Treatment Options for Multiple Sclerosis: Current and Emerging Therapies

Kristen M. Gawronski, Pharm.D.; Michelle M. Rainka, Pharm.D.; Malti J. Patel, M.D.; Francis M. Gengo, Pharm.D., FCP


Pharmacotherapy. 2010;30(9):916-927. 

In This Article

Emerging Therapies: Monoclonal Antibodies

Monoclonal antibodies are biologic agents that recognize specific target antigens exclusively. They cause immune responses, including cellular apoptosis or inhibition of ligand-receptor binding. Because of this, the adverse-effect profile is of concern with all monoclonal antibodies. They have the ability to deplete many cell lines and can lead to serious infections. Three types of monoclonal antibodies are available: murine, chimeric, and humanized. Murine antibodies are generally not used for therapeutic purposes because the immune system recognizes them as foreign and reacts. Rituximab is a chimeric monoclonal antibody, which consists of a murine antigen-binding domain and complement sequence on a human immuno-globulin G framework. These antibodies can sometimes cause infusion reactions or auto-antibody formation. Daclizumab, alemtuzumab, and natalizumab are humanized monoclonal antibodies. These are less immunogenic to the immune system than either the murine or chimeric monoclonal antibodies, since the only nonhuman portion of the antibody is the complement sequence.[8]

Humanized Monoclonal Antibodies

Alemtuzumab Alemtuzumab is a humanized monoclonal antibody that is FDA-approved for the treatment of fludarabine-resistant chronic lymphocytic leukemia.[8] It has also been investigated in the treatment of transplant rejection and various other autoimmune disorders.[16,31] It works by targeting CD52 on lymphocytes and monocytes, thereby causing extended reduction in the number of circulating T cells. Alemtuzumab has been evaluated for efficacy and safety in both RRMS and SPMS.[17,31]

Patients with SPMS were given monotherapy with alemtuzumab after treatment failure with other disease-modifying agents or if their disease course was rapidly progressing as evidenced by a high relapse rate.[16] Alemtuzumab was administered as an intravenous infusion of 20 mg/day over 4 hours for 5 days. Patients were generally pretreated with methylprednisolone 1 g on days 1–3 to prevent infusion reactions. Infusion reactions related to cytokine release occur commonly, and symptoms include rigors, fever, nausea or vomiting, rash, and hypotension. These symptoms can occur in up to 90% of patients receiving alemtuzumab if not appro-priately pretreated.[8] The depleting effects of alemtuzumab on CD4+ and CD8+ cell counts are prolonged: 61 months and 30 months, respectively. In this study, B cell counts returned to pretreatment levels at approximately 27 months.[16] Adverse effects observed included infections related to alemtuzumab, including spirochetal gingivitis, measles, herpes zoster, varicella zoster, recurrent aphthous ulcers, and pyogenic granuloma. A major adverse effect experienced by approximately 27% of patients receiving treatment was the development of Graves disease.

Although alemtuzumab was effective at suppressing inflammation as seen on MR images, the clinical course of the disease continued to progress. At first, the progression of disability appeared to be halted (> 90% of patients maintained their pretreatment EDSS score for 1 yr), but after that time point, disability as measured by EDSS continued to worsen at a rate of 0.2 points/year, which was statistically significant (p<0.001) compared with EDSS progression over 1 year before treatment. This finding led researchers to hypothesize about the mechanism of efficacy of alemtuzumab in each stage of the disease. If inflammation is preexisting at a high level, and the patient already has widespread axonal damage, inhibition of this process with alemtuzumab will not limit the clinical progression of the disease. They then decided to begin treatment earlier in the disease course, in the RRMS stage, in patients who had failed existing treatments. Although promising results were seen, such as reduction in relapse rate by 94%, the authors suggested that more evaluation is necessary to determine the proper phase of treatment. Based on the results of this study, it appears that alemtuzumab may provide more benefit in RRMS versus SPMS (Table 3).

In a phase II study, treatment-naive patients with RRMS were assigned to receive either alemtuzumab as annual intravenous infusions of either 12 or 24 mg/day for 5 days or interferon β-1a 44 μg subcutaneously 3 times/week.[17] Efficacy was determined by relapse rate and time to accumulation of disability measured by EDSS. The MR imaging outcomes were also evaluated as a secondary measure of drug efficacy. No significant differences in clinical outcomes were noted between the 12- and 24-mg dose groups. Both doses were efficacious at reducing the annualized relapse rate, with a reduction of 69% for 12 mg and 79% for 24 mg. Overall relapse rate with alemtuzumab was reduced by 74% compared with interferon β-1a therapy. Eighty percent of patients remained relapse free throughout the study, compared with 52% treated with interferon β-1a. Alemtuzumab also reduced the risk of disability by 71% compared with interferon β-1a, and EDSS score improved by an average of 0.39 points with alemtuzumab, whereas it worsened by 0.38 points during interferon β-1a treatment over 36 months. The MR imaging measures of efficacy improved in all three treatment groups; however, the difference in brain atrophy improvement was more significant for alemtuzumab.

Hematologic changes were observed during treatment with alemtuzumab, consistent with its mechanism of action. T-cell counts dropped significantly and remained low for the duration of the 36-month study, taking from 6–9 months for CD4+ counts to return to levels above 200 cells/mm3. B-cell counts were also affected; however, they regenerated more rapidly, taking 3–6 months to return to prestudy levels. Alemtuzumab-binding antibodies were detected during the study, but they do not appear to affect drug efficacy or cause adverse drug reactions such as infusion-site reaction or lymphocytopenia. Infusion reactions, including rash, headache, pyrexia, fatigue, pruritus, nausea, and chills, were observed, occurring in up to 90% of patients. Table 2 lists other observed adverse effects. Of note, opportunistic infections such as progressive multifocal leukoencephalopathy, cytomegalovirus, or pneumocystis pneumonia were not observed during alemtuzumab therapy.

Phase III studies are currently enrolling patients, investigating alemtuzumab versus interferon β-1a given subcutaneously.[32] Alemtuzumab will be given at a dosage of 12 or 24 mg intravenously once/day for 5 days then once/day for 3 days 1 year later. The comparator, interferon β-1a, is given 3 times/week for 2 years. Approximately 700 patients will be enrolled, and data are estimated to be available in early 2012.

Daclizumab Daclizumab is a humanized monoclonal antibody that antagonizes the α subunit of interleukin-2 on activated lymphocytes, inhibiting CD25–IL-2 complex formation.[2,33] The drug is FDA approved to prevent kidney transplant rejection episodes in combination with immunosuppressive drugs.[8] Interleukin-2 is responsible for upregulation of the immune system, apoptosis of T cells, and inhibition of T-helper 17 cells. It has been proposed that the CD25–IL-2 complex in patients with multiple sclerosis is abnormal, and daclizumab may be effective by inhibiting abnormal lymphocyte complexes from becoming activated.[2,33] Several phase II trials have evaluated the safety and efficacy of daclizumab in both RRMS and SPMS.[2]

One such trial studied daclizumab versus placebo as an adjunctive agent in patients who showed significant disease progression while receiving interferon β monotherapy.[18] The primary efficacy end point was reduction in gadolinium-enhancing lesions over the total duration of the study. Daclizumab was given by intravenous infusion every 2 weeks at a dose of 1 mg/kg for two doses, then monthly for five doses, in combination with interferon β. Therapy with interferon β was discontinued at this point if MR images showed a decrease in gadolinium-enhancing lesions by greater than 75%. If not, interferon β was continued, and the daclizumab dose was doubled to 2 mg/kg. Total numbers of gadolinium-enhancing lesions seen on MR images were reduced by 77% with daclizumab therapy, and new lesions were reduced by 72%. The EDSS scores were improved as well. It was observed that a decrease in CD4+ and CD8+ T cells was more robust in the daclizumab monotherapy group compared with patients who required daclizumab plus interferon β.

Adverse effects included systemic immune responses including mouth ulcers, photosensitivity rash, transient formation of autoantibodies requiring discontinuation of daclizumab, lymphopenia, lymphadenopathy, and transient increases in bilirubin concentration. This study showed that daclizumab is safe and effective as monotherapy or as an adjunctive agent to interferon β early in the disease course. There appears to be an additive benefit when daclizumab plus interferon β therapy is given to patients with more aggressive disease.

The adverse-effect profile has been relatively similar between daclizumab 1 mg/kg, 2 mg/kg, and placebo (Table 2). Antibodies to daclizumab have not been detected after treatment, and PML (a life-threatening adverse effect reported with natalizumab) has not been reported thus far.[2]

Daclizumab will likely be used as monotherapy in patients RRMS and SPMS, or as an adjunct to interferon β therapy in patients with RRMS. Another phase II study is recruiting patients with RRMS to assess the efficacy and safety of two doses of subcutaneous daclizumab compared with placebo.[34] Daclizumab will be given at a dosage of either 150 or 300 mg subcutaneously every 4 weeks for 48 weeks. Primary efficacy will be measured by MR imaging outcomes, including number and volume of gadolinium-enhancing lesions. This study finished enrolling participants at the end of 2009, and data should be published by late 2010. Additional phase II extension trials are under way assessing 150- and 300-mg doses of daclizumab given subcutaneously every 4 weeks for 52 weeks in patients with RRMS who have already completed a primary trial. These results should be published by late 2012.[34]

Chimeric Monoclonal Antibodies

Rituximab Rituximab is a chimeric monoclonal antibody that is FDA approved for the treatment of non-Hodgkin's lymphoma and as an adjunctive agent for rheumatoid arthritis. It causes cytotoxicity by selectively depleting CD20+ pre-B cells and B cells.[8,35] Rituximab has been investigated in several ongoing clinical trials in patients with PPMS and RRMS.[8]

A recently completed phase II trial assessed the efficacy and safety of rituximab over 48 weeks in patients with RRMS.[19] Rituximab was compared with placebo at a dose of 1 g on days 1 and 15. The primary efficacy end point evaluated was total number of gadolinium-enhancing lesions observed on MR images. Relapse rate, annual rates of relapse, and new enhancing lesions were assessed as secondary measures of efficacy. Gadolinium-enhancing lesions were decreased by 91% compared with placebo. This effect was observed beginning at week 12 and remained so throughout the evaluation period. Relapse rate was decreased, with approximately 20% of patients experiencing a relapse in the treatment group compared with 40% of the placebo group. Rituximab was effective at decreasing new gadolinium-enhancing lesions compared with placebo.

Over 75% of patients reported infusion reactions consisting of chills, headache, nausea, pruritus, pyrexia, and fatigue. Patients were pretreated with acetaminophen and diphenhydramine 30–60 minutes before the rituximab infusion to combat infusion-associated reactions. Other adverse events occurring in greater than 10% of patients receiving rituximab are listed in Table 2. Rates of infection were similar between treatment and placebo groups, and the occurrence of opportunistic infections was not noted during this study period. The CD20+ cellular depletion as measured by CD19+ expression occurred rapidly and at levels of greater than 95% after rituximab infusion. This effect was prolonged, with levels only rising to 30% of baseline by the conclusion of the study. Antichimeric antibodies were observed in approximately 25% of patients, but this did not appear to affect clinical efficacy or adverse effects.

Rituximab will likely be used in patients with RRMS, as well as those with PPMS, a phase for which we do not yet have available treatments. A phase II–III trial assessing the efficacy and safety of rituximab in patients with PPMS was recently completed, and final results will be available soon.[36] Patients were assessed over a 96-week period and evaluated on clinical and MR imaging measures, including time to disease progression, number and volume of lesions detectable with MR imaging, and adverse events such as hematologic changes, thyroid function, and antibody formation.


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