#ECTRIMS2021: no loss of effectiveness with 6-weekly natalizumab

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If you are on natalizumab and are JC virus seropositive, you are at increased risk of developing PML (progressive multifocal leukoencephalopathy). If you transfer from 4-weekly infusions or standard interval dosing (SID) to 6-weekly or extended interval dosing (EID) you reduce the risk of getting PML by close to 90%. 

Does shifting from SID to EID affect the efficacy of natalizumab? In short NO. 

The following data was presented at ECTRIMS 2021 and should reassure both patients and HCPs

The NOVA trial was designed to estimate the difference in efficacy between EID and

SID dosing in a population that was clinically stable on SID dosing.

 Although a small difference in efficacy between EID and SID dosing was estimated for the primary endpoint (number of new or newly enlarging T2 lesions at week 72) this was driven by two subjects in the EID arm with very high lesion values. The one subject had 30 lesions that occurred 3 months after natalizumab discontinuation, which represents rebound disease activity. The other subject had 25 lesions at week 72 and was subsequently diagnosed with asymptomatic progressive multifocal leukoencephalopathy (PML). The latter could have been PML lesions and not MS lesions. 

When you exclude these 2 patients or outliers there is no difference in the primary endpoint between EID and SID.  This study shows that patients who are stable on natalizumab SID dosing can switch to EID dosing without a meaningful loss of efficacy.

I hope you now feel confident enough to switch from SID to EID without worrying about rebound or loss of efficacy. 

Foley_NOVA_ECTRIMS2021_P970_Final

Foley et al. Primary  results  of  NOVA:  a  randomized  controlled  study  of  the  efficacy  of  6‑week  dosing  of natalizumab  versus  continued  4-week  treatment  for  multiple  sclerosis. ECTRIMS 2021, P970. 

Background:  Natalizumab  4-week  dosing  (Q4W)  with  300  mg  is  approved  for  treatment  of  relapsingremitting  multiple  sclerosis.  Dosing  frequency  of  approximately  6  weeks  (Q6W)  is  associated  with  lower progressive  multifocal  leukoencephalopathy  (PML)  risk  in  retrospective  analyses.  Real-world  data suggest similar  effectiveness,  but  NOVA  is  the  first  randomized  trial  to  assess  Q6W  efficacy.

Objective:  Evaluate  the  efficacy  of  natalizumab  Q6W  in  patients  previously  treated  with  natalizumab  Q4W for  ≥12  months  compared  with  continuation  of  Q4W  over  72  weeks.

Methods:  NOVA is  a  randomized, contro led,  open-label,  rater-blinded  phase  3b  trial.  Included  patients  were treated  with  natalizumab  Q4W  without  relapse  for  ≥12  months  and  had  no  enhancing  lesions  at  screening. Patients  were  randomized  1:1  to  Q6W  or  Q4W  arms. The  primary  endpoint  was  number  of  new/newly enlarging  T2  (N/NET2)  hyperintense  lesions  analysed  by  negative  binomial  regression  with  baseline  (BL) weight,  prior  natalizumab  exposure,  and  region  as  covariates.  Secondary  endpoints  included  relapses  and  24week  confirmed  disability  worsening  (CDW).  Primary  estimand  used  a l  observed  data;  secondary  estimand treated  post-intercurrent  event  data  as  missing.  Missing  data  were  imputed  by  worst  value  on  treatment  or multiple  imputation  depending  on  discontinuation  reason.

Results:  195/248  (79%)  Q4W  patients  and  207/251  (82%)  Q6W  patients  completed  NOVA.  BL  characteristics were  wel  balanced.  Proportions  of  patients  with  N/NET2  lesions  among  observed  data  were  low  in  both arms  (Q4W:4.1%;  Q6W:4.3%).  Mean  N/NET2  lesions  in  the  Q4W  and  Q6W  arms  with  the  primary  estimand were  0.05  and  0.20  (P=0.0755)  and  0.06  and  0.31  (P=0.0437)  with  the  secondary  estimand.  The  difference was  mainly  due  to  2  Q6W  patients  with  high  values:  (1)  30  lesions  that  occurred  3  months  after  natalizumab discontinuation  and  (2)  25  lesions  that  occurred  with  asymptomatic  PML  observed  at  week  72.  The  sum  of  a lother  N/NET2  lesions  in  NOVA  was  18  with  no  other  patient  having  >2.  Relapse  occurred  in  2.1%  and  2.8% (P=0.64)  and  CDW  occurred  in  8%  and  10%  (P=0.40)  of  patients  in  the  Q4W  and  Q6W  arms, respectively. Safety  data  were  consistent  with  the  known  drug  profile  and  similar  between  groups.

Conclusions:  Despite  a  sma l  difference  in  efficacy  between  arms,  NOVA  data  suggest  the  vast  majority  of patients  stable  on  Q4W  dosing  can  switch  to  Q6W  dosing  with  no  clinica ly  meaningful  loss  of  efficacy.  No conclusions  on  PML  risk  can  be  drawn  from  NOVA.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

6 thoughts on “#ECTRIMS2021: no loss of effectiveness with 6-weekly natalizumab”

  1. Does the same apply to SC natalizumab? Or will another trail have to be done for the SC dose.

    Is there good evidence that SC natalizumab is as efficacious as the infusion

  2. After 10+ stable years on Tysabri, and having switched to 6-weekly of my own volition, I started relapsing half way through the second 6-week interval.

    Ignoring n=1 people like me is one thing. But ignoring inconvenient outliers within the actual experiment? Well, it’s certainly is an easy way to get the answer you want!

  3. Hopefully the data will now surface to explain the biology of how the extended dosing interval inhibts NS but gets rid of JC virus……The answer wasnt T-time:-)

  4. With the availability of other therapies it would seem prudent to switch from NZ once a patient becomes JC pos. Why risk PML?

    1. I agree, if natalizumab was the only high-efficacy option then risking PML would be better than risking ineffectively treated MS, but we have alemtuzumab and HSCT so why stay on natalizumab after the first two years? It seems to me that natalizumab these days is best used in the style of the ATTACK-MS trial (put someone on it in the short term while confirming the MS diagnosis, then switch off to another high-efficacy drug).

  5. Prof G,

    “The one subject had 30 lesions that occurred 3 months after natalizumab discontinuation, which represents rebound disease activity.”

    Surely the rebound shows that something is going on in the CNS (?EBV) and when you unleash the immune system ie stop Natalizumab, it piles into the CNS from the periphery to attack the culprit. Is any research team doing work on this ie to find out what’s going on in the CNS?

    The Sizomus trial is targeting plasma cells in the CNS which are producing antibodies. Perhaps the plasma cells are doing what they should be doing ie there’s something going on in the CNS and the plasma cells are producing antibodies against the culprit!

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