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. ProfG is a co-author so can fill you in on that score

CoI Multiple

14 comments:

  1. Fantastic - now what is the next step before people with progressive MS can get it in the UK.

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    1. It needs to be approved by the EMA first, then NICEd

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  2. Let's hope it gets licensed and (in UK) past NICE. I know so many people hoping for ocrelizumab (could be a long wait) since it made the news and sipo will be the same. It's a kinda weird age, brilliant to hear about all the MS newbies and youngsters getting alemtuzumab (which let's face it is the nearest to a 'cure' we have) yet quite hard to live with knowing you were 'born too early'.

    Keep doing the research! (please)

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  3. I'm confused about the conclusions here. Am I correct in thinking that this drug was effective in patients with relapses and/or enhancing lesions, but failed in patients with no relapses and/or enhancing lesions?

    This appears to be what MD says in his final note, but I have trouble pulling this out of the abstract. Is it only obvious when reading the full paper?

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    1. I think it worked in those with and without relapses. I removed some stuff from post to make it less confusing

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  4. Just adding so that I will be notified via email when new comments are posted. Neglected to tick the box in my previous comment.

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  5. Geez, didn't take the box again in my last note. Chalking that one up to brain disease…

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  6. and do you think this drug will again exclude wheelchair users?

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    1. has this always been the case that wheelchair users do not qualify for new drugs as I know many people with MS in wheelchairs who have had Tysabri and Lemtrada or is it because of this new blueteq?

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  7. The definition of robust equals strong, healthy, vigorous. I would consider this anything but a "robust positive effect on disability progression" and more a media-spin by pharma and pharma-funded neurologists.

    21% (not statically significant) and 26% decrease (p< 0.006) compared to placebo at 3 months and 6 months for confirmed disability progression is not "robust". How can decisions on disability progression be made in such short intervals, at 3 and 6 months, when SPMS patients are so variable? Why, in fact, did Gilenya not work on PPMS patients as it works by the exact same mechanism as siponimod, especially when PPMS and SPMS are indistinguishable on pathology? Who cares about MRI results and ARR in SPMS patients as this has little correlation with the progressive clinical decline in SPMS patients?

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