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

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