Fingolimod for multiple sclerosis: a review for the specialist nurse Kitty Harrison
Key words: Fingolimod ■ FTY720 ■ Gilenya ■ Multiple sclerosis ■ Specialist nurse
M
ultiple sclerosis (MS) is the leading cause of disability in young and middle-aged people in the developed world (KochHenriksen and Sorensen, 2010; Multiple Sclerosis International Federation, 2013). It is a chronic, autoimmune, inflammatory and neurodegenerative disease of the central nervous system (CNS) in which autoimmune responses lead to destruction of the myelin sheaths that surround neuronal axons (Peterson and Fujinami, 2007). The variation in symptomatology reflects the range of CNS sites at which damage occurs (Lees et al, 2008). As repair processes within the CNS begin to fail, the disease advances and irreversible damage results in physical and cognitive disability (McQualter and Bernard, 2007). Most patients present with the relapsing–remitting form of MS, which is characterised by unpredictable acute attacks, followed by periods of remission (Compston and Coles, 2002). Kitty Harrison is Neurology Nursing Specialist, Department of Neurology, Tergooiziekenhuizen, Blaricum, Netherlands Accepted for publication: April 2014
582
Through an evidence-based understanding of MS, the role of the MS specialist nurse has evolved from a supportive role to that of a highly skilled, knowledgeable and specialised professional. As part of a multidisciplinary team dedicated to a patient’s continuing care, MS nurses provide psychological support, assist with medication management, and help patients gain access to new treatments (Hartung and Ross, 2010). In a European survey of MS nurses, 30% considered themselves to be the day-to-day patient adviser (Hartung and Ross, 2010). Given the chronic and progressive nature of MS, the individualised support provided by the MS nurse is essential, particularly with regard to long-term treatment (Miller, 2007). Therefore, the present-day MS nurse’s repertoire must include a practical knowledge of the therapeutic options available to his or her patients, as well as a sensitivity to the everyday needs of patients and caregivers (Costello et al, 2003). The pharmacological management of relapsing MS has improved from purely symptomatic treatments to disease-modifying therapies that slow or halt the irreversible progression of disease. During the past 20 years, interferon betas (Avonex, Biogen Idec; Betaferon, Bayer; Extavia, Novartis
Fingolimod mechanism of action The presence of autoreactive peripheral lymphocytes in CNS compartments is central to demyelination and neuronal tissue damage observed in MS. Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. It is a chemical derivative of myriocin, a metabolite of the fungus Isaria sinclairii (Fujita et al, 1994), known for its anti-inflammatory properties (Fujita et al, 1994). S1P is a bioactive sphingolipid that plays an important role in a diverse range of physiological and pathophysiological functions, including regulation of immune cell trafficking and cell communication in the CNS (Brinkmann, 2007). Originally, fingolimod was investigated as a potential anti-rejection therapy following organ transplant. However, as its unique mechanism of action was further uncovered, focus shifted to the development of fingolimod
© 2014 MA Healthcare Ltd
Abstract
The availability of treatments for multiple sclerosis (MS) has increased substantially over the past decade. Once-daily fingolimod 0.5 mg capsules (Gilenya, Novartis Pharma) were approved in the European Union in March 2011 as the first oral disease-modifying therapy for patients with relapsing MS. This review summarises the efficacy and safety of fingolimod, and discusses practical considerations for MS specialist nurses. Fingolimod has demonstrated efficacy in the treatment of relapsing‒remitting MS, as assessed by relapse measures, inflammatory disease activity and brain volume loss. Evaluation of its safety profile suggests a need for monitoring procedures for specific adverse events, including transient, mostly asymptomatic, reductions in heart rate, blood pressure increases, macular oedema and liver enzyme elevations. The MS nurse is likely to be involved in monitoring treatment initiation, providing support in the case of adverse events and promoting patient adherence to the prescribed treatment regimen.
Pharma) and glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) have been the mainstay of disease-modifying therapy in the European Union (EU). More recently, the monoclonal antibody natalizumab (Tysabri, Biogen Idec) has become available for patients with highly active relapsing–remitting MS. In 2011, once-daily oral fingolimod 0.5 mg (Gilenya, FTY720, Novartis Pharma) was approved by the European Medicines Agency for patients with highly active relapsing– remitting MS despite treatment with interferon beta, as well as patients with rapidly evolving severe relapsing–remitting MS (European Medicines Agency, 2012a). Fingolimod was the first disease-modifying therapy that can be administered orally. It has a novel mechanism of action and may, therefore, be effective in patients who fail to respond to other approved classes of therapy (Brinkmann, 2007). In acknowledgement of the critical role of the specialist nurse in the multidisciplinary management of MS, this review aims to summarise, for the nursing audience, key clinical data relating to the efficacy and safety of fingolimod. In addition, practical considerations relating to patient suitability, monitoring and counselling are discussed.
British Journal of Nursing, 2014, Vol 23, No 11
British Journal of Nursing.Downloaded from magonlinelibrary.com by 130.113.086.233 on January 8, 2015. For personal use only. No other uses without permission. . All rights reserved.
NEUROLOGY as a disease-modifying therapy for relapsing forms of MS (Brinkmann et al, 2010). Preclinical studies demonstrated that fingolimod targets four of the five G-proteincoupled S1P receptor subtypes. It has highest affinity for S1P receptor subtype 1 (S1P1) and it modulates lymphocyte trafficking via lymphocytic and endothelial S1P1. On encountering lymphocytic cell-surface S1P1, fingolimod first acts as a potent agonist, rapidly activating these receptors and causing their overstimulation. Subsequently, the continuous exposure of cells to fingolimod leads to S1P receptor desensitisation, as receptors uncouple from their G-proteins, are internalised, and undergo endocytic degradation, reducing all signal transduction via S1P1. With chronic fingolimod exposure, the decrease in S1P1 numbers on the surface of cells is maintained. It is this downregulation of S1P receptors on lymph node T cells that renders lymphocytes unresponsive to the normal S1P egress signal, preventing infiltration of pathogenic T cells into the CNS (Chun and Hartung, 2010). Fingolimod selectively and reversibly retains naïve and central memory T-lymphocytes within lymph nodes, as effector memory T-lymphocytes are less dependent on S1P signaling. Thus, effector-memory T-lymphocytes, which mainly circulate in peripheral tissues, are largely unaffected by fingolimod and continue to provide peripheral immune surveillance (Pinschewer et al, 2000; Brinkmann et al, 2010). Additionally, it was noted that fingolimod crosses the blood–brain barrier (Foster et al, 2007), due to its lipophilic nature, and further data indicated that the drug also down-modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS (Matloubian et al, 2004; Noda et al, 2013; Groves et al, 2013).
As a promising first-in-class oral diseasemodifying therapy, the drug was taken to the next stage of development and proof-ofconcept trials in MS were initiated.
Efficacy of fingolimod Positive outcomes were observed in a proofof-concept phase 2 trial, which studied doses higher than the approved fingolimod 0.5 mg dose (Kappos et al, 2006). In the long-term, open-label, phase 2 study extension, patients switched to the fingolimod 0.5 mg dose following approval, and low disease activity (based on both magnetic resonance imaging (MRI) and clinical disease parameters) was demonstrated in patients remaining on therapy for up to 7 years (Antel et al, 2012). Data on the licensed dose are available from three pivotal, randomised, doubleblind, placebo-controlled phase 3 studies. TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in Relapsing– remitting Multiple Sclerosis), FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) and FREEDOMS II were all studies of patients aged 18–55 years with relapsing–remitting MS (Cohen et al, 2010; Kappos et al, 2010; Calabresi et al, 2014). In each, the primary efficacy endpoint was treatment effect on the annualised relapse rate (ARR).
TRANSFORMS TRANSFORMS was a 1-year, randomised, double-blind, double-dummy, parallelgroup study (ClinicalTrials.gov number: NCT00340834) (Cohen et al, 2010). The trial, which was completed by 89% of the 1292 randomised patients, was designed to compare the efficacy of once-daily oral fingolimod 0.5 mg and 1.25 mg with that of an approved first-line injectable therapy
(intramuscular (IM) interferon beta-1a 30 μg weekly (Avonex, Biogen Idec)). Both doses of fingolimod were significantly more effective than IM interferon beta-1a in reducing the ARR; fingolimod 0.5 mg reduced the ARR by 52% (relative reduction) over 1 year, compared with IM interferon beta-1a treatment (ARR: 0.16 (95% CI, 0.12 to 0.21) in the 0.5 mg fingolimod group versus 0.33 in the IM interferon beta-1a group (95% CI, 0.26 to 0.42); P
Key words: Fingolimod ■ FTY720 ■ Gilenya ■ Multiple sclerosis ■ Specialist nurse
M
ultiple sclerosis (MS) is the leading cause of disability in young and middle-aged people in the developed world (KochHenriksen and Sorensen, 2010; Multiple Sclerosis International Federation, 2013). It is a chronic, autoimmune, inflammatory and neurodegenerative disease of the central nervous system (CNS) in which autoimmune responses lead to destruction of the myelin sheaths that surround neuronal axons (Peterson and Fujinami, 2007). The variation in symptomatology reflects the range of CNS sites at which damage occurs (Lees et al, 2008). As repair processes within the CNS begin to fail, the disease advances and irreversible damage results in physical and cognitive disability (McQualter and Bernard, 2007). Most patients present with the relapsing–remitting form of MS, which is characterised by unpredictable acute attacks, followed by periods of remission (Compston and Coles, 2002). Kitty Harrison is Neurology Nursing Specialist, Department of Neurology, Tergooiziekenhuizen, Blaricum, Netherlands Accepted for publication: April 2014
582
Through an evidence-based understanding of MS, the role of the MS specialist nurse has evolved from a supportive role to that of a highly skilled, knowledgeable and specialised professional. As part of a multidisciplinary team dedicated to a patient’s continuing care, MS nurses provide psychological support, assist with medication management, and help patients gain access to new treatments (Hartung and Ross, 2010). In a European survey of MS nurses, 30% considered themselves to be the day-to-day patient adviser (Hartung and Ross, 2010). Given the chronic and progressive nature of MS, the individualised support provided by the MS nurse is essential, particularly with regard to long-term treatment (Miller, 2007). Therefore, the present-day MS nurse’s repertoire must include a practical knowledge of the therapeutic options available to his or her patients, as well as a sensitivity to the everyday needs of patients and caregivers (Costello et al, 2003). The pharmacological management of relapsing MS has improved from purely symptomatic treatments to disease-modifying therapies that slow or halt the irreversible progression of disease. During the past 20 years, interferon betas (Avonex, Biogen Idec; Betaferon, Bayer; Extavia, Novartis
Fingolimod mechanism of action The presence of autoreactive peripheral lymphocytes in CNS compartments is central to demyelination and neuronal tissue damage observed in MS. Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. It is a chemical derivative of myriocin, a metabolite of the fungus Isaria sinclairii (Fujita et al, 1994), known for its anti-inflammatory properties (Fujita et al, 1994). S1P is a bioactive sphingolipid that plays an important role in a diverse range of physiological and pathophysiological functions, including regulation of immune cell trafficking and cell communication in the CNS (Brinkmann, 2007). Originally, fingolimod was investigated as a potential anti-rejection therapy following organ transplant. However, as its unique mechanism of action was further uncovered, focus shifted to the development of fingolimod
© 2014 MA Healthcare Ltd
Abstract
The availability of treatments for multiple sclerosis (MS) has increased substantially over the past decade. Once-daily fingolimod 0.5 mg capsules (Gilenya, Novartis Pharma) were approved in the European Union in March 2011 as the first oral disease-modifying therapy for patients with relapsing MS. This review summarises the efficacy and safety of fingolimod, and discusses practical considerations for MS specialist nurses. Fingolimod has demonstrated efficacy in the treatment of relapsing‒remitting MS, as assessed by relapse measures, inflammatory disease activity and brain volume loss. Evaluation of its safety profile suggests a need for monitoring procedures for specific adverse events, including transient, mostly asymptomatic, reductions in heart rate, blood pressure increases, macular oedema and liver enzyme elevations. The MS nurse is likely to be involved in monitoring treatment initiation, providing support in the case of adverse events and promoting patient adherence to the prescribed treatment regimen.
Pharma) and glatiramer acetate (Copaxone, Teva Pharmaceutical Industries) have been the mainstay of disease-modifying therapy in the European Union (EU). More recently, the monoclonal antibody natalizumab (Tysabri, Biogen Idec) has become available for patients with highly active relapsing–remitting MS. In 2011, once-daily oral fingolimod 0.5 mg (Gilenya, FTY720, Novartis Pharma) was approved by the European Medicines Agency for patients with highly active relapsing– remitting MS despite treatment with interferon beta, as well as patients with rapidly evolving severe relapsing–remitting MS (European Medicines Agency, 2012a). Fingolimod was the first disease-modifying therapy that can be administered orally. It has a novel mechanism of action and may, therefore, be effective in patients who fail to respond to other approved classes of therapy (Brinkmann, 2007). In acknowledgement of the critical role of the specialist nurse in the multidisciplinary management of MS, this review aims to summarise, for the nursing audience, key clinical data relating to the efficacy and safety of fingolimod. In addition, practical considerations relating to patient suitability, monitoring and counselling are discussed.
British Journal of Nursing, 2014, Vol 23, No 11
British Journal of Nursing.Downloaded from magonlinelibrary.com by 130.113.086.233 on January 8, 2015. For personal use only. No other uses without permission. . All rights reserved.
NEUROLOGY as a disease-modifying therapy for relapsing forms of MS (Brinkmann et al, 2010). Preclinical studies demonstrated that fingolimod targets four of the five G-proteincoupled S1P receptor subtypes. It has highest affinity for S1P receptor subtype 1 (S1P1) and it modulates lymphocyte trafficking via lymphocytic and endothelial S1P1. On encountering lymphocytic cell-surface S1P1, fingolimod first acts as a potent agonist, rapidly activating these receptors and causing their overstimulation. Subsequently, the continuous exposure of cells to fingolimod leads to S1P receptor desensitisation, as receptors uncouple from their G-proteins, are internalised, and undergo endocytic degradation, reducing all signal transduction via S1P1. With chronic fingolimod exposure, the decrease in S1P1 numbers on the surface of cells is maintained. It is this downregulation of S1P receptors on lymph node T cells that renders lymphocytes unresponsive to the normal S1P egress signal, preventing infiltration of pathogenic T cells into the CNS (Chun and Hartung, 2010). Fingolimod selectively and reversibly retains naïve and central memory T-lymphocytes within lymph nodes, as effector memory T-lymphocytes are less dependent on S1P signaling. Thus, effector-memory T-lymphocytes, which mainly circulate in peripheral tissues, are largely unaffected by fingolimod and continue to provide peripheral immune surveillance (Pinschewer et al, 2000; Brinkmann et al, 2010). Additionally, it was noted that fingolimod crosses the blood–brain barrier (Foster et al, 2007), due to its lipophilic nature, and further data indicated that the drug also down-modulates S1P1 in neural cells/astrocytes to reduce astrogliosis, a phenomenon associated with neurodegeneration in MS (Matloubian et al, 2004; Noda et al, 2013; Groves et al, 2013).
As a promising first-in-class oral diseasemodifying therapy, the drug was taken to the next stage of development and proof-ofconcept trials in MS were initiated.
Efficacy of fingolimod Positive outcomes were observed in a proofof-concept phase 2 trial, which studied doses higher than the approved fingolimod 0.5 mg dose (Kappos et al, 2006). In the long-term, open-label, phase 2 study extension, patients switched to the fingolimod 0.5 mg dose following approval, and low disease activity (based on both magnetic resonance imaging (MRI) and clinical disease parameters) was demonstrated in patients remaining on therapy for up to 7 years (Antel et al, 2012). Data on the licensed dose are available from three pivotal, randomised, doubleblind, placebo-controlled phase 3 studies. TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in Relapsing– remitting Multiple Sclerosis), FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) and FREEDOMS II were all studies of patients aged 18–55 years with relapsing–remitting MS (Cohen et al, 2010; Kappos et al, 2010; Calabresi et al, 2014). In each, the primary efficacy endpoint was treatment effect on the annualised relapse rate (ARR).
TRANSFORMS TRANSFORMS was a 1-year, randomised, double-blind, double-dummy, parallelgroup study (ClinicalTrials.gov number: NCT00340834) (Cohen et al, 2010). The trial, which was completed by 89% of the 1292 randomised patients, was designed to compare the efficacy of once-daily oral fingolimod 0.5 mg and 1.25 mg with that of an approved first-line injectable therapy
(intramuscular (IM) interferon beta-1a 30 μg weekly (Avonex, Biogen Idec)). Both doses of fingolimod were significantly more effective than IM interferon beta-1a in reducing the ARR; fingolimod 0.5 mg reduced the ARR by 52% (relative reduction) over 1 year, compared with IM interferon beta-1a treatment (ARR: 0.16 (95% CI, 0.12 to 0.21) in the 0.5 mg fingolimod group versus 0.33 in the IM interferon beta-1a group (95% CI, 0.26 to 0.42); P
