Issues around natalizumab (Tysabri) dosing during COVID-19

The COVID-19 NHS crisis is a double-whammy for pwMS. First, it is redeploying staff away from MS services to work on the front-line. Secondly, the message has gone out to stop pwMS coming to NHS hospitals, or even connecting with other healthcare facilities such as GP practices, in an attempt to prevent them from being exposed to SARS-CoV-2. Most MS centres, including ours, have converted all of our clinics to telemedicine. Saying that I saw a very anxious patient with recently diagnosed highly-active MS in our urgent face-2-face neurology clinic yesterday. She needed to be seen as she was in the middle of an attack and in my opinion, should start on a high-efficacy DMT as soon as possible (possibly natalizumab). I am not prepared to make her wait 3, 6, 9, 12 or 18 months to access a high-efficacy therapy and bridging her on a low efficacy DMT would not be in her best interests. If time is brain why should we be compromising on her treatment because of COVID-19? Do you agree?

Seeing this patient face-2-face yesterday helped. She was very anxious and being face-2-face allowed me to counsel her properly. The consultation felt right and is a possible example of why you can’t necessarily do everything using a telemedicine portal.

One of the consequences of COVID-19 is that some pwMS are finding it difficult getting hold of NHS staff and getting their questions answered. Some centres such as ours have converted all our patients on natalizumab onto 6-weekly infusions, others have pushed this out to 8 weeks and some patients from other centres are reporting that their natalizumab infusions have been suspended indefinitely. The mixed messages around dosing and/or suspending dosing is causing a lot of anxiety.

Is it safe to suspend natalizumab infusions?

No, it is not safe. I am particularly concerned that some patients are having their natalizumab infusions stopped without a definite date for recommencing their infusions or at least transitioning them onto another DMT to prevent rebound disease activity, which can on rare occasions be life-threatening.

How does extended interval dosing work?

Yes, EID looks safe. Real-life data suggest from a clinical perspective it is not associated with an obvious increase in disease activity (relapses). However, the data on this is preliminary and Biogen is currently doing a study to address whether or not EID is associated with any loss of disease activity. This is called the NOVA trial and will include MRI monitoring as part of the outcome. One thing that is clear is that EID reduces the risk of PML in JCV positive patients substantially.

The theory behind EID is that some cells are less sensitive to the effects of natalizumab and that if you delay the next natalizumab infusion by 1 or 2 weeks the saturation of their surface receptors drops below a threshold and allows these cells to traffic into the central nervous system. If these less natalizumab-sensitive cells are the antiviral CD8+ T-cells and/or the natural-killer cells that fight viruses then this could allow immune surveillance of the CNS to occur that will prevent PML from occurring. If you get the EID right the desaturation of the immune cells causing MS, possibly the memory B cells, is insufficient not to allow these cells to traffic and to reactivate MS. It is clear that not all cells are made equal when it comes to the effect of natalizumab. Importantly, there are several other adhesion molecules on cells that impact on their adhesion (stickiness) to the blood vessels in the CNS. It could also be a delicate balance between the availability of different accessory adhesion molecules that makes the difference.

How safe is extended interval dosing and does it matter if it is every 6 or 8 weeks?

Everyone gets a standard natalizumab dose of 300-mg every 4 weeks. This means a 50-kg person gets double the relative dose compared to a 100-kg person. The half-life of antibody therapies, such as natalizumab, is linked to how much drug or antibody is given. Therefore for the 50-kg smaller person, 8 weeks may be fine, but for the larger 100-kg person 8 weeks is too long a gap. Based on the real-life data 6 weeks seems to be a good compromise. Therefore I personally would not be comfortable recommending an 8-week interval for all patients. Slide 38 in the deck below demonstrates that as the dosing interval increases so does the impact of body weight on natalizumab’s efficacy.

In reality every person with MS on natalizumab should probably have personalised dosing based on actual saturation of the VLA-4 molecule or equivalent biomarker (e.g. sVCAM-1). This would get us away from guessing and optimising the effectiveness of natalizumab at the same time as decreasing the risk of PML or other CNS complication linked to reduced immunosurveillance.

Zhovtis Ryerson et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):885-9.

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.

Date & Disclaimer: 03-April-2020; please note this information will be time limited and will change as new data emerges.