August 2015, Vol 3, No 8 - Inside Drug Update
Loretta Fala

Multiple sclerosis (MS), a chronic, inflammatory disease of the central nervous system, disrupts the communication between the brain, spinal cord, and other areas of the body.1 Aside from being potentially debilitating, MS can result in irreversible nerve deterioration.1 The incidence and prevalence of MS are not consistently tracked in the United States; it is estimated that 400,000 Americans are currently affected by the disease.2

The most common symptoms associated with MS are fatigue, numbness, spasticity, vision problems, and bowel and bladder problems.1,3 The symptoms of MS can vary widely from one person to another, depending on which nerves are affected and the extent of nerve damage.1

The 4 types of this condition are relapsing-remitting MS (RRMS), secondary-progressive MS, primary-progressive MS, and progressive-relapsing MS. RRMS is the most common type, accounting for 85% of initial diagnoses of MS, whereas the progressive type of the disease accounts for 10% to 15% of cases.3 RRMS is characterized by temporary periods of relapses or exacerbations of neurologic functioning, followed by periods of disease remission, in which partial or complete recovery occurs.4

MS, particularly if untreated or in the advanced phase, is associated with multiple symptoms that can impose a substantial burden on the patient’s mobility, daily activities, cognitive function, physical well-being, and overall quality of life. Patients with MS are also at risk for depression, osteoporosis, pressure sores, and other complications.5 Furthermore, MS has a profound impact on caregivers, as well as on the healthcare system.

A systematic review of MS-related healthcare cost studies published between 2007 and 2012 showed that the total all-cause direct and indirect costs for MS ranged from $8528 to $54,244 per patient annually.6 The direct costs accounted for an average of 77% of the total healthcare costs, and the indirect costs accounted for approximately 23% of the total costs.6 In fact, the direct all-cause healthcare costs for MS ranked second to congestive heart failure when compared with other chronic conditions. This review did not take into account some of the recent, more costly treatments, or the costs associated with increasing disability, early retirement, or diminished quality of life associated with MS.6

It is crucial to diagnose and treat MS early to hinder permanent neurologic damage.7 A number of effective strategies are available to help slow the progression of the disease, manage symptoms, and improve physical and neurologic functioning. Most notable of the strategies include the disease-modifying therapies, which have been shown to reduce disease activity and disease progression in many patients with relapsing forms of MS.1

Until recently, these disease-modifying therapies included the beta interferons, glatiramer acetate (Copaxone), nat­alizumab (Tysabri), and the 3 oral therapies fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera).1

Other treatments include corticosteroids to reduce inflammation during a relapse, and dalfampridine to improve walking in patients with MS.

Alemtuzumab: A Novel Option for Patients with Relapsing Multiple Sclerosis

On November 14, 2014, the US Food and Drug Administration (FDA) approved alemtuzumab (Lemtrada; Genzyme), a CD52-directed cytolytic monoclonal antibody, for the treatment of relapsing forms of MS.8 Because of its safety profile, the use of alemtuzumab should generally be reserved for patients who have had an inadequate response to 2 or more drugs indicated for the treatment of MS.8,9

Alemtuzumab (Campath; Genzyme) was initially approved by the FDA in 2001 under its accelerated approval process for previously treated patients with B-cell chronic lymphocytic leukemia (CLL).10 In September 2007, alemtuz­umab received an FDA approval and an expanded indication as a single agent for the treatment of B-cell CLL.10

The FDA approved alemtuzumab for MS with the condition of the drug being available only through a restricted distribution program, as part of its Risk Evaluation and Mitigation Strategy (REMS) program.11 The alemtuzu­mab REMS program is intended to inform prescribers, pharmacies, healthcare facilities, and patients about the potential risks associated with alemtuzumab and the recommended monitoring at period intervals for 48 months after the last dose.11

According to Edward Fox, MD, PhD, Director of the Multiple Sclerosis Center of Central Texas, “The unmet need in MS remains high. It is a great day for people living with relapsing forms of MS in the United States, who will now have access to this new meaningful treatment.”8

Timothy Coetzee, PhD, Chief Advocacy, Services and Research Officer at the National MS Society, commented, “The FDA approval of Lemtrada is a significant milestone for people living with relapsing MS in the United States. We are pleased that the voices of the MS community have been recognized and that people with relapsing MS will now have access to a new, needed treatment option.”8

Dosing

Alemtuzumab is administered via intravenous infusion over 4 hours for 2 treatment courses—the first course is 12 mg daily on 5 consecutive days, and the second course is 12 mg daily on 3 consecutive days 12 months after the first treatment course.9

Premedication with corticosteroids is given before the infusion of alemtuzu­mab for the first 3 days of each treatment course. The administration of antiviral agents for herpetic prophylaxis should be started on the first day of alemtuzumab dosing, and should be continued for a minimum of 2 months after the completion of alemtuz­umab dosing or until the CD4+ lymphocyte count is more than 200 cells/mL, whichever occurs later. Alemtuzumab must be diluted before its administration.9

Alemtuzumab is available as a 12-mg/1.2-mL (10-mg/mL) injection in a single-use vial.9

Mechanism of Action

Alemtuzumab is a recombinant humanized immunoglobulin G1 kappa monoclonal antibody directed against the cell surface glycoprotein CD52. Although the precise mechanism by which alemtuzumab exerts its therapeutic effects in MS is unknown, it is presumed to involve the binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. After cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.9

Clinical Studies

The efficacy of alem­tuzumab 12 mg was dem­onstrated in 2 phase 3 studies (CARE-MS I and CARE-MS II) in patients with RRMS.12,13 In these studies, alemtuzumab was administered by intravenous infusion once daily for 5 days, followed 1 year later by intravenous infusion once daily for 3 days.9

Both studies included patients who had at least 2 relapses during the 2 years before trial entry and at least 1 relapse during the year before trial entry. Neurologic examinations were conducted every 12 weeks and at the time of the suspected relapse. Magnetic resonance imaging (MRI) evaluations were performed annually. For both studies, the clinical outcome measures were the annualized relapse rate over 2 years and the time to confirmed disability progression. The MRI outcome measure was the change in T2 lesion volume.9

CARE-MS I Study

The CARE-MS I study was a 2-year randomized, controlled, open-label, rater-blinded trial that compared alemtuzumab 12 mg with interferon beta-1a 44 mcg (administered subcutaneously 3 times weekly) in previously untreated patients with RRMS (mean age, 33 years; mean disease duration, 2 years; mean Expanded Disability Status Scale [EDSS] score, 2).9,12

Patients receiving alemtuzumab demonstrated a significantly lower annualized relapse rate (a 55% relative reduction) than patients receiving interferon beta-1a (Table 1).

Table 1

No significant difference was seen between the treatment groups for the time to confirmed disability progression and the primary MRI end point (change in T2 lesion volume). At year 2, 78% of the patients receiving alemtuzumab remained relapse-free compared with 59% of the patients receiving interferon beta-1a.9,12

CARE-MS II Study

The CARE-MS II study was a 2-year randomized, controlled, open-label, rater-blinded trial that compared alemtuz­umab 12 mg with interferon beta-1a 44 mcg (administered subcutaneously 3 times weekly) in patients with RRMS that relapsed despite first-line disease-modifying therapy (mean age, 35 years; mean disease duration, 4.5 years; mean EDSS score, 2.7).9,13

In the alemtuzumab group, the annualized disease relapse rate was significantly lower (a 49% relative reduction) than in patients who received interferon beta-1a (Table 2). Moreover, the time to onset of 6-month confirmed disability progression at 2 years was significantly delayed in the alemtuzumab group (a 42% relative risk reduction) compared with the interferon beta-1a group. No significant difference was found between the treatment groups in change in T2 lesion volume.9,13 At year 2, 65% of patients in the alemtuzumab group were relapse-free versus 47% of patients in the interferon beta-1a group.9,13

Table 2

Safety

The most common adverse reactions (incidence ≥10% and greater than interferon beta-1a) with alemtuzumab were9:

Rash  53% Fungal Infection  13%
Headache 52% Arthralgia  12%
Pyrexia  29% Pain in Extremity  12%
Nasopharyngitis  25% Back Pain  12%
Nausea  21% Diarrhea  12%
Urinary Tract Infection 19% Sinusitis  11%
Fatigue 18% Oropharyngeal Pain  11%
Insomnia  16% Paresthesia  10%
Upper Respiratory Tract Infection 16% Dizziness  10%
Herpes Viral Infection  16% Abdominal Pain  10%
Urticaria 16% Flushing  10%
Pruritus  14% Vomiting  10%
Thyroid Gland Disorders  13%    

Contraindications

The use of alemtuzumab is contraindicated in patients infected with HIV.9

Warnings and Precautions

Boxed warning
Alem­tuzumab was approved with a boxed warning stating that alemtuzumab may cause serious, sometimes fatal, autoimmune conditions, such as immune thrombocytopenia and antiglomerular basement membrane disease, as well as serious and life-threatening infusion reactions and an increased risk for malignancies.9

Autoimmunity
Alemtuzumab can result in the formation of autoantibodies and can increase the risk for serious autoimmune-mediated conditions. Complete blood counts should be monitored with differential, serum creatinine levels, and urinalysis with urine cell counts at periodic intervals for 48 months after the last dose of alemtuzumab.9

Immune thrombocytopenia occurred in 2% of patients receiving alemtuzu­mab in clinical studies in MS. Complete blood counts with differential should be obtained before the initiation of treatment with alemtuz­umab and at monthly intervals thereafter until 48 months after the last infusion.9

Infusion reactions
Alemtuzumab causes cytokine release syndrome, resulting in infusion reactions, some of which may be serious and life-threatening. The drug must be administered in a setting that can appropriately manage anaphylaxis or serious infusion reactions. Patients should be monitored for 2 hours after each infusion and be advised that serious infusion reactions can also occur after the 2-hour monitoring period.9

Malignancies
Alemtuzumab may cause an increased risk for malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders. Baseline and annual skin examinations should be performed.9

Thyroid disorders
Thyroid function tests should be obtained before treatment and every 3 months until 48 months after the last infusion of alemtuzumab.9

Other autoimmune cytopenias
Complete blood counts should be monitored monthly until 48 months after the last infusion of alemtuzumab.9

Infections
In patients with active infections, delaying the initiation of alemtuzumab should be considered until the infection is fully controlled. Live viral vaccines should not be administered after a course of alemtuzumab.9

Other warnings
Glo­merular nephropathies and pneumonitis have been associated with the use of alemtuz­umab. If alemtuzumab is considered for the treatment of MS in a patient who has previously received alemtuzu­mab (Campath) for B-cell CLL, increased vigilance should be exercised in watching for any additive and long-lasting effects on the immune system.9

Use in Specific Populations

Pregnancy
There are no adequate and well-controlled studies in pregnant women. Alemtuzumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.9

Nursing mothers
It is not known whether alemtuzumab is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from alemtuzumab in nursing infants, a decision should be made whether to discontinue nursing or to discontinue alemtuzumab, taking into account the importance of the drug to the mother.9

Pediatric use
The safety and effectiveness of alemtuzumab in patients aged <17 years have not been established.9

Geriatric use
Clinical studies of alemtuzumab did not include sufficient numbers of patients aged ≥65 years to determine whether they respond different from younger patients.9

Conclusion

The FDA’s approval of alemtuzumab marks the availability of another treatment option for patients with relapsing forms of MS. The efficacy of alemtuz­umab was demonstrated in a clinical development program that included nearly 1500 patients with more than 6400 patient-years of safety follow-up.8

In clinical studies, alemtuzumab significantly reduced the annualized relapse rates over a 2-year period as first-line treatment and in previously treated patients with relapsing forms of MS compared with interferon beta-1a therapy. Because of its safety profile, the use of alemtuzumab should generally be reserved for patients who have had an inadequate response to 2 or more drugs indicated for the treatment of MS.9

Copyright © 2015 American Health & Drug Benefits. All rights reserved.




References

  1. Mayo Clinic staff. Diseases and conditions: multiple sclerosis. July 10, 2014. www.mayoclinic.org/diseases-conditions/multiple-sclerosis/basics/definition/CON-20026689. Accessed April 23, 2015.
  2. National Multiple Sclerosis Society. MS prevalence: estimating the prevalence of MS. www.nationalmssociety.org/About-the-Society/MS-Prevalence. Accessed April 24, 2015.
  3. National Multiple Sclerosis Society. Relapsing-remitting MS (RRMS). www.nationalmssociety.org/about-multiple-sclerosis/relapsing-ms/relapsing-remitting-ms-rrms/index.aspx. Accessed April 23, 2015.
  4. National Multiple Sclerosis Society. Managing relapses. www.nationalmssociety.org/Treating-MS/Managing-Relapses. Accessed April 24, 2015.
  5. National Multiple Sclerosis Society. Living with advanced MS. www.nationalmssociety.org/about-multiple-sclerosis/living-with-advanced-ms/index.aspx. Accessed April 23, 2014.
  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. National Multiple Sclerosis Society. Adherence. www.nationalmssociety.org/Treating-MS/Medications/Adherence. Accessed April 24, 2014.
  8. Drugs.com. FDA approves Lemtrada: FDA approves Lemtrada (alemtuzumab) for relapsing forms of multiple sclerosis. Press release. November 2014. www.drugs.com/newdrugs/fda-approves-lemtrada-alemtuzumab-relapsing-forms-multiple-sclerosis-4110.html. Accessed April 22, 2015.
  9. Lemtrada (alemtuzumab) injection [prescribing information]. Cambridge, MA: Genzyme Corporation; November 2014.
  10. US Food and Drug Administration. Drugs@FDA: FDA approved drug products: Campath. Label and ap­prov­al history. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo. Accessed April 22, 2015.
  11. Genzyme. Lemtrada REMS (Risk Evaluation and Mitigation Strategy) program. www.lemtradarems.com/. Accessed April 23, 2015.
  12. Cohen JA, Coles AJ, Arnold DL, et al; for the CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819-1828.
  13. Coles AJ, Twyman CL, Arnold DL, et al; for the CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380:1829-1839.
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