快樂小藥師 Im pharmacist nichts glücklich

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) with presumed inflammatory and degenerative elements. MS entered the rather small ranks of neurologic diseases with disease-modifying therapies in 1993. Since then, 6 agents have received regulatory approval. Five of these agents are indicated for treatment of the relapsing forms of MS and 1 agent for more severe, worsening forms. No therapy is approved or has shown efficacy in treating primary progressive MS. All of the currently available agents are immunomodulatory, strongly supporting the evidence that the pathogenesis of MS relates to an immune aberration. MS has much in common with autoimmune diseases of other organs; although there are abundant data supporting a dysimmune state in patients with MS, the proof of autoimmunity is not yet available. The successful employment of immunomodulating therapies also raises questions about the potential role of other putative causes for MS. Although it had been hoped that increased knowledge of the immunopathogenesis of MS would lead to more focused therapies, that goal has only been partially realized.

Current Agents

The first-line therapeutic agents include glatiramer acetate and 3 versions of interferon beta: 2 regimens of beta-1a and 1 regimen of beta-1b. All are administered parenterally (intramuscularly or subcutaneously) by injection from once weekly to daily. In addition to demonstrated efficacy in relapsing-remitting MS, these agents are efficacious when employed after a first attack of demyelination, before a secure diagnosis of MS can be made. Interferon has several potential mechanisms of action that could be at work in treating MS. These include shoring up the blood-brain barrier, an antiproliferative effect on lymphocytes, downregulation of helper T-cell functions, antagonizing interferon gamma, and shifting of immune function from helper mode to regulatory mode. Glatiramer acetate is thought to act primarily by shifting the immune system from helper to regulatory functions through generation of glatiramer acetate-reactive T cells. It also has effects on other immune elements and potential neuroprotective actions.^[1]

Second-line agents include natalizumab, which has demonstrated excellent efficacy in relapsing-remitting MS, but because of a more challenged safety profile compared with the first-line agents, it is usually employed after failure of the first-line agents. Natalizumab is a monoclonal antibody directed against the adhesion molecule VLA-4.

Blockade of VLA-4 limits the egress of lymphocytes from the bloodstream into the CNS. In clinical trials of early MS, natalizumab demonstrated significant improvement in reducing relapse rate and accrual of disability.^[2]Natalizumab was also effective in treating individuals with evidence of disease activity while on low-dose interferon.^[3] Natalizumab is associated with development of progressive multifocal leukoencephalopathy, a viral infection of the brain, the risk of which increases with time on the therapy.^[4] Mitoxantrone, a chemotherapeutic agent is also used second line, especially in those who transition to secondary progressive MS. Mitoxantrone is broadly immunosuppressive of all immune elements.^[5] As a chemotherapeutic agent, mitoxantrone has a number of significant toxicities. Both of these agents are administered by intravenous infusion.

All of these agents are partially effective. Head-to-head studies have suggested that higher doses of interferon are more effective than lower doses, and that higher-dose interferon and glatiramer acetate have equivalent clinical efficacy.^[6,7] Although natalizumab has impressive efficacy data, there are no head-to-head studies comparing it with the first-line therapies.

The current therapeutic needs in relapsing-remitting MS are for more effective, safer, and easier-to-administer agents that will treat all forms of MS. This review explores how none of the pipeline agents are likely to fulfill all 3 of these criteria. Therefore, the pipeline is quite full with new and interesting molecules that have the potential to enhance our ability to treat this illness.

In addition to the new agents that are discussed below, emerging therapies might include more efficient use of current molecules, such as longer-acting forms of interferon or the introduction of generic versions. Combination approaches also may be developed.

Emerging Therapies

All of the agents in late-stage testing have effects on the immune system and have shown success in earlier phase 2, proof-of-principle clinical trials. Two have also shown efficacy in pivotal studies (phase 3, those on which regulatory approval can be sought). Most are being tested in additional phase 3 studies.

Oral Agents

Several oral agents are in the developmental pathway, and 2 agents have completed pivotal studies. If approved, they would fulfill the therapeutic need for an easier-to-administer agent, and for some there is the potential for better efficacy as well. If successful, the availability of oral agents would be most welcome for individuals with MS whose current options have been limited to injections.

Oral agents with completed phase 3 studies.

Fingolimod. Also known as FTY720, this agent is a modulator of the sphingosine-1-phosphate receptor, which leads to internalization of the receptor.^[8] Absence of the receptor on the cell surface removes the signal needed for activated lymphocytes to egress from lymph nodes into the systemic circulation. This sequestration of activated lymphocytes produces a reduction in circulating lymphocytes and thus fewer cells available for entry into the CNS. This mechanism of action differs from natalizumab, which establishes a blockade of VLA-4 that inhibits the ability of lymphocytes in the circulation to traffic across the blood-brain barrier into the target CNS. Natalizumab increases the number of circulating lymphocytes, whereas fingolimod produces a decrease. The net effect in each case is to limit access to the CNS by autoreactive lymphocytes.

In 2006, a phase 2, proof-of-concept study of 255 patients with relapsing MS tested 2 daily oral doses of fingolimod (1.25 mg and 5 mg) against placebo.^[8] The primary outcome measure was the total number of gadolinium-enhanced lesions seen on T1-weighted MRI at monthly intervals for 6 months. Both the 1.25-mg and 5-mg doses were associated with significant reductions in mean total number of gadolinium-enhanced lesions on MRI compared with placebo. The annualized relapse rate was also significantly lower in both treatment arms. The incidence of serious adverse events was similar in all 3 groups, and there were no deaths. Adverse events were higher in the 5-mg group than in the 1.25-mg or placebo group. The most frequent adverse events were nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Asymptomatic lymphopenia and liver enzyme elevations were the most common laboratory abnormalities.

Results of a phase 3 pivotal study of fingolimod in 1272 patients with relapsing-remitting MS were reported in early 2010 (Efficacy and Safety of Fingolimod in Patients With Relapsing-remitting Multiple Sclerosis [FREEDOMS] study).^[9] This was a 24-month, randomized, placebo-controlled trial of 0.5 mg and 1.25 mg of oral fingolimod daily. The primary outcome measure was annualized relapse rate, and the key secondary outcome was time to confirmed disability progression. The annualized relapse rates were 0.18 for fingolimod 0.5 mg, 0.16 for 1.25 mg, and 0.40 for placebo. Both doses of fingolimod were significantly better than placebo. The probability of confirmed progression was 17.7%, 16.6%, and 24.1% in the 0.5-mg, 1.25-mg, and placebo groups, respectively. Both doses were significantly better than placebo. Both doses also were superior to placebo in MRI metrics -- number of new or enlarged lesions, gadolinium-enhancing lesions, and brain volume. Of interest, the fingolimod groups had less loss of brain volume than placebo at each timepoint from 6 months through 24 months. This brain volume result has not been seen in prior pivotal studies of other anti-inflammatory agents. The incidence of adverse events was similar in all 3 groups. Adverse events leading to discontinuation of study drug were most common in the 1.25-mg dose. Serious adverse events occurred in 10.1% of the 0.5-mg group, 11.9% of the 1.25-mg group, and 13.4% of the placebo group. Three deaths occurred in the study. Two deaths were in the placebo group (pulmonary embolism and traffic accident) and 1 death in the 1.25-mg group (suicide). Lower respiratory infections were more common in those receiving fingolimod. Transient bradycardia was seen after the first dose of fingolimod. This started 2 hours after the first dose and peaked at 4-5 hours. The mean decrease was 8 beats per minute and 10 beats per minute for the low and high doses of fingolimod, respectively. Six events were symptomatic and 2 events required treatment. There was also a mild increase in mean systolic and diastolic blood pressures. Macular edema was seen in 7 participants in the 1.25-mg dose group. There was no increase in malignancies seen in the treated groups. A reduction of greater than 70% in lymphocyte counts was seen with fingolimod after 1 month on therapy and remained stable thereafter. Abnormal liver enzyme levels were seen more often in the 1.25-mg fingolimod group.

A second pivotal study compared oral fingolimod 0.5 mg and 1.25 mg daily with interferon beta-1a 30 µg intramuscularly weekly in a 12-month, multicenter, randomized, double-blind, double-dummy, parallel-group design with 1153 patients (Efficacy and Safety of Fingolimod in Patients With Relapsing-Remitting Multiple Sclerosis With Optional Extension Phase [TRANSFORMS] study).^[10] The primary endpoint was the annualized relapse rate with similar secondary endpoints to the FREEDOMS study. The resultant annualized relapse rate was significantly better in both fingolimod groups (0.16 in the 0.5-mg group and 0.2 in the 1.25-mg group) than in the interferon group (0.33). The clinical results were similar in the subgroup of patients who were treatment naive vs those who had previously been treated with another MS therapy. MRI results were similarly improved with fingolimod, including significant differences in brain volume reduction. Progression of disability was uncommon across all groups in this 1-year study. Serious adverse events were greater in the fingolimod groups, primarily bradycardia and atrioventricular block. Two deaths were reported in the fingolimod 1.25-mg group. One death was caused by a primary disseminated varicella infection. The second was from herpes simplex encephalitis. Herpetic infections were more common in the 1.25-mg group. Although numbers were too small to attribute causality, 5 basal cell carcinomas were seen in the fingolimod groups and 1 in the interferon group. Three melanomas were seen in the fingolimod 0.5-mg group, and 1 squamous cell carcinoma was discovered in the interferon group. There were 2 breast cancers in each fingolimod group. Other adverse events were similar to those seen in the FREEDOMS trial.

Another randomized controlled, relapsing-remitting MS study is under way as well as a study of primary progressive MS with fingolimod.

In short, fingolimod performed well in 2 pivotal trials demonstrating efficacy in both clinical and MRI metrics when compared with placebo or interferon beta-1a. In terms of the 3 therapeutic needs discussed above, fingolimod provides excellent efficacy that is superior to interferon beta-1a when administered once weekly, and with a more convenient dosing route (oral). Safety thus far has been acceptable, but will likely be more of an issue than with current agents. The efficacy data are similar for both doses of fingolimod, but the lower dose had a better safety profile. This agent has been submitted and is under review by the US Food and Drug Administration (FDA) for approval as a new drug for treatment of relapsing MS.

Cladribine. This cytotoxic agent has selective actions on lymphocytes, and is currently approved for parenteral use as an antineoplastic agent for treatment of hairy cell leukemia. The active metabolite of cladribine, 2-chlorodeoxyadenosine triphosphate, accumulates intracellularly resulting in disruption of cellular metabolism, inhibition of DNA synthesis, and cellular apoptosis. Because lymphocytes are dependent on adenosine deaminase activity to maintain proper concentrations of triphosphorylated nucleotides, they are preferentially susceptible to the toxic effects of cladribine. After administration, there is a rapid and sustained depletion of CD4 and CD8 T cells. B cells are affected to a lesser extent. This reduction in lymphocytes is the presumed mechanism of action for this agent.^[11,12]

Unlike the other agents discussed in this review, there are no modern phase 2, proof-of-principle studies of cladribine in MS. Several single-site studies were performed in the 1990s as well as a multicenter trial in patients with progressive disease using parenteral formulations.^[13] In the latter study, there was no evidence of clinical effect but there was a reduction in MRI activity.

A phase 3 pivotal study was completed and reported more recently. The CLAdRIbine tablets Treating multiple sclerosis orallY (CLARITY) study -- a randomized, double-blind, placebo-controlled study of 2 doses of oral cladribine and placebo -- was composed of 1326 patients with relapsing-remitting MS.^[11] Participants received either 3.5-mg/kg or 5.25-mg/kg cumulative doses of cladribine or matching placebo given in 2 or 4 short courses in the first year (at day 1, week 5, week 9, and week 13), and then 2 short courses at weeks 48 and 52. Each course consisted of one or two 10-mg tablets daily for the first 4 or 5 days of each 28-day cycle. The long-lasting lymphopenic effects of cladribine allowed for this abbreviated dosing schedule. If after week 24 patients experienced more than 1 relapse or a sustained worsening of Expanded Disability Status Score (EDSS), they could go on rescue therapy with subcutaneous interferon beta-1a, 44 µg 3 times weekly. The primary outcome measure was the rate of relapse at 96 weeks. The results were that those on either the 3.5-mg/kg or 5.25-mg/kg dose of cladribine had a significantly lower annualized relapse rate than placebo (0.14 and 0.15, respectively, for cladribine, 0.33 for placebo). The cladribine groups also had lower risk for sustained disability accrual (hazard ratio 0.67 for the 3.5-mg/kg group and 0.69 for the 5.25 mg/kg group). Both doses of cladribine demonstrated reduced MRI activity compared with placebo. Adverse events, serious adverse events, and adverse events leading to drug discontinuation were highest in the 5.25-mg/kg group and lowest in the placebo group. Six deaths were associated with the study, equally distributed across study groups. Lymphocytopenia (usually graded mild or moderate) occurred more commonly in the cladribine groups, in keeping with the agent's mechanism of action. Three patients on cladribine had severe neutropenia, whereas 1 patient on the high dose had severe thrombocytopenia and pancytopenia as well as exacerbation of latent tuberculosis. At the end of the first year, there was a median residual reduction of 35.6% in lymphocyte counts in the 3.5-mg/kg group and 49.6% in the 5.25-mg/kg group. After the second year these were 43.5% and 48.3%, respectively. There were 8 herpes zoster infections in the 3.5-mg/kg group and 12 in the 5.25-mg/kg group. Herpes zoster was reported as a serious adverse event in 3 participants receiving cladribine and in 2 patients in the 5.25-mg/kg group. There was an inverse correlation between the incidence of infection and the lowest lymphocyte count in the cladribine groups. There were 10 neoplasms in the cladribine groups, but none in the placebo group. Of these, 5 were uterine leiomyomas. There were a melanoma, carcinoma of the pancreas, carcinoma of the ovary, and a precancerous cervical lesion.

One well-designed, pivotal study of 2 dosages of oral cladribine demonstrated excellent efficacy results vs placebo in clinical and MRI metrics. The efficacy assessments were similar for both doses of cladribine, but the lower dose had a better safety profile. The issue of infections and neoplasia will need further monitoring before firm conclusions can be drawn. Participants from the CLARITY study are being followed in an extension phase. A phase 3 study is under way comparing oral cladribine with placebo in patients with a clinically isolated syndrome (the Oral Cladribine in Early Multiple Sclerosis [ORACLE MS] study). Also, a phase 2, placebo-controlled study is under way to determine the safety and efficacy of adding cladribine tablets to patients on interferon beta-1a 44 µg 3 times weekly who experience breakthrough disease activity (the Phase II Cladribine Add-on to Interferon-beta [IFN-b] Therapy in MS Subjects With Active Disease [ONWARD] study).

Oral agents with completed phase 2 studies with phase 3 studies under way.

Teriflunomide. Teriflunomide is a metabolite of leflunomide, an immunomodulating agent approved for treatment of rheumatoid arthritis. As an orally available agent, teriflunomide binds the enzyme dihydroorotate dehydrogenase inhibiting the pyrimidine synthesis pathway primarily in rapidly dividing cells. In a phase 2 study performed to test the safety and efficacy of oral teriflunomide, 179 patients with relapsing forms of MS were randomly sampled to receive either 7 mg or 14 mg teriflunomide daily or placebo for 36 weeks.^[14] The primary outcome measure was the number of combined active lesions (gadolinium-enhancing T1 lesions and new or enlarging T2 lesions) on MRI scans performed every 6 weeks during the treatment period. The number of active lesions was significantly lower in both teriflunomide groups compared with placebo. Patients in the 14-mg/day group had a significant reduction in T2 lesion disease burden and showed less increase in disability. There was a trend for lower relapse rates in the teriflunomide groups. The treatment was reasonably well tolerated. Adverse events and serious adverse events were similar in all groups.

Another study added teriflunomide 7 mg/day or 14 mg/day or placebo for 116 patients taking interferon beta for 24 weeks.^[15] There were significantly fewer gadolinium-enhancing lesions in the groups receiving both doses of teriflunomide in addition to interferon compared with the placebo added to the interferon group. The effect was greater in the 14-mg/day group. No new safety issues were noted in this combination study. A similar study was performed in patients treated with glatiramer acetate.^[16] The same 2 doses of teriflunomide and placebo were added. The results revealed a reduction in gadolinium-enhancing lesions in the treatment groups, but not as impressive as seen with interferon.

Several phase 3 studies of teriflunomide are under way in relapsing-remitting MS and clinically isolated syndrome.

Laquinimod. Laquinimod is an orally available immunomodulating agent that is believed to exert its effects through a shift from Th1 to Th2. Laquinimod is structurally related to roquinimex, a molecule that was tested in MS but was withdrawn during a phase 3 study due to side effects. Laquinimod thus far has demonstrated a better safety profile. An initial phase 2, placebo-controlled study over 24 weeks revealed that oral laquinimod 0.3 mg daily was superior to placebo in suppressing gadolinium-enhancing lesions.^[17] A second phase 2 study in relapsing-remitting MS was performed comparing 0.3 mg and 0.6 mg of laquinimod with placebo using a randomized, double-blind, 36-week protocol.^[18] The primary outcome measure was the cumulative number of gadolinium-enhancing lesions at weeks 24, 28, 32, and 36. The 0.6-mg dose produced a significant reduction in disease activity as measured by MRI, both for gadolinium-enhancing lesions and new T2 lesions and a reduction in cumulative T1 hypodensities. The 0.3-mg dose did not reveal a significant difference. There was a trend for lower relapse activity in the 0.6-mg group. Safety was similar in all groups. There was a case of Budd-Chiari syndrome in a participant in the 0.6-mg group with an underlying hypercoagulable state. There were also transient elevations of liver enzymes. Two randomized, controlled, phase 3 studies are under way: one comparing laquinimod 0.6 mg with placebo over 24 months and a second comparing laquinimod 0.6 mg with interferon beta-1a 30 µg weekly and placebo over 24 months.

Dimethyl fumarate (BG-12). An oral form of dimethyl fumarate, a fumaric acid ester, is being tested in MS. Fumaric acid has immunomodulating properties and has been used to treat psoriasis.^[12] BG-12 has several putative mechanisms of action, both on peripheral immune function and as a potential neuroprotective agent acting against oxidative stress-induced cell death in CNS cells. An open-label pilot study suggested that BG-12 could reduce MRI activity in MS.^[19] A 24-week, phase 2, multicenter, randomized, placebo-controlled, double-blind study of oral BG-12 was undertaken in 257 patients with relapsing-remitting MS.^[20] Patients received 120 mg daily, 120 mg 3 times daily, or 240 mg 3 times daily of oral BG-12, or placebo. The primary outcome measure was total number of new gadolinium-enhancing lesions on brain MRI scans at weeks 12, 16, 20, and 24. The results were that the 240-mg thrice-daily dose of BG-12 reduced the mean number of gadolinium-enhanced lesions by 69% compared with placebo. Moreover, that BG-12 group demonstrated 48% fewer T2 lesions and 53% fewer T1 black holes compared with placebo. The highest dose also showed a trend toward reduced relapse rate. The lower doses did not show a significant benefit. Adverse events that were more common in patients given BG-12 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG-12 included headache, fatigue, and feeling hot. Two phase 3 studies are under way: one on the effect of BG-12 240 mg twice and thrice daily vs placebo and the other on the same doses vs placebo and glatiramer acetate as an active control.

Monoclonal Antibodies

The other major class of emerging therapies involves monoclonal antibodies directed against an aspect of the immune system. These therapies look to match or surpass the success of the approved monoclonal antibody natalizumab (discussed above).

Rituximab. Recent success in other immune-mediated diseases, such as rheumatoid arthritis, has drawn attention to B-cell-directed therapies as a treatment for MS. Rituximab is a genetically engineered chimeric monoclonal antibody that depletes CD20+ B cells through a combination of cell-mediated and complement-dependent cytotoxic effects. CD20 is an antigen present on pre-B and mature B lymphocytes. However, CD20 is not found on hematopoietic stem cells, plasma cells, or in normal tissues. Rituximab is currently FDA approved for the treatment of non-Hodgkin's lymphoma, refractory rheumatoid arthritis, and diffuse B-cell lymphoma.^[21] A 48-week, phase 2, randomized, double-blind, placebo-controlled study of intravenous rituximab 1000 mg or placebo dosed on days 1 and 15 was carried out.^[22] The primary outcome measure was the total count of gadolinium-enhancing lesions detected on MRI scans of the brain at weeks 12, 16, 20, and 24. Patients on rituximab had significantly reduced numbers of gadolinium-enhanced lesions at each of these time periods compared with placebo. The rituximab group had a 91% relative reduction in mean number of lesions over the 24 weeks. These results were sustained over 48 weeks. The rituximab-treated group also had a significant reduction in annualized relapse rate at week 24 and a trend at week 48. The percentage of patients with a relapse was significantly lower in the rituximab group at weeks 24 and 48. There was a significant reduction in T2 lesion volume at weeks 24 and 36. More patients in the rituximab group had adverse events within 1 day of the first infusion, the majority of which were graded mild or moderate. After the second infusion, adverse events were lower in the rituximab group. No opportunistic infections were evident. There are no ongoing phase 3 trials with rituximab in MS. A phase 2 trial of a humanized anti-CD20 monoclonal antibody, ocrelizumab, in relapsing-remitting MS has been completed, but results have not been published or presented as yet. A trial of rituximab in primary progressive MS failed to achieve its primary outcome measure of time to sustained disability.^[23]

Beyond its encouraging results, the Clinical Trial Comparing Treatment of Relapsing-Remitting Multiple Sclerosis (RR-MS) has brought new attention to the role of B cells and humeral immunity in MS.^[24] The effect seen in this study was sufficiently rapid to suggest that the mechanism of action was in the peripheral immune response in MS, rather than within the CNS. An expanded role of B cells has been postulated both in the peripheral immune system, as in antigen presentation, and within the CNS both as an element in humeral-mediated tissue damage and as a potential pathogenic role of the B-cell follicles reported in the subarachnoid space.

Alemtuzumab. Alemtuzumab is a humanized monoclonal antibody that binds to the CD52 antigen on the surface of lymphocytes (both T and B) and monocytes. It is FDA approved for the treatment of fludarabine-resistant chronic lymphocytic leukemia. Binding to the CD52 antigen results in antibody-dependent lysis, and rapid removal of lymphocytes from blood, bone marrow, and organs. This T-cell depletion lasts for an extended period of time.^[21,25] Early studies in secondary progressive MS revealed that the agent suppressed disease activity but failed to halt progressive disease.^[26] More recently, alemtuzumab has been tested in early relapsing-remitting MS. A phase 2, randomized, blinded study compared intravenous infusions of alemtuzumab, 12 mg/day or 24 mg/day, with interferon beta-1a 44 µg subcutaneously 3 times weekly for a planned 36 months.^[25] Alemtuzumab was given by intravenous infusion on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24. The primary outcome measures were time to sustained accumulation of disability and rate of relapse. Because of a safety concern (immune thrombocytopenic purpura, see below), dosing of alemtuzumab was suspended during the trial after 99% of participants had received their second dose cycle, at month 12. Because there were no significant differences in the results from the 2 alemtuzumab doses, their results were pooled. The alemtuzumab-treated group had a 71% reduced risk for sustained disability compared with the interferon-treated group. There was a 74% reduction in the rate of relapse in the alemtuzumab group (annualized relapse rate, 0.010) compared with interferon (annualized relapse rate, 0.36). There was a significant difference in the proportion of patients who were relapse free at 6 months (80% for alemtuzumab vs 52% for interferon). The effect on relapses appeared to be waning in the alemtuzumab group in the last year of the study, when the dosing was interrupted. The alemtuzumab groups had better outcomes for MRI metrics. The major safety concern with alemtuzumab was development of autoimmunity. Twenty-three percent of participants developed thyroid autoimmunity and 6 developed immune thrombocytopenic purpura (1 fatal). Infections were more common in the alemtuzumab group, but no serious opportunistic infections were seen.

These phase 2 clinical results with alemtuzumab demonstrate clear efficacy compared with high-dose interferon. If confirmed in the ongoing phase 3 trials, this agent holds the promise of providing dramatic reduction in relapse activity. This will need to be balanced with the potential for serious autoimmune adverse events and careful observation for other immunocompromising complications. Because alemtuzumab was not effective in delaying progressive MS, it will be interesting to watch the long-term efficacy of this agent. If patients treated early with alemtuzumab do not enter a later progressive phase, then it could be concluded that suppressing inflammatory activity early in the disease abrogates the progressive phase and limits neurodegeneration. If progressive disease occurs in these patients, the implication would be that progressive disease, and perhaps neurodegeneration, occur independent of the inflammatory stage of MS.

Daclizumab. Daclizumab is a humanized monoclonal antibody that is directed against the alpha chain of the IL-2 receptor (anti-CD25), which is upregulated on activated T cells. IL-2 signaling may play an important role in T-cell-mediated autoimmunity. However, T-cell function studies in patients treated with daclizumab demonstrated normal T-cell proliferation and cytokine production. The suspected mechanism of action for daclizumab is thought to be through expansion of a subset of natural killer cells (CD56^bright) that alter T-cell responses.^[27] Open-label studies of daclizumab added to patients already on interferon suggested a beneficial response. A 24-week, phase 2, randomized, double-blind, placebo-controlled, multicenter study was undertaken on patients who were on interferon beta and had evidence of continued disease activity.^[28] Patients were continued on interferon and randomly sampled to 3 groups to receive daclizumab 2 mg/kg subcutaneously every 2 weeks for 11 doses, daclizumab 1 mg/kg subcutaneously every 4 weeks for 5 doses (with placebo every 4 weeks for 4 doses), or placebo every 2 weeks for 11 doses. The primary outcome measure was the total number of new or enlarged gadolinium contrast-enhancing lesions on MRI scans done every 4 weeks between weeks 8 and 24. There were fewer new or enlarged gadolinium-enhancing lesions in the higher-dose daclizumab group. The higher-dose daclizumab group also had less increase in the total volume of new or enlarged gadolinium-enhancing lesions. There was no difference between the groups in the volume of T1 hyperintensities or volume of T2 lesions. There was also no difference in annualized relapse rate. More patients in the daclizumab groups had grade 3 adverse events, most commonly infections and infestations. Serious adverse events were more common in the daclizumab groups, most commonly infections. There were no opportunistic infections. Common adverse events were equally distributed across all groups. Of interest, this study confirmed the finding that treatment with daclizumab causes an expansion of the CD56^bright natural killer cells. A phase 3 trial of daclizumab is under way.

Combination Therapies

There has been ongoing interest in combining immunomodulatory agents to take advantage of potential additive or synergistic effects of differing mechanisms of action of agents while limiting possible toxicity. A comprehensive review of this topic has been reported by Conway and Cohen.^[29] The aforementioned daclizumab study is a combination study, but as an add-on after development of some measure of inadequate response to an initial therapy. A similar approach was taken with natalizumab in the Safety and Efficacy of Natalizumab in Combination with Avonex® (IFNbeta-1a) in Patients with Relapsing-Remitting MS (SENTINEL) study, the ACT-128800 in Patients With Relapsing-remitting Multiple Sclerosis -Extension Study (ACT), and other ongoing studies. A potentially more interesting approach is to begin therapy with a combination. The Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (CombiRx) study, which is currently under way, has taken this approach in comparing the efficacy of combining interferon beta and glatiramer acetate with either agent alone.^[30] Results are due in early 2012. The recently reported cycles of MEthylprednisolone in COMBINation (MECOMBIN) study took a similar approach by comparing treatment-naive patients with relapsing-remitting MS with weekly intramuscular interferon beta and oral methylprednisolone 500 mg/day for 3 days monthly vs interferon alone.^[31] Although the study failed to meet its primary outcome of time to sustained progression, the combined interferon/steroid group showed significant reductions in annualized relapse rate, mean MS Functional Composite (MSFC) scores, and change in T2 lesion volume.

An even more intriguing potential role for combination therapy would be the use of an immunomodulatory agent and a neuroprotective agent, once we have found a successful neuroprotective molecule.

Other Potential Emerging Strategies

Additional dosing data on current agents would be of benefit. Thus far, doubling the dose of interferon and glatiramer acetate has not shown benefit. Other dosing opportunities are being explored, such as less frequent administration of glatiramer acetate. Longer-acting interferons are also being studied. Although the hope of an antigen-specific therapy has been searched for in MS (and most other autoimmune diseases), the results of trying to block myelin antigen-specific immune responses in MS have been uniformly disappointing.

Conclusions

As detailed above, the therapeutic pipeline of emerging agents to treat MS is cause for great enthusiasm. The potential for better efficacy is clear. The issue of new safety concerns is also a reality as we employ more potent immunomodulating agents. The possibility of oral agents is quite real. As we move forward, we look for better efficacy, better safety, and/or more convenient dosing regimens. A major therapeutic aim is the development of agents that control the progressive aspect of MS, the major unmet therapeutic goal in MS treatment.

Supported by an independent educational grant from Teva Neuroscience.

1. Which of the following available agents for multiple sclerosis is believed to suppress proliferation of lymphocytes?

1. Glatiramer acetate
2. Interferon
3. Mitoxantrone
4. Natalizumab

2. Which of the following investigational agents targets interleukin (IL)-2 receptors on T cells as a way of affecting autoimmunity?

1. Alemtuzumab
2. Cladribine
3. Daclizumab
4. Fingolimod

3. Which of the following investigational agents has been associated with development of neoplasms in clinical trials?

1. Cladribine
2. Dimethyl fumarate (BG-12)
3. Laquinimod
4. Teriflunomide

4. The investigational agents in development discussed in this program, including fingolimod, cladribine, teriflunomide, and laquinimod, consistently have shown superiority vs placebo in which of the following outcomes?

1. Annualized relapse rate
2. Number of new gadolinium-enhancing lesions
3. Time to disease progression
4. All of the above

解答：

1.Answer: Interferon 

Currently available immunomodulating agents for multiple sclerosis target a number of presumed mechanisms of action. Interferon is believed to have an antiproliferative effect on lymphocytes in addition to shoring up the blood-brain barrier and downregulating helper T-cell functions. Glatiramer acetate is thought to shift the immune system toward a regulatory function, whereas natalizumab prohibits lymphocytes from entering the central nervous system. Mitoxantrone is broadly immunosuppressive.

2.Answer: Daclizumab 

Investigational agents use a variety of mechanisms to modify disease progression. Daclizumab targets IL-2 receptors to influence T-cell activation. Other agents, such as alemtuzumab and cladribine, are cytotoxic for lymphocytes, whereas others, such as fingolimod, prevent lymphocytes from exiting the lymphatic system.

3.Answer: Cladribine 

Both cladribine and fingolimod have been associated with increased risk for neoplasms in phase 3 clinical trials. Other adverse events associated with investigational therapies include herpes zoster (cladribine), increased risk for infections (daclizumab), abdominal pain (dimethyl fumarate [BG-12]), and elevated liver enzymes (laquinimod).

4.Answer: Number of new gadolinium-enhancing lesions 

Of the agents described in this program, only fingolimod and cladribine have completed phase 3 trials with data on disease progression, confirmed disability, or relapse rate. Phase 2 trials commonly use number of new or enlarged lesions as a measure of disease activity.

References

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