Data published in The Lancet show Novartis siponimod significantly delays disability progression in patients with secondary progressive MS
Mar 23, 2018
EXPAND shows oral siponimod (BAF312) is the first potential therapy to meaningfully delay disability progression in typical secondary progressive MS (SPMS) patients1
Phase III results demonstrate siponimod also had beneficial effects on clinical relapses and MRI disease activity, including brain volume loss (brain shrinkage)1
Novartis is committed to bringing innovative medicines to MS patients in need of new treatment options, and plans to file siponimod for US and EU approval throughout 2018
Frimley, UK [23 March 2018] – Novartis today announced that The Lancet has published full results from the Phase III EXPAND study of oral, once-daily siponimod (BAF312) in secondary progressive multiple sclerosis (SPMS). These pivotal results show significant reductions in the risk of three- (primary endpoint) and six-month confirmed disability progression with siponimod versus placebo1 and favourable outcomes in other relevant measures of MS disease activity1. If approved, siponimod would be the first oral disease-modifying therapy to delay disability progression in SPMS patients, including those who had reached a non-relapsing stage and a high level of disability.
Around 5,000 people in the UK are diagnosed with MS every year2, of which approximately 80% will be diagnosed with relapsing-remitting MS (RRMS) 3, the most commonly diagnosed type of MS4,5. Studies have shown that after approximately 19 years, around 50% of these will go on to develop SPMS6. SPMS leads to progressive, irreversible disability, which can impact the type of services, treatment options and support needed by patients6. There is a high unmet medical need for new treatments which are effective for patients with SPMS7.
“The EXPAND study is the first trial to demonstrate a clear delay in the accumulation of disability in established secondary progressive MS. It shows siponimod to be a well-tolerated daily tablet that can effectively slow down the development of disability in SPMS,” said Dr Ben Turner, Consultant Neurologist and Honorary Senior Lecturer at Barts and The London NHS Trust. “Siponimod is a major step forward in the treatment of MS, and in particular, in a group of patients with no established treatment options.”
For people living with SPMS, disability tends to get steadily worse and treatment is typically aimed at managing symptoms and/or delaying disability progression6. In EXPAND, siponimod significantly reduced the risk of a patient’s disabilities worsening over a three-month period by over a fifth (21%; p=0.013) versus placebo. Data also show siponimod led to reductions in disability progression versus placebo over a six-month period (26%; p=0.0058). When looking at neurological degradation caused by MS, siponimod was also shown to slow the rate of brain volume loss by 23% (relative difference; mean across 12 and 24 months, p=0·0002) and limit increases in T2 lesion volume by approximately 80% when compared to placebo (mean over 12 and 24 months, p<0.0001)8. Patients’ annualised relapse rate was also reduced by over half (55%; p<0.0001), though there was no significant difference in the Timed 25-Foot Walk test and MS Walking Scale. Alongside the encouraging efficacy seen, the safety profile of siponimod was shown to be comparable to other drugs in the same class1.
“Novartis is dedicated to breaking new ground in neurology by delivering innovative medicines that have the potential to really make a difference to the lives of people living with complex and debilitating conditions, such as SPMS,” said Dr Mark Toms, Chief Scientific Officer at Novartis UK. “The EXPAND data provide hope that a much needed, new treatment option may be on the horizon for SPMS, and we will continue working with regulatory agencies to make siponimod available for patients as quickly as possible.”
Novartis has initiated a scientific advice consultation with the European Medicines Agency and, pending its outcome, plans to file in Q3 2018. The EXPAND results have previously been presented at scientific congresses.
About the EXPAND study The EXPAND study is a randomised, double-blind, placebo-controlled Phase III study, comparing the efficacy and safety of siponimod versus placebo in people with secondary progressive multiple sclerosis (SPMS)1,9. It is the largest randomised, controlled study in SPMS to date, and included 1,651 people with SPMS from 31 countries1,10. 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 study1,9. They also had an Expanded Disability Status Scale score between 3.0 and 6.5 inclusive, with a median score of 6.0, which corresponds to the use of a unilateral walking aid (e.g. a cane or a crutch) 1,9. Patients were randomised to receive either 2mg siponimod once-daily or placebo, in a 2:1 ratio1,9.
About siponimod (BAF312) Siponimod is an investigational, selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor11. Siponimod binds to the S1P1 sub-receptor on lymphocytes, which prevents them from entering the central nervous system (CNS) of patients with MS12,13. This leads to the anti-inflammatory effects of siponimod12,13.
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) 14. 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 SPMS14-16. The receptor specificity and pharmacokinetic properties of siponimod (e.g. the faster elimination) compared with first-generation S1P modulator fingolimod facilitates treatment initiation, while improving its safety and convenience profile11.
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 condition2. 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 loss17. The evolution of MS results in an increasing loss of both physical (e.g. walking) and cognitive (e.g. memory) function. There are three main types of MS: RRMS, SPMS and primary progressive MS (PPMS) 5. SPMS is characterised by gradual worsening of neurological function over time6. This leads to a progressive accumulation of disability, largely independent of relapses, which can severely affect patients’ abilities to carry out everyday activities6. There remains a high unmet need for effective and safe treatments to help delay disability progression in SPMS7.
About Novartis in Multiple Sclerosis The Novartis MS portfolio includes Gilenya® (fingolimod, an S1P modulator), which is indicated for 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), 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 provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2017, the Group achieved net sales of USD 49.1 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 122,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com.
In the UK, Novartis develops, manufactures and markets innovative medicines, devices and diagnostic tests which help improve patient outcomes. Based on four sites across the north and south of England, we employ approximately 1,500 people to serve healthcare needs across the whole of the UK, as well as supporting the global operations of Novartis by manufacturing the active pharmaceutical ingredients used worldwide in many medicines. In 2017 Novartis invested almost £30million in R&D and is a leading sponsor of clinical trials in the UK. For more information, please visit www.novartis.co.uk.
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.
Kappos L et al. Efficacy of siponimod in secondary progressive multiple sclerosis: results of the Phase 3 study. Plenary session presentation at the 69th American Academy of Neurology Annual Meeting; April 22-28, 2017, Boston, Massachusetts, USA. Presentation number P4.
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.
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.