I had many requests for my #ECTRIMS2019 ‘Hot Topic’ slides on ‘what remains to be achieved from DMTs’. You can download the slides from my SlideShare site.
My message is blunt and to the point. Let’s not let ourselves be lulled into a false sense of security with our current crop of DMTs. They are simply not good enough. If we want to ‘maximise the lifelong brain health’ of MSers we need to do better; much, much better than what we are currently doing.
In my presentation I made the case for new treatment approaches in particular combination therapies and a true induction strategy, i.e. an induction therapy followed by a maintenance or consolidation therapy. I also made the case for making our current DMTs safer and promoted the holistic management of MS using the principle of ‘marginal gains’.
I didn’t pull my punches and questioned if we have equipoise when it comes to randomising MSers to an escalation or high-efficacy (flipping the pyramid) treatment approach.
After my #1 highlight #ECTRIMS2019 post, I was sent an email by Antoinio Scalafari, a like-minded colleague, to remind me of their real-life data at Imperial College on alemtuzumab in clinical practice. It mirrors the trial experience and needs a platform for discussion (see below).
In parallel, I heard via the MS grapevine that the MS community does not appreciate me questioning the ethics of the DELIVER-MS and TREAT-MS Trials. Why not? These are pragmatic trials to compare escalation therapy with the strategy of flipping the pyramid (high-efficacy therapy first-line).
Don’t I have a right to an opinion? I finish my commentary with a simple question for the trialists:‘The real litmus test for the investigators of the DELIVER-MS and TREAT-MS trials is the question they should all ask themselves: “If I had multiple sclerosis, how would I want to be treated?” Given the evidence, patients deserve the choice of being treated with a high-efficacy DMT first-line’.
Why shouldn’t MSers with active MS not have the option of being treated with alemtuzumab, or for that matter HSCT?
Most of you know by now that I am one of the main proponents supporting EBV as the primary cause of MS. I think EBV is actively driving MS disease activity. The corollary to this statement is that we may be able to treat MS with anti-EBV drugs. We have suggested that all MS DMTs work by affecting memory B-cell biology and that this is the cell that host the EB virus. At Barts-MS, we have an active research programme to test anti-EBV drugs in MS.
One way of targeting EBV is via immunotherapy and Michael Pender, from Brisbane, has been promoting this strategy for over a decade. His data on using autologous ant-EBV CTLs (cytotoxic T-lymphocytes) is impressive. Almost too good to be true! Most of the MS community has dismissed his data as being biased due to being unblinded and from one centre. However, if you drill down into his data you will see that most of the MSers he has treated have had quite advanced disease with high EDSS scores and the improvements in disability have been so profound that it would be difficult to ascribe this to biased EDSS-rating. I am convinced that Michael Pender is onto something big and something very important.
This is why the ATARA Bio early phase 1b data is my one of my #ECTRIMS2019 highlights. Instead, of autologous cells, ATARA Bio is using MHC-matched allogenic CTLs. The good news from their poster presentation is that these cells seem safe as a treatment and at the high doses they are reproducing Pender’s single-centre results.
I agree it is too early to be jumping up and down and that we need to wait for the results of a randomised double-blind controlled study, but imagine a world in which we treat MS with anti-EBV CTLs and our MSers notice profound improvements in disability? This would be a true paradigm shift, a black swan event! Overnight MS would be classified as an infectious disease. Could you imagine what would happen to the MS DMT market? I sincerely hope for the MS community that this remarkable story pans out to be true.
Introduction: Evidence suggests Epstein-Barr virus (EBV) infection is associated with multiple sclerosis pathogenesis. In patients (pt) with progressive forms of MS (pMS), autologous EBV-specific T cells may prevent progression and improve symptoms (Pender, et al. JCI Insight. 2018).
Objectives: To evaluate ATA188, an off-the-shelf, allogeneic, EBV-targeted T cell immunotherapy comprised of HLA-matched, in vitro-expanded, cytotoxic T lymphocytes in a first-in-human, multicenter, 2-part study in adults with pMS (NCT03283826). Preliminary data are reported.
Methods: Eligible pt (age 18‒< 66) are EBV-seropositive with pMS and an Expanded Disability Status Scale (EDSS) score of 3‒7. Cohorts (cht) 1‒4 (6‒9 pt/cht) receive escalating doses of ATA188. 1° endpoints: safety and identification of the recommended phase 2 dose (RP2D) of ATA188. Efficacy criteria: EDSS, MS Impact Scale-29, Fatigue Severity Scale, and 12-Item MS Walking Scale scores; timed 25-foot walk; 9-hole Peg Test; and visual acuity. A responder (R) has sustained ≥ minimal clinically significant (MCS) improvement from BL in 2 consecutive evaluations on ≥2 efficacy criteria; a partial responder (PR) has ≥ MCS improvement from baseline (BL) in any 1 evaluation on ≥2 efficacy criteria; and a non-responder (NR) has ≥ MCS decline from BL in any 1 evaluation on ≥2 efficacy criteria (if both criteria are met, pt is NR). Plasma inflammatory biomarkers (IL-2, IL-1β, TNF-α, IL-6) are monitored throughout treatment.
Results: As of 27 May 2019, 19 pt (53% male; median age, 56 years) have enrolled (6 in each of cht 1‒3; 1 in cht 4) and received ≥1 dose of ATA188. Treatment-emergent AEs (TEAE) occurred in 63% (12/19) pt and treatment-related AEs (TRAE) in 37% (7/19) pt; 1 pt (cht 2) had a grade ≥ 3 TEAE, and 1 (cht 4) had a serious TRAE. No dose-limiting toxicities or fatal TEAE have been reported. Efficacy data are available for cht 1 and 2: cht 1, 1 R, 1 PR, and 4 NR at 6 months and 1 R, 0 PR, and 1 NR at 12 months; cht 2, 2 R, 4 PR, and 0 NR at 6 months. On measures of disability, 3/6 showed improvement and 3/6 showed decline in cht 1; 4/6 showed improvement and 1/6 showed decline in cht 2. Inflammatory cytokines remained at or near baseline.
Conclusion: Preliminary data indicate ATA188 is well tolerated and improves efficacy measures in adults with pMS, even at lower doses. These results support continuing part 1 to identify RP2D for part 2, (randomized, double-blind, placebo-controlled portion).
BACKGROUND: Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.
METHODS: An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro-expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.
RESULTS: Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test).
CONCLUSION: EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.
TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12615000422527.
FUNDING: MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.
Just back from ECTRIMS 2019 in Stockholm. My highlight was the alemtuzumab 8-year longterm extension data; the brain volume data is quite extraordinary (figure 5). In short, apart from HSCT, there is nothing that comes close to alemtuzumab in radically slowing-down or preventing end-organ damage.
I was also disappointed to hear the rumour that the EMA’s article 20 procedure was not triggered by an EU member country, but by the EMA itself. A colleague told me that the adverse events reporting from Genzyme were so poor that the EMA could not establish whether or not the new adverse events were causally related to alemtuzumab. So to get some clarity on the new adverse events the EMA triggered their own article 20 procedure to simply get Genzyme to do the work they should have done in the first place.
If this is the case it saddens me that people with MS may not be able to access alemtuzumab early in the course of their disease due to poor internal procedures at Genzyme.
If I had MS I would want to have the option of being treated with alemtuzumab. This is why I wrote the following open letter to the European Medicine Agency. I sincerely hope they listened. I have yet to receive a response from them, but I hope someone at the EMA has MS or has a friend or family with MS and understands why treating MS early and effectively is so important.
Open letter the EMA sent on the 20th August 2019
European Medicines Agency Amsterdam
Dear Sir/Madam
Alemtuzumab has transformed the MS treatment landscape. It not only provides superior short term efficacy, but a significant number of patients treated with alemtuzumab note improvement in disability. However, its main advantage over other DMTs is that a large proportion of patients go into longterm remission and normalise the rate of their brain volume loss. In regard to the latter, this is unprecedented in comparison to other licensed MS disease-modifying therapies, with the possible exception of haemopoietic stem cell transplantation (HSCT), which is not licensed and hence not widely available to treat patients with MS in Europe. Alemtuzumab, therefore, is the only realistic alternative to HSCT, which has become a very popular treatment choice amongst people with multiple sclerosis, in particular, ‘digital natives’ who get their information online. As with all DMTs the earlier you use them the more effective they are and the greater the benefit to the individual patient. Alemtuzumab is, therefore, an important treatment option for people with MS; being able to offer alemtuzumab early as a treatment option is an important factor in my clinical practice to dissuade many Britsih patients from travelling abroad for HSCT.
At our centre, Barts Health NHS Trust, we have now treated over 250 patients with alemtuzumab with over 40% being treated with alemtuzumab first-line. Patients receiving alemtuzumab first-line tend to have more active disease and less favourable baseline prognostic profile. Despite its side effect profile and the need for monthly monitoring, many patients are willing to take on the risks and the burden of monitoring to be treated with the most effective licensed DMT first-line. All our patients are extensively counselled about the risks and benefits of alemtuzumab treatment and sign an informed consent and a patient contract agreeing to the mandatory monitoring programme. We feel the use of alemtuzumab in the correct environment is relatively safe and the adverse events manageable. Not having alemtuzumab for use in early active disease would mean patients having to wait to fail several other, less effective, licensed DMTs prior to accessing alemtuzumab. I firmly believe in the concept that ‘time is brain and spinal cord’ in MS and delaying access to the most effective treatment would limit our ability to optimise the management of MS in patients with more active disease and in those with a poor prognostic profile. In addition, shifting the use of alemtuzumab to a population of patients with more advanced disease would unfavourably change the benefit-risk profile of alemtuzumab and make it less appealing as a treatment option.
The real-life data of alemtuzumab clearly supports it as being the most effective DMT on the market and its other attributes in relation to its posology make it a very appealing therapy; for example in women wanting to start or extend their families.
In summary, limiting alemtuzumab to a third-line, last resort DMT, will severely limit our treatment options for managing this devastating disease. Alemtuzumab offers many patients with MS a real hope of living as normal a life as possible, however, this option does depend on using alemtuzumab early in the course of the disease. I, therefore, appeal to the MS community and the European Medicine Agency to consider these factors when reviewing the benefits and risks of alemtuzumab as a treatment for MS.
It is time to set in stone our #CrowdThink competition results. We had over 110 responses; thank you. If you want to know more about the rationale behind this competition you need to read my post on the DODO trial and the post explaining the rationale behind the COMPETITION.
Study 1: Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM).
The Crowd has predicted that ponesimod will reduce the ARR (relative annualised relapse rate) and CDP (confirmed disability progression) compared to teriflunomide by 33.8% (interquartile range=24.5-44.3%) and 21.2% (interquartile range=10.0-25.0%), respectively.
This would suggest that ponesimod is probably batting in the same league as fingolimod. I wouldn’t put too much weight on the TRANSFORMS study that compared fingolimod to interferon-beta-1a. The majority of subjects were failing interferon who went into that study and were then randomised to fingolimod or back onto interferon-beta-1a. This study inflated fingolimod’s relative efficacy as it was being compared to interferon-beta failures on interferon-beta.
Study 2: Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I & II)
The Crowd has predicted that ofatumumab will reduce the ARR (relative annualised relapse rate) and CDP (confirmed disability progression) compared to teriflunomide by 41.2% (interquartile range=34.0-49.0%) and 29.3% (interquartile range=20.0-37.3%), respectively.
These results are interesting and broadly put ofatumumab in the same ballpark as ocrelizumab as well; 41% is close enough in my book to 47% for it not to register as being meaningfully different to ocrelizumab. In comparison, 29.3% for CDP is too far away from 40% to be dismissed. The question is this because of ofatumumab being inferior to ocrelizumab? Or teriflunomide is superior to interferon-beta-1a (Rebif)? I would favour the latter interpretation. The former interpretation would support the hypothesis for the need to target intrathecal B-cells and that the higher dose of ocrelizumab is superior at doing this compared to the smaller but more frequent ofatumumab dosing. These results would support us pushing for the DODO study to be done.
However, would it not be a more interesting story if ofatumumab out-performed ocrelizumab? This would be against my predictions, but it opens a new vista on how anti-CD20 therapies work. If ofatumumab outperforms ocrelizumab it would argue for a peripheral mode of action, i.e. keeping peripheral B-cells depleted continuously, rather than using intermittent depletion paradigm of rituximab and ocrelizumab. It would also challenge the hypothesis that we need to have CNS penetration for targeting of the intrathecal B-cell compartment.
The peripheral B-cell hypothesis would raise very interesting questions about whether or not anti-CD20 therapy is working as an anti-EBV agent and keeping the memory B cell compartment, which hosts EBV, suppressed.
I have already been criticised by a few people at this conference for my musings on the potential results of these trial. Don’t we live in a world where free and open thought is allowed? I speculate and write these sorts of posts deliberately to be controversial. But I would hope that they stimulate you to think more deeply about MS and what these results could mean for us and in particular people with MS.
Let’s hope it is not the same-old, same-old; i.e. another me too study of an anti-CD20. Let’s hope the results support either the central B-cell depletion hypothesis or the peripheral-continuous B-cell depletion hypothesis. The former supports our programme of activities to scrub the brain clean of B-cells and plasma cells and the latter to treat MS with anti-virals, in particular, anti-EBV drugs.
To conclude, I was very disappointed that two-thirds of you chose the MRI lego set over my #ThinkSocial T-shirt as a prize. I am clearly not a very good T-shirt designer ;-(
I arrived in Stockholm this morning on one of the first flights out of Heathrow. Terminal 2 was chaos. I assume everyone who was meant to be on one of the BA flights that was cancelled, transferred onto a competitor airline in Terminal 2. My flight was full and I am sure I was allocated the last seat on the plane. A small half-sized seat at the far left of the plane. The seat was up against the toilets and didn’t tilt. It was very uncomfortable. Fortunately my discomfort was short-lived and temporary, not like having MS.
I have given my first talk this afternoon around a case study of the ‘real MS’; smouldering MS in someone who is relapse and MRI activity free on fingolimod, but is getting markedly worse. Do you tell them they have SPMS and stop their fingolimod? Or do you escalate their treatment and hope for the best?
The problem with labelling someone as having SPMS is unhelpful without another treatment option or strategy in place for them. Telling someone with MS you now have SPMS is like telling them they have a terminal disease, i.e. it is now all downhill from here. At least having a potential new treatment for SPMS will allow us to offer some hope. The problem that I have is I have no evidence that switching someone who is NEDA2 with worsening MS onto another DMT will make any difference to them. This is an evidence vacuum that needs filling.
I am involved in another meeting tomorrow afternoon run by the MS in the 21st Century initiative to tackle this thorny issue about when and how to tell someone they have progressive MS. In reality, I think this is an academic exercise in that there is now ample evidence from a biological perspective that everyone has both relapsing and progressive MS together and the latter is there from the start. What we are trying to do with our treat early and effectively message is to protect brain reserve so that clinically apparent worsening stage of MS occurs much much later in life, Do you agree or not?
At the afternoon and evening meetings I attended, I was asked if there would be anything new being presented at the ECTRIMS. To be honest with you I don’t think so. Sure there will the positive ponisemod and ofatumumab studies, but these are really old news. Both these drugs are ‘Me Toos’; ponisemod being the 4th in-class S1P modulator and ofatumumab a 3rd generation anti-CD20 monoclonal antibody. There is really nothing new here. Me toos are very low hanging fruit for Pharma with much less risk associated with their development. Believe me, there is nothing transformational that is going to happen on Friday when we get new sets of data; only old news. What we will be arguing over is the percentage differences in relative efficacies between DMTs. We won’t be saying wow what an interesting finding; this is teaching us something new about MS.
What the MS field needs is some novelty, something new in terms of a mode of action, a new class of therapy, a new insight, a new paradigm, etc. That is what I will be looking out for and not the same old, same old.
The MouseDoc and I want to have a little bit of fun in anticipation of the late-breakers at ECTRIMS and at the same time do a thought experiment.
We want to see how wise the crowd is when it comes to predicting trial results.
Aware crowds may be wiser than individuals. In the book ‘The Wisdom of Crowds: Why the Many Are Smarter Than the Few and How Collective Wisdom Shapes Business, Economies, Societies and Nations’ James Surowiecki argues that the aggregation of information in groups, results in decisions that are often better than could have been made by any single member of the group. He opens the book with an anecdote about Francis Galton’s surprise that the crowd at a county fair accurately guessed the weight of an ox when their individual guesses were averaged (the average was closer to the ox’s true butchered weight than the estimates of most crowd members).
We want to see how wise you are when it comes to guessing the outcome of the two phase 3 trials programmes being presented at ECTRIMS. We know they are positive, but how positive is the question? To make it a competition we will be giving away two prizes; a lego MRI scanner set or one of our #ThinkSocial Bart-MS T-shirts. You can choose your prize.
Lego MRI scan set
Barts-MS #ThinkSocial T-shirt
Study 1: Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM)
Please note the Janssen Pharmaceutical Company announced positive top-line results stating the study met its primary and most secondary endpoints. As you know ponesimod is a second-generationn S1P modulator. The question is how good will it be compared to Teriflunomide? It may help to remind you that fingolimod, the first licensed S1P modulator, reduced the annualised relapse rate by 52% compared to interferon-beta-1a (Avonex) in the TRANSFORMS study, but had no significant effect on disability progression.
Study 2: Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I & II)
Novartis has announced that both of their phase 3 trials of ofatumumab vs. teriflunomide met their primary outcome. In ASCLEPIOS I and II, ofatumumab (OMB157) met primary endpoints to reduce the annualized relapse rate over Aubagio (teriflunomide) in patients with relapsing forms of MS (RMS) and that key secondary endpoints of delaying time to confirmed disability progression were also met.
Ofatumumab is a 3rd-generation anti-CD20 monoclonal antibody. Ocrelizumab is already licensed and was compared to interferon-beta-1a (Rebif) in two parallel phase 3 trials (OPERA I & II); ocrelizumab reduced the annualised relapse rate by 47% and the rate of 3-month confirmed disability progression by 40% compared to interferon-beta in these trials.
I have recently argued that ofatumumab may be underdosed and that as a result, it won’t do as well against teriflunomide (which has similar efficacy to Rebif), compared to what ocrelizumab did against Rebif. Do you agree with me or not?
So please complete the survey below and leave your email address and name if you want to enter the draw for the prize.
The Barts-MS blog turns 10 today. The first blog post on the 3rd September 2009, on the 2007 Association of British Neurologists’ DMT prescribing guidelines, is now obsolete. The link does not even work. What started as a small experiment has turned into an almost full-time job for us at Barts-MS. Please let us know what the blog means to you and whether or not you want any changes going forward. As always a publication needs to serve its readers.
The more I read, think and assimilate information the more I realise that the real pathology behind MS is not the new acute lesion or relapse, but what is going on behind the scenes in the so-called slowly expanding chronic MS lesion or SEL.
MS is a smouldering disease.
In an analysis of the ocrelizumab-PPMS or ORATORIO trial, it is clear that SELs already existed in the brains of PPMSers when they started the trial and best predicted their clinical course during the trial. In contrast, brain atrophy or brain volume loss and new lesion activity did not predict disability progression. What is nice about this analysis is that it is in a PPMS population with a very low relapse rate, which excludes relapses as a confounder.
I am not that concerned about brain volume loss not predicting outcome in this population, because it is out of sync with clinical outcomes; i.e. brain volume loss today is caused by pathology 2-3 years ago and hence needs to be correlated with clinical outcomes in the past.
What is important in this study is that new MRI activity in the form of new T2 lesions did not predict disability worsening. In other words, focal inflammation is not associated with clinical outcome. In comparison, SELs or smouldering MS predicted clinical outcome. Based on basic medical philosophical principles around the definition of surrogate markers it is clear that new T2 lesions can’t be the disease we call MS, but SELs can.
It is clear to me that MS is a biological disease and not an MRIscopic disease, i.e. what you see on MRI is the tip, of the tip, of the iceberg and that most of MS pathology is hidden from view when using conventional MRI. This is why you still deteriorate despite being NEDA (with no evident new disease activity). The NEDA in this context is referring to the absence of focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind the worsening despite being NEDA is driven by the delayed neuroaxonal loss from previous damage, ongoing diffuse inflammation which has become independent of focal lesions (innate activation), ageing mechanisms or focal inflammatory lesions that are too small to be detected with our monitoring tools. Of all the processes listed here, the last one is the only one that is realistically modifiable by our current DMTs.
The really important question this analysis raises is that when you treat someone with a DMT and they become NEDA how do you know they don’t have ongoing smouldering MS and hence would benefit from being escalated to a more effective DMT or should be included in add-on combination therapy trial? This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. Only then will we be able to start answering important questions. For example, does changing treatment in people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab result in them doing better? The ORATORIO analysis below would suggest the treatment effect in this situation is small. This is why we are going to need a new generation of add-on treatments that target CNS pathology, for example, hot microglia, antivirals (EBV and HERVs), CNS-penetrant anti-B-cell and plasma cell agents, neuroprotectives, etc.
I have made the point that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease. I don’t buy this because a proportion of pwMS who have been treated early on with an immune reconstitution therapy or IRT, in particular, alemtuzumab or HSCT, appear to be in very longterm remission and may even be cured of their MS (see the previous post on this topic). Some would argue, I included, that this group of patients has not been followed up for long enough to be sure they have been cured. I agree and this is why we need a deep phenotyping study to assess whether or not these patients have any evidence of ongoing MS disease activity. This study would help define smouldering MS, by looking for its absence.
The MRI-centric view of MS has lulled many of us into a false sense of security and has resulted in us classifying MS as a focal inflammatory autoimmune disease of the CNS. In reality, MS is a diffuse disease of the CNS and the focal inflammatory events are simply the immune response to what causes MS. This is why the field hypothesis of MS is so relevant and fundamentally challenges our worldview of MS.
If we don’t change our worldview of MS and explore what is happening in the trenches alongside the one we currently have our heads buried in we will be letting down the next generation of MSers.
Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/ evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1- weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.
When you are fighting a war, even if it is only a marketing war, small effects can be the difference between winning and losing.
The TENERE study below would indicate that teriflunomide has similar efficacy to interferon-beta-1a (Rebif). However, this study was underpowered to show a difference between these two DMTs. Based on this and other data I suspect teriflunomide is more effective than IFN-beta. Why?
(1) Teriflunomide is the only DMT to have a consistent effect on disability progression; i.e. both phase 3 placebo-controlled trials were positive on this outcome. (2) Teriflunomide also has a significant effect on brain volume loss compared to placebo; in comparison, subcutaneous IFN-beta-1a does not. (3) Teriflunomide is also more effective when used 2nd and 3rd line. Teri is the only DMT to show the latter and this observation was seen in both phase 3 studies, which makes it likely to be a real finding. (4) Finally, teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS.
Putting all these factors together I think teriflunomide will perform better than expected in head-2-head studies than Rebif has done in the past. Why is this important? Two of our top guns alemtuzumab and ocrelizumab were compared to Rebif and had a relative reduction in relapses of ~45%.
A 45% relative reduction in relapse rate has to be the new target in phase 3 active comparator trials. This is if you want your DMT to bat in the same division as alemtuzumab and ocrelizumab.
Yesterday Novartis announced that both of their phase 3 trials of ofatumumab vs. teriflunomide met their primary outcome. The following is an excerpt of Novartis’ press release:
In ASCLEPIOS I and II, ofatumumab (OMB157) met primary endpoints to reduce the annualized relapse rate over Aubagio (teriflunomide) in patients with relapsing forms of MS (RMS).
Key secondary endpoints of delaying time to confirmed disability progression were also met; additional secondary endpoints will be presented at ECTRIMS
Ofatumumab, a potent, fully-human antibody targeting CD20 positive B-cells, delivered sustained efficacy with a favourable safety profile
Novartis plans to initiate submissions to health authorities by the end of 2019. If approved, ofatumumab will potentially become a treatment for a broad RMS population and the first B-cell therapy that can be self-administered at home
If ofatumumab’s relative reduction in annualised relapse rate is not in the order of 45% the MS community is going to assume it is not as effective as alemtuzumab and ocrelizumab. Based on my comments above I suspect the relative reduction will be less than 40%. In other words, the effectiveness of teriflunomide may have been underestimated. Or the effectiveness of ofatumumab may have been over-interpreted and over-modelled.
An aspect that needs to be considered is that ofatumumab may be underdosed in these trials. Ofatumumab is being given at a dose of 20mg subcutaneously monthly. This dose was chosen to keep B-cells depleted, but not severely depleted, so as to allow rapid repopulation of peripheral B-cells numbers if ofatumumab is stopped. In other words, B-cell depletion is relatively mild compared to ocrelizumab 600mg every 6 months. With ocrelizumab, it takes 6 months or longer to start to see B-cell reconstitution. Is this important? I suspect yes.
At the AAN this year Stephen Hauser presented early data suggesting that when it comes to disability progression, not relapse rate or MRI activity, the extent of exposure to ocrelizumab makes a difference. The greater the ocrelizumab exposure the more effective it was. This could be related to deep tissue and end-organ B-cell depletion. There is mounting evidence that the B-cells and plasma cells within the brain and spinal cord of MSers are driving some of the slow-burn we see clinically and on MRI (smouldering MS).
Slide from Hauser et al. AAN 2019.
What I am trying to say is that if ofatumumab does not bat in the same league as ocrelizumab when it comes to relative relapse reduction to an active platform comparator then all these factors will come to the fore and make ocrelizumab 600mg 6-monthly a more effective anti-CD20 than ofatumumab 20mg sc monthly.
My response to the Stephen Hauser’s presentation at AAN was to immediately design a study of double-dose (1200 mg) vs standard-dose (600 mg) ocrelizumab 6-monthly (DODO study) to see if the higher dose of ocrelizumab has a bigger impact on the intrathecal B cell response than the standard dose. The study will include next-generation MRI and other biomarkers to test the hypothesis. If this study was positive it will not only tell us a lot about how anti-CD20 therapies work in MS, but it may answer the question of whether or not we need to target the intrathecal or CNS B-cell response in MS. The latter hypothesis is being tested by our group in two studies at present. We would love to add a third study to the portfolio.
So please watch this space. We will soon hear about the ofatumumab results; they are being presented at ECTRIMS in 2 weeks time. And if you work at Roche please tell the powers that be that we are really, really, interested in doing the DODO study 😉
BACKGROUND: In previous studies, teriflunomide significantly reduced the annualised relapse rate (ARR) and disability progression.
OBJECTIVE: This phase 3, rater-blinded study (NCT00883337) compared teriflunomide with interferon-beta-1a (IFNβ-1a).
METHODS: Patients with relapsing multiple sclerosis were randomised (1:1:1) to oral teriflunomide 7-or 14 mg, or subcutaneous IFNβ-1a 44 µg. The primary composite endpoint was time to failure, defined as first occurrence of confirmed relapse or permanent treatment discontinuation for any cause. Secondary endpoints included ARR, Fatigue Impact Scale (FIS) and Treatment Satisfaction Questionnaire for Medication (TSQM). The study was completed 48 weeks after the last patient was randomised.
RESULTS: Some 324 patients were randomised (IFNβ-1a: 104; teriflunomide 7 mg: 109; teriflunomide 14 mg: 111). No difference in time to failure was observed. There was no difference in ARR between teriflunomide 14 mg and IFNβ-1a, but ARR was significantly higher with teriflunomide 7 mg. FIS scores indicated more frequent fatigue with IFNβ-1a, though differences were only significant with teriflunomide 7 mg. TSQM scores were significantly higher with teriflunomide. There were no unexpected safety findings.
CONCLUSION: Effects on time to failure were comparable between teriflunomide and IFNβ-1a. There was no difference between teriflunomide 14 mg and IFNβ-1a on ARR, though ARR was higher with teriflunomide 7 mg. The teriflunomide safety profile was consistent with previous studies.
