When I state that the real MS is smouldering MS and that relapses and focal MRI activity are not the disease I really mean it.
PwMS who are NEDA-2, without relapses and with no new MRI lesions, but getting worse must have something going on in their brains and spinal cords. This is why we need to go beyond NEIDA (no evidence of inflammatory disease activity) as a treatment target in MS and focus on protecting the end-organ so that pwMS can have enough reserve to cope with normal ageing when they get older.
One example or ugly fact to illustrate the disconnect between inflammation (relapses and focal MRI activity) and the end-organ (brain volume loss) is the recent ofatumumab vs. teriflunomide trials.
Brain volume loss (↓~0%): Ofatumumab = teriflunomide
If ofatumumab is so much more effective as an anti-inflammatory than teriflunomide why doesn’t it protect the end-organ more than teriflunomide? I don’t know but is clear, at least to me, that there is something else going on that is driving the end-organ damage in MS that is not linked to focal inflammation. Could something about teriflunomide’s mode of action that is downstream of focal inflammation be telling us something fundamental about the cause of MS?
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
What should be our therapeutic target in MS? Reducing relapses and MRI activity, NEDA (no evident disease activity) or saving the end-organ (brain volume loss)?
I have been pushing the for the latter, i.e. the most important treatment target must be protecting the end-organ and saving or protecting as many neurons, axons and synapses as possible in people with MS (pwMS) so that can age normally and live as near normal life as possible. To achieve this we need to diagnose and treat MS as effectively as possible (Time is Brain) and to promote a brain-healthy lifestyle and to treat MS holistically (minimal gains hypothesis).
This principle of protecting the end-organ is not new and was probably first promulgated by the kidney doctors in relation to loss of kidney function in chronic kidney disease; every nephron (the kidney’s equivalent of a neuron) is sacred. Every neuron is sacred! The difference between kidney doctors and neurologists is that they can always put their patients on dialysis and offer them kidney transplants. We, neurologists, don’t have that luxury and what awaits our patients with progressive loss of end-organ (brain atrophy) is unemployment, worsening cognitive impairment and physical disabilities and the consequences (bladder, bowel, falls, walking aids, wheelchairs, dementia, etc).
What is interesting is that not all DMTs are made equal when it comes to protecting the end-organ. At the top of the rankings are HSCT and alemtuzumab followed by natalizumab and then there are the also-rans. What is interesting is the impact on brain volume loss is not necessarily linked to the DMTs ability to switch of focal lesions (relapses and MRI activity). A good example of this is teriflunomide, which has only a modest effect on relapses (~35% reduction in relapse rate) compared to say anti-CD20 therapies, which after 6 months of treatment almost completely stop relapses and MRI activity, but these two classes of therapy have a similar impact on slowing down brain volume loss.
Teriflunomide is clearly doing something at the level of the end-organ that anti-CD20 therapies are not. This study below in subjects with CIS shows that teriflunomide works very well, on the end-organ, even early on in the disease, but not all subjects are responders. This begs the question; what is it about teriflunomide’s mode of action that explains its remarkable effects on brain atrophy? I have hypothesised in the past about teriflunomide’s broad-spectrum anti-viral effects and have proposed doing the iTeri study, i.e. using an anti-CD20 or other depleting DMT as true induction therapy and then using teriflunomide (or another DHODH inhibitor) as the maintenance therapy. The hypothesis is to allow peripheral B-cell reconstitution or recovery to occur in the presence of anti-EBV agents, which will prevent EBV-infected autoreactive (MS causing) B-cells returning. The problem we are having with the iTeri study is trial design; i.e. how do you design a trial that will convince the regulators of its efficacy and get the drug licensed as a maintenance therapy? Would the regulators accept non-inferiority or safety design? Another reason for this study design is to derisk anti-CD20 therapies. The doubting Thomas in me is saying there is no way someone with MS can stay on an anti-CD20 therapy indefinitely.
Maybe I am wrong, but let’s not stick our heads in the sand. Relapses and focal MRI activity are not MS. The real MS is smouldering MS and all the processes that cause accelerated brain volume loss. Let’s focus on smouldering MS and ask questions about what needs to be done to tackle these processes. What is ot about HSCT, alemtuzumab, natalizumab and possible teriflunomide that differentiates the DMTs into two classes. For example, could it be the T-cell?
Background: We explored the effect of teriflunomide on cortical gray matter (CGM) and whole brain (WB) atrophy in patients with clinically isolated syndrome (CIS) from the phase III TOPIC study and assessed the relationship between atrophy and risk of conversion to clinically definite MS (CDMS).
Methods: Patients (per McDonald 2005 criteria) were randomized 1:1:1 to placebo, teriflunomide 7 mg, or teriflunomide 14 mg for ⩽108 weeks (core study). In the extension, teriflunomide-treated patients maintained their original dose; placebo-treated patients were re-randomized 1:1 to teriflunomide 7 mg or 14 mg. Brain volume was assessed during years 1-2.
Results: Teriflunomide 14 mg significantly slowed annualized CGM and WB atrophy versus placebo during years 1-2 [percent reduction: month 12, 61.4% (CGM; p = 0.0359) and 28.6% (WB; p = 0.0286); month 24, 40.2% (CGM; p = 0.0416) and 43.0% (WB; p < 0.0001)]. For every 1% decrease in CGM or WB volume during years 1-2, risk of CDMS conversion increased by 14.5% (p = 0.0004) and 47.3% (p < 0.0001) during years 1-2, respectively, and 6.6% (p = 0.0570) and 35.9% (p = 0.0250) during years 1-5. In patients with the least (bottom quartile) versus most (top quartile) atrophy during years 1-2, risk of CDMS conversion was reduced by 58% (CGM; p = 0.0024) and 58% (WB; p = 0.0028) during years 1-2, and 42% (CGM; p = 0.0138) and 29% (WB; p = 0.1912) during years 1-5.
Conclusion: These findings support the clinical relevance of CGM and WB atrophy and early intervention with teriflunomide in CIS.
If you enjoy reading this blog you may want to support Prof G’s challenge
After his recent accident in which he sustained a broken pelvis and cervical spine, he has set himself a rehab challenge to walk 5 km unsupported by the end of the year (‘Prof G’s bed to 5km Challenge’). He is raising money for Queen Mary University of London to support Dr Ruth Dobson and Dr Angray Kang’s COVID-19 MS Antibody Study. So please donate if you can, every little helps and will get this study completed on time.
Just catching up with my reading. Whilst I was away on holiday the ASCLEPIOS I and II trials was published in the New England Journal of Medicine.
There is little doubt that ofatumumab is superior to teriflunomide when it comes to suppressing focal inflammation, i.e. relapses, MRI activity and peripheral blood neurofilament levels. However, ofatumumab’s effectiveness against teriflunomide on the real MS (delaying disability progression and reducing the relative loss of brain volume) is less impressive. Is this just another example of a dissociation between the anti-inflammatory effects of an anti-CD20 therapy and its impact on the end-organ as measured using brain volume loss or is it telling us something about teriflunomide and the cause of MS?
It is clear, at least to me, that MS the disease is not due to focal inflammation. Based on the Prentice criteria for disease surrogates, 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 critically 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).
So why does ofatumumab do so poorly on these metrics relative to teriflunomide, when you would expect it do better? I think teriflunomide is the outlier and this opinion is based on several observations.
Teriflunomide has effects on disability progression that are way and above what you expect from its impact on relapses and focal MRI activity; i.e. both teriflunomide phase 3 placebo-controlled trials were positive on disability progression, despite a moderate reduction in relapse rate (~33% vs. placebo).
Teriflunomide also has a significant and unexpected effect on brain volume loss compared to placebo, which again is out of proportion to its anti-inflammatory effects.
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.
Finally, 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? Could it be an anti-EBV agent? Although teriflunomide’s antiviral mode of action needs more study, I suspect this is the reason why teriflunomide is the outlier that disproves the dogma.
Despite these observations, I suspect the MS community is going to propel ofatumumab to blockbuster status within the first 12 months of its launch. However, I want to reiterate that I think anti-CD20 therapies are lulling us into a false sense of security, i.e. because anti-CD20 therapies are so good at suppressing relapses and focal MRI activity we think we have sorted out the treatment of MS. However, when you look carefully at the end-organ of pwMS on anti-CD20 it is clear that their brains are still being shredded by smouldering MS. It is clear to me that we need to go way and beyond ofatumumab and anti-CD20 therapies to target whatever is causing smouldering MS. This is why we need to think combination therapies and find an add-on therapy, possibly an antiviral, that normalises brain volume loss in people with MS who are rendered free of focal inflammatory activity.
BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known.
METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume.
RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, −0.11; 95% confidence interval [CI], −0.16 to −0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, −0.15; 95% CI, −0.20 to −0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P=0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P=0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P=0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups.
CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231).
Please don’t panic! The coronavirus or COVID-19 pandemic is a problem but needs a calm and considered public health approach, which is happening in the UK. At the moment the general public, including pwMS, are overreacting.
Another patient emailed me yesterday to inform me they are going to stop their ocrelizumab and asked what the consequences will be. In the short-term very little, but if you decide to stop ocrelizumab it may provide an opportunity to test a hypothesis.
The treatment effect of ocrelizumab lasts many months and probably years after stopping the treatment. In the phase 2 ocrelizumab extension study, the group of patients who had been treated with ocrelizumab had no disease activity 18 months later. The latter is what underpins one of our proposed treatment arms in the ADIOS study and suggests that anti-CD20 could be used in a similar way to IRTs (immune reconstitution therapies), i.e. alemtuzumab, cladribine and HSCT.
What about safety? B-cells and b-cell responses don’t return immediately after stopping ocrelizumab. They take about 6-12 months to reconstitute. The B-cells that return are not memory B-cells, but initially naive cells that later mature with memory B-cells taking several years to reappear. The bigger issue is circulating immunoglobulin levels. With time as more patients develop hypogammaglobulinaemia on anti-CD20 therapies, the serious infection risk will go up. This is clearly seen in the Swedish rituximab data (see below), which shows that by 6 years approximately 50% of rituximab-treated patients have had a serious infection. This will almost certainly occur with ocrelizumab and ofatumumab and the other emerging anti-CD20 therapies.
Therefore stopping ocrelizumab, rituximab, ofatumumab or another anti-CD20 is not going to reverse your immune defects overnight; it will take months and possibly years to have a fully functional and reactive B-cell and plasma cell repertoire. Some argue that you can reverse these defects with immunoglobulin replacement therapy. Yes and no! Yes, in terms of broad-spectrum population-type immunity, but no in terms of antibodies against new infectious agents such as COVID-19. For the latter to be covered you would need immunoglobulin from COVID-19 exposed survivors. I suspect Chinese medical entrepreneurs will be working on this strategy already. Organism-specific, in this case, COVI-19 specific, hyperimmune globulin therapy is a well-trodden path and may yet prove to be an effective treatment strategy in managing high-risk COVID-19 infected patients as an emergency.
The latter may be relevant in the context of COVID-19 as the pandemic will play out over months to years. Similarly, if a COVID-19 vaccine is developed you may want to be in a position to maximise your benefit from any future vaccine by not being on an anti-CD20 or other immunosuppressive therapy.
What should you do if you want to derisk your immunosuppression, increase your vaccine responsiveness and keep your MS in remission? This is where the immunomodulators will see a resurgence, in particular teriflunomide. I have hypothesised in the past that teriflunomide is the ideal maintenance therapy post-induction with an anti-CD20; I called this the iTeri study. My grant application for the iTeri study was rejected by Genzyme-Sanofi; I suspect because the patent-life of teriflunomide was too short to make this study worthwhile. However, the iTeri data may emerge spontaneously from real-life data as a result of the COVID-19 pandemic. Let’s say 5,000-10,000 pwMS derisk their treatment from an anti-CD20 onto teriflunomide the data will emerge from registers on how good teriflunomide in keeping these people in remission.
Please be aware that I have always referred to teriflunomide as the dark horse DMT; COVID-19 may prove to be the stimulus that allows teriflunomide to run free outside its small paddock.
Importance: Although highly effective disease-modifying therapies for multiple sclerosis (MS) have been associated with an increased risk of infections vs injectable therapies interferon beta and glatiramer acetate (GA), the magnitude of potential risk increase is not well established in real-world populations. Even less is known about infection risk associated with rituximab, which is extensively used off-label to treat MS in Sweden.
Objective: To examine the risk of serious infections associated with disease-modifying treatments for MS.
Design, setting, and participants: This nationwide register-based cohort study was conducted in Sweden from January 1, 2011, to December 31, 2017. National registers with prospective data collection from the public health care system were used. All Swedish patients with relapsing-remitting MS whose data were recorded in the Swedish MS register as initiating treatment with rituximab, natalizumab, fingolimod, or interferon beta and GA and an age-matched and sex-matched general population comparator cohort were included.
Exposures: Treatment with rituximab, natalizumab, fingolimod, and interferon-beta and GA.
Main outcomes and measures: Serious infections were defined as all infections resulting in hospitalization. Additional outcomes included outpatient treatment with antibiotic or herpes antiviral medications. Adjusted hazard ratios (HRs) were estimated in Cox regressions.
Results: A total of 6421 patients (3260 taking rituximab, 1588 taking natalizumab, 1535 taking fingolimod, and 2217 taking interferon beta/GA) were included, plus a comparator cohort of 42 645 individuals. Among 6421 patients with 8600 treatment episodes, the mean (SD) age at treatment start ranged from 35.0 (10.1) years to 40.4 (10.6) years; 6186 patients were female. The crude rate of infections was higher in patients with MS taking interferon beta and GA than the general population (incidence rate, 8.9 [95% CI, 6.4-12.1] vs 5.2 [95% CI, 4.8-5.5] per 1000 person-years), and higher still in patients taking fingolimod (incidence rate, 14.3 [95% CI, 10.8-18.5] per 1000 person-years), natalizumab (incidence rate, 11.4 [95% CI, 8.3-15.3] per 1000 person-years), and rituximab (incidence rate, 19.7 [95% CI, 16.4-23.5] per 1000 person-years). After confounder adjustment, the rate remained significantly higher for rituximab (HR, 1.70 [95% CI, 1.11-2.61]) but not fingolimod (HR, 1.30 [95% CI, 0.84-2.03]) or natalizumab (HR, 1.12 [95% CI, 0.71-1.77]) compared with interferon beta and GA. In contrast, use of herpes antiviral drugs during rituximab treatment was similar to that of interferon beta and GA and lower than that of natalizumab (HR, 1.82 [1.34-2.46]) and fingolimod (HR, 1.71 [95% CI, 1.27-2.32]).
Conclusions and relevance: Patients with MS are at a generally increased risk of infections, and this differs by treatment. The rate of infections was lowest with interferon beta and GA; among newer treatments, off-label use of rituximab was associated with the highest rate of serious infections. The different risk profiles should inform the risk-benefit assessments of these treatments.
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).
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 ;-(
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.
I have previously made the case that warts, both cutaneous and genital, are a relative contraindication to alemtuzumab therapy. I had one patient who has a torrid time with cutaneous warts after receiving alemtuzumab treatment. Fortunately, her immune system rejected them when it reconstituted and she is now fine.
At least with alemtuzumab and other IRTs (immune reconstitution therapies) you can rely on the immune system reconstituting; not so with continuous immunosuppressants.
I saw someone with MS yesterday who is on fingolimod with cutaneous warts, which are spreading, getting worse and causing a lot of discomfort. They were bleeding and were obviously causing her some distress. The bottom line is that the warts are unlikely to clear whilst she remains on fingolimod. Fingolimod is a drug that was repurposed from the solid-organ transplant field and is a chronic high-level immunosuppressant targeting both T and B cell responses of the immune system.
Warts on fingolimod is not a new problem; it is well described. In the case series below warts only responded to treatment and cleared when fingolimod was stopped. The problem is what to do about MS and MS rebound when you stop the fingolimod? In my opinion, the only solution is to go onto a DMT that is not a systemic immunosuppressive; these include interferon-beta, glatiramer acetate, teriflunomide and natalizumab. Another option is ocrelizumab as it selectively targets B-cells and leaves the T-cell compartment relatively intact, i.e. for the CD8+ cytotoxic T-cells to fight the viral infection that is causing warts.
The main problem we have in the NHS is the NHS England’s handcuffs in terms of eligibility for specific DMTs. This particular patient has previously failed the injectables so she is not going back onto those, she would not eligible for natalizumab as she does not have rapidly-evolving severe MS, which leaves only teriflunomide and ocrelizumab as viable options. The advantage of teriflunomide is that it is an oral agent, it has known antiviral effects and has a reversible mode of action. In comparison, ocrelizumab is a more effective DMT on average than teriflunomide, but as ocrelizumab is a depleting monoclonal antibody its action is irreversible. Ocrelizumab is also immunosuppressive and there is a definite herpes zoster signal with ocrelizumab, compared to interferon-beta and placebo. Ocrelizumab may, therefore, affect T-cell antiviral responses to HPV to some degree. Therefore based on a scientific rationale I would think the best agent for this patient is teriflunomide and if she is not keen on a de-escalation strategy, i.e. dropping down to a less effective agent, then she should switch to ocrelizumab. Do you agree?
She should also see a virologist to get the human papillomavirus causing warts genotyped. If this genotype is one that is covered by the polyvalent HPV vaccine (Gardasil-9) she may be able to receive this vaccine to boost her immunity to the virus once she is off fingolimod and on teriflunomide.
BACKGROUND: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster.
METHODS: We present five cases of chronic and treatment-refractory warts associated with fingolimod therapy.
RESULTS: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod.
CONCLUSION: Cutaneous warts are associated with human papillomavirus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.
