https://academic.oup.com/eurheartj/advance-article-pdf/doi/10.1093/eurheartj/ehab697/41157731/ehab697.pdf

ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: part 2—care pathways, treatment, and follow-up

Since the approval in 2010 of fingolimod 0.5 mg (Gilenya; Novartis Pharma AG, Basel, Switzerland) in the USA as an oral therapy for relapsing forms of multiple sclerosis, long-term clinical experience with this therapy has been increasing. This review provides a summary of the cumulative dataset from clinical trials and their extensions, plus postmarketing studies that contribute to characterizing the efficacy and safety profile of fingolimod in patients with relapsing forms of multiple sclerosis. Data from the controlled, phase III, pivotal studies [FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis), FREEDOMS II and TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis)] in relapsing-remitting multiple sclerosis have shown that fingolimod has a robust effect on clinical and magnetic resonance imaging outcomes. The respective study extensions show that effects on annualized relapse rates are sustained with continued fingolimod treatment. Consistent, significant reductions in magnetic resonance imaging lesion counts and brain volume loss have also been sustained with long-term treatment. The safety profile of fingolimod is also examined, particularly in light of its long-term use. A summary of the adverse events of interest that are associated with fingolimod treatment and associated label guidelines are also considered, which include cardiac effects following first-dose administration, infections, lymphopenia, macular edema and pregnancy. Historic hurdles to the prescription of fingolimod and how these challenges are being met are also discussed.

https://journals.sagepub.com/doi/pdf/10.1177/1756285616628766

Fingolimod in the treatment of relapsing–remitting multiple sclerosis: long-term experience and an update on the clinical evidence

Introduction: Fingolimod was the first oral and the first in class disease modifying treatment in multiple sclerosis that acts as sphingosine-1-phospathe receptor agonist. Since approval in...

Fingolimod hydrochloride for the treatment of relapsing remitting multiple sclerosis.

Cardiac autonomic dysfunction (CAD) has been reported in patients with multiple sclerosis (MS). This systematic review summarizes the evidence for the types and prevalence of CAD in MS patients, as well as its association with MS type, disease characteristics, fatigue and immunotherapies used to treat MS. The analysis revealed that CAD is correlated with pathophysiological processes of MS, can trigger serious cardiovascular complications that may reduce life expectancy, and may have implications for treatment with immunotherapies, especially fingolimod. Numerous mainly small case-control or cohort studies have reported various measures of CAD (particularly heart rate variation) in MS patients, showing higher rates of abnormality versus controls. A smaller number of studies have reported on cardiac autonomic symptoms in MS, including orthostatic intolerance/dizziness in around 50% of patients. CAD also appears to be associated with disease duration and to be more common in progressive than relapsing-remitting MS. However, although a substantial evidence base suggests that assessing CAD in people with MS may be important, standardised methods to evaluate CAD in these patients have not yet been established. In addition, no studies have yet looked at whether treating CAD can reduce the burden of MS symptoms, disease activity or the rate of progression.

https://www.mdpi.com/2077-0383/9/2/335/pdf

Cardiac Autonomic Dysfunction in Multiple Sclerosis: A Systematic Review of Current Knowledge and Impact of Immunotherapies

Multiple sclerosis (MS) is a chronic disease which usually begins in young adulthood and is a lifelong condition. Individuals with MS experience physical and cognitive disability resulting from inflammation and demyelination in the central nervous system. Over the past decade, several disease-modifying therapies (DMTs) have been approved for the management of relapsing-remitting MS (RRMS), which is the most prevalent phenotype. The chronic nature of the disease and the multiple treatment options make benefit-risk-based sequencing of therapy essential to ensure optimal care. The efficacy and short- and long-term risks of treatment differ for each DMT due to their different mechanism of action on the immune system. While transitioning between DMTs, in addition to immune system effects, factors such as age, disease duration and severity, disability status, monitoring requirements, preference for the route of administration, and family planning play an important role. Determining a treatment strategy is therefore challenging as it requires careful consideration of the differences in efficacy, safety and tolerability, while at the same time minimizing risks of immune modulation. In this review, we discuss a sequencing approach for treating RRMS, with importance given to the long-term risks and individual preference when devising a treatment plan. Evidence-based strategies to counter breakthrough disease are also addressed.

Sequencing of disease-modifying therapies for relapsing–remitting multiple sclerosis: a theoretical approach to optimizing treatment

Background First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring. Methods START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate  Results Thirty-one patients (0.8%) developed bradycardia ( Conclusions Continuous Holter ECG monitoring in this large real-life cohort revealed that bradycardia and AV conduction abnormalities were rare, transient and benign. No further unexpected abnormalities were detected. The data presented here give an indication that continuous Holter ECG monitoring does not add clinically relevant value to patients’ safety. Trial registration NCT01585298 ; registered April 23, 2012.

/pdf/electrocardiographic-assessments-and-cardiac-events-after-1pmzakppr1.pdf

Electrocardiographic assessments and cardiac events after fingolimod first dose – a comprehensive monitoring study

OBJECTIVE: 
The START-study (cFTY720DDE17) characterizes the first dose effects of fingolimod in RRMS patients after treatment initiation.
 BACKGROUND: Fingolimod was the first oral therapy approved for the treatment of RRMS. As a sphingosine 1-phosphate receptor (S1PR) modulator, it activates S1PR at the surface of cardiac myocytes after treatment initiation. This activation results in transient pulse rate reduction and in rare cases in atrioventricular conduction blocks.
 DESIGN/METHODS: The START study is a prospective, 1-week, multicenter, open-label study enrolling up to 7,000 RRMS patients in more than 250 centers in Germany, according to the EU label criteria of fingolimod. The study includes a screening period, a baseline visit at which the first fingolimod dose is taken, and a final visit after one week. The procedure at baseline is as follows: prior to the first intake of fingolimod, a 12-lead ECG is recorded. After the first dose, a continuous 6h Holter ECG is carried out, while pulse and blood pressure are measured simultaneously, every hour. A final 12-lead ECG is performed afterwards. All ECG recordings are centrally evaluated by cardiologists.
 RESULTS: 
The latest interim analysis was based on 1640 patients (August 2014). 1[percnt] of the patients developed bradycardia ( nd degree AV-block Mobitz type I or higher.At the AAN, data of the first 2500 START patients will be presented focusing on an in-depth Holter-ECG-analysis of those patients having developed bradycardia or AV-block 2 nd degree and higher.
 CONCLUSIONS: 
This detailed analysis of the first 2500 START patients will extend our knowledge of the cardiac safety during fingolimod treatment initiation, which has already been documented in the pivotal multicenter trials, leading to approval.
 Study Supported by: Novartis Pharma GmbH Disclosure: Dr. Limmroth has received personal compensation or research support for activities with Bayer Pharmaceuticals Inc., Biogen Idec, Novartis, Roche Diagnostics Corp., Sanofi-Aventis Pharmaceuticals Inc., and Teva Neuroscience. Dr. Haverkamp has received personal compensation for activities with Novartis as a consultant. Dr. Dechend has received personal compensation for activities with Novartis Pharma GmbH as a consultant. Dr. Hoyer has received personal compensation for activities Novartis Pharma GmbH as an employee. Dr. Lang has received personal compensation for activities with Novartis, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, EDM Serono, and Genzyme. Dr. Haas has received personal compensation for activities with Bayer Schering, Teva Aventis, Merck Serono, Biogen Idec, Allergan, Octapharma as a consultant. Dr. Stephan has nothing to disclose. Dr. Wagner has nothing to disclose. Dr. Schmidt has received personal compensation for activities with Bayer, Biogen Idec, Merck Serono, Teva, Sanofi, and Novartis. Dr. Ziemssen has nothing to disclose.

First Dose Effects of Fingolimod: An in-depth Analysis of the first 2500 START Patients (S4.005)

OBJECTIVE: The START-study characterizes the cardiac safety profile of fingolimod treatment initiation in a RRMS patient population.
 BACKGROUND: Fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, was the first oral therapy approved for the treatment of RRMS. Following treatment initiation, fingolimod activates S1PR at the surface of cardiac myocytes, resulting in transient pulse rate reduction, and in rare cases in atrioventricular conduction blocks.
 DESIGN/METHODS: The START study is a prospective, 1-week, multicenter, open-label study enrolling up to 7,000 RRMS patients in more than 250 centers in Germany, according to the EU label criteria of fingolimod. The study consists of a screening period, a baseline visit during which the first fingolimod dose is taken, and a final visit after one week. The procedure at baseline is as follows: prior to the first intake of fingolimod, a 12-lead ECG is recorded. After the first dose, a continuous 6h Holter ECG is carried out, while pulse and blood pressure are measured simultaneously, every hour. A final 12-lead ECG is performed afterwards. In 200 patients, diagnostics include a 24h ECG during screening and at baseline. All ECG recordings are centrally evaluated by cardiologists.
 RESULTS: In a first, interim analysis based on 599 patients, there was no Mobitz type II 2 nd degree AV-block. Only 1.4% and 0.3% of patients developed a Mobitz type I 2 nd degree block and a 2:1 2 nd degree AV block, respectively. Additionally, data regarding QT intervals after fingolimod treatment initiation will be available. The new data set will also be analyzed with regard to the potential impact of co-medications frequently prescribed in RRMS-patients, as symptomatic treatments upon occurrence of cardiac events.
 CONCLUSIONS: This national study confirms the good cardiac safety profile of fingolimod, which has already been documented in the previous pivotal multicenter trials, leading to approval. Additionally, the possible impact of co-medication on AV-conduction, relevant for sub-groups of RRMS patients, is addressed. Study Supported by: Novartis Pharma GbmH Disclosure: Dr. Limmroth has received personal compensation or research support for activities with Bayer Pharmaceuticals Inc., Biogen Idec, Novartis, Roche Diagnostics Corp., Sanofi-Aventis Pharmaceuticals Inc., Serono Inc., and Teva Neuroscience. Dr. Hoyer has received personal compensation for activities with Novartis. Dr. Schmidt has received personal compensation for activities with Bayer Pharmaceuticals Corp., Biogen Idec, Merck Serono, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals Inc., and Novartis. Dr. Schmidt has received research support from Bayer Pharmaceuticals Inc., and Merck Serono. Dr. Lang has received personal compensation for activities with Novartis, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, Serono Inc., and Genzyme Corp. Dr. Lang has received research support from Novartis, Biogen Idec, Bayer Pharmaceuticals Corp., Teva Neuroscience, Serono Inc., and Genzyme Corp. Dr. Ziemssen has received personal compensation for activities with Almirall, Biogen Idec, Bayer, Genzyme Corporation, GlaxoSmithKline, Inc., MSD, Merck Serono, Novartis, Sanofi, Teva Neuroscience, and Synthon. Dr. Ziemssen has received research support from Bayer, Biogen Idec, Merck Serono, Novartis, Teva, and Sanofi.

Susanne Hoyer

Papers

Electrocardiographic assessments and cardiac events after fingolimod first dose – a comprehensive monitoring study

First Dose Effects of Fingolimod: An in-depth Analysis of the first 2500 START Patients (S4.005)

Good Cardiac Safety In Patients With Relapsing Remitting Multiple Sclerosis Upon First Fingolimod Dose (P2.197)