You may recall Barts-MS held a competition before ECTRIMS to see if any of you could guess the results of OPTIMUM and ASCLEPIOS trials, i.e. “Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM)” and “Efficacy and Safety of Ofatumumab Compared to Teriflunomide in Patients With Relapsing Multiple Sclerosis (ASCLEPIOS I & II)”.
We now have our winners.
Heather Davies (UK) won the prize for the best average predictions of OPTIMUM results & Michael Heindel (Germany) for the ASCLEPIOS trials. Well done.
Here you can see Heather’s daughter constructing and then showing off her Barts-MS Lego creation.
Michael chose a Barts-MS T-shirt as a prize, but when we heard he had young sons we sent him a lego set as well. It looks like his sons enjoyed the challenge.
Finally, after a week or more of thinking and contemplation my opinion about the ofatumumab vs. teriflunomide trial data (ASCLEPIOS I and II); another of my ECTRIMS highlights.
The result of the ASCLEPIOS I and II are not unexpected and in line with the treatment effects of anti-CD20 therapies with some caveats.
Both ASCLEPIOS I and II studies met their primary endpoints in patients with relapsing forms of MS (RMS); overall ofatumumab (OMB157), a subcutaneous, potent, fully-human antibody targeting CD20 positive B-cells, delivered efficacy with a favorable safety profile
RMS patients on ofatumumab had a reduction in annualized relapse rate (ARR) by 50.5% (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25) compared to Aubagio®* (teriflunomide) (both studies p<0.001) in ASCLEPIOS I and II studies respectively
Ofatumumab showed highly significant suppression of gadolinium (Gd) T1 lesions when compared to Aubagio®, demonstrating a profound suppression of new inflammatory activity
Ofatumumab showed a relative risk reduction of 34.4% in 3-month confirmed disability progression (CDP†) (p=0.002) and 32.5% in 6-month CDP (p=0.012) versus Aubagio® in pre-specified pooled analyses
Ofatumumab, if approved, will potentially become a treatment for a broad RMS population and the first B-cell therapy
My interpretation:
Inflammation: relapse rate, focal MRI activity (Gd-enhancing & new T2 lesions) and neurofilament data.
I have made the point that these three markers measure focal inflammation, driven by adaptive immunity, and there is little doubt that ofatumumab is superior in suppressing inflammation compared to teriflunomide. Does this make ofatumumab superior to other very high efficacy DMTs, such as natalizumab, rituximab, ocrelizumab, alemtuzumab and HSCT? I suspect not. To prove this we would need head-2-head studies. I also think there are floor effects on these outcomes, i.e. you can only reduce relapse rates to around 0.1 to 0.2 and no lower. Why? I suspect some relapses are pseudo-relapses and are due to intermittent symptoms in relation to infections, fatigue and possibly hidden symptoms.
Please note that I don’t consider peripheral blood neurofilament levels (pbNFL) to be a neurodegenerative marker in the context of MS. All the data I have seen to date indicates that it is linked to focal inflammatory activity. Clearly more needs to be done in progressive MS with pbNFL to understand what it means in inactive or smouldering MS.
End-organ damage: disability progression and brain volume data
I was disappointed with how ofatumumab did against teriflunomide in delaying disability progression and reducing the relative loss of brain volume. This will be ofatumumab’s Achille’s heel. Why? It is clear that MS the disease is not focal inflammation; I have made the point that based on the Prentice criteria, both relapse and focal MRI activity don’t predict disability outcomes in natural history studies and placebo arms of clinical trials. If focal inflammation was MS then relapses and focal MRI activity would predict outcome whether or not you are on a DMT. The point I making here may be a philosophical one, but it a very important one.
In comparison, sustained or confirmed disability progression has to be MS and is based on the pathological correlates that define MS (demyelination, neuroaxonal loss and gliosis).
Why did ofatumumab do so poorly on these metrics relative to teriflunomide? It could be that teriflunomide is the outlier and this opinion is based on several observations.
Teriflunomide is the only DMT to have a consistent effect on disability progression; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on this outcome. In addition, the treatment effect or impact of teriflunomide on disability progression has always been greater than what you would expect from its impact on relapses. For the tuned-on readers, you would have noticed the same disconnect between relapses and disease progression was observed in the ponesimod vs. teriflunomide trial.
Teriflunomide also has a significant effect on brain volume loss compared to placebo, which again is out of proportion to its impact on relapses (see picture below).
Teriflunomide is 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, and a very important, finding.
Teriflunomide is a broad-spectrum antiviral agent, which may be part of its mode of action in MS. Could teriflunomide be targeting the viral cause of MS independent of its effects on the immune system’s response to that virus? This needs more study, but teriflunomide is the outlier, or exception, that disproves the dogma.
Is ofatumumab being underdosed?
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.
I don’t buy this argument. The repopulation kinetics with ofatumumab are based on relatively short-term dosing studies in which deep tissue and in bone marrow B-cell depletion is likely to be relatively modest. I suspect with long-term dosing with ofatumumab deep tissue and bone marrow B-cell depletion is more likely and hence the B-cell repopulation kinetics will mimic that of rituximab and ocrelizumab.
I also think rapid B-cell repopulation is likely not to be relevant as the new B-cells will almost certainly be bone marrow-derived naive B-cells and not memory B-cells.
The question I have is the 20mg per month of ofatumumab sufficient to penetrate the CNS and clear the intrathecal of CNS resident B-cell follicles?
At the AAN this year Stephen Hauser presented data indicating that when it comes to disability progression, not relapse rate or MRI activity, the extent of exposure to ocrelizumab is very important.
The greater the ocrelizumab exposure the more effective it was at delaying disability progression. This could be related to deep tissue (peripheral) and end-organ (central) 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). What I am saying is that ocrelizumab could be superior to ofatumumab when it comes to scrubbing the brain clean of pathogenic B-cell follicles. Therefore it more important than ever to test this hypothesis in a head-2-head study of ocrelizumab vs. ofatumumab (OVO study) or the DODO study comparing double-dose (1200 mg) vs standard-dose (600 mg) ocrelizumab (DODO study) to see if the higher dose of ocrelizumab has a bigger impact on the intrathecal B cell response than the standard dose.
I would suggest these studies include next-generation MRI and other biomarkers to test the CNS penetration hypothesis. If these studies are positive, i.e. ocrelizumab is superior to ofatumumab and double-dose ocrelizumab is superior to single-dose ocrelizumab, 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 and fourth study to the portfolio. If you work for Novartis or Roche please tell the powers that we are really, really, interested in doing both the OVO and the DODO studies.
What about teriflunomide?
Don’t forget that the implications from the ponesimod vs. teriflunomide and ofatumumab vs. teriflunomide trials are quite profound. Teriflunomide is quite a remarkable DMT and we need to explore its antiviral effects in MS in more detail and understand what it is doing in MS independent of its rather weak anti-inflammatory effects. This is why I have proposed using teriflunomide as a maintenance therapy post-induction. In my ECTRIMS hot topic presentation, I called the trial the iTeri study (see slide show above).
If you work for Genzyme-Sanofi please tell the powers that be that we are really, really, interested in an induction-maintenance trial with both teriflunomide (iTeri study) and a second with your BTK inhibitor (iBruT study).
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.
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.
My #ECTRIMS2019 highlight #3 is the elevation of fatigue to be the first secondary outcome measure in a clinical trial. Was this genius or a marketing coup? I would have loved to be a fly on the wall when the steering committee of the OPTIMUM study made the decision to bump fatigue to the top of the secondary outcomes.
If you have MS you know that the most troubling symptom the majority of MSers complain about is fatigue. Therefore for a DMT to be able to claim it reduces fatigue is a big deal. I suspect MSers will find the promise of fatigue reduction a very compelling reason to choose one DMT over another.
The Oral Ponesimod Versus Teriflunomide In Relapsing MUltiple Sclerosis (OPTIMUM) study was positive. Compared to teriflunomide ponesimod reduced the relative annualised relapse rate (ARR) by 30.5% (P<0.0003) and3-month CDP (confirmed disability progression) by 17% (not significant).
If you recall this study was one of the studies we asked the Crowd to predict the results of. In fact, they were almost spot-on; they predicted that ponesimod would reduce the ARR and CDP compared to teriflunomide by 33.8% (interquartile range=24.5-44.3%) and 21.2% (interquartile range=10.0-25.0%), respectively. My interpretation is that the Crowd did very well; well done!
Please note that I will be contacting the winners of the #ECTRIMS competition very soon. There will two awards one for the OPTIMUM study and a second award for the ASCLEPIOS I & II studies.
When it comes to the S1P wars ponesimod is setting itself up very nicely to go head-2-head with newer entrants, i.e. siponimod and ozanimod. In my opinion, the safety profile of ponesimod is reasonably good, the lack of need for 1st-dose monitoring will put it alongside ozanimod in the S1P Me-Too wars. The question everyone is now asking ‘Will fatigue be the trump card?’. What do you think?
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.
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.
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.
