Novartis data at AAN show positive effect of siponimod on cognition in secondary progressive MS
May 08, 2019
New analysis shows that siponimod had significant functional benefits on cognitive processing speed (CPS) vs. placebo in secondary progressive multiple sclerosis (SPMS) patients1
Cognitive impairment affects up to 70% of people with MS and is more severe in SPMS patients than those with relapsing remitting MS (RRMS)2,3
EXPAND study findings demonstrate that SPMS patients treated earlier in the course of the disease benefited most, suggesting early treatment leads to better cognitive outcomes1
Frimley, UK, May 8, 2019– Novartis today announced a new subgroup analysis of the Phase III EXPAND study of oral, once-dailysiponimod (BAF312) in patients with secondary progressive multiple sclerosis (SPMS). The results show siponimod, the first and only oral drug to delay disability progression in SPMS patients, has significant functional benefit on cognitive processing speed (CPS), the cognitive function most frequently affected by MS1,2,4
The new findings, presented at the 2019 American Academy of Neurology Annual Meeting (AAN) in Philadelphia, Pennsylvania, USA, show that patients treated earlier in their disease course with less cognitive impairment benefited most from siponimod treatment vs. placebo1. This suggests that earlier treatment can lead to better cognitive outcomes, reinforcing the potential of siponimod in addressing a high unmet need for effective treatment of SPMS.
Cognitive changes, including problems with memory, attention span, decision making, and understanding, can significantly impact quality of life, affecting a person’s ability to work and fulfil day-to-day responsibilities5,6. Up to 70% of people living with MS will experience cognitive impairment, which is more severe in patients with SPMS than relapsing remitting MS (RRMS)2,3.
“Cognitive decline is a key concern for people living with MS, and the value of being able to slow deterioration cannot be underestimated,” said Dr Matthew Craner, Consultant Neurologist at University of Oxford. “Building on previous EXPAND results, the results of this subgroup analysis support the need for early diagnosis and management of SPMS to help improve cognitive outcomes for people living with MS.”
It is estimated that there are over 100,000 people living with MS in the UK, of which approximately 85% have been diagnosed with RRMS7,8. Studies have shown that between 24% and 40% of people with RRMS progress to SPMS within 10 years from diagnosis9,10,11. SPMS leads to progressive, irreversible disability, and once diagnosed can impact the condition management options available to patients12. There are currently no licensed oral disease modifying therapies available for the estimated 38,000 people in the UK living with SPMS12,13,14.
“At Novartis, we are committed to delivering groundbreaking innovations that have the potential to redefine what it means to live with complex and debilitating conditions such as SPMS," said Dr Mark Toms, Chief Scientific Officer, Novartis UK. “The significant positive effects of siponimod on cognition further demonstrate the impact it could bring, and we will continue working closely with regulatory bodies to make sure this new treatment is made available for those who it could benefit.”
In EXPAND, CPS was measured using the Symbol Digit Modalities Test (SDMT), the recommended gold standard measure of CPS in MS clinical studies1,15. The results demonstrated a significantly greater proportion of patients treated with siponimod experienced a sustained SDMT improvement than those receiving placebo, whether or not patients showed cognitive impairment at baseline1.
The marketing authorisation application for siponimod is currently under review by the EMA, with decisions anticipated in Q4 2019. Siponimodwas FDA approved for the treatment of adults with relapsing forms of multiple sclerosis, including SPMS with active disease, RRMS and clinically isolated syndrome (CIS) in March 2019.
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About the EXPAND Study EXPAND is a randomised, double-blind, placebo-controlled Phase III study, comparing the efficacy and safety of siponimod versus placebo in people with SPMS with varying levels of disability, Expanded Disability Status Scale (EDSS) scores of 3.0 to 6.54. It is the largest randomised, controlled study in SPMS to date, including 1,651 people with SPMS from 31 countries4. Siponimod reduced the risk of three-month confirmed disability progression (CDP) by a statistically significant 21% (p=0.013; primary endpoint)4. CDP was defined as a 1-point increase in EDSS, if the baseline score was 3.0 to 5.0, or a 0.5-point increase, if the baseline score was 5.5 to 6.5. No significant differences were found in the T25FW, however, T2 lesion volume was reduced by 79% as compared to placebo4.Additional secondary endpoints included a relative reduction in the ARR by 55%, and compared to placebo, more patients were free from gadolinium-enhancing lesions (89%) and from new or enlarging T2 lesions (57%)4.
In the EXPAND subgroup analysis, the Symbol Digit Modalities Test (SDMT) was conducted at baseline and at 6-monthly intervals. “Sustained” change was defined as change from baseline by ≥4 points sustained on all subsequent assessments. Results demonstrate that compared to placebo, the proportion of patients with a sustained SDMT improvement was:
Greater in siponimod-treated patients with or without cognitive impairment at baseline, reaching statistical significance for those without impairment (p=0.0126)1
Greater in siponimod-treated patients with baseline SDMT ≥ median and < median, reaching significance for those with baseline SDMT ≥ median (p=0.0094)1
In addition, compared to placebo, the proportion of patients with a sustained deterioration in SDMT was:
Significantly less in siponimod-treated patients with and without cognitive impairment (p=0.0269 and p=0.0477, respectively)1
Significantly less in siponimod-treated patients with baseline SDMT < median (p=0.0071), and numerically less for those with baseline SDMT ≥ median1
In the EXPAND Phase III study, siponimod demonstrated a safety profile that was overall consistent with the known effects of S1P receptor modulation. Adverse events observed included lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions4.
About siponimod(BAF312) Siponimod is an investigational, selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor16. Siponimod binds to the S1P1 sub-receptor on lymphocytes, which prevents them from entering the central nervous system (CNS) of patients with MS4,17,18. This leads to the anti-inflammatory effects of siponimod17,18. As shown by pre-clinical data, siponimod also enters the CNS and binds to the S1P5 sub-receptor on specific cells in the CNS (oligodendrocytes and astrocytes)19. By binding to these specific receptors, siponimod has the potential to modulate damaging cell activity and help to reduce the loss of neurological function associated with SPMS4,19,20,21.
About Multiple Sclerosis It is estimated there are over 100,000 people with MS in the UK, and each year around 5,000 people are newly diagnosed with the condition7. Multiple sclerosis (MS) is a chronic disorder of the central nervous system (CNS) that disrupts the normal functioning of the brain, optic nerves and spinal cord through inflammation and tissue loss22. The evolution of MS results in an increasing loss of both physical and cognitive functions (e.g. mobility problems, numbness, bladder and bowel problems, and problems with thinking, learning and planning)23. There are three types of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)24. SPMS is characterised by gradual worsening of neurological function over time25. This leads to a progressive accumulation of disability, largely independent of relapses, which can severely affect patients’ ability to carry out everyday activities25. There remains a high unmet need for effective treatments to help delay disability progression in SPMS26.
About Novartis in Multiple Sclerosis The Novartis multiple sclerosis (MS) portfolio includes Gilenya® (fingolimod, an S1P modulator), which is indicated in Europe for the treatment of adult patients and children and adolescents 10 years of age and older with relapsing remitting forms of MS. Extavia® (interferon beta-1b for subcutaneous injection) is approved in Europe to treat people with RRMS, SPMS with active disease and people who have had a single clinical event suggestive of MS.
Investigational compounds include siponimod (BAF312, a selective modulator of the S1P receptor subtypes 1 and 5), for SPMS, and ofatumumab (OMB157), a fully human monoclonal antibody in development for relapsing MS. Ofatumumab targets CD20, and is currently being investigated in two Phase III pivotal studies.
Novartis is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach more than 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 130 000 people of nearly 150 nationalities work at Novartis around the world. Find out more at www.novartis.com.
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Benedict R, Fox R, Tomic D, et al. Effect of Siponimod on Cognition in Patients with Secondary Progressive Multiple Sclerosis (SPMS): Phase 3 EXPAND Study Subgroup Analysis. Poster presentation. 2019 American Academy of Neurology Annual Meeting, May 7, 2019
Chiaravalloti N, DeLuca J. Cognitive impairment in multiple sclerosis. The Lancet Neurology. 2008;7(12):1139-1151.
Planche V, et al. Cognitive impairment in a population-based study of patients with multiple sclerosis: differences between late relapsing-remitting, secondary progressive and primary progressive multiple sclerosis. Eur J Neurol 2016;23:282-289.
Kappos L, Cree B, Fox R, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. The Lancet. 2018;391(10127):1263-1273.
Benedict R, DeLuca J, Phillips G, LaRocca N, Hudson L, Rudick R. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Multiple Sclerosis Journal. 2017;23(5):721-733.
Gergely P et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol 2012; 167(5):1035-47.
Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 2010; 9(11): 883-97.
Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33(2): 91-101.
Tavares A et al. Brain distribution of MS565, an imaging analogue of siponimod (BAF312), in non-human primates. Neurology 2014; 82(10 (Suppl)): P1.168.
Aslanis V et al. Siponimod (BAF312) (and/or its metabolites) penetrates into the CNS and distributes to white matter areas. Mult Scler J 2012; 18(10(suppl)): P792.
Brana C et al. Immunohistochemical detection of sphingosine-1-phosphate receptor 1 and 5 in human multiple sclerosis lesions. Neuropathol Appl Neurobiol 2014; 40(5): 564-78.