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

Barts-MS rose-tinted-odometer: ★★★★★
Lime green and purple Thursday, #32cd32 & #6a0dad 

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

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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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. 

How important is your brain volume?

Barts-MS rose-tinted-odometer: ★★★★(A blue sky and sunflower yellow Tuesday; #87CEEB #ffda03)

I bang on about treating-2-target beyond NEIDA (no evident inflammatory disease activity) and targeting the end-organ, i.e. to try and normalise brain volume loss (BVL). The aim is to get pwMS to old age with a healthy brain so that they can age normally. Who wants to be at risk of premature ageing and being demented earlier than you have to be?

When it comes to  BVL, not all DMTs are made equal. At the top of the ladder are HSCT and alemtuzumab, then natalizumab. Behind these come the anti-CD20 therapies, the S1P modulators, cladribine, teriflunomide and the also-rans.

In the smallish real-life study below pwMS who have been on natalizumab for at least 2 years appear to lose brain volume at a similar rate as normal controls. I wonder what would happen over a longer period of time? Natalizumab is very effective but it does not necessarily get on top of smouldering MS, so some patients will be doing better than others. Don’t be lulled into a sense of security by the average effect; 50% of people do worse than average (median) and 50% of people do better than average (median).

Please be aware that BVL is complicated with many physiological (day-2-day), biological (age), disease factors(duration, level of disability, lesion load, comorbidities) and other Influences (e.g. genomic factors) affecting the brain volume and rate of BVL. Despite BVL not being assessed in routine clinical practice, it is one of the metrics that need to be taken into account when choosing your DMT. Just maybe BVL should be the most important factor to consider in terms of efficacy?  What do you think? 

Yes, the volume of your brain predicts disability outcomes, cognition and how well you will do in old age.

Alvarez et al. Brain atrophy rates in patients with multiple sclerosis on long term natalizumab resembles healthy controls. Mult Scler Relat Disord. 2021 Jul 24;55:103170. 

Background: Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs).

Methods: MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms.

Results: Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups.

Conclusion: Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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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.

To switch or not to switch that is the question

Barts-MS rose-tinted-odometer: ★★★

The one good thing about thinking aloud is that your colleagues’ chip in and provide feedback. Case 2 from my ‘ethical quandary post‘ is generating an important debate about whether to support this patient’s decision to switch therapy or not.

As a reminder, this is the 40-year old woman who started natalizumab as a first-line therapy 11 years ago after presenting with two disabling relapses in a four-month period. She has done exceptionally well on natalizumab, i.e. she is NEDA-3 (no relapses, no MRI activity and no change in her EDSS). In fact, her original disabilities from the two relapses recovered. At present she is fully functional, working full-time and very active physically. For example, she plays competitive tennis in her local sports club and ran the London marathon 2 years ago. Her current EDSS is 1.0.

The problem is that her serial annual MRI studies demonstrate that she has progressive macroscopic (visible by the naked eye) brain volume loss. Being an intelligent woman and a self-taught MS expert she knows this is a poor prognostic sign and she wants to stop natalizumab and have HSCT or alemtuzumab. She is aware from reading The MS-Blog (formerly the Barts-MS blog) that alemtuzumab and HSCT have a greater impact than natalizumab on end-organ damage or brain volume loss. After HSCT and alemtuzumab treatment brain volume loss is on average in the normal range (please see BEYOND NEDA).

What I didn’t say to you is that this lady has already made the decision that she wants to be treated with AHSCT, either on the NHS (not possible at present), abroad at one of the reputable private BMT units or in the private sector within the UK. The problem we have is that we have no idea what will happen to her BVL once she makes the switch. I suspect she will have accelerated BVL in the first year post-AHSCT, which is well described and is likely to be due to the neurotoxicity of the chemotherapy. After year-1 the BVL may or may not normalise. We have no idea what happens to the MS brain after being subjected to smouldering MS pathology on natalizumab for a decade.

Fortunately, we do have data from interferon-beta to alemtuzumab switching and, yes, after 2 years of interferon-beta therapy switching to alemtuzumab does normalise BVL. What is clear from the 8-year alemtuzumab follow-up data (see below) is that the rate of brain volume loss is age-dependent. Being in the 35-45 year age group the BVL was 0.13% per annum ((1.51-0.71)/6) on alemtuzumab. When you compare this to the 0.06% per annum in study subjects 18-25 years of age ((1.24-0.87)/6) you realise how important age is in determining treatment effects. 

Figure from MSARDs.

Is this data sufficient to talk this young woman down from her decision to have AHSCT and to go with alemtuzumab? What do you think? If this patient is reading this blog post will it affect your decision?

Another thing this ‘thinking out loud’ exercise has taught me is that having annual BVL measurements on our patients with MS on DMTs could be very helpful. I also think we should ask around to see if we can get a case series of natalizumab to alemtuzumab switchers to see what happens to the trajectory of BVL before, on natalizumab, and after the switch to alemtuzumab. At least then we will have data to inform such difficult decisions.

Bass et al. Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years. Mult Scler Relat Disord. 2021 Apr;49:102717. 

Background: Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]).

Methods: Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years).

Results: Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22-0.24 vs. 0.38-0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%-92% vs. 62%-88%; achievement of 6-month confirmed disability improvement [CDI]: 20%-31% vs. 13%-25%), increased proportions free of MRI disease activity (70%-86% vs. 42%-63% per year), and slowed brain volume loss (BVL; -0.45% to -0.87% vs. -0.50% to -1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%-2.2% vs. >45 years: 8.1%) and deaths (0%-1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts.

Conclusions: Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.

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Preventive Neurology

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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.

#MSCOVID19: summertime

To me three swallows make a summer; one from Sweden, a second from Iran and now a third from Italy. I have little doubt more will emerge soon.

A few weeks’ ago I explained that having asymmetrical information is never a good thing. Tragically I have known about the data published yesterday on the Lancet’s pre-publication archive for several weeks.

The new data shows that ocrelizumab-treated Italian pwMS were more likely to get COVID-19 and severe COVID-19 compared to other DMTs. This now supports the Swedish rituximab data presented by Jan Hillert on the iWiMS COVID-19 webinar in May and the Iranian survey data on rituximab (see Safavi et al. below). The message across these three data sets is now quite consistent; anti-CD20 therapies affect the biology of COVID-19 differently to other DMTs. 

How anti-CD20 therapy increases your chances of getting COVID-19 suggests it either (1) increases your exposure to the SARS-CoV-2 virus, which to me is not plausible unless it is due to increased exposure to the virus as a result of attending hospitals for infusions, or (2) it reduces your chances of having an asymptomatic infection. To me, the latter seems most likely and is meanable to study.

The immune responses to other human coronaviruses, the ones that cause the common cold, may cross-react with SARS-CoV-2 and help keep the virus in check and explains why some people get asymptomatic or mild infections. Having had a common cold in the recent past has given you some built-in protection against getting COVID-19 and severe COVID-19.  

I hypothesise that if you were B-cell depleted from being on an anti-CD20 when you had that common cold your immune system doesn’t make the necessary high-quality or high-affinity cross-reactive antibodies that you now need to protect yourself from getting symptomatic COVID-19 and potentially severe COVID-19. 

Should this data on anti-CD20 therapy change clinical practice? If you are already on an anti-CD20 therapy there is little you can do about your preexisting immunity to community-acquired coronaviruses; you either have immunity or you don’t. Similarly, you can’t simply revere the action of anti-CD20 therapies as it takes months to years to reconstitute your peripheral B-cell pool. Therefore I would simply recommend that if you are on an anti-CD20 therapy being extra-vigilant when it comes to trying to avoid being exposed to SARS-CoV-2 (social isolation, personal hygiene and avoiding high-risk environments). 

What about starting an anti-CD20 therapy? The decision to do this must be individualised and weighed against the risk of getting COVID-19. In countries where this risk is very low anti-CD20 therapies will be safe. 

The issue of vaccine readiness may affect your decision to be treated with anti-CD20 therapy.  People who are B-cell depleted, as a result of anti-CD20 therapies, make blunted vaccine responses. This is not surprising because anti-CD20 treated patients lack germinal centres in their lymph nodes and spleen. Germinal centres are the immunological equivalent of a university. It is in the germinal centres that T-cells help B-cell mature, class switch their antibodies, i.e. go from IgM to IgG for example, and to then undergo affinity maturation of the antibody genes to produce high-quality antibodies. Without germinal centres, your immune system can’t educate your B-cells to make high-quality antibodies and hence vaccine response are poor. 

For people on anti-CD20 therapies, if they want to maximise your chances of responding to a vaccine you are going to have to pause your treatment to allow your immune systems to recover before receiving a coronavirus vaccine. When should you do this? Not now. I would not recommend this until an effective vaccine emerges. Only cross bridges when they are built and only if you need to cross them. 

There is still a relatively high chance that all of the 150+ SARS-CoV-2 vaccine candidates will fail; vaccine development for respiratory viruses is notoriously difficult.

These data is likely to be relevant to ofatumumab and other anti-CD20 therapies. 

Not surprisingly interferon-beta which is an antiviral protects you from COVID-19 and exposure to high-dose methylprednisolone in the last 4 weeks increased your chances of severe COVID-19. The latter supports our current policy of asking patients to shield for 2 weeks after steroids and to be extra-vigilant. 

Interestingly, there is a strong trend in the Italian data suggesting that natalizumab-treated patients may be at increased risk of COVID-19. Whether this is a real signal or not waits further data, but again the Swedish data supports this. This observation would not be surprising as we know natalizumab reduces trafficking of lymphocytes to mucosal membranes, which may be relevant in early anti-coronavirus immunity.

I suspect these observations will have implications for other infectious diseases. I would not be surprised when we study the immune responses and outcomes to other viral infections, for example, seasonal influenza the same patterns will emerge. Now that we have set-up COVID-19 registries I would urge the MS community to keep them open so that we can study what happens with the next influenza epidemic emerges, which is only months away. 

Sormani et al. Disease-Modifying Therapies and COVID-19 Severity in Multiple Sclerosis. The Lancet Preprint 8-Jul-2020.

Background: Immunosuppressive and immunomodulatory therapies are a major issue during the current coronavirus disease 2019 (Covid-19) pandemic, and in anticipation of possible next waves. 

Methods: In a nationwide study we retrospectively collected data of persons with Multiple Sclerosis (PwMS) with suspected or confirmed Covid-19. We assessed the association of therapies for MS with Covid-19 by comparing their observed frequency with the one expected in non-pandemic conditions (expressing the association by Odds Ratios [OR]). We evaluated baseline characteristics and MS therapies associated to a severe Covid-19 course by multivariate logistic models.

Findings: Of 784 PwMS with suspected (n=593) or confirmed (n=191) Covid-19 and a median follow-up of 84 days (range=30-135), 13 (1·66%) died: 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-three (4·2%) were admitted to an Intensive Care Unit; 90 (11·5%) had a radiologically documented pneumonia; 88 (11·2%) were hospitalized. We found an excess of patients treated with Ocrelizumab (OR=1·84,95%CI=1·31-2·56, p<0·001) and a reduction of patients treated with Interferon (OR=0·47,95%CI=0·33-0·67, p<0·001) as compared to the frequency of use of these DMTs in the Italian MS population. After adjusting for region, age, sex, progressive MS course and recent methylprednisolone use, the therapy with an anti-CD20 agent (Ocrelizumab or Rituximab) was significantly associated (OR=2·59,95%CI=1·43-4·67, p=0·002) with an increased risk of severe Covid-19 course. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR=6·0,95%CI=2·2-16·5, p=0·007).

Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, the study detected elements of risk and protection with respect to Covid-19 in MS. These will need to be considered in countries where the pandemic is persisting and in preparation for post-pandemic scenarios.

Funding: Roche donated the web-Platform and funded a fellowship to the University of Genoa.

Safavi et al B-cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID-19 epidemic in Iran. MSARDS Published:May 12, 2020.

Objective: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.

Methods: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.

Results: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).

Conclusions: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Shen et al. Delayed Specific IgM Antibody Responses Observed Among COVID-19 Patients With Severe Progression. Emerg Microbes Infect. 2020 Dec;9(1):1096-1101.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide since it was confirmed as the causative agent of COVID-19. Molecular diagnosis of the disease is typically performed via nucleic acid-based detection of the virus from swabs, sputum or bronchoalveolar lavage fluid (BALF). However, the positive rate from the commonly used specimens (swabs or sputum) was less than 75%. Immunological assays for SARS-CoV-2 are needed to accurately diagnose COVID-19. Sera were collected from patients or healthy people in a local hospital in Xiangyang, Hubei Province, China. The SARS-CoV-2 specific IgM antibodies were then detected using a SARS-CoV-2 IgM colloidal gold immunochromatographic assay (GICA). Results were analysed in combination with sera collection date and clinical information. The GICA was found to be positive with the detected 82.2% (37/45) of RT-qPCR confirmed COVID-19 cases, as well as 32.0% (8/25) of clinically confirmed, RT-qPCR negative patients (4-14 days after symptom onset). Investigation of IgM-negative, RT-qPCR-positive COVID-19 patients showed that half of them developed severe disease. The GICA was found to be a useful test to complement existing PCR-based assays for confirmation of COVID-19, and a delayed specific IgM antibody response was observed among COVID-19 patients with severe progression.

CoI: multiple

#MSCOVID19 – natalizumab extended interval dosing

More questions around managing MS during the COVID-19 pandemic; this time in relation to natalizumab (Tysabri) dosing.

The COVID-19 NHS crisis is a double-whammy for pwMS. First, it is redeploying staff away from MS services to work on the frontline. 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, which is one the reasons I started the MS-Selfie COVID-19 & MS microsite. 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 (see my daily Q&A sessions on MS-Selfie). 

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 300mg every 4 weeks. This means a 50kg person gets double the relative dose compared to a 100kg person. The half-life of antibody therapies, such as natalizumab, is linked to how much drug or antibody is given. Therefore for the 50kg smaller person, 8 weeks may be fine, but for the larger 100kg 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.

CoI: multiple

#COVIDMS Will COVID-19 mutate?

Human coronaviruses are predominantly associated with respiratory tract infections. This group of viruses includes viruses that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and now the COVID-19 pandemic.

One human coronavirus HCoV-OC43 is generally associated with mild upper respiratory tract infections, although it has been shown to have neuroinvasive properties. Studies in mice have shown that HCoV-OC43 can infect neurons and cause encephalitis and has also been shown to cause persistent infections in human neural-cell lines.

There are case reports that have identified HCoV-OC43 RNA in the cerebrospinal fluid or brain of children with acute disseminated encephalomyelitis and acute encephalomyelitis (see below).

Why are these observations important? They are important because it suggests that coronaviruses are potentially neurotropic and hence can infect the central nervous system. As coronaviruses are RNA viruses they have low fidelity, i.e. their reproduction results in many variants or mutations. The so-called wild-type strain tends to mutate very rapidly and hence may produce neurotropic strains quite quickly. The latter is particularly important in the context of natalizumab and potentially fingolimod and other S1P modulators.

As natalizumab blocks immune surveillance of the CNS, a person on natalizumab who develops a COVID-19 encephalitis would be in danger of major complications of the infection and possibly succumbing to the infection. The latter is analogous to PML, which is also viral encephalitis, and herpes-simplex and varicella -zoster encephalitis and CMV retinitis that have all been described in people with MS on natalizumab. 

The reason why these complications happen on natalizumab is that natalizumab blocks trafficking of anti-viral lymphocytes into the central nervous system and so if a virus gets into the CNS it will cause damage unchecked by the immune system. The EMA’s summary of product characteristics (SmPC) for natalizumab is very clear on this issue:

Infections including other opportunistic infections 

TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI (see section 4.8). If herpes encephalitis or meningitis occurs, the medicinal product should be discontinued, and appropriate treatment for herpes encephalitis or meningitis should be administered. Acute retinal necrosis (ARN) is a rare fulminant viral infection of the retina caused by the family of herpes viruses (e.g. varicella zoster). ARN has been observed in patients being administered TYSABRI and can be potentially blinding. Patients presenting with eye symptoms such as decreased visual acuity, redness and painful eye should be referred for retinal screening for ARN. Following clinical diagnosis of ARN, discontinuation of TYSBABRI should be considered in these patients. Prescribers should be aware of the possibility that other opportunistic infections may occur during TYSABRI therapy and should include them in the differential diagnosis of infections that occur in TYSABRI-treated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be suspended until such infections can be excluded through further evaluations.

What to do about this knowledge in the current COVID-19 pandemic is very difficult. Professor Julian Gold, an HIV and infectious disease consultant in our group, is adamant that we need to relay this information to our patients and let them make the decision if they want to stop natalizumab or fingolimod. However, as stopping these agents can result in rebound MS disease activity it would be advisable for these patients to switch to an alternative or safer DMT, i.e. interferon-beta, glatiramer acetate or teriflunomide. Professor Gold favours interferon-beta or teriflunomide as they have been shown to have antiviral effects. 

As there is no consensus on this I am doing a survey via the MS Academy to find out what the wider MS community of HCPs feels about this and other issues. Just maybe the wisdom of the crowd will be better than an individual or small group opinion. 

In the event of widespread COVID-19 epidemic, the logistics of derisking natalizumab and fingolimod is this way may not be feasible. A better way of managing this problem is reverse quarantine, i.e. at-risk patients stay on natalizumab or fingolimod and self-isolate at home to prevent themselves from becoming infected with the virus. 

The other issue I have already raised is when a vaccine emerges for COVID-19 pwMS may want to be on a DMTs that allows to receive the vaccine and mount a good response to the vaccine. Some DMTs blunt the vaccine responses.

I hope you appreciate that formulating advice when there is no evidence base is not easy. At the moment whilst the epidemic has yet to show its true extent in the UK I would advise MS patients on natalizumab or fingolimod to continue with treatment for now but to be extra-vigilant about hygiene measures. This advice may change or it may need to be personalised.

Finally, as soon as the ABN and MS Academy produce consensus guidelines I will post them on the blog. The problem about consensus is that it is often a compromise and in the absence of data may not be the best advice.

Yeh et al. Detection of Coronavirus in the Central Nervous System of a Child With Acute Disseminated Encephalomyelitis. Pediatrics January 2004, 113 (1) e73-e76.

We present a case in which human coronavirus was detected in the cerebrospinal fluid of a child presumed to have acute disseminated encephalomyelitis. In murine models, coronavirus has been found to cause a chronic demyelinating condition that resembles multiple sclerosis. Additionally, there is in vitro evidence of human coronavirus’s ability to infect neural cells. This case report provides additional support for the hypothesis that coronavirus may be an important etiologic factor in the pathogenesis of demyelinating disease in humans.

Morfopoulou et al. Human Coronavirus OC43 Associated with Fatal Encephalitis. N Engl J Med 2016; 375:497-498.

Excerpts:

….. Here we report the use of deep sequencing of a brain biopsy sample obtained from an 11-month-old boy with severe combined immunodeficiency who had symptoms of viral encephalitis with negative results on conventional diagnostic polymerase-chain-reaction (PCR) assay. 

….. The boy underwent unconditioned cord-blood transplantation, which resulted in T-cell engraftment. Nonetheless, his condition continued to deteriorate, and he died 1.5 months after receiving the transplant. RNA sequencing of a brain biopsy sample obtained 2 months after the onset of symptoms showed the presence of human coronavirus OC43 (HCoV-OC43), which was subsequently confirmed on real-time PCR (threshold cycle, 24) and brain immunohistochemical analysis. 

CoI: multiple

N.B. MOUSEDOC HERE So AS YOU KNOW THERE ARE ALREADY MUTATIONS IN THIS VIRUS THE ORIGINAL S VARIANTAND THE L VARIANT

Do no harm

Primum non-nocere is a Latin phrase that means “first, do no harm”. 

On the tube this morning I recognised one of our medical students reading Henry Marsh’ book “Do no harm”.  He is a semi-retired neurosurgeon, turned author, who uses his past patients to discuss ethical dilemmas and to criticise the NHS. His book does showcase the life of a surgeon, warts and all.  It is clear that to be a good neurosurgeon you have to be a team player. In surgery, it is critical to get the clinical decision-making correct, i.e. when and when not to operate. Surgery is also a technical speciality above all else; from the age of about 55 a surgeon’s skills deteriorate so it is best to be operated on by someone who is in their prime. In short, if you make the wrong clinical decision and you get things wrong technically then you will get a suboptimal outcome; i.e. you will do harm. 

I remember from very early on in my medical school career being told to do no harm. It is important to understand that this phrase dates back from a bygone era; an era when we hardly had any treatments that worked. 

Wikipedia: It is often said that the exact phrase “First do no harm” is a part of the original Hippocratic oath. Although the phrase does not appear in the AD 245 version of the oath, similar intentions are vowed by, “I will abstain from all intentional wrong-doing and harm”. The phrase “primum non nocere” is believed to date from the 17th century. Another equivalent phrase is found in Epidemics, Book I, of the Hippocratic school: “Practice two things in your dealings with disease: either help or do not harm the patient”. The exact phrase is believed to have originated with the 19th-century English surgeon Thomas Inman. 

In the modern era, we have to walk a tightrope of treating people to prevent future harm from a specific disease, knowing well that a small number of patients will be harmed from the side effects of the treatment. In other words, modern medicine has become a balancing act between the outcome of a population of patients at the expense of a small number of patients with adverse events. 

In the MS space, natalizumab epitomises this dilemma. Natalizumab is one of our most effective DMTs; it is very effective, easy to use and has few adverse events, which are uncommon. Unfortunately, however, in JC virus-positive individuals it may result in PML  a life-threatening infection of the brain. A lot has been done to derisk this complication, but unfortunately, there are still pwMS developing PML as a complication of natalizumab.

One industry analyst said to me that he had no idea why natalizumab was still on the market. He felt it should have been withdrawn after the PML crisis emerged. I said to this individual that he clearly hasn’t seen the impact that natalizumab has on people with MS’ lives. Natalizumab is a truly a transformative drug, which is why I refer to the treatment of MS as being represented by two eras; pre- and post-natalizumab. 

It is clear that pwMS understand that to maximise outcomes for pwMS some individuals have to pay the price of suffering adverse events. This is why it is not surprising that pwMS are prepared to take greater risks than their risk-averse neurologists (see below). I recall working with a rheumatologist who made the point that if he didn’t have a few of his patients dying each year from the complications of his treatment decisions then he was not treating his patients actively enough. The corollary is that a rheumatologist without a body count is being too conservative. 

Could the same analogy be levelled at neurologists? I think yes. I am still seeing far too many pwMS for second or third opinions who are very disabled from watchful waiting, slow escalation or sideways switching when they should have been treated with high efficacy treatments years ago. We really need to change the behaviour of MSologists from being risk-averse to becoming risk-takers. This also means pulling no punches and telling pwMS how bad MS really is and that to maximise your outcome you need to treat the disease effectively early on. 

At Barts-MS we are taking this principle to the extreme with our #AttackMS trial. As always the ideas underpinning this trial are already being adopted by our team so that by the time we get the trial funded and up and running we may not be able to do the study because we would have lost equipoise. 

Wikipedia: Clinical equipoise, also known as the principle of equipoise, provides an ethical basis for medical research that involves assigning patients to different treatment arms of a clinical trial. In short, clinical equipoise means that there is genuine uncertainty in the expert medical community over whether a treatment will be beneficial. 

I would be interested to know the MS Community’s opinions on the #AttackMS trial

Heesen et al. Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists. Mult Scler. 2010 Dec;16(12):1507-12. 

BACKGROUND: Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients’ and physicians’ risk estimates and attitudes towards natalizumab treatment.

METHODS: Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet.

RESULTS: After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects.

CONCLUSION: Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.

CoI: multiple

The Time-to-Think DMT

At an MS Masters Forum in Rome yesterday I was teaching MSologists and MS clinical nurse specialists using a recently created board game, which I like to think of as being MS Monopoly. MS monopoly is based on a game of chance that lets you discuss case scenarios and make treatment choices. Then you roll a dice, which determines the outcome of your choice. 

Two things emerge from playing the game. Firstly, how choosing an immune reconstitution (IRT) addresses so many of the treatment aims and longterm issues of safety. The question I ask is why aren’t the IRTs dominating the treatment landscape?

Secondly, it became clear how many times natalizumab was considered as a treatment option and discarded because of its PML risk. From yesterday’s discussions it clear to me that natalizumab is the ‘time-to-think’ DMT, i.e. you start someone on natalizumab for 6-12 months whilst you make the necessary long-term decisions. This may be necessary to wait for lymphopaenia to recover, to complete a vaccination programme (e.g. the three-dose HPV polyvalent vaccine), to wait to get the all-clear on a previously-treated malignancy, to prevent rebound on stopping fingolimod so that the woman with MS can fall pregnant, or to complete a diagnostic work-up. The latter indication underpins our #AttackMS trial design.

Another indication for natalizumab is to prevent CNS adverse events associated with cancer immunotherapy. I recently recommended that a patient with MS who had disseminated bowel cancer and was about to start an immune checkpoint inhibitor go onto natalizumab despite being JCV positive to prevent exacerbation of her MS. The rationale being that the polyclonal activation of her T-cells in the periphery, including her autoimmune cells responsible for her MS, would not traffic to the brain and spinal cord and cause an MS relapse. The downside of this strategy is that if she had occult secondaries in her CNS then natalizumab will prevent her T-cells finding and clearing these cells. As bowel cancer rarely metastasizes to the CNS we thought this was a risk worth taking. Last I heard she was doing well from the MS perspective, but not that well in relation to her bowel cancer. 

I am sure natalizumab will prevent the CNS complications associated with CAR-T cell therapies. Could this be a repurposing opportunity for natalizumab?

What makes natalizumab so uniquely special as a DMT are the observations that it has the most rapid onset of action of all the DMTs, it has very high efficacy, its mode of action can be reversed with plasma exchange and natalizumab does not cause systemic immunosuppression. The only downside of natalizumab therapy is the long-term PML and other CNS infection risk and the emerging CNS lymphoma risk. These are all due to reduced CNS immune surveillance. The fact that extended interval dosing (EID) reduces the PML risk by over 80% suggests natalizumab may make a resurgence and all these CNS side effects may be preventable. However, for this to happen we need to be able to prescribe natalizumab more liberally as a first-line treatment for active MS. If anyone from Biogen is reading this blog post can you please ask the powers that be in Biogen to consider asking the EMA to reconsider natalizumab’s label? By not doing this you are denying many pwMS access to natalizumab, albeit for a short period of time as highlighted above.

The good news is that the EMA has accepted the EID data and it is now in natalizumab’s summary of product characteristics. 

New text in the EMA’s SmPC: In a pre-specified, retrospective analysis of US anti-JCV antibody-positive natalizumab patients (TOUCH registry), the risk of PML was compared between patients treated with the approved dosing interval and patients treated with extended interval dosing as identified in the last 18 months of exposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patients dosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The interim analysis showed a lower risk of PML in patients treated with EID (hazard ratio = 0.06 95% CI of hazard ratio = 0.01- 0.22). The efficacy of natalizumab, when administered with EID, has not been established, and therefore the benefit/risk balance of EID is unknown (see section 4.4).

For those interested, I have included the latest PML figures from Biogen.

8 picograms

What does your DMT say on the tin? 

Some advice on what to say to your neurologist, or HCP, the next time you see them; “I now know why I am not expecting to get anything more out of this DMT than what it says on the tin”

Our current crop of DMTs can only do what they are designed for, i.e. stopping the focal inflammatory activity or new lesions from forming.  They are not designed to switch-off smouldering MS, restore neurological function or scrub the brain clean of the damaging B-cells and plasma cells. Based on this we need to readjust our treatment goals for DMTs. 

This is why one of my #ECTRIMS2019 highlights was as a post-hoc analysis that showed the best predictors of treatment response to natalizumab was (1) MRI activity (Gd-enhancing lesions and new T2 lesions),  (2) neurofilament levels and (3) relapses. All the other factors did not contribute anything to predicting treatment response. Why not? The answer lies in the biology of MS. Relapses, focal MRI activity and raised neurofilament levels are the triumvirate of inflammatory disease activity

Calabresi et al. Disease control beyond NEDA: The value of non-clinical disease activity measures to determine treatment response to natalizumab. ECTRIMS Online Library. Calabresi P. Sep 13, 2019; 278615; P1415

Based on the analyses in this poster our treatment goal with anti-inflammatory DMTs should be NEDA based on these three variables. All the other factors (EDSS, 9HPT, 25TW, BVL, PASAT) that we analysed added zero to the predictive model. The reason for this is that all these additional variables measure disability worsening or end-organ damage that is the consequence of the previous inflammatory activity. 

This is why we should not expect our DMTs to do more than what they are designed to do. If you want to prevent worsening from occurring you have to get your MS treated early and effectively and prevent the accrual of early damage. 

Another message from this analysis is that relapses were the weakest member of the triumvirate; MRI and NFL levels trumped relapses. The implications of this are that you need to have your disease activity monitored; yes, measured on a regular basis. If your neurologist suggests that you don’t need an MRI, or in the future peripheral blood NFL measurements, can I suggest you tell them they are wrong? 

Another implication of this study is potentially a cut-off for what is an acceptable peripheral blood neurofilament level, i.e. you need your NFL levels kept below 8pg/mL. This cut-off will separate the ‘men from the boys’; the only DMTs that are effective enough to reduce average levels consistently below this point are the high efficacy DMTs. 

One final message. Natalizumab continues to teach us about MS. It is the one drug that has transformed MS in so many ways and it has taught me more about MS than anything else. As I have said before there are two phases to the history of MS; the phase before natalizumab and the phase after natalizumab

CoI: multiple