-
Analyses of the EXPAND study
showed that siponimod (BAF312) reduced the risk of disability
progression largely disassociated from relapses in patients with
secondary progressive multiple sclerosis (SPMS)[1]
-
In EXPAND, siponimod also had a
meaningful benefit on patients' cognitive processing
speed[2]
-
Findings add to clinical
evidence for siponimod in SPMS, an area with a high unmet need for
well-tolerated and effective new therapies[3]
Basel, April 20, 2018
- Novartis today announced new analyses from
the Phase III EXPAND study of oral, once-daily siponimod (BAF312)
in patients with secondary progressive multiple sclerosis (SPMS).
In pre-specified statistical analyses, treatment with siponimod
consistently reduced the risk of confirmed disability progression
in SPMS patients, with and without relapses[1]. In addition, new
post-hoc analyses using more accurate methods to estimate the
treatment effect on disability progression, now substantiate that
the risk reduction with siponimod is largely disassociated from
relapses. Siponimod also showed a significant benefit on cognitive
processing speed, the key cognitive function impacted by MS, which
frequently deteriorates in people with the disease[2]. These
results are being presented at the 70th American
Academy of Neurology (AAN) Annual Meeting, in Los Angeles, USA,
April 21-27, 2018.
As previously reported for the overall study
population, treatment with siponimod resulted in a statistically
significant risk reduction in disability progression sustained for
three- and six-months[4]. The new EXPAND study analyses, using a
more advanced model-based approach, show an estimated risk
reduction for disability progression, sustained at three-months
that ranged from 14-20% compared to placebo (calculated by
principal stratum analysis) for non-relapsing patients. For
disability sustained at six-months, estimated risk reduction was
even greater, spanning from 29-33%. Other complementary statistical
approaches[1] assessing the effect of siponimod on disability
progression disassociated from relapses showed consistent
results.
"Siponimod's beneficial effect on preventing
disability progression, independent from its reduction in
relapse frequency, demonstrates that patients with secondary
progressive MS could benefit from this treatment," said study
steering committee member Bruce Cree, MD, PhD, MAS, Clinical
Research Director and Associate Professor, University of
California, San Francisco, School of Medicine. "This is very
exciting because many people diagnosed with relapsing-remitting MS,
the most common form of the disease, will ultimately transition to
SPMS, where without effective new therapies, they experience
gradual worsening of disability despite infrequent relapses."
In pre-specified and post hoc analyses,
siponimod's effect on cognitive processing speed was evaluated, as
measured by the Symbol Digit Modalities Test (SDMT). SDMT is the
only cognitive test with established clinical relevance of change
in MS and is widely accepted by patients and physicians[5]. Other
tests included the Paced Auditory Serial Addition Test (PASAT,
assessing cognitive processing speed) and the Brief Visuospatial
Memory Test-Revised (BVMT-R, assessing memory)[6],[7]. From
baseline to month 24, treatment with siponimod showed a significant
benefit on cognitive processing speed, compared to placebo, for all
patients (SDMT, p=0.0004), and also in those who had relapses
within two years before starting the trial (SDMT p=0.0151; PASAT
p=0.0275) and those who did not (SDMT p=0.0099; PASAT not
statistically significant)[2]. Treatment with siponimod did not
result in significant differences in memory (BVMT-R)[2].
"A decline in the ability to rapidly process
information affects more than half of MS patients and is more
severe in secondary progressive MS than relapsing-remitting MS.
These data show that siponimod could have a meaningful impact on
these patients' daily lives," said Danny Bar-Zohar, Global Head
Neuroscience Development, Novartis. "Furthermore, the advanced
models used in the new analyses help us to better understand the
relationship between relapses and disability and the effect of
siponimod on these parameters. We are encouraged by these latest
findings, which further solidify the clinical evidence for
siponimod as a potential new, much needed treatment option for
SPMS."
Novartis has initiated the submission of siponimod
for US approval in SPMS in the first half of 2018. Filing for EU
approval is planned to follow later in 2018.
About the EXPAND
study
The EXPAND study is a randomized, double-blind, placebo-controlled
Phase III study, comparing the efficacy and safety of siponimod
versus placebo in people with secondary progressive MS
(SPMS)[4],[8]. It is the largest randomized, controlled study in
SPMS to date, and included 1,651 people with SPMS from 31
countries[4],[9]. 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 years[4]. Patients had received a diagnosis of
SPMS, and also demonstrated progression of disability in the two
years prior to study[4],[8]. 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 unilateral
walking aid (e.g., a cane or a crutch)[4],[8]. Patients were
randomized to receive either 2mg siponimod once-daily or placebo,
in a 2:1 ratio[4],[8]. Patients continued on siponimod treatment in
the open-label long-term extension part of the study[4].
About siponimod
(BAF312)
Siponimod is an investigational, selective modulator of specific
subtypes of the sphingosine-1-phosphate (S1P) receptor[10].
Siponimod binds to the S1P1 sub-receptor on lymphocytes, which
prevents them from entering the central nervous system (CNS) of
patients with multiple sclerosis and is believed to contribute to
the anti-inflammatory effects of siponimod[11],[12].
Siponimod also enters the CNS and binds to the
S1P5 sub-receptor on specific cells in the CNS (oligodendrocytes
and astrocytes)[13]. By binding to these specific receptors,
siponimod has the potential to modulate damaging cell activity and
may help to reduce the loss of neurological function associated
with SPMS[13]-[15]. The receptor specificity and pharmacokinetic
properties of siponimod facilitate treatment initiation, and
contribute to its safety and convenience profile[10].
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
loss[16]. 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: relapsing remitting MS (RRMS),
secondary progressive MS (SPMS) and primary progressive MS
(PPMS)[17].
SPMS is characterized by gradual worsening of
neurological function over time[18]. This leads to a progressive
accumulation of disability, largely disassociated from relapses,
which can severely affect patients' abilities to carry out everyday
activities[18]. It follows an initial phase of RRMS, which accounts
for approximately 85% of all MS diagnoses; almost a quarter of
people with RRMS will go on to develop SPMS within 10 years of
their initial RRMS diagnosis, rising to more than three-quarters
after 30 years[19],[20]. There remains a high unmet need for
effective and safe treatments to help delay disability progression
and improve cognition in SPMS[3].
MS affects approximately 2.3 million people
worldwide[18].
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 pediatric 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.
Investigational compounds include siponimod
(BAF312), under investigation in MS, 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.
In the US, the Sandoz Division of Novartis markets
Glatopa® (glatiramer
acetate injection) 20 mg/mL and 40 mg/mL, generic versions of
Teva's Copaxone®.
*Copaxone® is a
registered trademark of Teva Pharmaceutical Industries Ltd.
Disclaimer
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References
[1] Cree B, Fox R, Giovannoni G, et al. Uncoupling the
Impact on Relapses and Disability Progression: Siponimod in
Relapsing and Non-relapsing Patients With Secondary Progressive
Multiple Sclerosis in the Phase III EXPAND Study. Abstract no. 005.
Oral presentation at the 70th Annual
Meeting of the American Academy of Neurology, Los Angeles, CA,
April 21-27, 2018.
[2] Benedict R, Cree B, Tomic D, et al. Impact of
Siponimod on Cognition in Patients With Secondary Progressive
Multiple Sclerosis: Results From Phase III EXPAND Study. Abstract
no. 004. Oral presentation at the 70th Annual
Meeting of the American Academy of Neurology, Los Angeles, CA,
April 21-27, 2018.
[3] Mehr SR and Zimmerman MP. Reviewing the unmet needs
of patients with multiple sclerosis. Am Health Drug Benefits. 2015;
8(6); 426-431.
[4] Kappos L et al. Siponimod versus placebo in
secondary progressive multiple sclerosis: a double-blinded
randomized, phase 3 study. The Lancet. 2018; 31;391(10127):
1263-1273.
[5] Benedict RHB et al. Validity of the Symbol Digit
Modalities Test as a cognition performance outcome measure for
multiple sclerosis. Mult Scler Journal. 2017; 23(5):
721-733.
[6] Drake AS et al. Psychometrics and normative data
for the Multiple Sclerosis Functional Composite: replacing the
PASAT with the Symbol Digit Modalities Test. Mult Scler. 2010;
16(2): 228-237.
[7] Tam JW, Schmitter-Edgecombe M. The role of
processing speed in the brief visuospatial memory test - revised.
Clin Neuropsychol. 2013; 27(6): 962-972.
[8] 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.
Accessed April 2018.
[9] 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.
[10] 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.
[11] Brinkmann V, et al. Fingolimod (FTY720): discovery and
development of an oral drug to treat multiple sclerosis. Nat Rev
Drug Discov 2010; 9(11): 883-97.
[12] Chun J, Hartung HP. Mechanism of action of oral fingolimod
(FTY720) in multiple sclerosis. Clin Neuropharmacol 2010; 33(2):
91-101.
[13] 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.
[14] 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.
[15] 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.
[16] PubMed Health. Multiple Sclerosis (MS).
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0024311/. Accessed
April 2018.
[17] Multiple Sclerosis Society. Types of MS.
https://www.mssociety.org.uk/what-is-ms/types-of-ms. Accessed April
2018.
[18] MS Society. Secondary Progressive MS (SPMS).
https://www.mssociety.org.uk/what-is-ms/types-of-ms/secondary-progressive-spms.
Accessed April 2018.
[19] Multiple Sclerosis International Federation. Atlas of MS 2013.
http://www.msif.org/wp-content/uploads/2014/09/Atlas-of-MS.pdf.
Accessed April 2018.
[20] Tremlett H, et al. The natural history of
secondary-progressive multiple sclerosis. Mult Scler. 2008; 14:
314-324
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