Novartis BAF312 reduces the risk of disability progression in pivotal phase III study in secondary progressive MS patients vs placebo
Sep 17, 2016
Largest randomised, controlled study in secondary progressive multiple sclerosis (SPMS) to date shows treatment with BAF312 (siponimod) reduced the risk of three-month confirmed disability progression by 21% vs placebo
SPMS is a progressive and highly disabling form of MS, and remains an area of unmet medical need
Novartis continues to build on its experience and expertise in MS to advance care for people with the condition
Frimley, UK, September 17, 2016 – Novartis today announced positive results of the Phase III EXPAND study showing that oral once-daily BAF312 (siponimod) significantly reduced the risk of disability progression compared with placebo in people with secondary progressive multiple sclerosis (SPMS)1.
SPMS is a form of MS characterised by continuous worsening of neurological function over time, independent of relapses2. Most people with relapsing remitting MS will eventually develop secondary progressive MS. It varies widely from person to person, but on average, around 65 per cent of people with relapsing remitting MS will develop secondary progressive MS 15 years after being diagnosed2.
Topline results of EXPAND were presented at 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), in London, UK.
BAF312 is a scientifically designed, selective sphingosine-1-phosphate (S1P) receptor modulator3. Initial data from the EXPAND study show:
Treatment with BAF312 reduced the risk of three-month confirmed disability progression by 21% compared with placebo (p=0.013). The risk reduction for six-month confirmed disability progression was greater, further supporting robustness of the data1.
A consistent reduction in the risk of confirmed disability progression across predefined subgroups, including patients without relapses1.
A significant difference in favour of BAF312 compared to placebo in annualised relapse rate, the per cent change in brain volume, and change from baseline in the volume of T2 lesions (brain lesions identified by a T2-weighted magnetic resonance imaging scan). Difference in change from baseline in the Timed 25-Foot Walk test (T25FW) was not significant1.
BAF312 was well tolerated, with a safety profile comparable to other drugs in the same class1.
“There are very few available treatment options to delay disease progression in SPMS,” said Dimitrios Georgiopoulos, MD and Chief Scientific Officer at Novartis Pharmaceuticals UK Ltd. “Novartis is the global leader in understanding the role of S1P receptor modulation in the treatment of MS, and the positive results of the EXPAND study are a continuation of our ongoing efforts to innovate and meet the needs of patients. These data are a positive stride forward, and we look forward to evaluating next steps with health authorities.”
EXPAND is the largest randomised, controlled study in secondary progressive multiple sclerosis to date4. Patients enrolled in EXPAND were representative of a general SPMS population1.They must have been diagnosed with SPMS and also demonstrated progression of disability in the two years prior to study1.The majority of patients had non-relapsing SPMS. The mean age at study entry was 48 years, and patients had a median Expanded Disability Status Scale (EDSS) score of 6.0, which corresponds to the use of walking aid1,5,6.
Novartis will complete full analyses of the EXPAND data and evaluate next steps in consultation with health authorities. The full study results, including data from primary and secondary endpoints, will be submitted for publication.
About the EXPAND study The EXPAND study is a randomised, double-blind, placebo-controlled Phase III study, comparing the efficacy and safety of BAF312 versus placebo in people with secondary progressive multiple sclerosis (SPMS)1,5. It is the largest randomised, controlled study in SPMS to date, and included 1,651 people with SPMS from 31 countries4. At the time of the study, individuals enrolled in EXPAND had a mean age of 48 years and had been living with MS for approximately 17 years1. Patients had received a diagnosis of SPMS, and also demonstrated progression of disability in the two years prior to study1. They also had an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5 inclusive, with a median score of 6.0, which corresponds to the use of a walking aid1,5,6. Patients were randomised to receive either 2mg BAF312 or placebo in a 2:1 ratio respectively1,5.
The primary endpoint of the study was the time to three-month confirmed disability progression, as measured by the EDSS, versus placebo1,5. Secondary endpoints included delay in the time to six-month confirmed disability progression versus placebo, the time to confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW), T2 lesion volume, annualised relapse rate (ARR), and the safety and tolerability of BAF312 in people with SPMS1,5.
About BAF312 (siponimod) BAF312 (siponimod) is a scientifically designed selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor.3 BAF312 binds to the S1P1 sub-receptor on lymphocytes, which prevents them from entering the central nervous system (CNS) of patients with multiple sclerosis (MS)7,8. This leads to the anti-inflammatory effects of BAF3127,8. The S1P receptor subtypes targeted by BAF312 are also found on the surface of cells in the CNS which play a role in the origin of secondary progressive MS (SPMS). In animal models, BAF312 enters the CNS and by binding to these specific receptors, has the potential to modulate damaging cell activity and help to reduce the loss of neurological function associated with SPMS3,9-11. The receptor specificity and pharmacokinetic properties (e.g. the faster elimination compared with first-generation S1P modulators) of BAF312 facilitate its ability to impact diseases such as SPMS3.
About Multiple Sclerosis 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 loss12. The evolution of MS results in an increasing loss of both physical (e.g. walking) and cognitive (e.g. memory) function.13 There are three main types of MS: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)14.
SPMS is characterised by gradual worsening of neurological function over time.2 This leads to a progressive accumulation of disability, independent of relapses, which can severely affect patients’ abilities to carry out everyday activities.2 It usually follows an initial phase of RRMS, which accounts for approximately 85% of all MS diagnoses. There remains a high unmet need for effective and safe treatments to help delay disability progression in SPMS15.
MS affects approximately 2.3 million people worldwide 16.
About Novartis in Multiple Sclerosis The Novartis multiple sclerosis (MS) portfolio includes Gilenya (fingolimod, an S1P modulator), which is indicated for relapsing forms of MS and is also in development for paediatric MS. Extavia® (interferon beta-1b for subcutaneous injection) is approved in the US for the treatment of relapsing forms of MS. In Europe, Extavia is approved to treat people with relapsing remitting MS, secondary progressive MS (SPMS) with active disease and people who have had a single clinical event suggestive of MS.
In addition to BAF312 (siponimod) in development in SPMS, investigational compounds include 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.
In the US, the Sandoz Division of Novartis markets Glatopa® (glatiramer acetate injection) 20mg/mL, the first generic version of Teva's Copaxone®* 20mg. *Copaxone® is a registered trademark of Teva Pharmaceutical Industries Ltd.
References: 1. Kappos L et al. Efficacy and safety of siponimod in secondary progressive multiple sclerosis – Results of the placebo controlled, double-blind, Phase III EXPAND study. Oral presentation presented at: 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 14-17, 2016; London, UK. 2. MS Society. Secondary Progressive MS. http://www.mssociety.org.uk/what-is-ms/types-of-ms/secondary-progressive-spms. Accessed August 2016. 3. 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. 4. Kappos L et al. Baseline Subgroup Characteristics of EXPAND: A Phase 3 Study of Siponimod (BAF312) for the Treatment of Secondary Progressive Multiple Sclerosis (P3.084). Neurology. 2016; 86(16):suppl. P3.084 5. ClinicalTrials.gov. Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND). https://clinicaltrials.gov/ct2/show/NCT01665144?term=BAF312+expand&rank=1 (link is external). Accessed July 2016. 6. MS Trust. Expanded Disability Status Scale. https://www.mstrust.org.uk/a-z/expanded-disability-status-scale-edss (Link is external). Accessed September 2016. 7. 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. 8. Chun J, Hartung HP. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33(2): 91-101. 9. 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. 10. 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. 11. 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. 12. PubMed Health. Multiple Sclerosis. http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024311/ (link is external). Accessed July 2016. 13. National Multiple Sclerosis Society. MS Symptoms. http://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms (link is external). Accessed July 2016. 14. National Multiple Sclerosis Society. Types of MS. http://www.nationalmssociety.org/What-is-MS/Types-of-MS (link is external). Accessed August 2016. 15. Mehr S.R. and Zimmerman M.P. Reviewing the unmet needs of patients with multiple sclerosis. Am Health Drug Benefits. 2015; 8(6);426-431. 16. Multiple Sclerosis International Federation. Atlas of MS 2013. http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf (link is external). Accessed August 2016.
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