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Multiple Sclerosis
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Emerging Therapies in Multiple Sclerosis— New Decisions in the Formulation of Treatment Strategies

Published Online: June 4th 2011 US Neurology, 2010;6(2):60-69 DOI: http://doi.org/10.17925/USN.2010.06.02.60
Authors: Guy J Buckle
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Abstract:
Overview

The therapeutic options available to neurologists treating multiple sclerosis (MS) are profoundly changing. Hitherto, disease modifying therapies (DMTs) were entirely administered by injection and were only able to retard disease progression. The frequency of site reactions and flu-like symptoms has made adherence to treatment problematic and resulted in resistance from some patients. The recent approval of the first oral DMT in MS (fingolimod) and the development of other oral agents will provide much more attractive options to both physicians and patients and may promote earlier commencement of treatment. The development of the monoclonal antibody alemtuzumab may for the first time provide a MS treatment that will, in certain patients with relapsing disease, restore some degree of lost neurologic function. Therefore these new medications will fundamentally change the decision-making process from diagnosis to choice of treatment. However, these treatments do not address progressive disease. The challenge will be which MS patients should receive the new treatments and how much benefit such treatments will provide over current strategies.
Acknowledgment: Editorial Assistance was provided by James Gilbart, PhD, at Touch Briefings.

Keywords

Multiple sclerosis, disease-modifying therapies, new treatments, decision-making process

Article:

Disease-modifying therapies (DMTs) for treating multiple sclerosis (MS) are entering a period of rapid and profound change that will greatly expand treatment options and improve quality of life for the approximately 2.5 million people worldwide who suffer from this chronic, disabling disease.1 Five of the currently-approved DMTs are given by injection at frequent intervals and have a range of adverse effects, notably ‘flu-like symptoms and injection site reactions. These effects can be a problem not only for patients who are newly prescribed the treatments, but also for some patients who experience ‘injection fatigue’ after years of continuous administration.2 The probable approval within the next few years of a more effective monoclonal antibody treatment (alemtuzumab)3 and several of the new oral DMTs (laquinimod, cladribine fingolimod, teriflumomide, and BG00012)2,4–7 will represent a landmark change that could substantially alter approaches to MS treatment. DMTs are widely used in the treatment of patients with MS in North America and have changed the prognosis in many patients for the better.8–10 However, in other territories they are often either not used commonly enough or not initiated early enough in the disease course to be effective. Factors including conservatism among physicians, delays in diagnosis and treatment initiation, fear of adverse events, and high cost or limited healthcare coverage can limit DMT use in these regions.

The aim of this article is to consider the way in which existing treatments have changed the outlook for MS patients and to assess the intravenous and oral treatments currently in late-stage development. Once given regulatory approval, these therapies are likely to have a dramatic effect on the choice and convenience of MS treatments. Therefore, it is timely to discuss the decision-making process neurologists go through prior to initiating treatment and during ongoing treatment and to reflect on the impact these novel therapies will have on this process.The Impact of Current Disease-modifying Therapies on Prognosis
In 1993, the first pivotal trial of interferon beta-1β (IFNβ-1β) was published, illustrating its efficacy in relapsing–remitting MS (RRMS).11 That same year, this drug was also made commercially available. Since then, a number of injectable DMTs have been approved for use in MS treatment, including IFNβ-1α and glatiramer acetate. These drugs all reduce relapse rates and magnetic resonance imaging (MRI) activity and appear to slow disease progression.12,13 Unfortunately, several factors hinder researchers from assessing the true impact that current therapies have on MS disease course. First, there is a lack of natural history data available, with only limited findings presented in older studies.14,15 Similarly, there have been few long-term, carefully controlled or prospective studies investigating the effects of the various treatments beyond the initial two to three years.16 Finally, patients in recent trials have experienced lower relapse rates compared with those in the earlier pivotal studies.

Trials employing the McDonald criteria for inclusion often observe an annualized relapse rate of only 0.3 (approximately one relapse every three patient-years). This makes it difficult to detect any changes due to treatment in short-term clinical trials, which typically last only two to three years. Despite these challenges in evaluation, it appears that DMTs have positively affected disease outcomes over the years. The prognosis for MS patients who receive DMTs at the time of diagnosis of clinically-isolated syndrome (CIS) or RRMS has improved significantly. The length of time between RRMS and secondary progressive MS (SPMS) has also increased, showing delayed disability progression.8 As patients advance to SPMS, treatments lose their positive effects.17–20 In these severe or rapidly-evolving cases, more potent treatments such as natalizumab or mitoxantrone may provide better efficacy and are often used as second-line therapy.21

While current treatment options have managed to reduce relapse rates to a more acceptable level, they are still by no means satisfactory. Anecdotal observations of fewer wheelchairs in MS treatment centers, however, suggest that patients today have less disability overall.22 This may be attributable to the recent advances in therapies.

Diagnosis of Multiple Sclerosis
A definite diagnosis of at least one clinical demyelinating event, often referred to as CIS, and evidence of typical magnetic resonance imaging (MRI) abnormalities indicating areas of prior asymptomatic inflammation are required by most neurologists prior to initiating therapy. Such a diagnosis enables more accurate judgment of whether or not a patient will develop RRMS.23 The value of treating individuals who have old lesions, as detected by MRI, but no recent clinical or MRI activity has not been demonstrated. As a result, many neurologists prefer to see dissemination in time (a second clinical attack or the appearance of new lesions on MRI) that is indicative of active disease before prescribing a DMT.24

The majority of MS cases can be diagnosed by clinical and imaging parameters alone. This is the case provided parameters are properly applied and other causes of CNS inflammatory white-matter disease (MS mimickers) are ruled out, usually by appropriate blood tests and occasionally by a negative cerebrospinal fluid analysis. A cerebrospinal fluid analysis that is positive for markers of abnormal intrathecal immunoglobulin synthesis (increased IgG index, synthesis rate, and/or oligoclonal bands) can also be useful in unusual presentations and in primary progressive MS, where imaging may be negative, especially early in the disease course.

Several diagnostic schemes designed to demonstrate dissemination in space and time were used prior to the advent of MRI for routine clinical use.25,26 Traditionally, the Poser criteria25,27 were the sole criteria used to diagnose MS in patients included in the early pivotal trials of available DMTs. These criteria required at least two documented relapses in order to make a diagnosis of clinically definite MS. An international panel chaired by W Ian McDonald reviewed pre-existing criteria for the diagnosis of MS to incorporate modern imaging techniques (i.e. MRI) into a diagnostic scheme. This scheme allowed the physician to satisfy a requirement for dissemination of lesions in time and/or space without having to wait for a second clinical manifestation of disease, as had previously been the norm.27 These criteria were revised in 200528 and the resulting set are presented in Table 1. Not long ago, a new set of criteria was put forward that relies solely on lesion location to provide evidence of dissemination in space. This has proved to be easier to use in practice without compromising specificity or accuracy.29,30 In fact, sensitivity was higher with these new criteria than the revised McDonald criteria (72 versus 60%, respectively).30 The new criteria simply state that dissemination in space requires one frequent rotation. Perhaps counter-intuitively, the flu-like symptoms patients may experience tend to diminish over time, particularly with IFNs given at more frequent dosing intervals.

Patients with Severe or Rapidly-evolving Disease
Natalizumab and mitoxantrone infusions are generally felt to be more potent than the other DMTs. They may therefore benefit patients with severe or rapidly-evolving MS that has not responded to first-line therapy with an IFN and/or glatiramer acetate,21 although natalizumab has never undergone clinical trial testing for this indication. While natalizumab has been shown to be effective in many patients with severe MS,40 immunosuppressive therapy with mitoxantrone is now less commonly prescribed in the US. This is due to the increasing incidence of serious adverse events, such as cardiomyopathy and treatment-related leukemia. However, prior to employing a stronger agent, many clinicians try switching from an IFNβ to glatiramer acetate or vice versa, since a patient who does not respond to one first-line treatment may respond to a drug with a different mechanism of action. Similarly, high-dose, high-frequency IFNβs have been shown to be more effective than low-dose, once-weekly IFN in head-to-head trials, though prospective, blinded, carefully controlled switching studies are lacking. The available open-label ‘breakthrough’ switching studies are subject to statistical artifacts, such as regression to the mean.

A major problem with natalizumab treatment in MS patients is its association with the opportunistic viral brain disease, progressive multifocal leukoencephalopathy (PML).41,42 Length of time on the drug and prior immunosuppressive therapy are risk factors for developing PML.43 To address this, the Tysabri Outreach Unified Commitment to Health (TOUCH) prescribing program44 as well as the Tysabri Global Observational Program in Safety—Rest of World (TYGRIS—ROW) started in 2006.45 These programs have generally increased confidence in the monitoring of patients on natalizumab for early detection of PML. Furthermore, in many US centers, patients are scanned every six months for any indication of the emergence of PML.46

A new enzyme-linked immunosorbent assay (ELISA) for prior exposure to JC virus is currently being developed by Biogen-Idec. This promises to be far more sensitive for detecting long-standing infection than the currently available quantitative polymerase chain reaction assay, which only detects active viral replication. This new assay will presumably allow more meaningful stratification of risk for development of PML and may return natalizumab to the class of first-line therapy for JC virus-negative individuals.

Novel Treatments Currently in Development
Parenteral Therapies

Monoclonal Antibodies
Three new monoclonal antibodies have shown encouraging results in phase II trials: alemtuzumab (anti-CD52),47 daclizumab (anti-CD25),48 and rituximab (anti CD-20).49 Both daclizumab and rituximab have been used as add-on therapy to IFN and other DMTs, but they are in an early phase of development for MS treatment and data are limited. Of the new monoclonals, alemtuzumab has shown the greatest efficacy against MS and is the furthest developed in clinical trials.

Alemtuzumab
Alemtuzumab is a fully humanized monoclonal antibody currently FDA-approved for use in the treatment of chronic lymphocytic leukemia, cutaneous T-cell lymphoma, and T-cell lymphoma. Alemtuzumab targets CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived.50 In current phase III trials in MS, alemtuzumab is administered intravenously in short (five-day) courses at annual intervals,21 making it extremely convenient for patients and giving it the potential to lower costs relative to current therapies. Previous phase II trials have shown very encouraging results, with significant reductions in disability in some patients.47 In 334 patients with RRMS given alemtuzumab 12 or 24mg courses over 36 months or IFNβ-1α 44μg three times weekly there was a 0.39 point improvement in expanded disability status scale values for alemtuzumab compared with a 0.38 point worsening for IFNβ-1α. There were also significant reductions in annualized relapse rates, sustained accumulation of disability (p<0.001 for both) and MRI lesions compared with IFNβ-1α. Alemtuzumab is undergoing several phase III trials, the results as yet unpublished. Serious adverse events have been noted, in particular acute idiopathic thrombocytopenic purpura, with one case leading to fatal intracerebral hemorrhage. Goodpasture’s syndrome and autoimmune thyroid disease are also issues that will require carefulOral Therapies Currently, several oral agents for the treatment of MS are in late-stage development, including laquinimod, teriflunomide, and BG00012.4–7 One agent, fingolimod, was recently approved by the FDA for use in relapsing forms of MS. Another oral agent, cladribine, is awaiting approval in the US. However, it has recently been refused marketing authorization in Europe, presumably due to increased cancer risk and insufficient benefit demonstrated at the doses used. The oral agents are generally well tolerated and obviate the need for injections. Therefore they are likely to completely change the face of MS treatment over a relatively short time period. With their relative ease of administration, oral therapies have the potential to improve adherence and quality of life1 and could prove to be the most significant advance in MS therapy since the initial introduction of injectable DMTs. All of the oral agents in development have shown promising results using MRI outcome measures in phase II trials. Two agents—cladribine and fingolimod—have shown moderate efficacy similar to current injectable medications in phase III trials in treating MS.

Fingolimod
Fingolimod is a first-in-class oral sphingosine-1-phosphate (SIP)-receptor agonist that has recently (September 21, 2010) been approved for treatment of relapsing forms of MS. Long-term efficacy and safety data are therefore currently lacking. Binding of phosporylated fingolimod in human tissues results in faulty internalization of the SIP receptor. This renders lymphocytes incapable of detecting the SIP gradients that are needed to enable them to migrate from the secondary lymphoid organs into the peripheral circulation and into the central nervous system. Fingolimod thereby diminishes inflammation and, possibly, neurodegeneration in MS.51

The Efficacy and Safety of Fingolimod in Patients With Relapsing–remitting Multiple Sclerosis (FREEDOMS) trial included 1,272 patients with RRMS treated with 0.5 or 1.25mg fingolimod or placebo.7 After two years of treatment, the annualized relapse rate was 0.18 with 0.5mg of fingolimod, 0.16 with 1.25mg of fingolimod, and 0.40 with placebo (p<0.001 for either dose versus placebo). Fingolimod significantly reduced the risk of disability progression (p=0.02) and reduced the cumulative probability of disability progression (confirmed after three months). Drug-related adverse events included bradycardia and atrioventricular conduction block, bronchiolar constriction, macular edema, and elevated liver-enzyme levels. In the 2008 Efficacy and Safety of Fingolimod in Patients With Relapsing–Remitting Multiple Sclerosis With Optional Extension Phase (TRANSFORMS) study, 1,292 patients with one or more recent relapses were treated with 1.25 or 0.5mg fingolimod/day or an active comparator, intramuscular IFNβ-1α 30μg/week (see Table 3).52 The annualized relapse rate was significantly lower with either dose of fingolimod than with IFNβ-1α (0.2, 0.16, and 0.33, respectively; p<0.001 for both comparisons). New and active MRI lesions were also significantly fewer in the fingolimod-treated patients. Fingolimod was associated with an increased incidence of viral infections, bradycardia, atrioventricular block, hypertension, macular edema, skin cancer, and raised liver enzyme levels. Two fatal herpes infections were seen, although these cases may not directly implicate the drug. The FREEDOMS II trial is currently investigating the efficacy and safety of fingolimod in a further 1,080 patients with RRMS (see Table 3). Cladribine
Cladribine is a nucleotide analog that, when phosphorylated, accumulates in lymphocytes leading to apoptosis. It is licensed as a parenteral treatment for hairy-cell leukemia and some long-term safety data are therefore available.53 In previous trials, parenteral cladribine showed promising reductions in new MRI lesions in both RRMS and SPMS with good safety and tolerability.54 After these findings, cladribine was developed as an oral treatment for MS.54 Of the three phase III trials initiated to further evaluate oral cladribine in MS, two are still ongoing, but the CLARITY study has been completed (see Table 3). In the Safety and Efficacy of Oral Cladribine in Subjects With Relapsing–Remitting MS (CLARITY) study, 1,326 RRMS patients were treated with either 3.5 or 5.25mg/kg cladribine or placebo (1:1:1 ratio) for two years. Annualized relapse rates were 0.14, 0.15, and 0.33, respectively.5 The relative reductions in relapses compared with placebo were 57.6 and 54.5% (p<0.001) for the low- and high-dose treatment arms, respectively. In addition, there was a reduction of 33% with 3.5mg/kg and 31% with 5.35mg/kg clabdribine in the three-month risk of disability progression. Cladribine produced profound and lasting lymphocytopenia, as expected from its mechanism of action, and some neutropenia, but there were only marginal increases in infections. The two ongoing trials are the Oral Cladribine in Early Multiple Sclerosis (ORACLE) study and the Prospective observational long-term safety registry of multiple sclerosis patients who have participated in cladribine clinical trials (PREMIERE). The ORACLE trial (n=600) is currently evaluating the effects of low-dose oral cladribine at 1.75mg/kg/year on conversion to clinically-definite MS and disability progression in CIS patients. The PREMIERE trial (n=1,500) is an open-label extension trial for participants who have previously received cladribine. It is designed to evaluate long-term safety (see Table 3). It is currently unclear where the failure to gain European marketing authorization will leave the further development of cladribine in MS. Laquinimod
Laquinimod, a once-daily immunomodulatory compound, has shown reasonable efficacy in a phase II, multicenter, double-blind, randomized trial evaluating two different doses of the drug relative to placebo in 209 patients with relapsing MS.55 A dose of 0.3mg was significantly superior to placebo, reducing the number of active lesions on MRI by 44%. The drug was well tolerated in this trial.

In a further phase II trial including 306 patients with RRMS, a higher dose of laquinimod (0.6mg/day) significantly reduced Gd-enhancing lesions compared with placebo over 36 weeks of treatment. There was also some improvement in relapse rate, with no new safety issue being identified.4 Patients who were switched from placebo to laquinimod showed marked reductions in Gd-enhancing lesions.

Given the potential safety issues with several other emerging oral therapies, the risk–benefit profile of laquinimod appears to be favorable. The drug was subsequently granted fast-track status by the FDA in February 2009. Phase III trials (Safety and Efficacy of Orally Administered Laquinimod versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis [ALLEGRO] and Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of interferon beta-1a [Avonex®; BRAVO] totaling 2,200 patients and powered to detect a difference in clinical outcomes (relapses) are currently in progress to further evaluate laquinimod’s efficacy, safety and tolerability.56,57

Teriflunomide
Teriflunomide inhibits immune function by decreasing DNA synthesis, thus limiting the proliferation of B- and T-cells. The active metabolite of teriflunomide, leflunomide, has been an approved treatment for rheumatoid arthritis for over 10 years and teriflunomide has shown efficacy in experimental allergic encephalitis, the animal model for studying MS.58 In a completed phase II trial including 179 patients with RRMS, oral teriflunomide produced significantly lower increases in disability, lower relapse rates, greater proportions of relapse-free patients and lower numbers of patients needing steroid treatment compared with placebo.59 Adverse events (nausea, increases in alanine aminotransferase, back pain, diarrhea and arthralgia) were increased, but not significantly more than placebo.

Teriflunomide is currently being assessed in the treatment of MS in one complete and three ongoing phase III randomized, controlled clinical trials that include a total planned population of 3,270 patients (see Table 3). Three of these trials are comparing teriflonomide with placebo and one with IFNβ-1α administered subcutaneously.

The Study of Teriflunomide in Reducing the Frequency of Relapse and Accumulation of disability in Patients with Multiple Sclerosis (TEMSO) has recently reported data for the randomized treatment period. A total of 1,088 patients with RRMS received either teriflunomide 7 or 14 mg or placebo once daily for 108 weeks. Both teriflunomide doses significantly reduced the annualized relapse rate compared with placebo (0.539, 0.370, and 0.369, for placebo, 7 and 14mg, respectively). In addition, the risk for disability progression was reduced by 23.7% (p=0.0835) and 29.8% (p=0.0279) in the 7 and 14mg groups.60 Both teriflunomide doses also significantly reduced various MRI parameters including total lesion volume (p<0.05 for both doses), Gd-enhancing T1 lesions (p<0.001 for both doses).61 Overall, teriflunomide was well-tolerated; similar numbers of patients in each group reported AEs and SAEs. Dimethyl Fumarate (BG 00012)
Dimethyl fumarate has diverse modulating effects on immune function by promoting apoptosis in T-cells and changing cytokine synthesis from a Th1 to a Th2 profile. It has been shown to have both anti-inflammatory and potential neuroprotective properties in animal models.62 In a phase II clinical study including 257 patients with RRMS, 720mg/day dimethyl fumarate significantly reduced Gd-enhancing, new T2 and T1-hypointense lesions compared with placebo (p<0.001, p=0.006, and p=0.01, respectively). It also produced a trend towards reduction in relapses.6 Dimethyl fumarate was generally well tolerated; adverse events included flushing, gastrointestinal symptoms, headache, fatigue, and elevation of liver enzymes in a small number of patients. Two phase III trials are in progress comparing relapse rates and the incidence of MRI lesions in a total of 2,243 RRMS patients. These patients are being treated with 480mg/day or 720mg/day dimethyl fumarate or glatiramer acetate in one study and these same doses of dimethyl fumarate or placebo in the other study (see Table 3).

Likely Impact of New Medications on the Treatment of Multiple Sclerosis
A possible decision-making process in MS treatment after the introduction of alemtuzumab and oral DMTs is given in Figure 2. If successfully licensed for the treatment of MS, alemtuzumab may prevent many patients from progressing to more advanced MS or at least slow disease progression to a greater degree than achieved with current medications. The superior efficacy and infrequent dosing interval of alemtuzumab will make it an attractive option for both physicians and patients. Frequent laboratory monitoring will be needed between doses, however, to ensure that patients have not developed thyroid disease, idiopathic thrombocytopenic purpura or Goodpasture’s syndrome.

The efficacy of the oral agents appears to be similar to or perhaps only slightly better than the current injectable treatments, with no compelling reason to alter therapy from an evidence-based approach. However, there will likely be enormous pressure from patients to be prescribed these much more convenient oral therapies. This may cause dilemmas for neurologists whose patients are well-controlled on existing agents that are known to be safe. Convincing the newly-diagnosed patient, in particular, to start therapy with frequent injections could be very difficult when oral options become available. As such, many patients will likely take the risk of the unpredictable or unknown safety profile of a new drug in order to obviate injections when initiating or switching therapies.

Cladribine may be an attractive option to patients due to its short and infrequent dosing course. Patients with breakthrough disease on cladribine, however, will unlikely be able to switch rapidly to another immune suppressive agent such as natalizumab or alemtuzumab as a result of prolonged lymphocytopenia.5 Fingolimod has more side effects than cladribine, necessitating a careful risk-management assessment. However, it may be a more acceptable alternative for many physicians, since its effects on lymphocyte counts are largely rapidly reversible.63

Some head-to-head trials comparing oral agents with intramuscular IFNβ-1α are under way or have been completed, including TRANSFORMS.52 This study showed the superior efficacy of two doses of daily fingolimod compared to the conventional dose of weekly intramuscular IFNβ-1α on all clinical and MRI primary outcome measures over a one-year period, as described above. The BRAVO study (laquinimod versus intramuscular IFNβ-1α),57 which is not yet complete, may show similar results. These results will provide valuable assessments of the relative efficacy and safety of new oral therapies versus an injectable DMT.As with any new drugs, it will take time for the new oral agents to be accepted and find a place in the MS treatment algorithm. However, over time oral medications for MS are likely to make treatment more acceptable to patients and increase the proportion of MS sufferers who receive DMTs. Oral agents may not become first-line options for CIS and RRMS immediately and may instead be limited to MS specialist centers until more safety and efficacy data are available. Long-term clinical experience with alemtuzumab and the new oral DMTs will likely increase confidence in them and lead to more widespread use of these therapies, barring any unforeseen safety issues.

If oral agents become first-line treatments in the long term, the existing injectable DMTs are likely to become second-line alternatives. Alemtuzumab and natalizumab will probably remain second-line treatments for severe or refractory disease for the time being. The widespread availability of sensitive and specific JC virus antibody testing for natalizumab patients, as well as increasing confidence in risk-management for alemtuzumab patients may, however, bring these therapies to the front line for treating severe cases in particular. It is unknown whether any of the newer agents will provide benefit to patients with primary or secondary progressive MS.17

The Future of Multiple Sclerosis Treatment
Current knowledge of the immune process in MS and its progression remains incomplete. Greater understanding of the underlying mechanism of MS is needed to aid in the development of better treatments in the future. In terms of diagnosis, MRI remains the only available paraclinical test that is sensitive to disease activity. The current dependence on MRI as a biomarker for disease activity is costly and inconvenient and is not readily available to patients in many world regions outside the US and Europe. The development of other biomarkers for MS, such as a blood test that is indicative of active disease or is predictive of a relapse or disease progression, is sorely needed. It would simplify diagnosis, help in the monitoring of patients receiving medications and allow for more targeted treatments. Available and new therapies are becoming ever more successful in tackling the inflammatory process in MS but do not halt progression once it is established. Although treatments may halt inflammatory disease activity for up to five years or more in some patients, many patients continue to exhibit irreversible brain atrophy and progressive disability despite the suppression of all visible markers of inflammation. Currently, no ‘neuroprotective’ agents are available to slow this phase of the disease course.

Medications that offer effective treatment for primary and secondary progressive MS are currently the largest unmet clinical need. The greatest challenge for the future remains to develop therapies that can provide superior neuroprotection, promote remyelination, and allow for CNS repair that would result in the restoration of neuronal function and actually reverse existing disability.

Article Information:
Disclosure

In the past 12 months, Guy J Buckle, MD, MPH, has received consulting fees from Acorda Therapeutics, Bayer, Biogen-Idec, EMD-Serono, Genzyme, Novartis, and Teva Pharmaceuticals.

Correspondence

Guy J Buckle, MD, MPH, Director of Clinical Care, Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, One Brookline Place, Suite 225, Brookline, MA 02445. E: gbuckle@partners.org

Received

2010-10-06T00:00:00

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