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#Post#: 1199--------------------------------------------------
Mayzent (siponimod, BAF312) for active SPMS, RRMS
By: agate Date: April 29, 2016, 9:58 am
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From the MSAA 2015 Research Update:
[quote]Siponimod (BAF312)
Data from a Phase II dose-finding study of siponimod in people
with RRMS were also reported in 2012. Siponimod has a relatively
short half-life compared to Gilenya, which means that the drug
does not stay in the body as long. Researchers hope that this
will minimize cardiac issues.
The trial had a complex design in which the goal was to
determine the most appropriate dosing regimen. One group of 188
patients received placebo or once-daily siponimod in doses of 10
mg, 2 mg, or 0.5 mg for six months. A second group of 109
patients were given one of two additional intermediate doses of
1.25 mg or 0.25 mg for three months.
At six months, the proportion of relapse-free patients as
compared to placebo was 84 percent for the 10-mg group, 92
percent for the 2-mg group, and 77 percent for the 0.5-mg group.
In the placebo group, 72 percent were relapse-free. After six
months, the ARR (annual relapse rate) was lower for the
individuals who were taking one of the three higher doses, as
compared to those taking one of the two lower doses or the
placebo. Additionally, MRI findings indicated that treatment
with siponimod was associated with a reduction in active lesions
on MRI. The 2-mg dose reached statistical significance versus
placebo, with a reduction in active lesions of approximately 80
percent.
A Phase III trial of siponimod in secondary-progressive MS (the
EXPAND trial)58 began recruitment in 2013, and is expected to
run through Fall 2016. This is the first S1P receptor modulator
to be studied in SPMS.[/quote]
HTML http://mymsaa.org/publications/msresearch-update-2015/siponimod/
#Post#: 1341--------------------------------------------------
MSAA update on siponimod--Phase III trial results promising for
SPMS
By: agate Date: August 26, 2016, 6:05 pm
---------------------------------------------------------
MSAA newsletter, August 26, 2016:
[quote]Experimental SPMS Medication Shows Positive Results
A Phase III study with siponimod, an experimental oral treatment
for MS, is showing positive results for individuals with
secondary-progressive multiple sclerosis (SPMS).
According to an August 25th press release from Novartis, the
pharmaceutical company developing siponimod, the Phase III
EXPAND study met its primary endpoint, which was to reduce the
risk of confirmed disability progression at three months, versus
a placebo. This improvement in the time to three-month confirmed
disability progression was determined according to measurements
on the expanded disability status scale (EDSS).
These study results are significant because no disease-modifying
therapy is available in the United States for the long-term
treatment of SPMS. This form of MS follows relapsing-remitting
MS (RRMS) and is characterized by a slow and steady progression,
with or without relapses. If relapses do occur, they usually do
not fully remit.
Novartis states that the EXPAND trial is the largest randomized,
double-blind, placebo-controlled study to date with individuals
diagnosed with SPMS and included 1,651 people with SPMS from 31
countries. Study participants received either 2 mgs of the oral
medication siponimod, taken once daily, or a placebo. These were
given in a 2:1 ratio, so twice as many participants were on the
active medication versus the placebo.
Siponimod, also known as BAF312, is in a class of
immunomodulatory drugs called “S1P-receptor modulators.”
According to MSAA’s MS Research Update in 2016, the structure of
these medications is similar to a naturally occurring component
of cell-surface receptors on white blood cells. These
medications block potentially damaging T cells from leaving
lymph nodes, lowering their number in the blood and tissues.
They may reduce damage to the central nervous system (CNS) and
enhance the repair of damaged nerves within the brain and spinal
cord.
MSAA’s MS Research Update in 2016 also notes that another oral
treatment for MS, Gilenya® (fingolimod), was the first
S1P-receptor modulator approved for treating relapsing forms of
MS and study data suggest that it may have neuro-protective
effects. Siponimod is a similar medication to Gilenya and has a
relatively short half-life, which means that the drug does not
stay in the body as long. Researchers hope that this will
minimize cardiac issues that are often seen with these types of
medications.
While Novartis announced that the study met its primary
endpoint, specific details on the results were not included.
According to the press release, secondary endpoints include
delay in the time to six-month confirmed disability progression
versus placebo, time to confirmed worsening of at least 20
percent from baseline in the timed 25-foot walk test (T25FW), T2
lesion volume, annualized relapse rate (ARR), and the safety and
tolerability of siponimod in people with SPMS. Initial results
of the EXPAND study, including primary and key secondary
endpoints, will be presented at the European Committee for
Treatment and Research in Multiple Sclerosis (ECTRIMS) annual
meeting, which will be held this September in London, England.
MSAA’s Chief Medical Consultant Dr. Jack Burks explains, “The
possibility of having a treatment available to individuals with
secondary-progressive MS is very exciting and brightens the
future for everyone with this form of the disease. Readers
should note that while the three-month data are encouraging, we
await the results of the six-month findings, other secondary
endpoints, and safety data. Additionally, we will get more
insight into siponimod’s effectiveness with non-relapsing as
well as relapsing SPMS patients. I look forward to learning
about these and other details when new data are presented at
ECTRIMS next month.”
...
____________________
Written by Susan Courtney, MSAA Senior Writer
Reviewed by Jack Burks, MD, MSAA Chief Medical Consultant
Portions of MSAA’s MS Research Update 2016, coauthored by
Stephen Krieger, MD and Michelle Fabian, MD, were also included
in this article.[/quote]
The article can be seen here
HTML http://mymsaa.org/experimental-spms-medication-shows-positive-results/.
#Post#: 1358--------------------------------------------------
(Abst.) Safety and efficacy of siponimod (BAF312) in RRMS
By: agate Date: September 13, 2016, 7:07 pm
---------------------------------------------------------
An abstract of an earlier study of siponimod.
From JAMA Neurology, September 2016:
[quote]Safety and Efficacy of Siponimod (BAF312) in Patients
With Relapsing-Remitting Multiple Sclerosis
Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study
Ludwig Kappos, MD1,2,3; David K. B. Li, MD4,5; Olaf Stüve, MD6;
Hans-Peter Hartung, MD7; Mark S. Freedman, MD8; Bernhard Hemmer,
MD9; Peter Rieckmann, MD10; Xavier Montalban, MD11; Tjalf
Ziemssen, MD12; Brian Hunter, PhD13; Sophie Arnould, PhD13; Erik
Wallström, MD13; Krzysztof Selmaj, MD14
Importance
This dose-blinded extension of the phase 2 BOLD (BAF312 on MRI
Lesion Given Once Daily) Study in relapsing-remitting multiple
sclerosis provides evidence on disease activity and safety of a
range of siponimod doses for up to 24 months.
Objective
To assess the safety and efficacy of siponimod for up to 24
months during the dose-blinded extension of the BOLD Study.
Design, Setting, and Participants
At extension baseline in a randomized clinical trial, patients
taking siponimod continued at the originally assigned dose and
patients taking placebo were rerandomized to the 5 siponimod
doses. Initial treatment was titrated over 10 days. A total of
252 eligible patients were treated at specialized multiple
sclerosis centers for this study conducted from August 30, 2010,
through June 3, 2013.
Interventions
Siponimod at 10-mg, 2-mg, 1.25-mg, 0.5-mg, and 0.25-mg doses.
Main Outcomes and Measures
Safety assessment included blood tests, documentation of
adverse events at regular scheduled visits and Holter
monitoring; key efficacy measures were annualized relapse rate
and magnetic resonance imaging lesion activity.
Results
Among the 252 eligible patients, the mean (SD) ages were 37.2
(8.4) years, 35.2 (9.1) years, 34.0 (7.6) years, 35.1 (9.2)
years, and 36.8 (9.1) years in the 0.25-mg, 0.5-mg, 1.25-mg,
2-mg, and 10-mg groups. Of the 252 patients, 184 (73%) entered
the extension and received siponimod (10 mg: n = 33;
2 mg: n = 29; 1.25 mg: n = 43; 0.5 mg:
n = 29; and 0.25 mg: n = 50); 159
(86.4%) completed the dose-blinded extension. The incidence of
adverse events was similar across treatment groups (10 mg:
87.9%; 2 mg: 89.7%; 1.25 mg: 88.4%; 0.5 mg: 96.6%; and 0.25 mg:
84.0%).
Nine patients reported serious adverse events (2 mg: 3/29
[10.3%], 1.25 mg: 1/43 [2.3%], 0.5 mg: 4/29 [13.8%], and 0.25
mg: 1/50 [2.0%]; no serious adverse event was reported for more
than 1 patient and no new safety signals occurred compared with
the BOLD Study. Dose titration mitigated symptomatic bradycardic
events. Reductions in mean (95% CI) gadolinium-enhancing T1
lesion counts from the last BOLD assessment were sustained in
the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups (0 [0-0], 0.1
[0-1.9], 0.1 [0-2.6], and 0.1 [0-2.8] at month 24,
respectively). At the 3 highest vs 2 lowest doses, the estimated
new/newly enlarging T2 lesion counts (95% CIs) were lower during
months 6 to 12 (0.5 [0.2-1.3], 0.4 [0.2-1.1], and 0.2 [0.1-0.6]
vs 1.3 [0.6-2.8] and 1.4 [0.7-2.7]), months 12 to 18 (0.4
[0.1-1.1], 0.4 [0.1-1.3], and 0.4 [0.2-1.0] vs 1.0 [0.4-2.6] and
3.6 [1.7-7.6]), and months 18 to 24 (0 [0-not estimable], 0.9
[0.1-7.6], and 0.1 [0-1.7] vs 1.6 [0.3-7.7] and 2.0 [0.4-9.5]).
Annualized relapse rates (95% CIs) up to month 24 were similarly
lower for the 3 highest doses: 0.22 (0.12-0.40) for 10 mg, 0.20
(0.10-0.38) for 2 mg, and 0.14 (0.08-0.26) for 1.25 mg vs 0.33
(0.19-0.56) for 0.5 mg and 0.33 (0.21-0.50) for 0.25 mg.
Conclusions and Relevance
For up to 24 months of siponimod treatment, multiple sclerosis
disease activity was low and there were no new safety signals;
investigation in phase 3 trials is encouraged.
Trial Registration clinicaltrials.gov Identifier:
NCT01185821[/quote]
#Post#: 1376--------------------------------------------------
(ECTRIMS) Efficacy and safety of siponimod in SPMS (Phase 3 EXPA
ND study)
By: agate Date: September 21, 2016, 3:44 pm
---------------------------------------------------------
Presented at the annual ECTRIMS conference (London, September
14-17, 2016):
[quote] Efficacy and safety of siponimod in secondary
progressive multiple sclerosis - results of the placebo
controlled, double-blind, Phase III EXPAND study
L. Kappos1, A. Bar-Or2, B. Cree3, R. Fox4, G. Giovannoni5, R.
Gold6, P. Vermersch7, S. Arnould8, T. Sidorenko8, C. Wolf9, E.
Wallstroem8, F. Dahlke8
1Neurologic Clinic and Policlinic, Departments of Medicine,
Clinical Research, Biomedicine and Biomedical Engineering,
University Hospital, Basel, Switzerland, 2Neuroimmunology Unit,
Montreal Neurological Institute and Hospital, McGill University,
Montreal, QC, Canada, 3Multiple Sclerosis Centre, University of
California San Francisco, San Francisco, CA, 4Mellen Centre for
Treatment and Research in Multiple Sclerosis, Neurological
Institute, Cleveland Clinic, Cleveland, OH, United States,
5Blizard Institute, Barts and The London School of Medicine and
Dentistry, Queen Mary University of London, London, United
Kingdom, 6Department of Neurology, St.
Josef-Hospital/Ruhr-University Bochum, Bochum, Germany,
7University of Lille, Department of Neurology, Lille City,
France, 8Novartis Pharma AG, Basel, Switzerland, 9Lycalis sprl,
Brussels, Belgium
Background:
There is high unmet need for treatments that delay disability
progression in secondary progressive multiple sclerosis (SPMS).
Siponimod (BAF312) is an orally active selective modulator of
the sphingosine-1-phosphate receptor subtypes 1 and 5. EXPAND is
the largest randomised controlled study in SPMS to date.
Objective:
EXPAND is a phase 3, multicentre, randomised, double-blind,
placebo-controlled study designed to evaluate the efficacy,
safety and tolerability of siponimod in treatment of SPMS.
Design/methods:
Patients with SPMS, defined by a progressive increase in
disability (of ≥6 months duration) in the absence of or
independent of relapses, aged 18‒60 years and an Expanded
Disability Status Scale (EDSS) score from 3.0‒6.5 were
enrolled.
Eligible patients were randomised (2:1) to receive either 2mg
once daily siponimod (following initial dose titration starting
at 0.25mg) or matching placebo. The event-driven study design
allowed the blinded Core study stop after a pre-specified number
of confirmed disability progression (CDP) events occurred.
The primary efficacy outcome was time to 3-month CDP measured by
EDSS. The key secondary outcomes were time to confirmed
worsening of ≥20% from baseline in the timed 25-foot walk
test and T2 lesion volume change from baseline.
Safety assessments included reporting of adverse events (AEs),
serious AEs (SAEs) and clinically notable laboratory
abnormalities. Patients who completed the Core phase were
offered to receive open-label siponimod in the Extension phase.
Results:
Overall, 1651 patients were randomised in 31 countries. Baseline
demographics and disease characteristics were previously
reported, and they are representative of a patient population
with SPMS. Overall, 1363 (83%) patients completed the Core
study. Median time on study at core study completion was 21
months with majority of patients (87%) participating for
≥1 year. There were 449 CDP events (each patient could
maximally contribute one event for the primary endpoint). AEs
were reported in 85.3% and SAEs in 16.7% of patients.
Conclusions:
Top line efficacy and safety results of the EXPAND study will be
presented. The results of this large controlled study that
recruited an active SPMS population with and without
superimposed relapses will determine if siponimod delays
disability progression in SPMS, and will contribute to a better
understanding of the natural history of SPMS in a
well-controlled trial setting.
_________________
Disclosure:
Funding source: This study is supported by Novartis Pharma AG,
Basel, Switzerland.
Ludwig Kappos' institution (University Hospital Basel) has
received in the last 3 years and used exclusively for research
support: steering committee, advisory board, and consultancy
fees from Actelion, Addex, Bayer HealthCare, Biogen Idec,
Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono
Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB,
and Xenoport; speaker fees from Bayer HealthCare, Biogen Idec,
Merck, Novartis, Sanofi, and Teva; support of educational
activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme,
Merck, Novartis, Sanofi, and Teva; royalties from Neurostatus
Systems GmbH and grants from Bayer HealthCare, Biogen Idec,
European Union, Merck, Novartis, Roche Research Foundation,
Swiss MS Society, and the Swiss National Research Foundation.
Amit Bar-Or has participated as a speaker in meetings sponsored
by and received consulting fees from Amplimmune, Biogen Idec,
Diogenix, Genentech, Sanofi-Genzyme, GlaxoSmithKline, Novartis,
Ono Pharma, Teva Neuroscience, Receptos Inc., Roche, and
Merck/EMD Serono and has received grant support from Amplimmune,
Biogen Idec, Diogenix, Genentech, Sanofi- Genzyme,
GlaxoSmithKline, Novartis, Ono Pharma, Teva Neuroscience,
Receptos Inc., Roche, and Merck/EMD Serono.
Bruce Cree has received personal compensation for consulting
from Abbvie, Biogen Idec, EMD Serono, MedImmune, Novartis,
Genzyme/Sanofi Aventis, and Teva Neurosciences; contracted
research support (including clinical trials) from Acorda, Biogen
Idec, EMD Serono, Hoffman La Roche, MedImmune, and Teva
Neurosciences.
Robert Fox has received compensation for serving as consultant
or speaker from Allozyne, Avanir, Biogen Idec, Novartis,
Questcor, and Teva Pharmaceutical Industries; he or the
institution he works for has received research support from
Novartis.
Gavin Giovannoni is steering committee member on the Daclizumab
trials for AbbVie, steering committee member on the BG12 and
Daclizumab trials for Biogen-Idec, has received consultancy fees
for advisory board meetings, honoraria for speaking at
Physicians summit, consultancy fees for advisory board meetings
and steering committee for oral cladribine trials for
Merck-Serono, steering committee member on Fingolimod and
Siponimod trials for Novartis, steering committee member on the
laquinimod trials for Teva, consultancy fees for advisory board
meetings for Genzyme-Sanofi, honoraria for speaking at several
medical education meetings, steering committee member on
Ocrelizumab trials for Roche, consultancy fees in relation to
DSMB activities for Synthon BV and Co-chief editor of Multiple
Sclerosis and Related Disorders (Elsevier).
Ralf Gold has received compensation for serving as consultant or
speaker from Bayer HealthCare, Biogen Idec, Merck Serono,
Novartis, and Teva Neuroscience, and he or the institution he
works for has received research support from Bayer HealthCare,
Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience.
Patrick Vermersch has received honoraria and consulting fees
from Biogen Idec, Genzyme-Sanofi, Bayer, Novartis, Merck Serono,
GSK and Almirall; research support from Biogen Idec,
Genzyme-Sanofi, Bayer, and Merck Serono.
Sophie Arnould, Tatiana Sidorenko, Erik Wallstroem and Frank
Dahlke are employees of Novartis.
Christian Wolf is a partner at Lycalis sprl. He is serving as a
consultant to Novartis and has also received compensation for
serving as a consultant for to-BBB, Desitin, Investitionsbank
Berlin, Keyrus, Synthon, Mylan and Teva.[/quote]
#Post#: 1383--------------------------------------------------
Siponimod may slow worsening in SPMS
By: agate Date: September 25, 2016, 11:03 pm
---------------------------------------------------------
An article about the study that appeared in MedPage Today,
September 19, 2016:
HTML http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/60297?xid=nl_mpt_DHE_2016-09-19&eun=g345846d0r&pos=10
HTML http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/60297?xid=nl_mpt_DHE_2016-09-19&eun=g345846d0r&pos=10
#Post#: 1387--------------------------------------------------
Re: Siponimod (BAF312)
By: ssalimi Date: September 28, 2016, 8:06 pm
---------------------------------------------------------
Interesting that it only targets S1P-1/5 receptors rather than
1-5 like Fingolimod. Hoping to soon see what the AEs and SAEs
were
#Post#: 1388--------------------------------------------------
Re: Siponimod (BAF312)
By: agate Date: September 28, 2016, 8:38 pm
---------------------------------------------------------
[quote author=ssalimi link=topic=956.msg1387#msg1387
date=1475111199]
Interesting that it only targets S1P-1/5 receptors rather than
1-5 like Fingolimod. Hoping to soon see what the AEs and SAEs
were
[/quote]
Yes. I'm not sure what this means, exactly:
[quote]Nine patients reported serious adverse events (2 mg: 3/29
[10.3%], 1.25 mg: 1/43 [2.3%], 0.5 mg: 4/29 [13.8%], and 0.25
mg: 1/50 [2.0%]; no serious adverse event was reported for more
than 1 patient and no new safety signals occurred compared with
the BOLD Study.[/quote]
If there were 9 patients reporting SAEs, how can it be stated
that "no serious adverse event was reported for more than 1
patient..."? Maybe I haven't read this right, or maybe there's a
misprint.
I'm very pleased that something is being developed for SPMS, and
it's encouraging that siponimod doesn't linger for very long in
the body.
#Post#: 1656--------------------------------------------------
Novartis fast tracks siponimod (BAF312) for RRMS
By: agate Date: April 26, 2017, 2:03 pm
---------------------------------------------------------
Fast on the heels of the approval of Ocrevus, BAF312 (siponimod)
is about to be made available to us. From MedPage Today, April
25--"Novartis Fast Tracks Early MS Drug":
HTML https://www.medpagetoday.com/Neurology/MultipleSclerosis/64789
HTML https://www.medpagetoday.com/Neurology/MultipleSclerosis/64789
#Post#: 2024--------------------------------------------------
Phase 3 trial results looking good for siponimod (and Novartis)
to treat SPMS
By: agate Date: March 23, 2018, 11:09 am
---------------------------------------------------------
Lancet article (March 22) on the Phase III siponimod
study--"Siponimod vs. placebo in secondary progress multiple
sclerosis (EXPAND): A double-blind, randomised, phase 3 study"
HTML http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)30475-6/fulltext
This is getting attention in the financial sector--from
Endpoints News, March 23--"Poised for an FDA pitch, Novartis
lays out all its Phase 3 cards on MS drug siponimod":
HTML https://endpts.com/poised-for-an-fda-pitch-novartis-lays-out-all-its-phiii-cards-on-ms-drug-siponimod/
#Post#: 2050--------------------------------------------------
Re: Siponimod (BAF312) for SPMS
By: agate Date: April 18, 2018, 1:29 am
---------------------------------------------------------
More study is needed, according to this. From NEJM Journal Watch
Neurology, April 13, 2018:
SUMMARY AND COMMENT | NEUROLOGY
April 13, 2018
Siponimod for Secondary Progressive Multiple Sclerosis
HTML http://response.jwatch.org/t?r=3963&c=4977&l=8&ctl=326D9:504826E9A16F346E0DB1ACACF4AA2655D2B71D9A95FA21D3&?query=etoc_jwneuro&jwd=000100983645&jspc=
Jaime Toro, MD
HTML http://response.jwatch.org/t?r=3963&c=4977&l=8&ctl=326DC:504826E9A16F346E0DB1ACACF4AA2655D2B71D9A95FA21D3&<br
/>reviewing Kappos L et al. Lancet 2018 Mar 31.
Is siponimod an effective and safe drug for the treatment of
patients with secondary progressive multiple sclerosis?
Secondary progressive multiple sclerosis (SPMS) is an MS subtype
characterized by worsening of disability that begins insidiously
in patients with preceding relapsing-remitting (RR) course,
which is the most common mode of onset. The risk for and timing
of transition from RRMS to SPMS is unpredictable; however, up to
90% of RRMS may evolve to SPMS over a 25-year time interval.
Several disease-modifying therapies have shown efficacy in
reducing relapses and disease activity in RRMS, but most of
these have failed to prevent disease worsening in progressive
MS.
This multicenter, randomized, double-blind, placebo-controlled,
manufacturer-funded phase 3 study was done at almost 300
hospital clinics and specialized MS centers in 31 countries.
Researchers randomized 1651 patients with a diagnosis of SPMS to
the investigational drug siponimod (1105 patients) or placebo
(546 patients). Of these, 1327 (80%) completed the study (82% on
siponimod vs. 78% on placebo). Median time on study was 21
months and median exposure to the drug was 18 months.
Three-month confirmed disability progression, the primary
outcome, occurred in 288 (26%) of 1096 patients receiving
siponimod and 173 (32%) of 545 patients receiving placebo, a
significant difference (hazard ratio, 0.79; relative risk
reduction, 21%). Adverse events were reported in more siponimod
than placebo recipients (89% of 1099 patients vs. 82% of 546
patients), including adverse events described previously with
other sphingosine-1-phophate receptor modulators (e.g.,
bradycardia, hypertension, varicella zoster reactivation) and
more serious adverse events (18% vs. 15%). Frequencies of
infections, malignancies, and mortality were the same in both
treatment groups.
COMMENT:
In this study, siponimod reduced the risk for disability
progression in a large population of patients, many of whom
entered the study having already reached the nonrelapsing stage
of SPMS with a high level of established disability. Although
siponimod also had a good safety profile, other studies must be
carried out to confirm that this drug could be an option in the
treatment of SPMS.
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