Extending the Dose interval of natalizumab


Extended interval dosing of natalizumab in multiple sclerosis.
Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, Pandey K, Donnelly S, Pawate S, Bomprezzi R, Smith D, Kolb C, Qureshi S, Okuda D, Kalina J, Rimler Z, Green R, Monson N, Hoyt T, Bradshaw M, Fallon J, Chamot E, Bucello M, Beh S, Cutter G, Major E, Herbert J, Frohman EM.J Neurol Neurosurg Psychiatry. 2016 Feb 25. pii: jnnp-2015-312940.

BACKGROUND:Natalizumab (NTZ), a monoclonal antibody to human α4β1/β7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days.

METHODS:A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks.

RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort.

CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

In this study they look at the effect of extending the dose interval from 4 weeks and report that by extending the dose interval to 8 weeks dose not dimish effectiveness to natalizumab to MS. They are doing this on the grounds of diminishing the risk to PML, ProfG commented on this view before but is this a case of treatment by numbers?

If delayed treatment was used there were less PML, less new lesions and less enhancing lesions. However the changes were small. If you have less lesions you would think you have less immune survelliance of CNS and greater chance of PML. However, if you delay giving drug and people get break though disease it is a worry. ProfG has reported on this.

Maybe the intelligent way is to work out if you need redosing is to work ot what is happening to the CD49d on the lymphocyte/monocyte surface. If it is completely blocked then the CD49d is blocked, them it cant interact with VCAM on the cell surface of the endothelia in the blood vessel and white blood cells can’t get into the CNS to cause lesions This could be tested with a blood test and the cells ability to cross endotheial barriers in a test tube. However is this type of personalisd medicine we should be aiming towards. Could it mean more frequent dosing

One person with MS called natalizumab their cocaine as they could tell when the drug was wearing-off and when it was time for their next fix.

Maybe the best way to avoid PMLif you are JC virus positive is to switch.  Maybe Prof G can give you his opinion

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  • this is a very timely post. I am a pwMS who after 9 years on Tysabri sero converted and am now JC +. After a brief holiday (12 weekss) and no rebound I am now on 8 week extended dosing with no changes in MRI or break through issues. I do agree with the comments above. It does seem just a matter of time before we may see the PML. My other comment would be that maybe the current dosing of Tysabri was just too high. I always asked if I could have blood drawn each week to see how saturated the cell receptors were.

    While I do understand Prof G suggestion to switch drugs, the idea of latent PML showing on another drug scares the daylights out of me.

    I look forward to any and all insights on this issue.

    • Another worry is whether natalizumab use moves the virus out of the bone marrow niche so increases your risk with any other DMT in the future.

      PML is going to be a worry with any potent immunosuppressive I am afraid

    • Thank you for your honest comment. I had no way of verbalizing my concern about moving to another DMT after 10 years on Tysabri. I have said before: better the devil you know than the one you do not. There is simply not enough data on this patient population on the newer drugs.

  • I could see that NICE in the UK would be very interested in extending the dosing interval to reduce the cost to the NHS.

    Anecdotally, almost all the people who have Tysabri on the same day at the same location as me experience a worsening of some MS symptoms, particularly fatigue, in the days running up to the next infusion.

  • Interesting that NICE is not interested in generic cladribine that would remove the price concern and one suspects much of the PML risk too as it doesn't wipe out CD8..:-(

    • It is not a drug being developed by pharma and so who would anyone go near this in the USA, the MS Societies?. There is no desire to have effective, low cost treatments for RRMS after all why pay $320 a year when you can pay $50,000-$80,000:-(

      Oral cladribine may come back if the FDA eventually let it, but until the EMA do this don't hold your breath, I suspect:-(

  • Thank you for your candor. I would be curious to know if any neuros are using off label in the US. Do you guys have patients on it?

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