Tuesday, 25 April 2017

Is progressive MS at long last getting the spotlight?

Drugs. 2017 Apr 20. doi: 10.1007/s40265-017-0726-0. [Epub ahead of print]

Pharmacological Approaches to the Management of Secondary Progressive Multiple Sclerosis.

Nandoskar A, Raffel J, Scalfari AS, Friede T, Nicholas RS.

Abstract

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term 'randomised controlled clinical drug trials in secondary progressive MS' in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.

One of the big paradoxes underlying MS treatment strategies has been the populism-fuelled belief that immunomodulatory/immunosuppressive treatments do not work in progressive MS. Yesterday at the AAN, Prof Gavin Giovannoni, eloquently made a case using numerous examples for RRMS and progressive MS (SPMS/PPMS) being one and the same disease, i.e. it is all simply MS; the key being how much reserve there is in the central nervous system - the take home message was treat early and for a lot longer. It would appear that time heals many a prediction, and for the first time neurologists in the audience started to question their treatment strategies; escalation (or stacking one treatment on top of another) vs induction treatments, risk vs risk-averse etc. Interestingly, cost was not on the list of discussions - why? treatments are expected to become cheaper as they come off-patent, it's simply a matter of time.

A review on the SPMS treatment pipeline is therefore timely. Nandoskar et al. have painstakingly reviewed from first principles the paradox of progressive MS treatment strategies: "There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS". Moreover, when they did a literature search of all randomised controlled trials in progressive MS since 1988, they found 34 trials (see table below) involving 21 different molecules!


Table 1: Completed trials in progressive MS

References

Treatment groups

N

MS type (%)

Mean (E)DSS baseline (SD) or (range)

Randomised trial duration (years)

Primary efficacy outcome

Main efficacy results

British Dutch Azathioprine group

Azathioprine

Placebo

354

67% RRMS

9% SPMS

14% PPMS

AZ 3.7 (1.5)

Plc 3.7 (1.6)

3

Change in EDSS and AI

Neutral

Ellison et al.

Azathioprine and methylprednisolone

Azathioprine

Placebo

98

PMS

AZ & MP 5.4 (1.3)

AZ 5.6 (1.2)

Plc 5.5 (1.0)

3

Rate of progression in ISS, SNE and DSS

Neutral

Ghezzi et al.

Azathioprine

Placebo

185

40% RRMS

60% SPMS

SPMS only

AZ 3.8 (1–6.5)

Plc 3.7 (1–7)

1.5

DSS progression

Neutral

The MS study group

Cyclosporine

Placebo

547

PMS

CsA 5.4 (1.2)

Plc 5.4 (1.2)

2

EDSS worsening

Positive—high and differential dropout

Bornstein et al.

Glatiramer acetate SC

Placebo

106

PMS

GA 5.6

Plc 5.5

2

EDSS progression

Neutral

Canadian Co-op MS Group

Cyclophosphamide IV

Cyclophosphamide oral and plasma exchange and prednisolone

Placebo

168

PMS

CPM 5.8 (0.6)

CPM and PLEX and Pred 5.7 (0.7)

Plc 5.8 (0.6)

2.5

Worsening in EDSS

Neutral

Beutler et al. 

Two-period, two-treatment crossover trial

Cladribine IV

Placebo

51

PMS

CL 4.8

Plc 4.6

2

Deterioration in EDSS/SNRS scores

Positive

Milanese et al.

Azathioprine

Placebo

40

48% RMS

52% PMS

AZ 3.4 (1.7)

Plc 3.1 (1.2)

3

EDSS progression

Neutral—high dropout rate

Goodkin et al.

Methotrexate

Placebo

60

70% SPMS

30% PPMS

MTX 5.5 (2.4)

Plc 5.3 (2.7)

2

EDSS, 9HPT, Box and Block Test, AI worsening

Positive

Karussis et al.

Linomide

Placebo

30

SPMS

Lin 4.9

Plc 4.7

0.5

MRI activity

Positive

European Study Group on Interferon β-1b in secondary progressive MS  

Interferon β-1b SC

Placebo

718

SPMS

IFNβ-1b 5.1 (1.1)

Plc 5.2 (1.1)

3

3 months confirmed EDSS progression

Positive

Noseworthy et al.

Linomide (3 doses)

Placebo

715

13% RRMS

87% SPMS

Lin 5.2 (2–6.5)

Plc 5.1 (3–6.5)

3

EDSS progression

Terminated 1 month after fully enrolled due to life-threatening side effects

Rice et al.

Cladribine SC (2 doses)

Placebo

159

70% SPMS

30% PPMS

CL 5.6

Plc 5.6

1

Mean change in EDSS

Neutral

SPECTRIMS

Interferon β-1a SC (2 doses)

Placebo

618

SPMS

IFNβ-1a 5.4 (1.1)

Plc 5.4 (1.1)

3

3 months confirmed EDSS progression

Neutral

Skurkovich et al.

IFNγ Antibodies IM

TNFα Antibodies IM

Placebo

45

SPMS

IFNγ Ab 4.5 (3–6.5)

TNFα Ab 4.0 (3–6)

Plc 4.1 (3–7)

1

EDSS progression

Positive—IFNg ab only

Cohen et al.

Interferon β-1a IM

Placebo

436

SPMS

IFNβ-1a 5.2 (1.1)

Plc 5.2 (1.1)

2

Baseline to month 24 change in the MSFC

Positive

Hartung et al.

Mitoxantrone IV (2 doses)

Placebo

194

SPMS

MIT 4.6 (1.0)

Plc 4.7 (1.0)

2

Change in EDSS, AI, SNS score, number of treated relapses and time to first treated relapse

Positive—12 mg/m2 MIT dose only

Anderson et al.

Interferon β-1a SC

Placebo

371

SPMS

IFNβ-1a 4.7

Plc 5.0

3

6 months confirmed EDSS progression

Neutral

Hommes et al.

Immunoglobulin IV

Placebo

318

SPMS

IVIG 5.3 (1.1)

Plc 5.2 (1.1)

2.25

3 months confirmed EDSS progression

Neutral

The North American Study Group on Interferon beta-1b in SPMS

Interferon β-1b SC (2 doses)

Placebo

939

SPMS

IFNβ-1b 5.2 (1.1)

Plc 5.1 (1.2)

3

6 months confirmed EDSS progression

Neutral

Warren et al.

MBP8298 IV

Placebo

32

69% SPMS

31% PPMS

MBP median 6.5 (5–7.5)

Plc median 6.3 (3.5–7)

2

EDSS progression

Neutral

Pöhlau et al.

Immunoglobulin IV

Placebo

231

85% SPMS

15% PPMS

IVIG 5.6 (1.1)

Plc 5.5 (1.2)

2

3 months confirmed EDSS progression, improvement in function defined by best EDSS

Positive—high dropout rate

Montanari et al.

Azathioprine and Interferon β-1b SC

Interferon β-1b SC

85

SPMS

Not available

2

Baseline to month 24 change in the MSFC

Neutral—high dropout rate

Kapoor et al.

Lamotrigine

Placebo

120

SPMS

LTG median 6.0 (4–7)

Plc median 6.0 (4–7.5)

2

Partial (central) brain volume atrophy rate

Neutral

Freedman et al.

MBP8298 IV

Placebo

612

SPMS

MBP 5.5 (1.0)

Plc 5.5 (1.1)

2

6 months confirmed EDSS progression

Neutral

Vermersch et al.

Masitinib

Placebo

35

SPMS

Mas 4.9 (1.2)

Plc 5.0 (1.1)

1

MSFC change from baseline

Neutral

Brochet et al.

Cyclophosphamide IV

Methlyprednisolone IV

138

SPMS

Not published by December 2016

2

Delay to confirmed EDSS progression

Neutral—high dropout rate

Zajicek et al.

Dronabinol

Placebo

498

SPMS

Dro 5.8 (0.7)

Plc 5.9 (0.7)

3

6 months confirmed EDSS progression, change from baseline in MSIS29 physical

Neutral

Chataway et al.

Simvastatin

Placebo

140

SPMS

Sim 5.8 (0.8)

Plc 5.9 (0.8)

2

Mean annualised whole brain atrophy rate

Positive

ASCEND

NCT01416181

Natalizumab IV

Placebo

889

SPMS

NTL 5.6 (0.9)

Plc 5.7 (0.9)

2

Confirmed progression in EDSS, T25FW, 9HPT

Neutral

Tourbah et al.

NCT02220933

Biotin

Placebo

154

PMS

Biotin 6.0 (0.8)

Plc 6.2 (0.5)

1

Improved EDSS or T25FW at 9 months confirmed at 12 months

Positive

RIVITaLISe, 2016

NCT01212094

Rituximab intrathecal and IV

Placebo

43

SPMS

Not published by December 2016

2

Brain atrophy

Early termination for futility: did not achieve CSF B cell depletion

Spain et al.

NCT01188811

Lipoic Acid

Placebo

54

SPMS

Lipoic acid median 5.5 (3–8)

Placebo median 6.0 (3–9)

2

Brain atrophy

Positive

EXPAND, 2016

NCT01665144

Siponimod (dose titration 0.25 mg to 2 mg)

Placebo

1649

SPMS

Not published by December 2016

3

Delay in time to confirmed EDSS progression

Positive

I would like to add one or two addendums to this list,;the ASCEND (natalizumab) study was protective of upper limb function, some of the interferons at long term review demonstrated a protective effect, and lamotrigine was protective on walking time and also demonstrated a drop in neurofilament levels.

Hidden in this list is are cyclosporine, methotrexate, IV cladrabine, and IV immunoglobulins; agents which are cheap and not taking-off like a Harrier jet as with the currently licensed treatments. In the UK, the NHS is currently requesting sustainability and transformation plans across 44 geographical areas in England (so-called 'footprints'), the end goal being to ensure its survival. Over the next few years, more MS centres will be filing their strategy, and this may just allow the UK to behave independently of the competitive pressures. Remember the costs of a monopoly are less choice, high price, asymmetric information (the monopolist may know more information than the consumer and exploit this knowledge to its own advantage), productive inefficiency (as there are no competitors, there is no incentive to reduce costs) and ultimately net welfare loss (bad news for the NHS).

20 comments:

  1. ...not primary progressive MS where disability accumulation occurs without prior relapses...

    Hmm...

    ReplyDelete
    Replies
    1. There is inflammatory activity in all forms of MS; ergo the ocrelizumab findings. We're just simply good at picking up this activity clinically. One of the mistakes is to believe that this disease has relapses and remissions. The reality is that there are only relapses.

      Delete
    2. As discussed elsewhere on this blog - not all PPMSers show active inflammation though. By the time my PPMS reared its head, most of the inflammation treatable by immune repression/destruction had probably been and gone. And now, who knows, but I wouldn't have much faith in Ocrelizumab any more, and that's before considering possible side effects.

      Delete
    3. Forgive me for playing devils advocate, but the Ocrevus trials were overloaded with patients displaying active inflammation (enhancing lesions), and underpowered in regards to separating out which patients the drug was actually most effective on. Based on the trial results, I don't think one can say with a large degree of confidence that the drug will be effective on patients without enhancing lesions. Certainly, the previous Rituxan PPMS trials only showed effectiveness on patients with enhancing lesions, and the mechanism of action of Ocrevus is quite similar to that of Rituxan. Please correct me if I am off-base…

      Delete
    4. So this is where the biology of the the disease is not the same as the clinical trial interpretation. As a biomarkers person when I talk about inflammatory phenotype in this trial - I mean the OCB+ participants, but others interpret the trial in terms of Gd+ lesions. From a biological proof of principle I don't see why it shouldn't work on this population. Neuroplasticity is a factor and may take longer in those who are more disabled with less reserve, but if this means loss of upper limb function vs not losing it - I'll take it.

      Delete
    5. NDG, I don't understand your last post. Obviously I don't do enough reading on my PPMS.

      "From a biological proof of principle I don't see why it shouldn't work on this population."

      Which population? I have no idea about whether I am OCB/Gd+ or not.

      "upper limb function vs not losing it - I'll take it"
      I kind of take issue with such a sweeping statement. Balancing the possible side effects with the possible benefits in someone like myself is not easy.

      Delete
    6. None of the comments I make in by blogs serve the intention of being sweeping statements. There is a lot of information out there about MS, and the information we present in this blog are impressions only.
      OCB stands for oligoclonal bands; these are active representation of B cells producing antibodies against the nervous system. You will only know if you are positive or not, if you have a lumbar puncture. If this is positive it would make sense to get rid of these to prevent continual damage (although I'm not certain that all antibodies formed by Bcells and plasma cells are bad).
      Say then you have lost use of your legs but can still use your hands - you'd want to conserve this, but the presence of continued immune activity (as represented by your OCB positivity) will mean that you'd eventually loose this as well. I really don't want my patients to face this given a choice, because this would mean that they'd be bed bound. Before the advent of interferons, as a trainee, I used to see a lot of this and it's not something I would like to see happening in this current era.
      Hope this helps.

      Delete
    7. What evidence is there that OCBs are "antibodies against the nervous system"? Just the rather flimsy epidemiological evidence that Professor Giovannoni presents on this blog? Is there any biological evidence?

      Delete
    8. I agree the evidence for OCBs being against cCNS antigens is flimsy at best. However, IMO what the antibodies bind to is irrrelevant, antibodies are able to stimulate microglia via their antibody binding Fc receptors and activated microglia are fingered as the slow killers in disease progression.

      Delete
    9. I still have difficulty believing that Ocrelizumab could help with progression in my body caused by immune system damage that happened many years ago. Nor am I convinced that progression is not in itself the beginning of MS. If only I knew I could be guaranteed not to become bed-bound by taking some drug. But thanks for the response NDG.

      Delete
    10. "antibodies are able to stimulate microglia via their antibody binding Fc receptors and activated microglia are fingered as the slow killers in disease progression."

      Sure, but whether this will is physiologically relevant will depend on the rate of antibody clearance from the CNS, the dose response from microglia, etc. What evidence is there that OCBs are actually causing damage in patients?

      Delete
    11. We don't know precisely what these antibodies are targeted against, it's not always myelin! In established MS, however there is coexistence of OCB deposition and complement-mediated demyelination in MS lesions.

      Delete
    12. "In established MS, however there is coexistence of OCB deposition and complement-mediated demyelination in MS lesions."

      Are you referring to Esiri's work? That work find antibodies in lesions, but it does not show that these are OCBs. The lesion antibodies may be clonally distinct, e.g. produced by short-lived plasma cells entering the CNS. OCBs may be an epiphenomenon.

      I'm not asking a general question about whether antibodies may cause damage in MS. I'm asking whether there's biological evidence for *OCBs* causing damage.

      Delete
    13. It's supposition and definitive proof will be very difficult, given that there are likely to be several components to disease progression. However, the mechanism is plausible that OCBs could stimulate pre-activated microglia via Fc receptors to release toxic factors, which even if at low level may be significant over time, given the long-term persistence of oligoclonal bands.

      Delete
    14. Don't you need concurrent binding of several Fc's? If so, antibody binding to their target(s) leads to their clustering, displays several Fc's in close proximity, and subsequent microglia activation would be more or less specific to the antibody target(s).

      Delete
    15. "However, the mechanism is plausible..."

      I think some quantitative, not qualitative, reasoning is necessary here. Otherwise, this is similar to health websites' discussions of whether some particular food is carcinogenic. Sure, it may cause cancer when administered at 1000 times the ordinary dose, but this is irrelevant for any decisions that people make.

      Delete
  2. Yo, Doc Gnanapavan, I need you to clarify something for me:

    Remember the costs of a monopoly are less choice, high price, asymmetric information...

    Maybe I'm a little dunce, but are you against the 'monopoly' of our NHS? You see, ever since I was born under a Thatcher government and stuff became less socialised, the claim has been that privatisation is rago because it will create competition and thus bring døwn prices.

    Our utility bills are pricier than ever. Privatisation has created cartels. My worry is that UK healthcare is headed this way.

    To more, the monopoly of the NHS is rago. Taxes need to rise to fund it better, though, not VAT. VAT directly targets the poor as they spend 10% of their income on VAT-able goods, whereas the richest only spend 5%.

    Mate, keep the Tories out. It's scary what is about to come about.

    Peace out, bredrins.

    ReplyDelete
    Replies
    1. I'm very much against privatisation of the NHS and the monopoly of privatisation. Healthcare is not a business model, and that would be a mistake - for it to be impartial it should make a loss. Privatisation began with Lord Sainsbury and the introduction of competition.

      The UK gov spends well below it's GDP on healthcare. Good health is the core of our society, if we can't have that we will regress as a society.

      Delete
  3. For sure, we don't know much about when (or if) inflammation stops in PPMS. Evidence of Gd enhancement is more of an indication of active disease than not and it would make clinical sense to put this group onto Ocrelizumab. Definitely the risk of cancers need to be taken into consideration. But this isn't how licensing of therapies happens, and triaging people on the basis of clear evidence of inflammatory activity would be difficult- we'll know more soon on pooled efficacy after more people are on it.

    ReplyDelete

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