the first year, 27.1% of patients on Gilenya achieved NEDA-4 compared to 9.1% on placebo. Switching from placebo to Gilenya after year two doubled the proportion of patients achieving NEDA-4 (12.7% to 27.4%) in year three. Of those patients on continuous Gilenya treatment, 31.2% to 44.8% had NEDA-4-status in each of the years three to seven. A separate follow-up analysis of data from the FREEDOMS and FREEDOMS II trials also confirmed for the first time that assessment of RMS based on NEDA-4 allowed physicians to better predict long-term disability and brain shrinkage outcomes than just assessing relapses, MRI lesions and disability progression. NEDA-4 status over the first year was a significantly better predictor of disability and brain shrinkage over the subsequent five years, as measured by patients reaching a stage of severe disability (EDSS >=6: patients require a crutch to walk approximately 100m) (p<0.0127) or having more than 0.4% mean annual brain volume loss[2]. These findings support the importance of assessing RMS with NEDA-4 to enable a more reliable prediction of long-term disease outcomes. * On September 10, 2014, Novartis announced that new data presented at the Joint ACTRIMS-ECTRIMS Meeting in Boston, USA, reinforces the clinical importance of measuring brain shrinkage (brain volume loss) in multiple sclerosis. An association between the rate of brain shrinkage and increased risk of long-term disability progression was confirmed in patients with MS. In pooled data from the phase III FREEDOMS core and extension studies, patients were categorized into four groups (quartiles) based on the mean change in brain volume from the start of the study to year-two. The analysis showed that 24.2% of patients who had the highest rate of brain shrinkage at 2 years had confirmed six-month disability progression at four years, compared to 15.4% of patients with the lowest rate of brain shrinkage (p=0.018). A separate analysis from the long-term follow-up extension study LONGTERMS, showed that the rate of brain shrinkage in patients treated with Gilenya® (fingolimod) remained similar throughout the six-year period, between 0.33% and 0.46%2. This was broadly in the range you would expect to see in people without MS, while the typical rate of brain shrinkage experienced by patients with MS is approximately 0.5% to 1.35% per year3-6. The rate of brain shrinkage for people with MS is around three to five times faster than people without the disease3-6, and what is lost cannot be recovered. Brain shrinkage can start early7-10, often goes unnoticed and is associated with a loss of physical and cognitive (i.e. memory) function for patients with MS11. Analyses of the pooled data from the phase III FREEDOMS core and extension studies showed that irrespective of treatment received brain shrinkage was associated with future long-term disability progression. * On October 4, 2013, Novartis has announced new data indicating that continued treatment with Gilenya® (fingolimod) led to a reduction in brain volume loss in patients with relapsing forms of multiple sclerosis (MS), and was associated with a higher proportion of patients remaining free of disability progression. These data were presented at the 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Copenhagen, Denmark. Brain volume loss is emerging as one of the best indicators of disability progression over the long-term in multiple sclerosis. • Collective four-year results from the pivotal FREEDOMS and FREEDOMS extension studies showed that patients who were treated continuously with Gilenya® 0.5 mg experienced up to one-third less brain volume loss than patients who switched to Gilenya after receiving placebo for two years. Thus, delay in starting treatment with Gilenya® by two years was associated with more brain volume loss.
• Overall, patients who remained free of disease had consistently lower rates of brain volume loss compared to patients who experienced disease activity and MS progression. However, the benefit of Gilenya® on brain volume loss was seen irrespective of whether patients were disease-free or had active disease. (Disease activity was evaluated by assessing measures that give a broad evaluation of MS: disability progression, relapses and new brain lesions detected on magnetic resonance imaging scans.)
• A separate analysis of three key studies (FREEDOMS, FREEDOMS II and TRANFORMS) showed a correlation between disability progression and increased brain volume loss, and this correlation increased over time.
• Higher baseline MRI lesion volume and baseline active lesions both predicted subsequent loss of brain volume during the studies but patients treated with Gilenya had less brain volume loss than those treated with placebo or IFN beta 1a IM, irrespective of baseline lesion volume and count.
* On March 21, 2013, Novartis has announced that new data presented at the 65th annual meeting of the American Academy of Neurology (AAN) show Gilenya® (fingolimod) significantly and consistently reduced the rate of brain volume loss. Results also showed that Gilenya® reduced annualized relapse rates across important subgroups; and additional data reinforce Gilenya®\'s safety profile in patients treated up to four years. In a new analysis of over 3,600 patients from three large Phase III studies (TRANSFORMS, FREEDOMS, and FREEDOMS II) Gilenya® showed a significant reduction in the rate of brain volume loss vs. a comparator - consistent with previously reported results. In the TRANSFORMS study over one year, Gilenya® reduced the rate of brain volume loss by -32% (p<0.001) compared to Avonex® (interferon beta-1a IM), a commonly prescribed injectable treatment. Over two years, Gilenya® reduced the rate of brain volume loss compared to placebo by 35% (p<0.001) in the FREEDOMS study, and by 33% (p<0.001) in the FREEDOMS II study, respectively.
The data also showed that brain volume, at baseline, consistently correlated with the level of disease severity and disability. Lower brain volume was linked with more severe disease and disability, while higher brain volume correlated with less severe levels. In addition, traditional markers of disease activity (such as MRI lesion counts) at baseline were predictive of the rate of brain volume loss over two years.
Separately, a recent subgroup analysis (n=1083) of FREEDOMS II, the third large Phase III Gilenya® study, supports the known efficacy of Gilenya® treatment. Specifically, results show Gilenya® consistently reduced annualized relapse rates (ARR) compared to placebo in patients with relapsing-remitting MS, across gender, age, prior treatment, and baseline disease activity.
New extension data from FREEDOMS II (n=632) reinforce the known safety profile of Gilenya in patients treated up to four years. More than eight out of ten patients (83%) completed the extension study, which identified no unexpected safety concern.
* On October 12, 2012, new data have been presented at the 28th congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) that reinforce the generally early and sustained efficacy benefit and long-term safety profile for Gilenya® (fingolimod). A new post hoc analysis of two large Phase III studies shows treatment with Gilenya® 0.5 mg led to significant benefits on relapse-related outcomes within the first three months and on brain volume loss by six months compared to placebo. There was a significant (p<0.05) Gilenya® treatment effect on time to first confirmed relapse within three months in both the pivotal FREEDOMS study (n=1272), and FREEDOMS II, the second large Phase III placebo-controlled study (n=1083). The differences between Gilenya and placebo became persistently significant by Day 82 in FREEDOMS and Day 64 in FREEDOMS II, respectively.
Furthermore, in the FREEDOMS study, patients-treated with Gilenya® 0.5 mg had on average a 35% reduction in brain volume loss compared with placebo at the first MRI evaluation after six months of treatment (mean percent brain volume change of -0.22 for Gilenya® vs. -0.34 for placebo; p=0.006). In FREEDOMS II, there was a 39% reduction in brain volume loss (mean percent volume change of - 0.23 for Gilenya vs. - 0.38 for placebo; p=0.012) at six months.
New data have also been published on real-world experience and patient adherence
First results from the PANGAEA observational study in Germany indicate that 90% of investigators and 91% of patients rated Gilenya® treatment success, defined as efficacy and tolerability, as \"Good\" or \"Very Good\". PANGAEA is a German registry study aimed to enroll a total of 4,000 patients with a follow-up of five years designed to investigate the efficacy and safety of Gilenya in everyday clinical practice. As of May 2012, one year after initiation of the registry, more than 1,850 patients were enrolled in 475 participating centers. These results also showed an overall safety profile in line with previously reported data.
In addition, a separate analysis of time to discontinuation of therapy among MS patients receiving Gilenya and other disease modifying treatments (DMTs) using pharmacy claims in the US (n=1891) show Gilenya-treated patients were significantly less likely to discontinue treatment over the 12 month observation period (Gilenya: 27.8%, other DMT cohorts: 42.7-54.5%; p<0.01) and discontinued later than patients using injectable DMTs.A new integrated analysis of safety data from Phase II, Phase III and study extensions for fingolimod (all doses, n=3553) show a safety profile generally consistent with previous results. The total fingolimod exposure was 9,070 patient years, with 1,510 patients treated for more than three years and some for more than seven years.
* On April 11, 2011, Novartis has announced that a new analysis of the phase III two-year FREEDOMS study demonstrated that Gilenya® reduced the risk of disability progression in patients with relapsing-remitting multiple sclerosis (RRMS), regardless of treatment history. The primary endpoint for the two-year FREEDOMS study was relapse rate, in which Gilenya® reduced relapses by 54% compared to placebo (p<0.001). In a key secondary endpoint, Gilenya® showed a 30% reduction (p<0.05) in the risk of 3-month confirmed disability progression as compared to placebo over two years. The FREEDOMS analysis showed that 0.5 mg Gilenya®-treated patients who were new to therapy (n = 493) had a 37% reduction in the risk of 3-month confirmed disability progression compared to placebo (HR: 0.63; 95% CI: 0.41-0.95) while those previously treated with alternate therapies (n = 350) Gilenya® 0.5 mg led to a 30% reduction in risk (HR: 0.70; 95% CI: 0.43-1.14). Consistent favorable effects on disability progression were observed for Gilenya®-treated patients compared to placebo for subgroups defined by age, gender, and disease severity as defined by EDSS score, relapse activity prior to study, magnetic resonance imaging (MRI) lesion burden or lesion activity at the time of the start of the study.
