Old but good news: children and adolescents get their first licensed DMT in Europe

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I personally want to thank all those involved in getting fingolimod licensed as the first disease-modifying therapy for children and adolescents with MS. Getting this trial done was a ‘mission impossible’. Novartis, the steering committee, investigators and all study participants must be congratulated on getting past the finish line. History will judge this as an important milestone for MSers and the wider MS community.


However, I am very disappointed that the EMA (CHMP) only licensed this for highly-active or rapidly-evolving severe MS. Why the restrictive label? When will the EMA beging to trust neurologist, MSers and their families to do the right thing? The way the EMA treat us is insulting and does not put MSers’ interests first. 

Surely it is time to change fingolimod’s label? We need fingolimod to be first-line. Why can’t we be trusted to use fingolimod wisely in the interests of our patients with active MS? Surely it is safer than alemtuzumab? Possibly safer than ocrelizumab? Can someone explain the thinking and logic behind the latest pair of EMA handcuffs?

The following is verbatim from the EMA’s website:

On 20 September 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of the marketing authorisation for the medicinal product Gilenya. The marketing authorisation holder for this medicinal product is Novartis Europharm Limited.

The CHMP adopted an extension to the existing indication as follows:

“Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following groups of adult patients and paediatric patients aged 10 years and older:


Patients with highly active disease despite a full and adequate course of treatment with at least one disease-modifying therapy (for exceptions and information about washout periods see sections 4.4 and 5.1).

or


Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.”

Detailed recommendations for the use of this product will be described in the updated summary of product characteristics (SmPC), which will be published in the revised European public assessment report (EPAR), and will be available in all official European Union languages after a decision on this change to the marketing authorisation has been granted by the European Commission.


The timing of this is fortuitous as the study has recently been published in the NEJM:

Chitnis et al. Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis. N Engl J Med. 2018 Sep 13;379(11):1017-1027.


BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population.


METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate.

RESULTS: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient).

CONCLUSIONS: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .).

Comment inTherapy in Multiple Sclerosis – Coming of Age. [N Engl J Med. 2018].


CoI: Multiple; in addition Prof G is a member of the PARADIGMS trial steering committee

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

17 comments

    • Because the payers won't pay for it and not many neurologists are keen to prescribe off-label. They are risk averse and not keen to take on the risks if anything untoward happens. In addition, off-label prescribing exacerbates inequality, i.e. those who have money to tend to be able purchase what they want and those who can't afford are left to the mercy of the system.

  • I have heard you speculate before that Novartis don't want Gilenya licensed as a first-line therapy. Do you still hold that position?

  • Maybe EMA thinks not all neurologist are cut from the same mould as barts. Some may decide to always recommend fingolimod to earn more commission from pharma (In directly via grants, chairs etc) thus putting patient lives at risk. Neurologists like society represents all shades of grey. There places in this world where you go for routine op and realise 1 of you kidneys have been sold to someone in the West. Thank God for EMEA!

    • Politicians have always been more corrupt than neurologists. Novartis has a pipeline of MS drugs to replace Gilenya the last thing they need is a generic 1st-line fingolimod to compete against. Pigeon-holing fingolimod as a 2nd-line drug is exactly what they want. I think neurologists have the upper hand in this debate.

      Neurologists 2: Novartis 2: EMA 0

    • I don't think broad generalisations are helpful in this context. It is not about corruption, but shared decision-making. The Australians have got the balance right. License the treatments for active MS and let the neurologists and MSers decide what is best for them. To suggest neurologists and regulators are or have been bribed is ludicrous. I am optimist and believe that we are all on the same side, which is to improve the lives of MSers.

      Please tell me why the world has become so cynical? What has happened to trust?

    • Fingolimod has recently had its patent extended so the implied incentive for keeping it 2nd-line does not really apply. Again I ask why the cynicism?

    • Thanks Prof G. I agree cynicism is not healthy. But it is the era we live. The end of the 60s generation of hope and liberalism. To era of trump.

    • It is so sad that liberalism is under attack from all sides. We need to remember the battles fought, lives lost and the principles that underpin why liberal values are so important. Can I suggest we try and uphold them on this blog? We don't, at least I don't, spend hours doing MS, including writing on this blog, for anything but honorable reasons. To suggest otherwise is upsetting.

    • As someone with PPMS who has come across a lot of spouting on treatments unlikely to help me, and a lot of accusations levelled at lazy neurologists and an NHS which supposedly cares more about the bottom line of its budget sheet than about people like me, I'm keeping my healthy cynicism and ability to think for myself – I'm not simply swallowing every sugar coated pill or (possibly disingenuous) piece of advice.

      We live in the real world, not a children's book with a customary happy ending.

      Liberalism is surely more about freedom for people to think for themselves and be thoughtfully and honestly outspoken than about trusting blindly.

  • This could be:

    Dear shareholder:

    I personally want to thank all those involved in getting fingolimod licensed as the first disease-modifying therapy for children and adolescents with MS. Getting this trial done was a 'mission impossible'. Novartis, the steering committee, investigators and all study participants must be congratulated on getting past the finish line.

    Hope this wil bring value to our company bottom line of

    49.1 bn
    Net sales (USD) worldwide

    Neuroscience (sales in usd millions

    Gilenya 2017 2016
    3 185 000$ 3 109 000 $

    Obrigado

  • I remain deeply concerned about the long term side effects of Gilenya in children given the immunosuppressive nature of this drug.

    Specifically, the risk of serious opportunistic infections, PML and malignancies, such as basal cell cancers and melanoma, with long term lack of immune surveillance caused by Gilenya.

    I really wonder if long term immunosuppressive drugs in children is the answer especially with Gilenya which limits lymphocyte egress from lymph nodes and migration into CNS. Especially when Gilenya is only shown to stop relapses by about 50% and progression by about 30% over placebo.

    One really has to ask about the current state of MS research focused and where are we going with a focus only mainly immunosuppressive drugs with no focus on prevention (EBV vaccine?), no remyelination, no neuroprotective and no neurorestoration drugs.

    In the current model, especially in children, with long term use, we are going to run in to diseases as bad or worse than MS itself, like malignancies.

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