IRT – Prof G's MS Blog Archive

Induction-maintenance

Barts-MS rose-tinted-odometer ★★★

By definition an immune reconstitution therapy (IRT) for MS is given as a short course, i.e. as a one-off treatment in the case of HSCT or intermittently as in the case of alemtuzumab or cladribine. IRTs are not given continuously and additional courses of the therapy are only given if there is a recurrence of inflammatory activity. IRTs have the ability to induce long-term remission and in some cases potentially a cure.

Immune reconstitution simply refers to the restoring of a competent immune system after a cycle, or cycles, of depletion. Immune competence in the context of an IRT refers to the ability of the immune system to respond to infection, in particular, opportunistic infections, mount an antibody response to vaccines and to perform normal systemic tumour surveillance.

Immune reconstitution has been best shown in the context of hematopoietic stem cell transplantation (HSCT). In the case of an IRT, for example, alemtuzumab or cladribine, which are given as short courses breakthrough disease activity can be used as an indicator to retreat rather than to necessarily switch therapy. Therefore, there a rebaselining MRI should be delayed until after the final initial course of therapy, e.g. 2 years, or close enough to the time when a third, or subsequent course, can be administered

A major concern in relation to the wide adoption of IRTs is the uncertainty about the duration of their effectiveness and the concern that disease activity may reoccur at a level below the clinical and MRI monitoring thresholds used in routine clinical practice. If disease activity does reoccur will it cause irreversible end-organ damage? In addition, some IRTs, in particular, alemtuzumab and HSCT, are associated with a high rate of secondary autoimmunity and rarely with early and severe rebound disease activity.

One strategy we are exploring is to use an IRT as true induction therapy and then maintain the treatment effect with safer maintenance therapies. In the case of alemtuzumab and HSCT, certain maintenance therapies could potentially prevent secondary autoimmunity and early rebound disease activity.

We are in the process of preparing a grant application to explore the safety of an induction-maintenance treatment. Would you be interested in helping by completing the following survey?

CoI: multiple

ADIOS

Yes, why can’t we use anti-CD20 therapies as an immune constitution therapy (IRT) or at least adapt the dose based on B-cell reconstitution kinetics? And if we can’t beat the Swedes why can’t we join them?

ADIOS = ADaptIve Ocrelizumab dosing Study

There is mounting evidence from NMO and rheumatology that anti-CD20 therapies can be used as either a maintenance therapy or an immune reconstitution therapy (IRT). Another way of using them is to adjust the dose based on memory B-cell reconstitution (MBR) kinetics.

Adapting the dose of anti-CD20 therapies using MBR or as IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and possibly the ability to respond to vaccines. It could also lead to better family planning by being able to expand the treatment-free period safely. Another plus would be cost-saving for the NHS and the other healthcare systems.

We are therefore in the process of designing a new trial to test standard interval dosing (SID) of ocrelizumab vs. adaptive dosing either using an MBR or an IRT protocol. What do you think? If you were on ocrelizumab would you sign up for this study? The advantage for you is that it may make your treatment safer in the long-term and it will potentially save the NHS millions.

CoI: multiple

Playing second fiddle to the Swedes

Why can’t we use anti-CD20 therapies as immune constitution therapies?

For some years we have been promoting our Barts-MS Essential DMT list to treat people with MS (pwMS) in resource-poor environments. One of the big guns on our list has been rituximab (anti-CD20). One of the problems is that rituximab at a dose of 1g every 6 months is still too expensive to accessible for the vast majority of MSers living in these environments. The good news is that several developments have brought the price of rituximab down.

The Swedes, who are treating more than half their MS population, have data showing that 500mg every 6 months is as good as 1g every 6 months in terms of NEDA, i.e. preventing new relapses and new MR lesions from forming.
Rituximab has come off patent and several cheap biosimilars are now entering the market.
The Swedes are also testing adaptive dosing, i.e. after 2 years of 6 monthly infusions, they are extending the interval between doses to 12 months or more and/or are even beginning to redose rituximab based on peripheral memory B-cell reconstitution. At a recent meeting, I was at one Swedish neurologist is beginning to use rituximab as an IRT (immune reconstitution therapy), i.e. only redosing with rituximab if and when disease activity re-emerges.

I classify anti-CD20 therapies as both a maintenance therapy and an IRT. At the last AAN in Los Angeles, I attended a meeting of like-minded clinical scientists to set-up a trial to test anti-CD20 as a maintenance therapy vs. an IRT. The retreatment arms of the trial were to test redosing based on the reemergence of disease activity or the repopulation of memory B cells. Using anti-CD20 therapies as an IRT has appeal as it will almost certainly be safer in terms of infections, the emergence of hypogammaglobulinaemia and ability to respond to vaccines.

I am therefore very interested in seeing the results of the Swedish experiment of testing rituximab as a maintenance therapy vs. rituximab as an IRT. Just maybe we can get the price of treating MS with rituximab down to affordable levels for low-income countries.

The following is a back of envelope calculations based on the current BNF prices:

Mabthera (Roche) 500mg = £873.15 per 500mg vial
Rixathon (Sandoz) = £785.84 per 500mg vial
Truxima (Napp) = £785.84 per 500mg vial

Standard dose (1g) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £8731.50 for the first 2 years and then £3492.60 annually.
Standard dose (1g) biosimilar maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £785.84 x 5 = £7858.40 for the first 2 years and then £3143.36 annually.
Reduced dose (500mg) Mabthera maintenance regimen: 1g Day 0, 1g Day 14 then 1g 6 monthly indefinitely = £873.15 x 10= £4365.75 for the first 2 years and then £1746.30 annually.
Reduced dose (500mg) biosimilar maintenance regimen: 1g Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.
Reduced dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly indefinitely = £785.84 x 5 = £3929.20 for the first 2 years and then £1571.68 annually.
Adaptive dose (500mg) biosimilar maintenance regimen: 500mg Day 0, 500mg Day 14 then 500mg 6 monthly for 2year and then 500mg approximately every 12 months = £785.84 x 5 = £3929.20 for the first 2 years and then £785.84 annually (the latter may be lower if redosing is done using peripheral B cell reconstitution).

Please note these figures are the list price and don’t include discounts, VAT nor the infusion costs. In reality, these costs could come down with central, say NHS, purchasing power. Unfortunately, they are still too high to help pwMS in low-income countries. Just maybe getting MS and anti-CD20 therapies onto the WHO Essential Medicines List may bring down the costs by creating political pressure on the Pharma industry or innovations in making cheap biosimilars may also help.

The Caveat

There is one major caveat I have about putting up anti-CD20 as the solution for MS is that we may be getting it wrong. I personally don’t think relapses and focal MRI activity are the disease we call MS; these markers are an inflammatory response to what is causing the disease. Therefore I suspect we may be lulling ourselves into a false sense of security with anti-CD20 therapies and ignoring what is really driving the disease, i.e. what is causing the end-organ damage in MS.

Do we know what is driving the slowly expanding lesion? What is causing the extensive cortical lesions in MS, which we can’t see on conventional MRI? What is driving the progressive brain volume and grey matter loss in MS? Don’t we need to go beyond NEDA as a treatment target? I know some would argue we have done this already, which is why so many MSers want HSCT as a first-line treatment option.

To B or not to B

Is targeting the B-cell sufficient to get on top of MS or do we need something extra?

I spoke at the MS Nurses’ MS@TheLimits2019 meeting at the Royal College of Physicians yesterday. My brief was to cover the role of B-cells in the pathogenesis of MS and to review the converging evidence that supports B-cells being the central player in the pathogenesis of MS.

It is clear that depleting B-cell therapies are very effective in controlling relapses and MRI activity. With a very favourable safety profile and relatively low treatment and monitoring burden, B cell therapies are likely to become one of the most widely prescribed classes of DMT. However, B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers, in particular, brain volume loss. Why? I wish I knew. But if I knew the answer to this question I would have a pretty good idea about the cause of MS.

A clue may be in the ‘Field Hypothesis‘. It is clear to me that relapses and focal MRI activity are not the primary events in MS. Focal inflammation is not MS. Focal inflammation is in response to what is causing MS and the cause is likely to be something in the CNS. Focal changes occur in the white matter weeks to months before you get a Gd-enhancing lesion. When you stop natalizumab and allow re-trafficking of lymphocytes you get rebound disease activity way and above what one would expect from pre-treatment baseline levels of disease activity. What is happening in the brain, or field, of these patients to trigger such a vigorous inflammatory response? Could it be a virus? Importantly, B-cells appear to be needed for the rebound response. Rituximab, and I suspect ocrelizumab, are very effective in preventing rebound. However, as both these agents target a small subset of T-cells you can’t claim categorically that the rebound is only driven by B-cells.

The difference between HSCT, alemtuzumab and natalizumab and the anti-B cell therapies (rituximab, ocrelizumab and possibly cladribine) is the former take out or inhibit trafficking of both T & B cells. As HSCT and Alemtuzumab have the best data in relation to long-term remission, or potential cures, you have to conclude that you need to target both B cell and T cells (substantial peripheral depletion) if this is your treatment aim.

Please note that I classify cladribine as a B-cell depelter and not a dual B and T cell depelter. The level of T-cell depletion with cladribine is modest at the licensed dose (~50%) which is not sufficient to put it into the same class as alemtuzumab and HSCT. This is one of the reasons why I refer to cladribine as being a SIRT (selective immune reconstitution therapy) and the others as NIRTs (non-selective immune reconstitution therapies).

I have always made the point that to treat MS you need much more than an anti-inflammatory and that you also have to have neuroprotective therapies and potentially remyelinating agents on board as well. If you have disabilities we need to be thinking about neurorestorative therapies and finally you need to target lifestyle and wellness to tackle the issue of comorbidities and ageing.

So in short, targeting B-cells is important, but not sufficient to get on top of the shredder.

You will see that a large part of my talk was covering the link between EBV, B–cells and MS. The B-cell hypothesis at least strengthens the case for EBV being the cause of MS and the need for an EBV vaccine for MS prevention trials. Please don’t forget that EBV lives inside memory B cells and hijacks the B cell’s biology in many ways that have potential relevance to MS and other autoimmune diseases.

My talk will be available online in a few weeks to help you interpret my presentation. In the interim you can download my talk from my slide sharing site.