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Switching To Gilenya® (Fingolimod) From Standard Interferon Offers Sustained Freedom From Disease Activity For People With Relapsing Remitting MS

Two new analyses from the pivotal Phase III TRANSFORMS study presented at the European Neurological Society (ENS) have shown early and sustained improvements in disease activity in patients who were switched from an interferon to Gilenya® (fingolimod). Improvements were seen within 12 months of the switch and were sustained up to 4.5 years, confirming the long term effectiveness of once daily pill fingolimod.1,2 The analyses showed that fingolimod was effective across key measures of disease activity-free status (defined as a combination of no relapses, no 3-month disability progression and no MRI activity) and brain volume loss.1,2

Dr Martin Duddy, Consultant Neurologist who leads an MS service based at The Royal Victoria Infirmary, Newcastle commented, “The goal of management in MS is to identify and treat the disease quickly, so that we can give people the best possible outcomes. The new data show that in the year after you switch to the once a day fingolimod pill, you are 50% more likely to be free from measurable disease activity compared to staying on the interferon injections. We can see the effectiveness of the fingolimod tablets sustained over the 4.5 years of the study.”

Fingolimod has been approved for use in the NHS since March 2012. These new data support the NICE guidance for fingolimod, which states that it is suitable for patients with the relapsing remitting form of the disease remaining highly active despite treatment with one year’s duration of interferon injection prior to switching treatment to fingolimod.3

Analysis one: the relationship between early disease activity and long term clinical outcomes1 The first new analysis evaluated the association between measures of disease activity (defined as relapses, 3-month disability progression or MRI activity) in the first year of therapy and long-term clinical outcomes.

After switching from interferon to fingolimod, the proportion of patients who were disease activity free increased by almost 50% (from 44.3% to 66.0%) between the end of years one and two respectively. Patients who were disease activity free in year one were most likely to remain clinically disease activity-free (defined as no relapses and no 6-month disability progression) till the end of the extension study (up to 4.5 years).

The authors of analysis one concluded that switching from an interferon to fingolimod resulted in favourable long term clinical disease activity free outcomes.

Analysis two: Long term efficacy of fingolimod in patients previously treated with an interferon beta-1a

A separate post-hoc analysis showed that treatment with fingolimod resulted in an annualised relapse rate (ARR) reduction in patients who had prior disease activity despite treatment with an interferon treatment.2

In patients who were switched from interferon to fingolimod after one year, the ARR was reduced by more than 50% (from between 0.33-0.37 ARR on interferon to 0.14-0.16 ARR on fingolimod treatment) and remained low to the end of the study (up to 4.5 years).2

In addition, further analysis showed that, irrespective of prior treatment and disease activity, brain volume loss was significantly reduced (by about 50%, from between -0.40 to -0.43 on interferon to -0.21 to -0.28 on fingolimod), after one year in patients taking fingolimod compared to those taking interferon and this low rate was sustained until the end of the study.2 Similarly, a slowing / decrease in the rate of brain volume loss was observed in patients that switched from interferon to fingolimod after one year2. Fingolimod is the only approved MS treatment shown to consistently reduce brain volume loss across studies with a significant effect seen as early as six months.4-6 A low rate of brain volume loss with fingolimod was sustained for up to four years in Phase III studies and for up to seven years in patients completing a Phase II study. 7,8 A recent paper identified that brain volume loss in MS occurs early and predicts long-term disability.9

The authors of analysis two concluded that treatment with fingolimod resulted in positive outcomes which were sustained up to 4.5 years for patients with high disease activity despite prior treatment with interferon beta-1a (IFN).2

Conclusion

The new analyses confirm the relationship between early disease activity and long term clinical outcomes, and highlight the importance of early and effective treatment decisions.1,2

Source

Notes

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 them5,6

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 therapy10

There is increasing experience of fingolimod’s long-term effectiveness and safety profile, and approximately 63,000 patients have received the treatment worldwide to date11

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.12

Licenced indication for fingolimod13

Fingolimod has been licensed 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.
Or

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.

NICE and SMC guidance on fingolimod

Fingolimod was recommended by the National Institute for Health and Care Excellence (NICE) on 16 March 2012 as an option for the treatment of highly active RRMS in adults, only if they have an unchanged or increased relapse rate or ongoing severe relapses compared with the previous year despite treatment with beta interferon. As stipulated by NICE, NHS funding for fingolimod became mandatory as of 25 July 2012.3

Fingolimod was approved by the Scottish Medicines Consortium (SMC) on 10 September 2012 for restricted use within NHS Scotland as a single disease modifying therapy in highly active RRMS in adult patients with high disease activity despite treatment with a beta-interferon with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.10

What is the clinical trial data for fingolimod?

Efficacy of fingolimod5,6

The authorisation of fingolimod was based on the submission of data from a large clinical trial programme, which included the TRANSFORMS and FREEDOMS studies

Annualised relapse rates5,6,14,15

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).

Disability progression6,15

Fingolimod significantly prolonged the time to disability progression confirmed after three months by 30% relative to placebo in the overall population (cumulative probability of disability progression confirmed after three months was 17.7% for fingolimod and 24.1% for placebo; n=843; HR 0.7; p=0.02)
- a post-hoc subgroup analysis of patients with highly active RRMS not responding to interferon therapy did not reach statistical significance over 24 months

Fingolimod significantly prolonged the time to disability progression confirmed after six months by 37% relative to placebo (cumulative probability of disability progression confirmed after six months was 12.5% for fingolimod and 19.0% for placebo; HR 0.63; p=0.01)

MRI T2 lesions5,14,16

Fingolimod significantly reduced the mean number of new or newly enlarged T2 lesions by 35% relative to interferon β-1a IM after one year in the overall population (n=860; 1.7 vs 2.6 T2 lesions; p=0.004)
- a post-hoc subgroup analysis of patients with highly active RRMS not responding to IFN therapy did not reach statistical significance (n=261)

In patients switched to fingolimod after one year of interferon β-1a IM treatment, the mean number of T2 lesions was significantly reduced from 2.1 after one year to 0.7 at two years (n=167; 67% relative reduction; p<0.0001)

Trial numbers17,18

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. 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.

Safety of fingolimod5,6,13

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
- The same first dose monitoring as for treatment initiation is recommended when treatment is interrupted for:

  • One day or more during the first two weeks of treatment
  • More than seven days during weeks three and four of treatment
  • More than two weeks after one month of treatment

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/

References

1. Hartung et al. Relationship between early disease activity and long-term clinical outcome: Results from the phase 3 TRANSFORMS study extension at 4.5 years in relapsing-remitting multiple sclerosis. European Neurological Society, June 9, 2013 P380.

2. Montalban et al. Long-term efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis previously treated with interferon beta-1a or disease-modifying therapies: A Post-hoc analysis of the TRANSFORMS 4.5 year extension study. European Neurological Society, June 10, 2013 P539.

3. National Institute for Health and Clinical Excellence. Single Technology Appraisal. Fingolimod for the treatment of relapsing-remitting multiple sclerosis [ID63].

4. Chin PS, Calabresi PA, Zhang Y, von Rosenstiel P, Kappos L. Early effect of fingolimod on clinical and MRI related outcomes in relapsing multiple sclerosis. Poster presented at: 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis; October 10-13, 2012; Lyon, France. Abstract P459.

5. Cohen JA, Barkhof F, Comi G, et al; for TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415.

6. Kappos L, Radue E-W, O’Connor P, et al; for FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.

7. 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.

8. Antel J, Montalban X, O’Connor P, et al. Long-term (7-year) data from a phase 2 extension study of fingolimod in relapsing multiple sclerosis. Poster presented at: 64th AAN Annual Meeting; April 21-28, 2012; New Orleans, LA. Poster P01.129.

9. Popescu V, Agosta F, Hulst HE, et al; on behalf of the MAGNIMS Study Group. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 March 23.

10.SMC assessment of fingolimod (as hydrochloride), 0.5mg hard capsules (Gilenya). 10 September 2012.

11.Novartis data on file. GIL13-08, Novartis March 2013.

12.Novartis data on file. February 2013.

13.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.

14.Havrdova E et al. Poster presented at ECTRIMS Congress, Amsterdam, The Netherlands,19-22 October 2011.

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.Khatri B et al. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol 2011; 10:520–529.

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.

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