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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