Fingolimod for the Treatment of Relapsing Multiple Sclerosis
Fingolimod for the Treatment of Relapsing Multiple Sclerosis
Fingolimod is the first oral agent approved in the USA for the treatment of relapsing forms of multiple sclerosis. Fingolimod is a sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phosphate receptors on lymphocytes, resulting in a downregulation of the receptor and a reversible sequestration of lymphocytes in lymphoid tissue. Effector memory T cells are not sequestered so that immune surveillance may be minimally affected. Two large-scale Phase III clinical trials have demonstrated the efficacy of fingolimod compared with placebo and intramuscular interferon β-1a in relapsing–remitting multiple sclerosis. Due to its mechanism of action, fingolimod administration may be associated with first-dose bradycardia and macular edema. Therefore, patients should be observed for 6 h at the time of their first dose and undergo ophthalmologic evaluation prior to treatment initiation and at 3–4 months after initiation.
Multiple sclerosis (MS) is one of the most common neurologic disease states affecting young and middle-aged adults in the USA. Estimates dating back to 1992 suggest that as many as 400,000 people are afflicted in the USA alone, and as many as 1 million are affected worldwide. These estimates are probably low, given recent progress in the recognition of MS symptoms and improvements in diagnosis that have occurred over the last decade. While the cause remains unknown, it is widely agreed that MS, at the very least, is an inflammatory demyelinating disease of the CNS. MS is also the leading cause of neurologic disability in young adults within the USA.
Approximately 85% of patients with MS present with a relapsing form of the disease (i.e., acute or subacute bouts of neurologic dysfunction characterized by objective neurologic deficits lasting at least 24 h in the absence of systemic illness). In most cases, the neurologic deficits that occur during the relapse last for weeks to months, and some estimates suggest that as many as 41% of MS patients have deficits persisting for at least 3 months following the onset of relapse. In some patients these deficits may be permanent. In relapsing–remitting (RR) MS, patients remain stable in between periods of relapse, but that is not to say they have returned to baseline or are symptom free. In the periods of neurologic stability (referred to as 'remission'), most patients suffer from constitutional symptoms such as fatigue, memory loss, pain and spasticity. The degree of disability does not define the disease course – patients with RRMS may have advanced disability despite having a disease course characterized by periods of relapse and remission.
Early in the course of RRMS, disease activity is characterized by a predominance of inflammation. It is also likely that there is a degenerative component of the disease process that is present from the initial phases of the disease. In the RR phase of MS, disability progression is probably mediated by damage from inflammatory lesions in the brain and spinal cord. After a variable period of time, patients with RRMS may transition to a secondarily progressive (SP) form of the disease. In SPMS, patients accumulate neurologic deficits in a progressive fashion with or without superimposed relapses. The inflammatory disease activity, so notable in the RR phase, declines so that inflammatory lesions are far less common. The degenerative component then becomes the dominant feature of the disease and is largely responsible for the progression of disability. In long-term studies of the natural history of MS, approximately 90% of untreated patients with RRMS will eventually transition to SPMS. In untreated MS, approximately 50% of patients require ambulatory assistance after 15 years. The median time to secondary progression is 10 years. There is some evidence that disease-modifying treatments (DMTs) decrease the rate at which patients transition from RRMS to SPMS. In the absence of treatment, most patients will develop significant neurologic disability resulting in impaired quality of life and decreased productivity.
There is considerable controversy as to whether MS is an autoimmune disease, or whether some other etiology is responsible. What is clear is that inflammation plays a crucial role in the evolution of the disease, and that all of the therapies approved by regulatory agencies to date act to decrease inflammation by one mechanism or another.
Abstract and Introduction
Abstract
Fingolimod is the first oral agent approved in the USA for the treatment of relapsing forms of multiple sclerosis. Fingolimod is a sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phosphate receptors on lymphocytes, resulting in a downregulation of the receptor and a reversible sequestration of lymphocytes in lymphoid tissue. Effector memory T cells are not sequestered so that immune surveillance may be minimally affected. Two large-scale Phase III clinical trials have demonstrated the efficacy of fingolimod compared with placebo and intramuscular interferon β-1a in relapsing–remitting multiple sclerosis. Due to its mechanism of action, fingolimod administration may be associated with first-dose bradycardia and macular edema. Therefore, patients should be observed for 6 h at the time of their first dose and undergo ophthalmologic evaluation prior to treatment initiation and at 3–4 months after initiation.
Introduction
Multiple sclerosis (MS) is one of the most common neurologic disease states affecting young and middle-aged adults in the USA. Estimates dating back to 1992 suggest that as many as 400,000 people are afflicted in the USA alone, and as many as 1 million are affected worldwide. These estimates are probably low, given recent progress in the recognition of MS symptoms and improvements in diagnosis that have occurred over the last decade. While the cause remains unknown, it is widely agreed that MS, at the very least, is an inflammatory demyelinating disease of the CNS. MS is also the leading cause of neurologic disability in young adults within the USA.
Approximately 85% of patients with MS present with a relapsing form of the disease (i.e., acute or subacute bouts of neurologic dysfunction characterized by objective neurologic deficits lasting at least 24 h in the absence of systemic illness). In most cases, the neurologic deficits that occur during the relapse last for weeks to months, and some estimates suggest that as many as 41% of MS patients have deficits persisting for at least 3 months following the onset of relapse. In some patients these deficits may be permanent. In relapsing–remitting (RR) MS, patients remain stable in between periods of relapse, but that is not to say they have returned to baseline or are symptom free. In the periods of neurologic stability (referred to as 'remission'), most patients suffer from constitutional symptoms such as fatigue, memory loss, pain and spasticity. The degree of disability does not define the disease course – patients with RRMS may have advanced disability despite having a disease course characterized by periods of relapse and remission.
Early in the course of RRMS, disease activity is characterized by a predominance of inflammation. It is also likely that there is a degenerative component of the disease process that is present from the initial phases of the disease. In the RR phase of MS, disability progression is probably mediated by damage from inflammatory lesions in the brain and spinal cord. After a variable period of time, patients with RRMS may transition to a secondarily progressive (SP) form of the disease. In SPMS, patients accumulate neurologic deficits in a progressive fashion with or without superimposed relapses. The inflammatory disease activity, so notable in the RR phase, declines so that inflammatory lesions are far less common. The degenerative component then becomes the dominant feature of the disease and is largely responsible for the progression of disability. In long-term studies of the natural history of MS, approximately 90% of untreated patients with RRMS will eventually transition to SPMS. In untreated MS, approximately 50% of patients require ambulatory assistance after 15 years. The median time to secondary progression is 10 years. There is some evidence that disease-modifying treatments (DMTs) decrease the rate at which patients transition from RRMS to SPMS. In the absence of treatment, most patients will develop significant neurologic disability resulting in impaired quality of life and decreased productivity.
There is considerable controversy as to whether MS is an autoimmune disease, or whether some other etiology is responsible. What is clear is that inflammation plays a crucial role in the evolution of the disease, and that all of the therapies approved by regulatory agencies to date act to decrease inflammation by one mechanism or another.