Tuesday, 25 April 2017

AAN Siponimod Phase III positive in Secondary Progressive MS

Safety and Tolerability of Siponimod in Patients with Secondary Progressive Multiple Sclerosis: Robert Fox , Ludwig Kappos , Amit Bar-Or , Bruce Cree , Gavin Giovannoni , Ralf Gold, Patrick Vermersch , Harold Pohlmann, Christian Wolf , Frank Dahlke , Erik Wallström , Tatiana Sidorenko

Objective: To present safety and tolerability results of the randomized, double-blind, placebo-controlled, Phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). 
Background: Siponimod, a selective sphingosine 1-phosphate (S1P) receptor-1/-5 modulator with peripheral and central effects was investigated in SPMS, a condition driven by neurodegeneration and inflammation in the central nervous system, where treatment options are limited. Efficacy results are reported separately. 
Design/Methods: In EXPAND siponimod significantly reduced the risk of 3-month confirmed disability progression. Safety and tolerability based on the safety analysis set for the double blind treatment period are reported. Patients were randomized (2:1) to receive once-daily siponimod 2mg or placebo (with a 6-day initial dose titration). 
Results: Of 1651 randomized patients, 1645 comprised the safety population (siponimod, N=1099; placebo, N=546). Mean age was 48 years (SD 7.87), median EDSS 6.0. At least one treatment-emergent adverse event (TEAE) was reported for 88.7% and 81.5% of siponimod and placebo patients; in 7.6% and 5.1% of patients, these led to treatment discontinuation. Most common TEAEs (>10% in any group) were headache, nasopharyngitis, urinary tract infection, falls and hypertension. Serious TEAEs were reported in 17.9% and 15.2%, including four deaths in each treatment group (0.4% and 0.7%). Incidence of infections and malignancies were similar (49.0% vs. 49.1%, 1.9% vs. 2.6%, respectively). Lymphopenia below 0.2x10˄9/uL was observed in 2.7% vs. 0.2% of patients and Liver Function Test elevations ≥3xULN – in 5.6% vs. 1.5%. The incidence of other AEs of interest were: bradyarrhythmias, 3.5% vs. 2.4%; hypertension, 12.6% vs. 9.3%; and macular oedema, 1.8% vs. 0.2%, respectively. With dose titration (during treatment initiation) there were only few bradyarrhythmic events. No cases of Mobitz II or higher degree AV-blocks were reported. Conclusions: The safety profile of siponimod appears to be in line with other S1P receptor modulators. 

Efficacy of Siponimod in Secondary Progressive Multiple Sclerosis: Results of the Phase 3 Study Ludwig Kappos , Amit Bar-Or , Bruce Cree , Robert Fox , Gavin Giovannoni , Ralf Gold , Patrick Vermersch , Sophie Arnould , Tatiana Sidorenko , Christian Wolf , Erik Wallström , Frank Dahlke

Objective: To present the efficacy results of the randomized, double-blind, placebo-controlled, phase 3 EXPAND study, evaluating siponimod versus placebo in patients with secondary progressive multiple sclerosis (SPMS). 
Background: Siponimod, a selective sphingosine 1-phosphate receptor-1 and -5 modulator with peripheral and central effects was investigated in SPMS, a condition for which treatment options are limited. 
Design/Methods: Patients were randomized (2:1) to once-daily siponimod 2mg or placebo. The primary endpoint of this event- and exposure-driven study was time to 3-month confirmed disability progression (CDP), assessed by the Expanded Disability Status Scale (EDSS). Key secondary endpoints were time to confirmed worsening of ≥20% from baseline in the Timed 25-Foot Walk test (T25FW) and T2 lesion volume (T2LV) change from baseline. Other secondary endpoints were 6-month CDP, annualized relapse rate (ARR), 12-item Multiple Sclerosis Walking Scale (MSWS-12), number of T1-Gd+ and T2 lesions and percent brain volume change (PBVC). For other secondary endpoints p-values are nominal (not corrected for multiplicity). Safety and tolerability are presented separately. 
Results: Overall, 1651 patients were randomized. Siponimod reduced the risk of 3-month CDP by 21% versus placebo (HR [95% CI]: 0.79 [0.65, 0.95]; p=0.013). Point estimates in favor of siponimod were consistently observed across predefined subgroups, including patients with no relapses in the 2 years prior to study and those without gadolinium-enhancing lesions at baseline. The risk reduction observed for T25FW was 6.2% and not statistically significant (p=0.440). Siponimod reduced the risk of 6-month CDP by 26% (p=0.006), ARR by 55.5% (p<0.0001), T1 Gd+ lesion number by 86.6% (p<0.0001), and new T2 lesion number by 81% (p<0.0001). Relative difference in change from baseline in T2LV, MSWS-12 and PBVC were 79.1% (p<0.0001), 39.7% (p=0.057) and 23.4% (p=0.0002), respectively, versus placebo. 
Conclusions: Siponimod had a robust positive effect on disability progression and other relevant outcomes in SPMS. 
So good news for secondary progressive MS. At last a **imod that does something so why did fingolimod not work in primary progressive. It is clear that it blocks the same targets. Points in favour was found in people without relapses or gadolinium enhancing diseased but no significance really means it had no activty and so failed. ProfG is a co-author so can fill you in on that score

CoI Multiple

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).