Mayzent (siponimod, BAF312) for active SPMS, RRMS

From the MSAA 2015 Research Update:

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.

MSAA newsletter, August 26, 2016:

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.”

...
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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.

The article can be seen here.

An abstract of an earlier study of siponimod.

From JAMA Neurology, September 2016:

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

Presented at the annual ECTRIMS conference (London, September 14-17, 2016):

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.

An article about the study that appeared in MedPage Today, September 19, 2016:

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

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

Yes. I'm not sure what this means, exactly:

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.

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.

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":

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"


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":

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


Jaime Toro, MD 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.

Clinical Trials Update in JAMA (May 22-29, 2018), "Drug slows disability progression in multiple sclerosis":

https://jamanetwork.com/journals/jama/fullarticle/2681741?utm_source=silverchair&utm_medium=email&utm_campaign=article_alert-jama&utm_content=etoc&utm_term=052218

From Multiple Sclerosis News Today, October 10, 2018--"FDA, EMA agree to review Novartis therapy siponimod to treat SPMS":

Studies are busily being done on the cost effectiveness of siponimod, to be known as Mayzent, according to this blog post from Multiple Sclerosis News Today (March 20, 2019)--"SPMS treatment with Mayzent could be cost-effective, ICER report says":

The FDA has approved Mayzent (siponimod) but not for "inactive SPMS"--that is, SPMS without relapses. The MSAA has this informative article about it (March 27):





Mayzent is scheduled to become available in the first week of April.

More on this in SeekingAlpha, March 27, 2019:


https://seekingalpha.com/news/3446145-novartis-prices-ms-med-mayzent-88k-year



Someone on another site stated that Mayzent (siponimod) is the generic form of Gilenya (fingolimod). This article (see link) states:

Siponimod, a synthetic derivative of fingolimod, is designed for an improved safety profile, including less deleterious effects on heart rate and nerves.

Is a "synthetic derivative" the same as a generic form?