Category: News and events

Short- or long-sighted

I saw three patients 9-and-half-years after starting treatment with alemtuzumab as first-line therapy, yesterday. It was a remarkable experience. Only one of the three patients had needed a third cycle of alemtuzumab. All are in long-term remission; i.e. flat-lining on the EDSS, relapse-free and with no MRI activity (NEDA-3). Their EDSS scores yesterday were 1.0, 1.5 and 2.0. All of them are fully functional, with no physical and cognitive restrictions and described themselves as being well. One patient suggested to me she doesn’t have MS anymore. One patient has had ITP and recovered from it. All three patients have normally functioning immune systems with normal total lymphocyte counts. None of them is concerned about infections, travel, vaccinations or secondary malignancies. This is why treating MS with an immune reconstitution therapy, such as alemtuzumab, is so appealing.

I have a dream that this will be the new normal and all people with MS in future will have similar experiences. I sincerely hope the EMA allows people with MS to be treated and managed the same way as these three patients of mine have. I still have had no response from the EMA to my letter below. Maybe they don’t care?

Can anybody tell me from testing their vision if they are short- or long-sighted?

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. 

Yours faithfully 

GAVIN GIOVANNONI

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. 

  1. 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. 
  2. 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). 
  3. 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. 
  4. 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

MS@TheLimits2020

The following is the programme for the 3rd MS@TheLimits meeting in London next year. The feedback for the last two meetings (2017 & 2018) has been surprisingly good, which augurs well for our 2020 meeting.

The following is the headline feedback from 2017 & 2018:

2017
98% of delegates found the meeting to be useful or extremely useful.
100% of delegates found the organisation to be good or excellent.
100% of delegates would recommend the meeting to colleagues.
100% of delegates would be interested in attending in the future.
99% of delegates liked London & the RCP as the venue.

2018
96% of delegates found the meeting to be useful or extremely useful.
95% of delegates found the programme to be good or excellent.
99% of delegates found the organisation to be good or excellent.
99% of delegates would recommend the meeting to colleagues.
100% of delegates would be interested in attending in the future.
99% of delegates liked London & the RCP as the venue.
47% of delegates said they would rather attend this than any other MS meeting (only 35% chose ECTRIMS and 18% others)

Our next meeting is being held on Thursday 23rd & Friday 24th January 2020 at the Royal College of Physicians, London, UK. Please register online if you want to attend.

Potential leader?

Earlier this year I asked the question “why should someone with MS who lives in place B get a different service to someone who lives in place A?” and argued that variance, when it comes to the provision of healthcare services, is a euphemism for inequality, representing the ‘haves’ and ‘have-nots’ in society. This was a prelude to our ‘Raising the Bar’ meeting in Birmingham. We have set an ambitious programme of work for the next three years and it is exciting to see the MS Academy who is organising the workstreams becoming de-facto the natural home in the UK for HCPs with a specialist interest in MS. 

The following are our Raising-the-Bar workstreams and the current leads:

  1. QUALITY AUDIT – Jeremy Hobart/Sue Thomas/MS Society/MS Trust ….
  2. BIG DATA – David Rog/Joela Mathews ….
  3. SOCIAL DETERMINANTS OF HEALTH – Helen Ford/Gavin Giovannoni …. 
  4. PATIENT PARTNER PROGRAMME – Shift.ms …. 
  5. HOLISTIC MANAGEMENT OF MS – Agne Straukien/TBC ….

To make these workstreams happen we are launching a leadership programme to train the next generation of collaborative leaders in the MS Space to make these workstreams happen and realise our dream of a better deal for people living with MS in the UK. 

To navigate the landscape of MS service provision in the UK, effective leadership is essential. However, the skills required to become a leader capable of impactful change are suboptimally developed at a time when they are most needed. The MS Academy has recognised this critical training gap and launched a 6-month multifaceted leadership programme tailored to MS experts.

The goals of the leadership programme are to (1) identify and develop future leaders from the MS field who have little leadership experience, (2) develop and implement a mentoring program between participants and established leaders and (3) enhance skills of those who have already assumed or are about to assume leadership roles within their Institutions, the MS field, and, more broadly, the field of neurology.

The programme will be run by Prof Gabriele De Luca (Consultant Neurologist, Oxford) and Barbara Hoese (Pentecore Coaching, Minnesota). Gabriele is an alumnus of the AAN emerging leaders leadership programme and is passionate about the field himself and Barbara set-up and runs the AAN emerging leaders programme. 

So if you have what it takes to be a next-generation leader and want to apply for the leadership course give it a go. We need young motivated people to realise our dreams. The skills you learn will allow you to do and accomplish extraordinary things.

Please see the MS Academy website for more details.

Derisking anti-CD20 therapy

An important highlight of ECTRIMS this year was the data on the safety of the anti-CD20 therapies as a class. It is clear that prolonged, and sustained, B-cell depletion is not safe. Hypogammaglobulinaemia will become a problem with the risk of both common and opportunistic infections. 

Stephen Hauser presented the 7-year ocrelizumab safety data and there is a clear uptick in infections in year 7. His poster also included a probable opportunistic infection signal.  As of January 2019, there were six potential serious opportunistic infections that had been reported from the ocrelizumab clinical trials.

  1. Systemic Pasteurella infection in a patient with RMS following a cat bite (resolved)
  2. Multisegmental herpes zoster infection in a patient with RMS, treated with intravenous (IV) acyclovir (resolved)
  3. Enterovirus-induced fulminant hepatitis in a diabetic patient with RMS, resulting in liver transplant
  4. Candida sepsis in a patient with PPMS who had stopped OCR treatment 11 months previously and was receiving cancer chemotherapy (resolved)
  5. Viral meningitis in a patient with RMS, cerebrospinal fluid positive for varicella-zoster, treated with IV acyclovir (resolved)
  6. Herpes zoster (monodermatomal) in a patient with RMS treated for a neutropenic fever (not assessed as an opportunistic infection) (resolved)

Continuous anti-CD20 therapy prevents you from forming germinal centres (where B-cells get educated and selected to make antibodies) in lymph nodes and the spleen. In other words, the anti-CD20 therapies result in what I refer to as a functional splenectomy. This causes a scotoma, or blind spot, in your immune system which means you can’t mount a vigorous immune response to new infectious agents or vaccines. In reality, your immune responses are muted. 

Image from Family Doctor

I highlighted in my hot topics talk on ‘DMTs in RRMS 2019: what remains to be achieved’ about the problems of having a functional splenectomy on anti-CD20 therapies. I recommended that all MSers be vaccinated with the polyvalent pneumococcal vaccine (Pneumovax) and possibly the vaccines for Haemophilus influenzae type B and Meningococcus. In addition, all MSers should have the annual flu vaccine, but with the inactivated component flu vaccine and not the live flu vaccine. In fact, MSers on anti-CD20 therapy should avoid coming into contact with recipients of the live flu vaccine in case it becomes more virulent and infects them. Please note the live flu vaccine is used in the UK in young children and it is recommended that children who have parents or family members at home on immunosuppressive therapies should not have this vaccine. 

Another option open to people on longterm anti-CD20 therapy is antibiotic prophylaxis against infections with these encapsulated bacteria. I suspect this may be necessary when MSers develop hypogammaglobulinaemia and recurrent infections, similar to the NMO cases described below. It is clear that anti-CD20 therapies will need annual immunoglobulin levels measured so that if hypogammaglobulinaemia develops MSers can we warned. I suspect immunoglobulin replacement therapy will only be required in the case of recurrent infections, for example, sinus or chest infections; for example, the NMO patient on longterm rituximab who developed bronchiectasis.  

I would also recommend that MSers on immunosuppressive therapies wear a medic-alert bracelet that states they are on an anti-CD20 therapy. This would help HCP in an emergency if you are too sick to provide a history. An American colleague told me about one of his ocrelizumab-treated patients, who was fit and well, who died suddenly in the emergency department after presenting with a high temperature and not feeling well. I suspect the cause of death was probably septic shock from one of the encapsulated bacteria discussed above. 

The facts that (1) the clinical development programme of ocrelizumab was stopped in rheumatoid arthritis and lupus because of infections and excessive number of deaths, (2) that there is a herpes zoster signal on ocrelizumab, (3) there is blunted vaccine response, in particular to pneumococcus, and (4) ocrelizumab reduces immunoglobulin levels explains why there are infectious complications on ocrelizumab.

So if you are on rituximab, ocrelizumab, ofatumumab or any othe anti-CD20 please be vigilant and take care. On the other side of the coin are the benefits of these treatments and their ease of use and low monitoring burden. As with all DMTs the risks need to be balanced against the benefits. 

Tallantyre et al. Secondary Antibody Deficiency and infection following B-cell depletion for CNS neuroinflammation. ECTRIMS Online Library. Oct 25, 2017; 199742; EP1722

B-cell depleting anti-CD20 monoclonal antibody therapies have demonstrated promising clinical efficacy in suppressing relapses in individuals with neuromyelitis optica (NMO) and multiple sclerosis (MS). However, uncertainties remain about the optimum treatment schedule. In rheumatological disease, anti-CD20 agents are most often employed for short-term induction therapy and are subsequently replaced by longer-term maintenance therapy. In contrast, repeated cycles of anti-CD20 monoclonal antibody therapy are proposed as maintenance therapy for CNS neuro-inflammatory disorders. Post-marketing surveillance will be essential to fully uncover the long-term safety profile of repeated B-cell depletion. Hypogammaglobulinaemia is a recognised consequence in a proportion of patients treated with medium- to long-term B-cell therapy and may play a role in the increased incidence of infection observed in the anti-CD20 arms of treatment trials. We report 5 cases of serious infection associated with hypogammaglobulinaemia occurring in patients receiving rituximab for NMO. The cases were all female, all had low IgG with variable reductions in IgM and IgA. The cases had a mean treatment duration of 3.1 years, but not all cases had had extensive exposure (treatment duration range 0.5 – 6.2y). We review the evidence relating to hypogammaglobulinaemia following anti-CD20 treatment for neuroinflammatory disorders and propose an algorithm for monitoring and treatment of this recognised complication.

CoI: multiple

Help

I have been tasked with designing an International MS Masterclass to teach neurologists and other HCPS (healthcare professionals) about MS. The idea is to run four 2-day courses. I have put together the following draft programme and would appreciate your thoughts on it.

If you have MS is there anything that you want to be added, i.e. is there anything that you would want your HCPs to know about?

If you are an HCP are there any glaring omissions that should be added? Is this the kind, of course, you would interested in attending? Thanks.

It is important to realise that there is a large unmet educational need to help general neurologists skill-up for managing MS.

Genius

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) and 3-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?

CoI: multiple

What remains to be achieved?

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.

CoI: multiple

Real Life

After my #1 highlight #ECTRIMS2019 post, I was sent an email by Antoinio Scalafari, a like-minded colleague, to remind me of their real-life data at Imperial College on alemtuzumab in clinical practice. It mirrors the trial experience and needs a platform for discussion (see below).

In parallel, I heard via the MS grapevine that the MS community does not appreciate me questioning the ethics of the DELIVER-MS and TREAT-MS Trials. Why not? These are pragmatic trials to compare escalation therapy with the strategy of flipping the pyramid (high-efficacy therapy first-line).

Giovannoni. Do we have equipoise when it comes to how we treat active multiple sclerosis? Lancet Neurol. 2019 Jul 30. pii: S1474-4422(19)30227-3. doi: 10.1016/S1474-4422(19)30227-3.

Don’t I have a right to an opinion? I finish my commentary with a simple question for the trialists: ‘The real litmus test for the investigators of the DELIVER-MS and TREAT-MS trials is the question they should all ask themselves: “If I had multiple sclerosis, how would I want to be treated?” Given the evidence, patients deserve the choice of being treated with a high-efficacy DMT first-line’.

Why shouldn’t MSers with active MS not have the option of being treated with alemtuzumab, or for that matter HSCT?

CoI: multiple

Black Swan

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.

Prof G’s ECTRIMS Highlight #2

Pender et al. Preliminary safety and efficacy of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus-targeted T-cell immunotherapy for patients with progressive forms of multiple sclerosis. ECTRIMS 2019 Abstract: P1657.

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).

Pender et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018 Nov 15;3(22). pii: 124714. doi: 10.1172/jci.insight.124714.

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.

CoI: multiple