iTeri Study – Prof G's MS Blog Archive

Ocrelizumab: DODO vs. ADIOS, who will win?

Barts-MS rose-tinted-odometer: ★★

In response to a question over the weekend about what has happened to the DODO and ADIOS studies. Both are alive and kicking. The more insightful question would be ‘how can I support both the DODO (double-dose ocrelizumab study) and the ADIOS (adaptive dosing ocrelizumab study) studies?’.

Surely, the DODO and ADIOS studies are incompatible with each other scientifically? How can I, on the one hand, support a higher dose of ocrelizumab and on the other hand suggest reducing the dose in the longterm. The hypothesis is all about timing and how you use anti–CD20 therapies.

You need higher doses of anti-CD20 therapy initially as an induction strategy to purge the various B-cell compartments of memory B-cells, which house latent EBV and the highly autoreactive population of B-cells that drive and maintain the MS-state. This population of cells may reside in the deep tissues and/or the central nervous system, which is why we are also testing CNS penetrant anti-B-cell strategies, simultaneously. Time is short so we need to run trials in parallel.

However, once you have purged these compartments say after 2 years of treatment you don’t need to maintain such high-doses of anti-CD20 therapies that are then suppressing normal B-cell biology and immune responses, which result in longterm complications. This is why we want to use ocrelizumab as an immune reconstitution therapy, i.e. high-dose upfront followed by no treatment and wait to see if MS remains in remission or disease-activity returns requiring additional courses. The latter is one of the arms of our proposed ADIOS study.

In reality, if we could convince a national funding agency, a pharma company or a wealthy philanthropist I would use anti-CD20 therapy as part of an induction-maintenance protocol. After two years of induction therapy with high-dose ocrelizumab, I would test different maintenance strategies in parallel. My agents of choice would be teriflunomide, leflunomide, IMU-838 (vidofludimus) or ASLAN003 (selective second-generation DHODH inhibitors), HAART (highly active antiretrovirals), famciclovir or another anti-EBV viral agent. The hypothesis is to allow B-cell reconstitution after anti-CD20 therapy in the presence of an anti-viral agent to prevent EBV reactivation and reinfection of new memory B cells. By doing this you will also be derisking the long-term immunosuppression associated with anti-CD20 therapies and prevent the development of hypogammaglobulinaemia. In addition, you will be allowing patients to respond to vaccines.

The problem with this trial proposal is the outcome measure; the power calculations are not trivial and the study would have to be very long. I also have reservations about whether or not the regulators will accept the induction maintenance strategy. Maybe we can sell it to them on safety, i.e. to prevent the development of hypogammaglobulinaemia and infections rather than on efficacy? If we go this route then there is only one agent we can use and that is teriflunomide, which is licensed to treat MS. As teriflunomide is coming off patent there is a chance the NHS may be interesting in funding such a trial; i.e. it would save them money. This is something I am exploring as a proof-of-concept trial.

The good news is that Roche-Genentech is testing the principles of the DODO study and announced at MSVirtual2020 two high-dose ocrelizumab trials (see below). These trials up the stakes in the anti-CD20 wars and I am confident that we need higher doses upfront to purge deep tissue and possibly CNS pools of B-cells. Please note that you don’t need higher doses of anti-CD20 therapy to suppress relapses and focal MRI activity you can do that with current or lower doses. I am confident both these studies will show that higher-dose ocrelizumab is superior to standard dose ocrelizumab on disability progression or smouldering MS, but not on focal inflammatory events. In relation to the latter, we have hit the ceiling already.

You need higher doses up-front to target the drivers of smouldering MS; i.e. disease progression independent of relapses, accelerated brain volume loss, slowly expanding lesions (SELs) and the subpial cortical lesions. If these higher-dose studies are positive it will put clear daylight between ocrelizumab and the other anti-CD20 therapies and it would mean the ofatumumab and rituximab are currently being underdosed, at least initially in the first two years. But don’t we have a hint of this already? Ofatumumab was not better than teriflunomide at slowing down brain volume loss in year two of the ASCLEPIOS I and II clinical trials (NCT02792218 and NCT02792231) despite being superior to teriflunomide on relapses and MRI activity. The latter is more proof that focal inflammatory disease (relapses and MRI activity) is not MS but in response to what is causing the disease. The real MS is what causes smouldering pathology and end-organ damage.

DODO vs. ADIOS vs. iTeri: which one would I prioritise? Almost certainly iTeri; the iTeri trial makes the most sense in terms of our current understanding of the pathogenesis of MS, mode of action of anti-CD20 therapies and the long-term risks of chronic B-cell depletion.

Hauser et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020 Aug 6;383(6):546-557.

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.).

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Teriflunomide’s secrets

Barts-MS rose-tinted-odometer: ★★★★★

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?

Zivadinov et al. Slowing of brain atrophy with teriflunomide and delayed conversion to clinically definite MS. Ther Adv Neurol Disord. 2020 Nov 11;13:1756286420970754.

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.

CoI: multiple

Twitter: @gavinGiovannoni

Medium: @gavin_24211

#COVIDMS Coronavirus creates an opportunity for teriflunomide

Should I switch to teriflunomide?

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.

Gustavo Luna et al. Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies. JAMA Neurol 2019; Oct 17 (online)

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.

CoI: multiple

OVO Study

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.

Novartis summary:

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).

CoI: multiple