Higher Dose, Fewer Weekly Injections of Copaxone (Glatiramer Acetate) Approved by the FDA for Patients with Relapsing Forms of Multiple Sclerosis

VBCN - July 2014 Volume 1, No 2 - Drug Updates
Loretta Fala

Multiple sclerosis (MS), a chronic inflammatory disease, is one of the leading causes of neurologic disability in young adults.1 In addition to damaging the myelin sheath of nerve fibers, MS causes degeneration of nerve fibers in the brain and spinal cord. MS can also lead to impaired movement, coordination, sensation, and cognition.1

An estimated 2.3 million people worldwide are affected by MS.2 Although the exact prevalence of MS in the United States is not known, it is estimated that 350,000 to 400,000 people may be affected by the disease.2,3 These estimates may be understated because individuals with mild forms of MS may go undiagnosed. MS is most common in Caucasians of northern European descent, and it is 2 to 3 times more common in women than it is in men—suggesting that hormones may contribute to susceptibility.4 Although MS can start in individuals aged between 10 and 80 years, it more often begins between the ages of 20 and 40 (mean age, 32 years).3

MS is generally associated with episodes of numbness, weakness, or dys­coordination in an arm, leg, or both.3 Symptoms may also include sensory or motor changes to one side of the body, diplopia, optic neuritis, or ataxia. Other symptoms of MS include bladder and bowel dysfunction, fatigue, decreased memory, and depression.3

MS imposes a substantial economic burden that encompasses direct medical costs and indirect costs result­ing from reduced productivity and health-related quality of life. In the United States, MS-related costs exceed $10 billion annually.3 Evidence suggests that indirect costs increase as the severity of MS progresses.5

A review of 15 studies showed that the total healthcare costs for MS ranged from $8528 to $54,244 per patient per year, with direct costs accounting for 77% and indirect costs accounting for 23% of the total costs.6 Another systematic review showed that although direct costs contributed to costs in the earlier stages of MS, they were exceeded by indirect costs incurred during later stages or increased disease severity, most likely because of relapses and lost productivity.7 Interventions that delay the progression of MS may help to improve patient outcomes (eg, quality of life) and reduce costs.3,7

MS is characterized by episodes of relapses that are initially followed by remissions. Over time, recovery may be incomplete, leading to a progressive decline.1 The 2 major clinical patterns of MS are relapsing disease, characterized by clearly defined relapses or exacerbations; and progressive disease, characterized by a gradual but steady worsening of disability.8 Relapsing-remitting MS (RRMS) involves episodes that last days to weeks, with full or partial recovery and no disease progression between attacks. An estimated 85% of patients with MS initially have the relapsing-remitting form of the disease. The progressive forms of MS include primary-progressive, secondary-progres­sive, and progressive-relapsing.8

MS is often difficult to diagnose and is challenging to manage, given the ebb and flow of the disease course and symptoms. Nevertheless, early diagnosis and treatment, as well as adherence to prescribed treatment, are essential for optimal outcomes.3 Early, appropriate treatment can substantially slow disease progression, but if left untreated, MS can lead to disability.3

The disease-modifying therapies have been shown to be effective at reducing disease activity and disease progression in many patients with relapsing forms of MS.9 The disease-­modifying therapies include the beta interferons (ie, interferon beta-1a and interferon beta-1b), glatiramer acetate, natalizumab, and 3 oral therapies, including fingolimod, teriflunomide, and dimethyl fumarate. Corticosteroids may also be used to reduce inflammation during a relapse.9 In March 2014, the American Academy of Neurology published evidence-based practice guidelines for alternative and complementary medicines for MS.10

Symptom-management strategies for MS include physical therapy, muscle relaxants, dalfampridine (to improve walking speed), medications to reduce fatigue, and medications for depression, pain, bladder, or bowel control. In addition, sufficient rest, exercise, balanced nutrition, and stress relief may help to alleviate MS symptoms.11

A New Therapeutic Option Requiring Fewer Weekly Injections
On January 28, 2014, the US Food and Drug Administration (FDA) approved a higher-dose (40 mg/mL), lower-frequency (3 times weekly) regimen for glatiramer acetate (Copaxone; Teva Pharmaceuticals) for the treatment of patients with relapsing forms of MS.12 In 1996, the FDA approved glatiramer acetate 20 mg/mL injection administered once daily for RRMS.13

The FDA approval of glatiramer acetate 40 mg/mL 3 times weekly was based on findings from the multicenter GALA trial.14 According to the principal study investigator Omar Khan, MD, Wayne State University School of Medicine, Detroit, MI, “The availability of 3 times a week Copaxone 40 mg/mL is a significant advancement for patients as they now have the option of effective and safe treatment with Copaxone, while reducing the number of injections by 60%.”12

Mechanism of Action
The exact mechanism by which glatiramer acetate exerts its effects is not fully understood. However, gla­tiramer acetate is thought to act by modifying immune processes that are believed to be responsible for the pathogenesis of MS.15

Dosing and Administration
Glatiramer acetate is for subcutaneous injection only. The dosing schedule is dependent on the drug strength that is selected. The recommended doses for glatiramer acetate are 20 mg/mL administered once daily, or 40 mg/mL administered 3 times weekly and at least 48 hours apart. The 20-mg/mL dose and the 40-mg/mL dose are not interchangeable.15

GALA: A Phase 3 Clinical Trial
The safety and efficacy of glatira­mer acetate 40 mg/mL were demonstrated in the GALA trial, a double-­blind, placebo-controlled trial of 1404 patients with RRMS who were randomized in a 2:1 ratio to receive either glatiramer acetate 40 mg/mL (N = 943) or placebo (N = 461) 3 times weekly for 12 months.14,15

In this trial, the patients had a median of 2 relapses within 2 years before screening, and they had not received any interferon-beta for at least 2 months before screening. The patients’ baseline Expanded Disability Status Scale scores ranged from 0 to 5.5, with a median score of 2.5. Neurologic evaluations were performed at baseline, every 3 months, and at unscheduled visits for a suspected relapse or early termination. Magnetic resonance imaging (MRI) was conducted at baseline, at months 6 and 12, or at early termination. Overall, 91% of patients assigned to glatiramer acetate and 93% of patients assigned to placebo completed treatment at 12 months.14,15

Efficacy
The primary outcome measure in the GALA study was the total number of confirmed relapses, defined as the persistence of neurologic symptoms for at least 24 hours and confirmed on examination with objective signs.14 Patients with RRMS who received glatiramer acetate 40 mg/mL 3 times weekly showed a 34% reduction in risk of confirmed relapses compared with patients receiving placebo (0.331 vs 0.505; P <.001; Table 1).14,15

The effect of glatiramer acetate on several MRI variables, including the number of new or enlarging T2 lesions and the number of enhancing lesions on T1-weighted images, was assessed at months 6 and 12.14 Compared with patients taking placebo, patients who received glatiramer acetate 40 mg/mL 3 times weekly had a 35% reduction in new or newly enlarging T2 lesions (3.650 vs 5.592; P <.001), and a 45% reduction in the cumulative number of T1 lesions (0.905 vs 1.639; P <.001; Table 2).12,14

Safety
The most common (≥10% and ≥1.5 times higher than placebo) adverse reactions in the GALA trial were injection-site reactions.14,15 Adverse reactions reported in ≥ 2% of patients receiving glatiramer acetate 40 mg/mL versus placebo are shown in Table 3.15

Warnings and Precautions
Contraindications. Glatiramer acetate is contraindicated in patients with known hypersensitivity to glatiramer acetate or mannitol.15

Immediate postinjection reaction. Flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria may occur immediately after injection. Generally, the onset of these symptoms occurs several months after initiation of treatment.15

Chest pain. Chest pain may occur in the context of immediate postinjection or on its own. In clinical trials, chest pain was usually transient, often unassociated with other symptoms, and appeared to have no clinical sequelae. Some patients had more than 1 such episode; these episodes usually began at least 1 month after treatment was initiated.15

Lipoatrophy and skin necrosis. Lipo­atrophy and, rarely, injection-site skin necrosis may occur at injection sites. To help minimize these events, patients should be advised to follow proper injection techniques and to rotate injection sites with each injection.15

Immune response modification. Because glatiramer acetate can modify the immune response, it may interfere with immune functions.15

Use in Specific Populations
Pregnancy. There are no adequate and well-controlled studies with glatira­mer acetate in pregnant wom­en. Glatiramer acetate should be used during pregnancy only if clearly needed.15

Nursing mothers. It is not known whether glatiramer acetate is excreted in human milk. Caution should be exercised when glatiramer acetate is administered to a nursing woman.15

Pediatric use. The safety and effectiveness of glatiramer acetate have not been established in patients aged <18 years.15

Geriatric use. Glatiramer acetate has not been studied in elderly patients.15

Conclusion
The recent FDA approval of gla­tiramer acetate 40 mg/mL 3 times weekly marks the availability of a new, more convenient therapeutic option for patients with RRMS—offering appropriate patients a treatment that requires fewer subcutaneous injections weekly.

In the phase 3 GALA trial, patients with RRMS who received glatiramer acetate 40 mg/mL 3 times weekly showed a significant reduction in risk of confirmed relapses compared with patients receiving placebo. Moreover, patients receiving glatiramer acetate had a significant reduction in new or newly enlarging T2 lesions and in the cumulative number of T1 lesions compared with patients taking placebo.

The most common adverse reactions associated with 40 mg/mL glatiramer acetate were injection-site reactions.

References

  1. National Institutes of Health. Multiple sclerosis. Fact sheet. Updated October 2010. http://report.nih.gov/nihfactsheets/Pdfs/MultipleSclerosis%28NINDS%29.pdf. Accessed June 17, 2014.
  2. National Multiple Sclerosis Society. MS prevalence. www.nationalmssociety.org/About-the-Society/MS-Prevalence. Accessed April 22, 2014.
  3. Fox RJ. Cleveland Clinic. Multiple sclerosis. August 1, 2010. www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis. Published August 1, 2010. Accessed April 21, 2014.
  4. National Multiple Sclerosis Society. Who gets MS? (Epidemiology). www.nationalmssociety.org/What-is-MS/Who-Gets-MS. Accessed April 22, 2014.
  5. Wundes A, Brown T, Bienen EJ, Coleman CI. Contribution of intangible costs to the economic burden of multiple sclerosis. J Med Econ. 2010;13:626-632.
  6. Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16:639-647.
  7. Naci H, Fleurence R, Birt J, Duhig A. Economic burden of multiple sclerosis: a systematic review of the literature. Pharmacoeconomics. 2010;28:363-379.
  8. National Multiple Sclerosis Society. Multiple sclerosis bilingual fact sheet. July 2007. www.nationalmssociety.org/NationalMSSociety/media/MSNational Files/Brochures/Brochure-Hoja-bilingue-de-informacion-sobre-la-esclerosis-multiple-Multiple-Sclerosis- Bilingual-Fact-Sheet.pdf. Accessed April 22, 2014.
  9. National Multiple Sclerosis Society. Medications. www.nationalmssociety.org/Treating-MS/Medications. Accessed April 22, 2014.
  10. Yadav V, Bever C Jr, Bowen J, et al. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis: report of the guideline development subcommittee of the American Academy of Neurology. Neurology. 2014;82:1083-1092.
  11. Mayo Clinic staff. Mayo Clinic. Diseases and conditions: multiple sclerosis. December 15, 2012. www.mayo clinic.org/diseases-conditions/multiple-sclerosis/basics/definition/con-20026689. Accessed April 22, 2014.
  12. Teva Pharmaceuticals. Teva announces U.S. FDA approval of three-times-a-week COPAXONE (glatira­mer acetate injection) 40 mg/dL. January 28, 2014. www.tevapharm.com/Media/News/Pages/2014/1894510.aspx?year=2014. Accessed April 22, 2014.
  13. Jeffrey S. FDA approves 3-times-a-week Copaxone in MS. Medscape Medical News. January 29, 2014. www.medscape.com/viewarticle/819910. Accessed April 16, 2014.
  14. Khan O, Rieckmann P, Boyko A, et al. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73:705-713.
  15. Copaxone (glatiramer acetate) injection [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; January 2014.
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