Gavin Giovannoni

#GuestPost & #ClinicSpeak: the burden of hidden disabilities in MS

Can we afford not to challenge physical disability as the primary outcome measure in MS trials? #ClinicSpeak #GuestPost

Summary: This study shows that hidden symptoms, in particular, pain, contributed most to pwMS perception of health. The invisible disability associated with MS is more important to patients’ sense of well-being than physical disability.

Which symptoms contribute the most to patients’ perception of health in multiple sclerosis? To answer this question we surveyed 1,865 persons with MS who were seen for routine care at two large tertiary MS centres in the New York metropolitan area. Each PwMS was asked to rate his health on a scale of 1-5 (‘In general, how would you rate your health today? Very good (1) – Good (2) – Moderate (3) – Bad (4) – Very bad (5)), and fill out symptoMScreen. SymptoMScreen asks patients to rate their symptom severity in 11 domains commonly affected by MS: mobility, dexterity, vision, fatigue, cognition, bladder function, sensory, spasticity, pain, depression, and anxiety.

Image from the MS Trust; Invisible symptoms: the unseen side of MS.

Before reading the results, I would ask you, gentle reader, to stop and ask yourself which symptoms would you rank as being the most impactful on PwMS perception of their health? What would be in your ‘top 3’? The answer from our study was somewhat unexpected: the domain that contributed the most to the perception of health in MS was pain, followed by gait problems and then fatigue. Our work suggests that ‘invisible’ symptoms are as important, or perhaps even more important, to patients’ sense of well-being as the ‘physical disability’ visible to the examiner. These findings call into question the overwhelming emphasis on ambulation and physical disability as the primary, and often the only, outcome measure in clinical trials and observational studies of MS.

Biography: Ilya Kister, a graduate Mount Sinai School of Medicine, received neurologic training at Albert Einstein College of Medicine in New York and neuro-immunologic training at NYU Multiple Sclerosis Care Center under the mentorship of the late Prof. Joseph Herbert. Dr Kister divides his time between clinical responsibilities at the NYU and Barnabas MS Centers in the greater New York area, and clinical research. He has a special interest in optimizing/personalizing use of MS therapies, symptomatology of MS, and clinical and radiologic course of Neuromyelitis Optica. Dr Kister is Associate Professor of Neurology at the NYU School of Medicine and directs NMO Treatment and Research Program, as well as, MS Fellowship at NYU.

Green et al. Which symptoms contribute the most to patients’ perception of health in multiple sclerosis? MSJ First Published September 5, 2017.

Background: Multiple sclerosis is a polysymptomatic disease. Little is known about relative contributions of the different multiple sclerosis symptoms to self-perception of health.

Objectives: To investigate the relationship between symptom severity in 11 domains affected by multiple sclerosis and self-rated health.

Methods: Multiple sclerosis patients in two multiple sclerosis centers assessed self-rated health with a validated instrument and symptom burden with symptoMScreen, a validated battery of Likert scales for 11 domains commonly affected by multiple sclerosis. Pearson correlations and multivariate linear regressions were used to investigate the relationship between symptoMScreen scores and self-rated health.

Results: Among 1865 multiple sclerosis outpatients (68% women, 78% with relapsing–remitting multiple sclerosis, mean age 46.38 ± 12.47 years, disease duration 13.43 ± 10.04 years), average self-rated health score was 2.30 (‘moderate to good’). Symptom burden (composite symptoMScreen score) highly correlated with self-rated health (r = 0.68, P < 0.0001) as did each of the symptoMScreen domain subscores. In regression analysis, pain (t = 7.00), ambulation (t = 6.91), and fatigue (t = 5.85) contributed the highest amount of variance in self-rated health (P < 0.001).

Conclusions: Pain contributed the most to multiple sclerosis outpatients’ perception of health, followed by gait dysfunction and fatigue. These findings suggest that ‘invisible disability’ may be more important to patients’ sense of well-being than physical disability, and challenge the notion that physical disability should be the primary outcome measure in multiple sclerosis.

Disclosures: IK has served on scientific advisory boards for Biogen Idec and Genentech and has received research support from Guthy-Jackson Charitable Foundation, National Multiple Sclerosis Society, Biogen Idec, Serono, Genzyme, and Novartis.

#GuestSpeak & #ThinkSpeak: a call to all researchers who read this blog

Guest bloggers needed; please contact us. #GuestSpeak #ThinkSpeak

You will have noticed over the last two weeks a few more guest posts and the inclusion of a short summary at the top of my posts. These are in response to some of your suggestions. As part of the evolution, and rejuvenation, of the blog, we would love to increase the volume of guest posts and reduce the volume of posts from Barts-MS. Why? Diversity is the spice of life and a lot of what we have to say is repetition. We don’t want to bore you and feel you need to hear from other experts in the field.

So this is a call to potential guest bloggers. If you have done a piece of research and you want to communicate it people with MS, and other MS stakeholders, please don’t hesitate to contact us (bartsmsblog@gmail.com).

Your intentions should be altruistic and in keeping with our blogging philosophy. We do not want to monetize the blog, therefore, no advertising or links to commercial sites. Please remember the views presented in each post have to be yours and have nothing to do with Barts-MS and our organisations (Queen Mary Universty London & Barts Health NHS Trust). We are also are not a platform for pseudo, or fake, science, nor fake news or alternative facts. We will, therefore, have final editorial control over what we accept and publish on the blog.

To post you have to provide a lay summary of the work with a link to the publication. In addition, we need a short biography, a disclosure statement and a picture. It is important that the readers know who you are. We also expect all guest bloggers to come back to the blog frequently to answer any questions from our readers.

#ClinicSpeak & #ECTRIMS2017: Cog-fog and self-monitoring

Natalizumab lifts cog-fog #ClinicSpeak #ECTRIMS2017 # SelfMonitoring

Summary: this post highlights the problem of cog-fog in pwMS and describes the science behind the symptom. It also presents the results of a study looking at the effects of natalizumab on cog-fog. The post concludes with an appeal to the community for help in developing a cog-fog-o-meter.

Every now and again a post on this blog catches the imagination of the readers and gives me insights into MS that I haven’t appreciated before. Yesterday’s post on the impact of MS on day-to-day functioning, albeit golf, that occurs at a level too subtle to be detected using our crude assessment tools was a revelation. It is clear this patient had ongoing inflammation, associated with a drop off in physical and cognitive functioning. I recall him complaining to me that he didn’t feel right on fingolimod, in particular, he had cog-fog.

What is cog-fog?

One of the first things I noticed when I started using natalizumab is that patients would come back after 3-4 months feeling better. They would often describe their ‘brain fog’ – now better known as ‘cog-fog’ – lifting, their ‘fatigue evaporating’, ‘having energy’, noting improvements in both ‘mood and anxiety’ and saying ‘I feel normal again’.

Please note this patient felt well on natalizumab and this is not unique to this patient. I often refer to natalizumab as being transformational and use it describe three eras in the management and study of MS:

The pre-DMT era (before IFNbeta ~1993)
The pre-natalizumab DMT era (1993-2004)
The post-natalizumab DMT era (after 2004)

The TYNERGY study below supports my anecdotal clinical observations. When patients with active MS went onto natalizumab a large number of their negative symptoms improved. I don’t think these observations are limited to natalizumab and are also seen with other highly effective therapies, but take longer for the improvements to be seen with the other high-efficacy DMTs. How do you include these effects in the benefit and risk profile of DMTs? A hard to quantify treatment effect.

The question that needs answering is how does an anti-inflammatory DMT such as natalizumab reduce fatigue? I have hypothesised that it works via suppressing inflammation in the brain that drives fatigue. Inflammation is known to cause sickness behaviour, a programmed behavioural response designed to conserve energy and allow the body to recover.

Sickness behaviour goes far back in the evolutionary tree so it must have given our evolutionary ancestors a survival advantage. Two mediators of inflammation, one called interleukin-1 (IL-1) and the other tumour necrosis factor alpha (TNF-alpha), are known triggers of this behavioural response. IL-1 and TNF-alpha cause fatigue, sleepiness (hypersomnolence), reduced appetite (anorexia), a raised body temperature (fever) and low mood (depression) that forces one to lie down, sleep and allow our sick bodies to recover. We all have experienced sickness behaviour before these are the typical symptoms we get when we have a systemic infection similar to how you feel when you have influenza. We know that in MS both IL-1 and TNF-alpha levels are increased in the brains of pwMS. Therefore, I am convinced as DMTs switch off inflammation in the brain and IL-1 and TNF-alpha levels drop fatigue improves as sickness behaviour disappears.

The following is an old slide presentation of mine on fatigue that includes a section on sickness behaviour. Some of the points covered in this slide presentation are quite technical; if they need more explanation please ask and I will do additional posts on this.

Now I need your help. I am giving several presentations at ECTRIMS this year, however, two of the talks are somehow related. The first is a hot topic talk on self-monitoring using web-based apps and the second is a TED-type talk in a satellite symposium on the need for routine cognitive testing in clinical practice. In these talks, I will be making the case for self-monitoring across multiple domains including cognition. However, I am not aware of any outcome measure that specifically captures sickness behaviour or cog-fog in pwMS. Do you think we can measure cog-fog? If yes, how?

To assess cog-fog we need to assess all of the components of sickness behaviour. The Illness Behaviour Questionnaire (IBQ) is a generic tool that has been developed to assess sickness behaviour. In my opinion is a too long to be used daily to track and follow sickness behaviour in pwMS. Any ideas to help develop a cog-fog-o-meter would be much appreciated.

What I am looking for is a simple self-monitoring tool for cog-fog.

Penner et al. Improvement in Fatigue during Natalizumab Treatment is Linked to Improvement in Depression and Day-Time Sleepiness. Front Neurol. 2015 ;6:18. doi: 10.3389/fneur.2015.00018. eCollection 2015

BACKGROUND: Fatigue is a frequent symptom in multiple sclerosis (MS) and often interrelated with depression and sleep disorders making symptomatic treatment decisions difficult. In the single-arm, observational phase IV TYNERGY study, relapsing-remitting MSers showed a clinically meaningful decrease in fatigue over 1 year of treatment with natalizumab.

OBJECTIVE: To evaluate whether fatigue improvement might be directly linked to improved depression and day-time sleepiness.

METHODS: MSers were assessed regarding fatigue, depression, and day-time sleepiness. The relation between changes of the two latter symptoms and changes in fatigue was analyzed.

RESULTS: After 1 year of natalizumab treatment, the majority of MSers (>92%) remained stable or improved in total, motor, and cognitive fatigue. Proportion of MSers without depression increased by 17% while proportions of mildly depressed MSers or MSers with potential major depression decreased by 5 and 12%, respectively. Proportion of MSers classified as not being sleepy increased by 13% while proportions of sleepy and very sleepy MSers decreased by 11 and 2%, respectively. Most importantly, improved depression and sleepiness were significantly related to improved fatigue.

CONCLUSION: Our findings highlight the importance of patient-reported outcomes in identifying potential benefits of drug treatment beyond its well-established effects on disease activity and disability progression.

CoI: multiple

#ClinicSpeak #SelfMonitoring: a picture is worth a thousand words

Could you use your golf handicap to monitor the impact of MS on your life? #ClinicSpeak #SelfMonitoring

Summary: One person’s story of using his golf handicap to monitor the impact of MS on his physical functioning.

In clinic yesterday one of my patients who had rapidly evolving severe MS sent me the picture below. I added his DMTs. He said it was his way of self-monitoring the impact of MS on his physical functioning. For the uninitiated, it represents his golf handicap over time. His best handicap in golf was two, which he achieved when he was younger and playing competitively.

Does any one want write the narrative to go along with the picture? One clue you need is that he was JCV seropositive, with a high titre, on natalizumab, which is why we decided to switch his treatment.

Please note that this person gave me permission to publish this picture on the blog.

CoI: multiple

#ClinicSpeak & #ResearchSpeak: the maven has landed and is ready for use

Do you know what a maven is? Is cladribine a maven? #ClinicSpeak #ResearchSpeak

Summary: This post describes why cladribine is a semi-selective immune reconstitution therapy or SIRT and some of the attributes that make cladribine such a good drug to treat MS.

I spoke at a meeting yesterday about my journey with oral cladribine. It began in 2002 with an advisory board to decide if Serono should in-license the oral formulation as a potential treatment for MS and we have finally got to the point of the drug becoming available in Europe a week ago. A journey that has taken 15 years. Who said drug development happens quickly? Another milestone in the history of oral cladribine was the publication of the CLARITY extension study; it came out as an e-publication yesterday.

At yesterday’s meeting, the chair introduced me as a maven; a compliment considering oral cladribine tablets have been named Mavenclad. Maven refers to an expert and is derived from the Yiddish word meyvn, meaning “one who understands”. As you can see the usage of the word has soared in the last decade or so. I assume this is because Maven has been popularised by Malcolm Gladwell in his book ‘The Tipping Point: How Little Things Can Make a Big Difference‘, which was published in 2000. Gladwell’s use of the word is a little bit broader than that of an expert.

Wikipedia Excerpt: Gladwell describes mavens as “information specialists”, or “people we rely upon to connect us with new information”. Mavens accumulate knowledge, especially about the marketplace, and know how to share it with others. Gladwell cites Mark Alpert as a prototypical Maven who is “almost pathologically helpful”, further adding, “he can’t help himself”. In this vein, Alpert himself concedes, “A Maven is someone who wants to solve other people’s problems, generally by solving his own”. According to Gladwell, Mavens start “word-of-mouth epidemics” due to their knowledge, social skills, and ability to communicate. As Gladwell states: “Mavens are really information brokers, sharing and trading what they know”.

Enough small talk. I have been heavily criticised by MD about the length of time it took us to get the CLARITY Extension study published. Three submissions later and six rounds of addressing reviewer’s comments it is finally out. This study not only confirms cladribine as an IRT (immune reconstitution therapy) but a SIRT (semi-selective IRT). Just 8-10 days of treatment in year-1 and a repeat cycle year-2 is sufficient to put the majority of subjects into long-term remission for up to 4 years and beyond. What proportion will need retreatment in the future is not known at present, but I suspect it will be in the same ballpark as alemtuzumab.

There is little doubt that oral cladribine is going to disrupt the MS DMT space. The fact that it is an IRT will make it more cost-effective than the maintenance treatments. Other advantages are that it is oral, easy to use, it is not associated with a cell lysis syndrome or infusion reactions, it does not take out the innate immune system so Listeria is not a problem and the monitoring requirements are minimal. There is no secondary autoimmune signal. The fact that it is a small molecule means there are no anti-drug antibodies, or NABs. We are also excited about the fact that it penetrates the CNS and may have activity on the B-cell and plasma cell biology within the brain and spinal cord. More importantly, it selectively targets the adaptive immune system in particular B-cells.

In summary, cladribine is as close to the most ideal DMT we have. Is there a down side? Yes, in an attempt to make it safe I think we have compromised on the dose. If only we can selectively target cladribine to B-cells and the leave the T-cell compartment intact we will have a real winner, an oral form of anti-CD19. Please note anti-CD19 and not anti-CD20. CD19 is expressed on a wider population of cells including plasmablasts and some plasma cells. The downside of anti-CD20 is that it does not touch plasma cells. I have previously hypothesized on the need to scrub the CNS free of pathogenic plasma cells to prevent ongoing gray matter damage and delayed worsening, or progression of MS.

Giovannoni et al. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
Mult Scler. 2017 Aug 1:1352458517727603.

BACKGROUND: In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS).

OBJECTIVE: To assess the safety and efficacy of cladribine treatment in a 2-year Extension study.

METHODS: In this 2-year Extension study, placebo recipients from CLARITY received cladribine 3.5 mg/kg; cladribine recipients were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo, with blind maintained.

RESULTS: A total of 806 patients were assigned to treatment. Adverse event rates were generally similar between groups, but lymphopenia Grade ⩾ 3 rates were higher with cladribine than placebo (Grade 4 lymphopenia occurred infrequently). In patients receiving cladribine 3.5 mg/kg in CLARITY and experiencing lymphopenia Grade ⩾ 3 in the Extension, >90% of those treated with cladribine 3.5 mg/kg and all treated with placebo in the Extension, recovered to Grade 0-1 by study end. Cladribine treatment in CLARITY produced efficacy improvements that were maintained in patients treated with placebo in the Extension; in patients treated with cladribine 3.5 mg/kg in CLARITY, approximately 75% remained relapse-free when given placebo during the Extension.

CONCLUSION: Cladribine tablets treatment for 2 years followed by 2 years’ placebo treatment produced durable clinical benefits similar to 4 years of cladribine treatment with a low risk of severe lymphopenia or clinical worsening. No clinical improvement in efficacy was apparent following further treatment with cladribine tablets after the initial 2-year treatment period in this trial setting.

CoI: multiple

#GuestPost & #ClinicSpeak: self-monitoring walking speed.

Are you up for monitoring your own walking speed? #GuestPost #ClinicSpeak

Summary: This guest post presents the results of a small validation study comparing the assessment of the timed-25-foot walk in clinic with that done at home by people with MS.

A simple reminder about who I am. My name is Nicolas Dubuisson. I completed my medical training in Belgium and so far I am 3 years through my Neurology training, so well on the way to becoming a Neurologist. I joined BartsMS as an ECTRIMS Clinical Training Fellow to ProfG four months ago. I plan to stay with Barts team until October 2017.

#ClinicSpeak: managing PPMSers expectations

Are you expecting to be eligible for ocrelizumab under the NHS? #ClinicSpeak #MSBlog #MSResearch

Summary: This post is an attempt to dampen enthusiasm amongst PPMSers for ocrelizumab and to manage expectations in relation to what we can expect from NICE.

It may seem to you that in recent days that HSCT has taken over the blog. It hasn’t so let’s get back to basics. I want to dampen down your enthusiasm for the emerging DMTs, i.e. ocrelizumab and oral cladribine. As with all DMTs their effectiveness will depend on how soon they are given. If they are started too late and you have acquired a lot of damage from your MS in the past, and you have already noticed worsening of disability prior to starting them, you may not necessarily notice a major treatment effect.

I have always warned that we should not expect too much from the first effective anti-inflammatory DMTs in more advanced MS (formerly progressive MS). They will not be miracle drugs. The ocrelizumab results in PPMS are in line with these predictions. I would like to remind you of the survey we did on this blog a few years ago (see slideshow below); about 40% of progressive MSers were expecting an effective DMT to improve their functioning or to result in a full recovery. This has not happened; at best ocrelizumab may stabilise your disease or more likely slow down the rate of disability worsening. Due to therapeutic lag, length-dependency and reduced neuronal reserve ocrelizumab is better at slowing down worsening in upper limb function compared to lower limb function. This is an important observation. Another factor is age. In the ORATORIO study pwPPMS had to be 55 years of age or younger. An analysis done for the ATGA (Australian Therapeutic Goods Administration) showed that pwPPMS 50 years of age or younger, and those with active MRIs, did better than older study subjects or those with out active baseline MRIs. This is not unique to ocrelizumab and was also seen in the Rituximab PPMS trial. The following is the paragraph from the ocrelizumab ATGA product information sheet:

‘A post-hoc analysis suggested that patients who are 50 years of age or below, or patients who have inflammation determined by MRI (Gd enchancing or T2 lesion) may receive a greater treatment benefit than patients who are over 50 years of age or patients who do not have inflammation by MRI.’

It will be interesting to see how age and MRI activity will affect the NICE cost-effectiveness analysis of ocrelizumab. I can envisage a scenario in which NICE may limit the prescribing of ocrelizumab on the NHS to patients with PPMS who are 50 years of age or younger and to those with active MRI scans. This may be very disappointing for older subjects, but in the era of austerity Britain, we need to be realistic about what the NHS can, and cannot, afford. To address this problem I think we need to start doing trials in older and more disabled patients targeting upper limb function as the primary outcome measure. The latter is one of the aims of our #ThinkHand campaign.

An even worse outcome will be if NICE says no to ocrelizumab in PPMS. This will create all sorts of problems for us, including inequity of access. This is one of the reasons why I ran the recent survey on this issue on the blog.

Despite my relative pessimism ocrelizumab as a moderately effective treatment for PPMS is a start and will allow us to begin to target different pathological processes in MS with the hope of developing add-on neuroprotective and neurorestorative therapies. Innovation tends to be incremental; having an effective anti-inflammatory therapy for progressive MS provides the treatment at the base of the pyramid; we now need to add the neuroprotective, remyelinative and neurorestorative tiers on top.

CoI: Multiple

#ResearchSpeak & #ECTRIMS2017: late-breakers at ECTRIMS 2017

What do you think of the late-breaking news scientific programme at ECTRIMS next month?

CoI: multiple

#ThinkSpeak: we need to make sure science happens the way it is meant to happen

Has HSCT become the new CCSVI? #ThinkSpeak

Summary: This post summarises the current scientific perspective of HSCT and attempts to put it as a treatment for MS into perspective.

Like most modern treatments that get adopted prematurely in MS, i.e. before the necessary science is done to convince the wider community, they are driven by social media. We have a lot of experience on this blog with CCSVI; in fact, CCSVI is one of the main reasons why I started this blog.

The question I now find myself asking has HSCT become the new CCSVI? Could the current support for HSCT as a treatment for MS getting ahead of the curve? Is the HSCT movement in MS becoming an anti-science movement, i.e. adopted against the predominant scientific opinion of the time? The wider MS community, pwMS, neurologists, scientists, charities, healthcare systems, etc. have agreed that there is a place for HSCT in the treatment of MS, but until we have better evidence of its relative benefits and risks compared to licensed DMTs we should be limiting HSCT to patients with more active MS who have failed at least one (high-efficacy), or two, established DMTs. In direct opposition, there are a group of HSCT-supporters who disagree and want everyone with MS to have the option of being treated with HSCT first-line. The latter recommendation is not supported by the science/data.

Sociological studies have identified 4 main social drivers of anti-science movements:

The ‘dissident scientists’ who lends credibility to the theory.
The ‘cultropreneurs’ who peddle the therapy.
The ‘living icons’ and ‘miraculous responders’ who have been treated.
The ‘praise-singers’, ‘journalists’ and ‘politicians’ who promote the theory

I agree that HSCT looks like a very effective treatment for MS. Does it cure MS? No, we can’t make that claim yet. Cohorts of HSCT-treated pwMS have not been followed long enough to justify this claim. Is it better than established or licensed DMTs? Possibly, indirect comparisons suggest it might be, but until we have head-2-head studies we can’t make that claim. Is it safer than established DMTs? It depends on what you are comparing it with and the specific outcome. For example, when it comes to the risk of neutropenic sepsis it is riskier than licensed therapies. Similarly, it has a much higher risk of ovarian toxicity (premature menopause) than established treatments. Safety, or relative safety, is another reason why we need large head-2-head studies to define the risks better in well-controlled randomised trials of sufficient size.

What should we tell pwMS? My message is simple. HSCT is a very effective therapy for treating MS. It has substantial risks associated with its use. We only offer HSCT to our patients who have active MS and have failed at least one high-efficacy DMT. We are however in the process of trying to obtain the necessary funding to compare the benefits and risk of HSCT to alemtuzumab. The latter is part of our scientific due diligence.

It is, however, reassuring to note that in the UK the costs of HSCT under the NHS appear very reasonable compared to licensed treatments. This could potentially make it a very cost-effective option for treating MS in the future. There are well established local and regional guidelines for HSCT and NICE is trying to establish national guidelines.

From a scientific perspective, we need to ask ourselves how HSCT is working? We think it is working via a B-cell mechanism, similar to other DMTs. If this is the case then do we need HSCT to achieve our therapeutic aims? Could we not get away with a more selective IRT (immune reconstitution therapy) that has a better safety profile? Clearly the latter would be much safer. The difference between scientists and anti-scientists is that we put forward testable hypotheses and they put forward beliefs. Unfortunately, it is difficult to challenge beliefs and you can’t test them in a scientific experiment.

I would urge anyone in England considering to travel abroad for HSCT to discuss your decision with your neurologist and MS clinical nurse specialist. If you are eligible for it under your local guidelines I would recommend having the treatment in England. The following are three relevant documents you may wish to read that we have published on the blog in the past.

1. London MS-AHSCT Collaborative Group eligibility criteria
2. The Bristol guidance document for pwMS considering HSCT abroad
3. NICE draft technology appraisal for HSCT as a treatment for MS in England.

CoI: multiple

#ResearchSpeak: how does ocrelizumab do in the NEDA stakes?

The need to rebaseline when using NEDA: ocrelizumab as an example. #ECTRIMS2016 #ResearchSpeak

Summary: This post looks at NEDA (no evident disease activity) as an outcome measure in clinical trials and in particular the issue of needing a new MRI scan, at a certain time point to set a new baseline, for comparison in the future. The latter is what is referred to as rebaseling.

In recent comments, the HSCT zealots have raised points about the use of NEDA as a treatment target and outcome measure to compare therapeutic strategies.

In the poster below there is little doubt that ocrelizumab is a highly effective DMT and shows why it is so important to rebaseline after an appropriate period of time before starting to monitor a treatment. For most maintenance DMTs 6 months is appropriate in that is pragmatic, logistically feasible and supported by data from clinical trials.

The analysis below shows that if you do this with ocrelizumab, then over 80% of subjects are NEDA from 6-24 months (figure 3). To the best of my knowledge this is the best NEDA data we have. I have yet to see HSCT rebaseling NEDA rates, but I suspect they will be in the same ballpark or higher.

The question I have asked my self is when is it appropriate to rebaseline after a IRT (immune reconstitution therapy)? I have argued in the past there is no point in doing it before you complete your course of treatment and are in a position to consider retreatment. For alemtuzumab and cladribine, this would be at 24 months. As an example, let’s say we have a patient who has been treated with alemtuzumab and you do an MRI at month 12 just before her second course of treatment and find they have a Gd-enhancing lesion. Are you going to say the alemtuzumab has failed? No, you are not, as this person has not had the full course of treatment. What you should do is give this person the second course of alemtuzumab and then wait until 24 months to do the baseline MRI and start the clock ticking again. Therefore NEDA rates in the first 12 and 24 months on alemtuzumab and cladribine and other IRTs are not that helpful. What about with HSCT? The issue with HSCT is it a one-off treatment or do you think it should be used more than once? If the former then it makes sense to rebaseline at 6 months. In comparison, if you want to offer it again then how soon can you do a second cycle of HSCT? If 12 months or 24 months you may want to use these time points for rebaselining.

It is worth highlighting in the data below is the remarkable observation that 57% of the IFN-beta (Rebif) treated participants were also NEDA in the 6-24 month epoch. Based on earlier interferon NEDA data, this is much better than one would expect. It looks as if from contemporary trials that the efficacy of Rebif has improved. Why? One reason could be that the population of trial participants have included subjects with more benign MS or just maybe Rebif’s efficacy has improved. I suspect both are correct. Most subjects in the Opera studies received RNF (Rebif new formulation). We know that RNF is associated with fewer NABs (neutralizing antibodies), which affect its efficacy; hence there are reasons to expect that Rebif’s efficacy has improved. I am sure a lot of people will jump on the Rebif NEDA data to support its continued use as an effective DMT in the ‘majority’ of MSers. If you are risk averse and subscribe to the slow stepwise or even rapid escalation, treatment strategies for MS, why not?

I am interested to see how the regulators, payers and/or healthcare commissioners respond to this data. I sincerely hope the EMA give ocrelizumab a liberal label that will allow first-line use in pwMS with active disease. This will then allow HCPs and their patients to decide on which DMTs they want to use. However, as always in price-sensitive markets the payers and commissioner may have a different take on things particularly if ocrelizumab is priced at a premium.

CoI: multiple