Gilenya® (Fingolimod) Demonstrates Consistent Benefits In Reduction Of Relapses And Brain Volume Loss In Relapsing-Remitting Multiple Sclerosis
Data presented at the 65th annual meeting of the American Academy of Neurology (AAN) show Gilenya® (fingolimod), the first and only once-daily oral therapy reimbursed to treat highly active relapsing-remitting multiple sclerosis (RRMS), significantly and consistently reduced the rate of brain volume loss and reduced relapse rates compared to interferon beta-1a IM or placebo.(1,2,4) The new data add to the growing body of evidence for fingolimod regarding its early efficacy benefits and long-term safety profile.
Consistent efficacy: reduction in rate of brain volume loss
Fingolimod continues to show a significant reduction in the rate of brain volume loss by nearly a third and within the first six months of treatment when compared to placebo or interferon beta-1a IM, a commonly prescribed injectable treatment.1 The new analysis of over 3,600 patients from three large Phase III studies (TRANSFORMS, FREEDOMS, and FREEDOMS II) was consistent with previously reported results.(1,5)
Loss of brain volume (also known as brain atrophy) has been observed to occur at higher rates in patients with MS than in the general population. The average rate of brain volume loss in a person without MS over one year is 0.1% to 0.3%.(6)
In the TRANSFORMS study over one year, fingolimod reduced the rate of brain volume loss by 31% compared to interferon beta-1a IM (mean percent brain volume change of -0.31 for fingolimod vs. -0.45 for interferon beta-1a IM; p<0.001). Over two years, fingolimod reduced the rate of brain volume loss compared to placebo by 36% (mean percent brain volume change of -0.84% for fingolimod vs. -1.31% for placebo; p<0.001) in the FREEDOMS study, and by 33% (mean percent brain volume change of -0.86% for fingolimod vs. -1.28% for placebo; p<0.001) in the FREEDOMS II study, respectively.(1)
Consistent efficacy: reduction in relapse rates
Throughout the extensive Phase III programme, fingolimod has consistently shown significant reductions in relapse rates. The most recent addition to this growing body of evidence is new data from the one-year TRANSFORMS extension study (n=341). The study, which included a predictive model to estimate the relapse rate had patients remained on interferon beta-1a IM, showed that patients who were treated with fingolimod experienced a two fold increase in the time-to-first relapse compared with interferon beta-1a IM.(4)
In addition, a subgroup analysis of FREEDOMS II showed fingolimod consistently reduced annualised relapse rates (ARR) compared to placebo in patients with RRMS, across gender, age, prior treatment, and baseline disease activity.(2)
Consistent safety profile: no unexpected safety concerns from new analysis New extension data from FREEDOMS II (n=632) reinforce the known safety profile of fingolimod in patients treated up to four years.7 More than eight out of ten patients (83%) completed the extension study, which identified no unexpected safety concerns.7 With up to seven years of clinical trial experience (Phase II and III) and over two years of real-world use, this adds to the increasing experience of the long-term effectiveness and safety profile of fingolimod in more than 56,000 patients worldwide.(3)
Novartis MS pipeline
The data presented at AAN underscore the depth and breadth of the Novartis MS portfolio and ongoing commitment to addressing unmet patient needs in MS. Alongside the data reinforcing the efficacy and safety profile of once-daily oral fingolimod in RRMS, new data was presented on its potential use in primary-progressive MS (PPMS). New efficacy and safety data were presented on investigational compound BAF312 (siponimod) from the Phase II extension BOLD study in RRMS.(8.9)
It is important to note that the news release contains data that is both within and outside of the UK marketing authorisation for fingolimod.
Additional information on fingolimod
Fingolimod is an effective once-daily oral MS treatment without market authorisation restrictions specific to treatment duration, making it a valuable option for appropriate people with highly active RRMS and the neurologists who treat them10,11
Fingolimod addresses an unmet clinical need and a significant gap in funded treatment options for patients with highly active RRMS who continue to relapse despite treatment with an interferon therapy12
There is increasing experience of fingolimod’s long-term effectiveness and safety profile, and approximately 56,000 patients have received the drug worldwide to date3
Fingolimod has been approved in more than 70 countries. In the EU, fingolimod has been launched and reimbursed in a number of markets, including Germany, France, Denmark, Sweden, Norway, Austria, Greece, Italy, Spain, Belgium, Portugal and the Netherlands. Fingolimod also has been launched and reimbursed in other key markets including the United States, Canada, Australia and Switzerland.(13)
Licenced indication for fingolimod(14)
Fingolimod has been licenced for use as a single therapy in the treatment of highly active RRMS in the following adult groups since March 2011:
Patients with high disease activity despite treatment with a beta-interferon. These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon. Patients should have had at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintense lesions in cranial MRI or at least one Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.
Patients with rapidly evolving severe RRMS defined by two or more disabling relapses in one year, and with one or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
Efficacy of fingolimod(10,11,15,16) The authorisation of fingolimod was based on the submission of data from a large clinical trial programme, which included the TRANSFORMS and FREEDOMS studies
TRANSFORMS showed that fingolimod 0.5 mg reduced the annualised relapse rate by 52% compared to interferon β-1a IM at one year
-this equates to a reduction in annualised relapse rates from 0.33 for interferon β-1a IM to 0.16 with fingolimod 0.5 mg (p<0.001)
FREEDOMS showed that fingolimod 0.5 mg reduced the annualised relapse rate by 54% versus placebo at two years
this equates to a reduction in annualised relapse rates from 0.40 for placebo to 0.18 with fingolimod 0.5 mg (p<0.001).
Consistent treatment effects were observed in the highly active subgroup for which fingolimod is licenced:
TRANSFORMS showed that fingolimod 0.5 mg reduced the annualised relapse rate by 61% compared to interferon β-1a IM
-this equates to a reduction in the annualised relapse rate from 0.51 for placebo to 0.20 with fingolimod 0.5 mg (p<0.001)
FREEDOMS showed that fingolimod 0.5 mg dose reduced the annualised relapse rate by 71% versus placebo
this equates to a reduction in the annualised relapse rate from 0.66 for placebo to 0.19 with fingolimod 0.5 mg (p<0.0001).
The clinical trial programme also demonstrated that fingolimod is generally well tolerated with a manageable safety profile when used in accordance with its approved marketing authorisation.10,11 Its benefit/risk profile has been studied in more than 4,000 clinical trial patients, some of whom are in their seventh year of treatment.(17,18)
Safety of fingolimod(10,11,14)
In clinical trials, the most common side effects were headache, liver enzyme elevations, influenza, diarrhoea, back pain, and cough.
Safety considerations in relation to fingolimod treatment:
Liver transaminases: in clinical trials, treatment with fingolimod was associated with asymptomatic liver transaminase elevations
- Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with fingolimod
- In the absence of clinical symptoms, liver transaminases should be monitored at Months 1, 3, 6, 9 and 12 on therapy and periodically thereafter
Macular oedema: in clinical trials, 0.4% of patients treated with fingolimod developed macular oedema, predominantly in the first 3-4 months
- An ophthalmological evaluation is recommended at 3-4 months after treatment initiation
Bradyarrhythmia: initiation of fingolimod treatment results in a transient decrease in heart rate and may also be associated with atrioventricular conduction delays, including the occurrence of isolated reports of transient, spontaneously resolving complete atrioventricular block
- Fingolimod is not recommended in patients concomitantly taking Class Ia or Class III antiarrhythmic medicines
- All patients should have an ECG and blood pressure measurement performed prior to and 6 hours after the first dose of fingolimod
- All patients should be monitored for a period of 6 hours for signs and symptoms of bradycardia with hourly heart rate and blood pressure measurement
- Continuous (real time) ECG monitoring during this 6 hour period is recommended
Infections: fingolimod may increase the risk of infections
- Before initiating fingolimod, a recent (within 6 months) complete blood cell count should be available to check peripheral lymphocyte count
- Before initiating fingolimod, patients without a history of chickenpox or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV
- Effective diagnostic and therapeutic strategies should be employed in patients with symptoms of infection while on therapy
- Suspension of fingolimod treatment should be considered if a patient develops a serious infection
Blood pressure: in clinical trials, fingolimod was associated with an increase in blood pressure after approximately one month of treatment
- Blood pressure should be regularly monitored during treatment with fingolimod
Pregnancy/breastfeeding: fingolimod may cause harm to an unborn child and women receiving fingolimod should not breastfeed
- Women of childbearing potential should be counselled regarding the potential for serious risk to a foetus and the need for effective contraception during treatment with fingolimod
- A negative pregnancy test is required before initiation of fingolimod treatment
The SmPC for fingolimod can be accessed here: http://www.medicines.org.uk/EMC/medicine/24443/SPC/Gilenya+0.5mg+hard+capsules/
1. Cohen J. et al. Fingolimod-effect on brain atrophy and clinical/MRI correlations in Three Phase 3 studies – TRANSFORMS, FREEDOMS and FREEDOMS II. Abstract presented at AAN, San Diego, March 2013.
2. Goodin D et al. Fingolimod reduces annualized relapse rate in patients with relapsing-remitting multiple sclerosis: FREEDOMS II study subgroup analysis. Abstract presented at AAN, San Diego, March 2013.
3. Novartis data on file. GIL13-02, Novartis 2013.
4. Meng X et al. Effect of switching from intramuscular interferon b-1a to fingolimod on time to relapse in patients with relapsing-remitting multiple sclerosis enrolled in a 1-year extension of TRANSFORMS.
5. Chin P.S. et al. Early effect of fingolimod on clinical and MRI related outcomes in relapsing multiple sclerosis. Abstract Presented at ECTRIMS, Lyon, France, October 2012.
6. Barkhof F et al. Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol. 2009; 5(5):256-266.
7. Rammohan K. et al. Long-term safety of fingolimod in patients with relapsing-remitting multiple sclerosis: Results from phase 3 FREEDOMS extension study. Abstract Presented at AAN, San Diego, March 2013.
8. Stuve O et al. Phase 2 BOLD extension study efficacy results for siponimod (BAF312) in patients with relapsing–remitting multiple sclerosis. Abstract presented at AAN, San Diego, March 2013.
9. Hartung H et al. Phase 2 BOLD extension study safety results for siponimod (BAF312) in patients with relapsing–remitting multiple sclerosis. Abstract Presented at AAN, San Diego, March 2013.
10.Cohen JA et al. Oral Fingolimod vs. intramuscular interferon in relapsing multiple sclerosis. N Eng J Med2010; 362(5):405-415.
11.Kappos L et al. Placebo-controlled study of oral fingolimod in relapsing multiple sclerosis. N Eng J Med 2010; 362(5):387-401.
12.SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya). 10 September 2012.
13.Novartis data on file. February 2013.
14.Gilenya Summary of Product Characteristics. 2013. http://www.medicines.org.uk/EMC/medicine/24443/SPC/Gilenya+0.5mg+hard+capsules. Last accessed 20 March 2013.
15.Devonshire V 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(5):420-8.
16.Havrdova E et al. Poster presented at ECTRIMS Congress, Amsterdam, The Netherlands,19-22 October 2011.
17.Novartis data on file. 2012.
18.O’Connor P et al. Oral fingolimod (FTY720) in MS. Two-year results of a phase II extension study. Neurology. 2009; 72:73-79.