Friday, 4 April 2014

Clinic speak: fingolimod and ramblings about the field hypothesis

Early treatment with fingolimod is better than later treatment. Why? #ClinicSpeak #MSBlog #MSResearch

Have you hear about the field hypothesis of MS? #MSBlog #MSResearch

"The following are the results of the second large phase 3 study of fingolimod in RRMS and a post-hoc analysis of the effect of fingolimod in MSers with early disease. These results of the FREEDOMS-2 study confirm that fingolimod is effective in RRMS and the second study which presents a post-hoc analysis of the TRANSFORMS and FREEDOMS-1 studies shows that fingolimod is more effective when used in early in the course of MS, i.e. within 3 years of first symptoms. The observation that DMTs are more effective the earlier you use them is not unique to fingolimod and is appears to be a general phenomenon across all DMTs, Why? To be honest I have no idea. It seems that once MS becomes established it may be more difficult to treat. Immunologists would say that this may relate to epitope spreading; i.e. with each attack there is damage to the end-organ (brain and spinal cord) that releases proteins or antigens that then stimulate additional T-cells to attack the end-organ. The more epitopes (antigens of protein fragments) that are recruited into the autoimmune attack the more difficult it is to modify the course of the disease. I don't buy into this hypothesis as there is very little evidence to support epitope spreading is actually occurring in MS. In fact there is little evidence to support any specific antigen as being the dominant auto-antigen in MS. One of the holy grails in MS is finding the pathogenic autoantigen; there are a lot of candidates, but none fulfill the so called Witebsky's postulates."

The field hypothesis: poppies (viruses) in a field (brain)
"Another hypothesis to explain the enhanced early treatment effect is the field hypothesis (I have just made this up). If MS is due to a virus and MS is due to the immune response to this virus the more of the nervous system that gets infected with this virus (larger field) the more difficult it is to prevent T-cells and other immune mediators finding the virus. The field hypothesis will also explain why we get rebound when you stop anti-cell-trafficking drugs such natalizumab and fingolimod. Natalizumab and fingolimod stop immune cells getting into the nervous system and finding the putative virus that causes MS, which allows the virus to spread and enlarge the field so that when you stop these drugs the immune system attacks many more sites; i.e. rebound. A good analogy of this is IRIS (immune reconstitution inflammatory syndrome) that occurs with PML. The larger the PML field the worse the IRIS. This is why we try and treat PML as soon as possible to prevent a large field, or infected brain volume."

"A large number of us are beginning to hypothesise that the best brains to study to find the MS virus is the natalizumab-treated brain. If the immune system destroys the virus and makes it difficult to find we need to look at brain tissue that is protected from immune attack, but is allowed to cultivate and grow the virus. To do this we would have to study brain biopsies of MSers on natalizumab or brain tissue from someone with MS who dies whilst on natalizumab from an MS-unrelated cause. This is why it is so important for MSers who are doing well on DMTs to please sign-up for brain donation in the event of you dying unexpectedly. You never know your brain may be the one that is the key to finding the cause of MS."

"I am aware that several MS virus hunters are looking for viruses using gray matter lesions. They believe that because MS gray matter lesions are less inflammatory it is more likely the virus will be detectable in these lesions. I am not sure; our immune systems are so effective at seeking and destroying viral intruders that it may be a difficult ask."

Epub: Calabresi et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014 Mar 27. pii: S1474-4422(14)70049-3.

BACKGROUND: Fingolimod has shown reductions in clinical and MRI disease activity in RRMSers. We further assessed the efficacy and safety of fingolimod in such patients.

METHODS: We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible MSers - those aged 18-55 years with MS - to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all MSers assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with, number NCT00355134.

FINDINGS: Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 MSers: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in MSers given placebo and 0·21 (0·17-0·25) in MSers given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] MSers vs 0 MSers), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 MSers given fingolimod 0·5 mg and 45 (13%) of 355 MSers given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] MSers vs two [1%] MSers), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]).

INTERPRETATION: Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis.

Epub: Agius et al. Fingolimod Therapy in Early Multiple Sclerosis: An Efficacy Analysis of the TRANSFORMS and FREEDOMS Studies by Time Since First Symptom. CNS Neurosci Ther. 2014 Mar 31. doi: 10.1111/cns.12235.

AIMS: The phase 3 TRANSFORMS and FREEDOMS studies established the efficacy of fingolimod in RRMS and magnetic resonance imaging lesions compared with intramuscular (IM) interferon (IFN) β-1a and placebo over 12 and 24 months, respectively.

METHODS: To investigate the efficacy of fingolimod at the approved 0.5 mg dose in MSer early in the MS disease course, post hoc subgroup analyses of TRANSFORMS (n = 272) and FREEDOMS (n = 217) data were conducted in MSers who experienced their first MS symptom <3 years before randomization.

RESULTS: Fingolimod 0.5 mg reduced annualized relapse rate by 73.4% (P = 0.0002) versus IFNβ-1a IM and by 67.4% (P < 0.0001) versus placebo in MSers with <3 years since first symptom; respective reductions were 45.4% and 51.4% in subgroups of MSers with ≥3 years since first symptom. For MSers with <3 years since their first symptom, significantly fewer new/newly enlarged T2 lesions were observed with fingolimod versus IFNβ-1a IM (mean number, 1.94 vs. 2.95; P = 0.036) or placebo (4.1 vs. 10.7; P < 0.001); the mean number of gadolinium-enhancing T1 lesions was significantly reduced versus placebo (0.3 vs. 1.1; P < 0.001).

CONCLUSION: Fingolimod 0.5 mg is highly effective in reducing relapses and MRI activity in patients early in the MS disease course.

CoI: multiple


  1. Does this mean that Gilenya should be used as a first line drug?
    With the risks associated with alemtuzumab should it also get a first line licence?

    1. Re: "Does this mean that Gilenya should be used as a first line drug?"

      Absolutely, it is being used as a 1st-line drug in the USA, Australia and Switzerland. I suspect the price that Novartis set for the drug in the USA affected the EMA's decision to make it 2nd-line. The drug costs too much for European Healthcare systems to allow it as a 1st-line drug. As always the losers are European MSers.

  2. Prof. G apart from PML and IRIS are there other examples to support the field hypothesis?

  3. The use of poppies conjures up images of war and death; appropriate analogies for MS.

  4. From what you have written above, it seems you are saying that the immune response may react innapropriately to a virus such as EBV in people with MS.

    I can totally agree with this line of logic but the problem is that this is vastly different than what you have been saying previously. In the past, you postulated that MS is cause by a virus (EBV) that directly attacks the immune system. This gives rise to the black swan posts, the autoimune blinders, etc, etc.

    You even came out and stated you disagree with Dr. Penners position on his results that he believes EBV is a catalyst in MS, not the direct cause.

    I would have more respect for you if you maintian your conviction that MS is caused by EBV instead of changing assumptions on the fly. You may want to state precisely why you think EBV is causing direct damage in MS. Otherwise, stop portraying yourself as a renegade.

    1. Scientific ideas are not a matter of conviction!
      Scientists need to keep an open mind while looking for an answer. They don't know what the answer is going to be, their pet theory may be proven wrong

    2. Re: ".... maintian your conviction that MS is caused by EBV ..."

      Conviction is a firmly held belief or opinion. I am not a believer. Beliefs are part of a religion. I am not religious I am an agnostic. However, I am a scientist and have the right to propose hypotheses; hypotheses differ from beliefs in that they can be falsified and rejected. The field hypothesis is just that, a hypothesis that needs to be shown to be false.

    3. Of course they need to keep an open mind, but this does not require them to be mindless. He keeps inferring EBV is the direct cause of ms but gives no evidence to support this. The fact that nearly all human adults have EBV, yet only a fraction of a fraction of all human adults have ms clearly calls into question his assumption. But don't pretend you are venturing into new territory by testing if you target EBV you will cure ms. It seems his views on this subject change from one week to another.

    4. RE: " In the past, you postulated that MS is cause by a virus (EBV) that directly attacks the immune system."

      All I have said is that EBV holes up in the B-cell. I have no idea how it causes MS. The evidence that EBV causes MS is based on epidemiological studies; if you don't have EBV you are protected from developing MS. They only way we are going to prove this is by doing a EBV vaccination study. The problem is there are currently no Pharma companies that we are aware of that are developing EBV vaccines. This project may need to be led by academia or government.

  5. P.S. No comments about cows and fertilizer allowed

  6. Another great post Prof G; this hypothesis fits in very well with the Prineas lesion, which argues against MS being an autoimmune disease. The fact that alemtuzumab and related drugs work in MS does not mean MS is an autoimmune disease. There are other explanations for their mode of action.

  7. Have you tested alemtuzumab treated patients to see if they are still sero-positive for EBV after treatment? And more interestingly, have you tested the EBV status of those who require a third round of alemtuzumab? If they are sero-negative for EBV post-treatment it would be interesting to monitor their on-going EBV status and see if those that relapse convert back to sero-positivity before the re-emergence of MS disease.


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