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