Fingolimod and cardiac risk: latest findings and clinical implications

Abstract

Fingolimod is an oral medication approved for the treatment of relapsing multiple sclerosis (MS). It is unique compared with other approved disease-modifying therapies for MS in that it is the first oral agent and it has a novel mechanism of action. In clinical trials and postmarket use, it demonstrates clear therapeutic efficacy. However, it is associated with certain risks including cardiac concerns. The recent reports of cardiac events potentially associated with the drug prompted a regulatory agencies review of the use of fingolimod for MS in the USA and Europe. After completion of their review, the US Food and Drug Administration and the European Medicines Agency concluded that its benefits outweighed the risks. However, certain recommendations were made for appropriate patient selection for fingolimod and for more cautious first-dose monitoring. We review the use of fingolimod for MS in light of the recently reported potential cardiac risks. We conclude that with appropriate patient selection and careful monitoring, it appears to have a favorable benefits/risks profile and can be a valuable treatment option for relapsing MS. Continued postmarketing surveillance and data from the extension phase of its clinical trials will be very important in understanding the long-term efficacy and safety of fingolimod and to help determine its place in the treatment algorithm for multiple sclerosis.

Introduction

Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating disease of the central nervous system. Since the introduction of the first disease-modifying treatment in 1993, the treatment options for MS have continued to expand and at present there are nine approved agents [Perumal and Khan, 2012]. Until the advent of fingolimod, all US Food and Drug Administration (FDA)-approved treatments for MS were administered parenterally [Vosoughi and Freedman, 2010]. These medications include glatiramer acetate which is a daily injectable form, interferons which are injectables as well, with the various forms having different dosing and administration schedules, natalizumab which is monoclonal antibody infused intravenously every 4 weeks and mitoxantrone, a chemotherapy agent administered intravenously [Castro-Barrero et al. 2012]. Fingolimod is the first oral medication currently approved for the treatment of relapsing–remitting forms of MS [Chun and Brinkmann, 2011]. It was approved by the FDA in September 2010 and by the European Medicines Agency (EMA) in March 2011.

After positive results in the treatment of MS in phase II studies [Comi et al. 2010; Kappos et al. 2006; O’Connor et al. 2009], the efficacy of fingolimod was investigated in two large, phase III trials [Cohen et al. 2010; Kappos et al. 2010]. In the FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) trial, patients were randomized to receive fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo for 2 years. The annualized relapse rate, which was the primary endpoint of this study, and cumulative probability of disability progression (confirmed after 3 months), the secondary endpoint, were superior with both doses of fingolimod compared with placebo. In the TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis) trial, patients were randomly assigned to receive fingolimod at a dose of 0.5 mg or 1.25 mg daily or interferon β-1a 30 µg by intramuscular injection every week for 12 months [Cohen et al. 2010]. The annualized relapse rate reduction, the primary endpoint, was greater for each fingolimod regimen compared with interferon. Fingolimod was superior to placebo and interferon β-1a in the magnetic resonance imaging outcomes as well in the respective trials.

Fingolimod was generally well tolerated in the clinical trials, but there were some safety concerns. There were two deaths in the TRANSFORMS trial, both in the group assigned to the 1.25 mg dose of fingolimod. One patient developed herpes simplex encephalitis, and the other developed a primary disseminated herpes zoster infection after exposure to chicken pox during a course of methylprednisolone treatment for a relapse of MS [Cohen et al. 2010]. Macular edema developed in 0.4% of the patients on fingolimod. Most cases of macular edema were asymptomatic and resolved within months of discontinuation of the medicine. Localized skin cancers (namely basal cell carcinoma and melanoma) and breast cancers were reported more frequently in the fingolimod groups than in the group receiving interferon β-1a in the TRANSFORMS trial.

Cardiac events including bradycardia and atrioventricular (AV) blocks were reported. In the FREEDOMS trial, bradycardia was seen in 9 (2.1%) patients on the 0.5 mg dose, 14 (3%) patients on the 1.25 mg dose and 3 patients on placebo [Kappos et al. 2010]. The majority of these events were reported to have occurred during the 6 h first-dose monitoring. Six patients who developed bradycardia were symptomatic and all cases resolved within 24 h. Although AV block was not significantly reported as an adverse event, electrocardiogram (ECG) performed within 24 h showed first-degree AV block in 20 patients receiving 0.5 mg and 37 patients receiving 1.25 mg fingolimod, and second-degree AV block was seen in 1 patient on 0.5 mg and 4 patients on 1.25 mg fingolimod. Similar to these findings, the TRANFORMS trial also reported bradycardia in 10 (2.4%) patients receiving 1.25 mg and 2 (0.5%) patients receiving 0.5 mg fingolimod [Cohen et al. 2010]. Second-degree AV block was seen in three patients on 1.25 mg and one patient on 0.5 mg fingolimod. In addition to the cardiac events, mild sustained increase in mean arterial blood pressure was also reported.

Mechanism of action of fingolimod

Fingolimod is a structural analogue of sphingosine 1 phosphate (SIP) [Chun and Hartung, 2010; Im, 2003]. SIP and its five known SIP receptors which are widely distributed in the human body serve diverse functions [Lee et al. 1998; Rivera et al. 2008; Spiegel and Milstien, 2003]. Once it is phophorylated, fingolimod binds to four of the five known SIP receptors: SIP₁ SIP₃, SIP₄ and SIP₅ [Cusack and Stoffel, 2010]. The therapeutic effect of fingolimod in MS is believed to be predominantly due to the effects of SIP receptors located on lymphocytes [Mandala et al. 2002; Matloubian et al. 2004; Ortaneda and Cohen, 2011]. Lymphocyte migration out of the lymph nodes is dependent on engagement of S1P₁ by S1P [Hla and Brinkmann, 2011]. The active form of fingolimod binds to S1P₁ and initially acts as an agonist but then eventually causes functional antagonism by downregulating expression of S1P receptors on the surface of lymphocytes [Graler and Goetzl, 2004; Schwab and Cyster, 2007]. This down modulation prevents lymphocyte egress and essentially traps lymphocytes within the lymph nodes and rapidly reduces lymphocyte counts in circulation which leads to decreased infiltration into the central nervous system and injury [Bartholomaus et al. 2009; Cohen and Chun, 2011]. Fingolimod might also have direct beneficial effects through modulation of SIP receptors in the central nervous system [Coelho et al. 2007; Brinkmann, 2009; Jackson et al. 2009]. Fingolimod is lipophilic and readily crosses the blood–brain barrier which is conducive to robust direct central nervous system effects [Foster et al. 2007].

In the cardiac tissue, SIP receptors are heavily expressed in atrial, ventricular and septal cardiomyocytes and the endothelial cells of blood vessels [Mazurais et al. 2002; Waeber et al. 2004]. The cardiac effects of fingolimod seem to be due to its binding of S1P receptors located in cardiac tissue [Brinkmann and Baumruker, 2006; Peters and Alewijnse, 2007]. Animal studies have demonstrated that engaging of SIP receptors causes transient lowering of the heart rate due to the initial agonistic action before the internalization of these receptors [Forrest et al. 2004; Guo et al. 1999].

Cardiac risks with fingolimod

Cardiac concerns with fingolimod include bradycardia and AV block. In clinical trials fingolimod induced a transient, dose-dependent decrease in heart rate, reaching a maximum 4–5 h after the first dose and attenuating over time with continued dosing as was seen in earlier studies with fingolimod [Schmouder et al. 2006]. No cases of symptomatic bradycardia occurred beyond 24 h after the first dose of fingolimod in its clinical trials. However, a recent case report mentioned prolonged bradycardia developing 24 h post initial dose of fingolimod [Faber et al. 2012]. Fingolimod is also known to slow conduction of the AV nodal system, in a dose-dependent fashion. In a pooled analysis of FREEDOMS and TRANSFORMS, first-degree AV block was the most common abnormality, with mean P–R prolongation of 4.5 ms with the 0.5 mg dose and 11.3 ms with the 1.25 mg dose [DiMarco et al. 2010]. Second-degree block (Mobitz type I and type 2:1) was rare but also more frequent with the 1.25 mg dose. Higher degrees of AV block were not seen in the clinical trials. In the postmarketing period, a recent case report described a 20-year-old man with MS who developed asystole and sustained bradycardia 21 h after the first dose of fingolimod [Espinosa and Berger, 2011]. This patient was also on risperidone, a psychotropic medication known to have well recognized cardiac conduction side effects including sinus bradycardia, conduction block, prolonged QT interval and asystole [Smiler, 2004].

In November 2011, there was a report of a patient in the USA who died within 24 h after receiving the first dose of fingolimod. The patient in this case was also treated with the β blocker metoprolol and the calcium channel blocker amlodipine. The patient had completed 6 h of monitoring after the first dose without incident, but died less than 24 h after the first dose. The exact cause of death was not established. This prompted the FDA to examine this case and also cases of cardiovascular deaths and deaths of unknown causes in patients taking fingolimod which had been reported as well [Lindsey et al. 2012]. As of May 2012, the FDA completed its review of the reports and also re-evaluated additional data from fingolimod’s clinical trials and postmarket data. After their review, the FDA concluded that there was no clear evidence that fingolimod played a role in the death of the patient who died within 24 h of the first dose of fingolimod, but stated that a possible link could not be definitively ruled out. The FDA also concluded that there did not appear to be a causal association with fingolimod in the other deaths. The FDA however made recommendations for patient selection, including listing contraindications for fingolimod use in certain patients and also revised its recommendations for first-dose observation. These have been incorporated into the updated prescribing information for fingolimod (see http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008lbl.pdf).

The EMA also conducted its review of fingolimod following the reports of deaths and cardiovascular events in patients taking fingolimod. They assessed 15 cases of sudden or unexplained deaths among the 30,000 patients who had ever been exposed to fingolimod until that point. Upon completion of its review, the EMA did not find the data conclusive as to whether fingolimod was the cause of these deaths. Similar to the FDA, they also concluded that with proper risk-minimization measures the benefits of fingolimod outweighed the potential risks and came out with recommendations for patient selection and fist-dose monitoring. The additional EMA recommendations for physicians include continuous ECG monitoring during the 6 h observation period and extending monitoring after the 6 h period if the following conditions apply [EMA, 2012]:

1. At the end of the 6 h period the heart rate is at its lowest since taking the first dose; in this case, the monitoring should be extended for at least 2 h more and until the heart rate increases again.

2. Patients develop any clinically relevant heart problem (such as bradycardia or AV block). If so, doctors are advised to extend the monitoring period at least overnight and until resolution.

Current recommended risk stratification for fingolimod in multiple sclerosis

Current updated prescribing information for fingolimod provides details for appropriate patient selection and first-dose monitoring (see http://www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf).

Patient selection parameters

For patients with contraindications, the selection parameters are as follows:

1. Patients with recent (within the last 6 months) history of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization or class III/IV heart failure.

2. History or presence of Mobitz type II second degree or higher AV block or sick sinus syndrome unless the patient has a pacemaker.

3. Patients with a baseline QTc interval of greater than or equal to 500 ms.

4. Patients receiving class Ia or Class III antiarrhythmics.

Patients who may take fingolimod but require special consideration and care include those with any of the following:

1. ischemic heart disease;

2. history of myocardial infarction;

3. congestive heart failure;

4. history of cardiac arrest;

5. cerebrovascular disease;

6. history of symptomatic bradycardia;

7. history of recurrent syncope;

8. severe untreated sleep apnea;

9. AV block;

10. sino-atrial heart block;

11. prolonged QT interval of greater than 450 ms in men and greater than 470 ms in women and those at additional risk for QT prolongation;

12. Patients taking heart-rate-lowering or QT-prolonging medications.

Patients without preexisting cardiovascular conditions and patients not taking heart-rate-lowering or QT-prolonging drugs are most suitable to receive fingolimod.

First-dose observation recommendations

The first-dose observation recommendations are as follows:

1. Perform ECG prior to dosing and at the end of the observation period.

2. Observe for 6 h with hourly pulse and blood pressure measurements.

3. Monitor until resolution patients with low heart rate, heart rate at lowest post dose value or new onset AV block at the end of the 6 h observation period.

4. Perform continuous ECG monitoring until resolution for patients with symptomatic bradycardia.

5. Perform continuous overnight ECG monitoring in a medical facility for patients with bradycardia requiring pharmacotherapy for patients with certain preexisting conditions, QT interval prolongation or receiving heart-rate-lowering or QT-prolonging drugs.

Conclusion

Fingolimod is an oral therapeutic agent with a novel mechanism of action for relapsing MS. It has demonstrated clear efficacy in the treatment of relapsing–remitting MS. In clinical trials, its efficacy was superior to placebo and an active comparator, interferon β-1a. Compared with the currently available treatment options for MS, fingolimod offers the advantage of ease of administration and adherence as it is a once-daily oral agent. It is also generally well tolerated. However, there were some safety concerns during clinical trials and also from postmarket experience, including certain cardiac risks. In light of the recent emergence of reports of a potential association between fingolimod and certain cardiac risks, its use in MS has undergone an extensive regulatory agency review in the USA and Europe. On completion of these reviews, the conclusion was that the benefits of fingolimod outweighed its potential risks. However, risk stratification measures for its use were recommended. These measures for careful patient selection and enhanced precaution during first-dose monitoring and follow up are aimed at mitigating the instances of cardiac complications. With appropriate patient selection and careful monitoring, fingolimod appears to have a favorable benefit–risk profile and may be a valuable treatment option for relapsing MS.

While its approval in the USA includes its use as first-line and second-line treatment, in Europe it is currently approved as a second-line treatment. As of August 2012, there were about 40,000 patients worldwide who have ever been exposed to fingolimod for the treatment of MS. Continued demonstration of safety from postmarketing surveillance and data from the extension phase of clinical trials could expand its use and help put fingolimod in its appropriate place in the treatment algorithm for MS.