Friday, 28 February 2014

Clinic Speak: switching from natalizumab to fingolimod

Rebound post-natalizumab can be prevented or reduced by early switch to fingolimod. #MSBlog #MSResearch #ClinicSpeak

"The study below confirms the results of the TOFINGO study, MSBase and several smaller studies, which show that if you have a wash-out period when switching from natalizumab you are  more likely to have a relapse  than if you don't have a washout. Why? Natalizumab has a circulating half-life close to 2 weeks; the half-life describes the period of time it takes for the levels to drop by 50%. It therefore takes about 10-12 weeks (5-6 half lives) for natalizumab levels to drop to low enough levels to allow lymphocytes to start trafficking back into the brain and spinal cord. If these cells are autoimmune cells they will set-up an local inflammatory response and trigger a relapse. This process takes several weeks. This is why we see rebound disease activity (relapses or MRI activity) about 3-4 months after stopping natalizumab. Therefore it is not a good idea to stop natalizumab without starting another DMT to prevent this rebound. Unfortunately, interferon beta and GA have not proven to be very effective post-natalizumab. What about oral drugs? We don't have data yet on teriflunomide (Aubagio) or BG12 (Tecfidera). However, fingolimod has been studied and provided it is started with 8 weeks of stopping natalizumab it can prevent most of the rebound. The sooner you start it the better. At the Royal London Hospital we have adopted this practice for sometime now. If the switch is in a JCV positive MSers we do an MRI for new white matter lesions and lumbar puncture to analyse the spinal fluid for JCV DNA. If these test are clear the likelihood of asymptomatic PML is low and we start fingolimod. This typically occurs at around week 3 or 4 after the last infusion of natalizumab. As it takes about 6 weeks for fingolimod to take an effect by the time natalizumab is out of your system fingolimod is working."

"If you are being switched from natalizumab to fingolimod and your neurologist wants to do a prolonged washout ask him/her why?"

"What is most intriguing about stopping natalizumab is the rebound activity that is often very severe and greater than that what was seen prior to starting natalizumab. Why? I suggest you read my post from last year on this topic; it generated a lot of discussion about MS and its potential cause."

Rebound activity post-natalizumab; image from Arch Neurol. 2011;68(2):186-191.

Cohen et al. Switching From Natalizumab to Fingolimod in Multiple Sclerosis: A French Prospective Study. JAMA Neurol. 2014 Feb 24. doi: 10.1001/jamaneurol.2013.6240.

IMPORTANCE: The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of MSers to our knowledge.


OBJECTIVE: To collect data from MSers switching from natalizumab to fingolimod.

DESIGN, SETTING, AND PARTICIPANTS: A survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod.

MAIN OUTCOMES AND MEASURES: Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod.

RESULTS: Thirty-six French MS tertiary referral centers participated. In total, 333 MSers switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for MSers receiving natalizumab. Twenty-seven percent of MSers relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). MSers who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of MSers relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05). 

CONCLUSIONS AND RELEVANCE: In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

CoI: multiple

10 comments:

  1. I am considering switching from natalizumab to fingolimod but am worried about the lack of statistical evidence. This study is really helpful about avoiding relapsing but what is the data on developing PML anyway once a person ceases to be on an immuno-suppressant drug (tysabri)? I have been told I have a 1 in 70 chance of developing PML if I stay on tysabri. What is thechance of deterioration if I come off it and what is the chance of developing PML if I come off it?

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  2. The results of the study do not support any presumed beneficial effect of Gilenya: 27% relapsed in the washout period and 20% relapsed within the first 6 months in Gilenya. 7% drop is insignificant, especially since there was no placebo arm.

    Are you just trying to expand the Gilenya market? I'm sure you are also offering Tysabri to disappointed Gilenya users, in order to maintain the pharma balance

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    1. Re: "Are you just trying to expand the Gilenya market? I'm sure you are also offering Tysabri to disappointed Gilenya users, in order to maintain the pharma balance."

      It is horses for courses and individualised care. Clinical decision-making has nothing to do with Pharma balance. The switch from natalizumab to fingolimod is about reducing the risk of PML.

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    2. Re: "The results of the study do not support any presumed beneficial effect of Gilenya: 27% relapsed in the washout period and 20% relapsed within the first 6 months in Gilenya. 7% drop is insignificant, especially since there was no placebo arm."

      Most of these relapses occurred in the period after Natalizumab was washed-out and fingolimod was not active. It takes 6-8 weeks for fingolimod to become active. The MSBase study and the TOFINGO study that have been presented clearly show that when you overlap the washout period with starting fingolimod so that MSers are not exposed to the period when fingolimod is not working do very well. The danger of this however is carry-over PML; there have been two cases that I am aware of developing PML in the first few months of going onto fingolimod. Why is this a problem? It is a problem because you rely on your immune system functioning to get rid of PML. It takes several months to wash fingolimod out of the system. Months in the life of someone with PML could be the difference between moderate and severe impairment or even worse life and death. This is why we try and make sure there is no evidence of sub-clinical PML before we make the switch. This will become even more critical with drugs such as alemtuzumab that we can't washout. Switching from natalizumab to alemtuzumab in MSers at high-risk PML is going to require some deep thought on how to de-risk the process completely.

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    3. TOFINGO trial has a very interesting history behind it: Initially, 600 patients were planned to take part, but only 142 made it since recruitment was halted by Novartis with the following excuse:
      https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&ved=0CCYQFjAA&url=https%3A%2F%2Fhelseforskning.etikkom.no%2FikbViewer%2FContent%2F267063%2FTOFINGO%2520Investigator%2520Communication%252027%2520Feb%252012%2520FINAL.pdf&ei=HywSU4m5CYLRhAf4noH4Bw&usg=AFQjCNG2ZPjLJq7s9NbBT5WEMtO1Cjv9JA&sig2=0gAUqHyshyAGLxnKxAgCGg&bvm=bv.62286460,d.ZG4&cad=rja

      Also, where is the full article regarding TOFINGO? Only the abstract seems available.

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    4. TOFINGO was a study to look at switching from tysabri to gilenya. There were a few papers published on the subject and there Novartis decided to pull the plug.

      As to publication this will have an uphill struggle as the trial was not completed and so referees will of had a field day.

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  3. Dr. G regarding wash-out period: is this the time between stopping natalizumab and initiating a DMT such as fingolimod? How do you manage/shorten the wash-out period? Does this mean start fingolimod before natalizumab is totally flushed from the systemb (i.e. less than 3 mos.)? Also, there was a paper in NEJM that followed a RRMSer upon cessation of natalizumab treated with maraviroc to prevent auto-immune t-cells into CNS.http://www.nejm.org/doi/full/10.1056/NEJMc1304828. Or is this only for active cases of PML?

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  4. NHS England does not fund the switching of JCV +ve patients from natalizumab to fingolimod. So how is this research relevant to current clinical practice??

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    1. Re: "NHS England does not fund the switching of JCV +ve patients"

      NHS England does fund switching if they failed IFNbeta or GA prior to going onto Natalizumab. It is the MSers who went onto Natalizumab as a first-line drug that you are referring to. The ABN have made a case to NHS England to allow this latter group to switch; this is based on safety concerns relating to PML. We are waiting to hear from them. At the moment there are a several MSers in our centre waiting anxiously to hear from NHS England. We will keep you posted.

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  5. NHS England is not the whole world and the readership is global
    profG is talking about his experience of switching within the nhs.

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