Reports

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MEDICAL FRONTIERS - 61st Annual Meeting of the American Academy of Neurology

Seattle, Washington / April 25-May 2, 2009

A circumspect analysis of promising data with novel agents for the treatment of multiple sclerosis (MS) is suggested by long-term studies with both new and established disease-modifying therapies (DMTs). These studies demonstrate that many of the complications as well as the mechanisms of action of these agents may not emerge for years after initiating therapy.

Rare Complication Leading to Brain Infection

For example, new evidence is revealing the very complex relationship between many monoclonal antibodies (MABs) such as natalizumab and risk of progressive multifocal leukoencephalopathy (PML), while improvement in neuronal mitochondrial function documented six years after initiating glatiramer acetate (GA) is providing new insight into the mechanism of protection offered by this therapy. The promising early clinical results with new strategies are important, but the long-term data are essential for navigating the risks and benefits of altering immune function.

The MABs that have demonstrated activity in autoimmune diseases “appear to be capable of increasing susceptibility to infections in the brain under certain circumstances,” reported Dr. Joseph Berger, University of Kentucky, Lexington. He identified latent JC virus, which is present in up to 85% of individuals worldwide, as the first of a series of conditions that must be met for PML to arise as a complication of MAB therapy. He listed more than five others, which not only explains why PML is a rare complication of MAB therapy but also why the balance between autoimmune suppression and risk of complications is complex and delicate, requiring large databases to adequately assess risks as well as benefits.

“By preventing normal trafficking of lymphocytes, MABs appear to inhibit the natural mechanisms that prevent JC viremia and the ultimate development of PML,” Dr. Berger explained. However, he emphasized that because other factors, such as B-cell maturity and the activity of adhesion molecules, are important to the sequence of events leading to PML, this complication of MABs such as natalizumab and rituximab has remained uncommon. Studies to understand the specific predictors of susceptibility to further narrow risk are ongoing.

NAA as Disease Marker

The progress in understanding the risks from agents that inhibit immune activity to treat MS is mirrored by progress in understanding the mechanisms of benefit. In new data with GA, there was a sufficient correlation between neuronal N-acetylaspartate (NAA) and outcome that this has been proposed as a routine clinical marker. In this study, relapsing-remitting MS (RRMS) patients were evaluated for NAA with ¹H-magnetic resonance spectroscopy (¹H-MRS). The study population was described as the largest cohort of RRMS patients evaluated with MRS long-term. Over the course of follow-up, NAA levels were preserved in patients on GA but declined in those untreated. Previous studies have established that decreased NAA levels are a marker of axonal injury.

“This study supports the use of NAA as a reliable marker for assessing long-term disease progression and therapeutic response,” reported Dr. Jai S. Perumal, Wayne State University School of Medicine, Detroit, Michigan. This study also “provides insight into the mechanisms of action of GA therapy.”

In this study, 49 patients underwent serial 1H-MRS for up to six years. In those who started GA at enrolment, the mean baseline level of NAA was 1.99 nM. At the end of six years, the mean NAA was 2.12 nM, a significant 6% increase (P<0.05), suggesting a decline in axonal injury. In untreated patients, there was a significant decline in NAA from baseline. According to Dr. Perumal, these data are consistent with other evidence that GA is thought to be neuroprotective. Study co-author Dr. Omar Khan, Director, Multiple Sclerosis Center, Wayne State University, indicated that these types of long-term data are useful for understanding how long-term treatment alters the natural history of MS. “The potential ability to prevent or repair brain tissue damage in RRMS patients is an important treatment consideration given the degenerative pathology of this life-long condition,” Dr. Khan reported. “These data further substantiate our previous research into the neuroprotective effect of GA as well as the use of NAA as a reliable maker of disease progression.”

BECOME Trial

Studies to evaluate whether similar preservation of NAA is achieved with one or more of the interferon beta (IFNß) therapies have not been performed, but the large trials comparing the IFNßs to each other or to GA generally demonstrate comparable efficacy on the basis of disease progression. Surrogate end points of activity, such as change in lesion volume on magnetic resonance imaging (MRI), have been more variable between treatments, but a new quantitative analysis from the BECOME (Betaseron Versus Copaxone in MS Patients Using Triple-dose Gadolinium and 3-Tesla MRI End Points) study using a very sensitive measure of volume analysis did not show a difference. “The volume of enhancement per scan with the optimized BECOME MRI protocol was much larger than previously reported in studies of monthly brain imaging of treated MS,” reported Dr. Jojy Cheriyan, University of Medicine and Dentistry of New Jersey, Newark. Specifically, using a monthly 3-T MRI with triple-dose gadolinium (Gd) to evaluate blood-brain barrier disruption in 75 patients in the BECOME study, “We found no differences in the volume of enhancement over the 12 months of evaluation” between the two study arms, Dr. Cheriyan reported.

However, another comparative study suggested that there may be differences between DMTs in a real-life clinical setting. In this study, drawn from a large US managed healthcare database with 51,162 individuals, outcomes were compared among MS patients taking any of the IFNßs or GA for at least two years. Of the 892 patients evaluated, 331 were taking IFNß-1a intramuscularly (i.m.), 308 were taking GA, 143 were taking IFNß-1a subcutaneously (s.c.) and 110 were taking IFNß-1b.

Unlike other studies, relapses were significantly less frequent on GA (2%) than IFNß-1b (11%), IFNß-1a s.c. (9%) and IFNß-1a i.m. (7%), according to Dr. Kenneth P. Johnson, Maryland Center for Multiple Sclerosis, University of Maryland, Baltimore. The differences persisted when multivariate analyses were conducted to control for demographic characteristics, general health status, comorbidities and medications prescribed such as corticosteroids, anticholinergics, anticonvulsants, CNS stimulants and musculoskeletal therapies.

While acknowledging that “recent head-to-head comparison studies of IFNs and GA suggest no superiority between the products in terms of reducing relapse,” Dr. Johnson indicated that the relative advantage of GA in this study may reflect the ease of use of this agent. Unlike rigorous trials which may generate greater rates of adherence for less well-tolerated therapies, this type of study may provide a better reflection of typical treatment patterns. According to Dr. Johnson, the significantly lower risk of relapse also translated into lower direct medical costs for GA relative to the IFNßs in the context of US payer calculations.

DMT Mechanism of Action

Previous controlled trials showing comparable efficacy between GA and the IFNßs is surprising because of the differences in the mechanism of action of these agents. While all of the DMTs are suspected of multiple actions in the control of MS, IFNßs are generally considered to alter cytokine production toward an anti-inflammatory phenotype. Other actions, such as reduction of T-cell migration, may also be important. In contrast, the primary mechanism of action of GA is widely thought to stem from its ability to shift T-cells from a pro-inflammatory Th1 to a regulatory Th2 response. In a new study led by Dr. Finn Sellebjerg, Glostrup Hospital, University of Copenhagen, Denmark, blood sampling in 29 RRMS patients on GA and 30 untreated patients demonstrated that expression of Th1 cell activation was reduced early after the initiation of GA and this reduction correlated with drug benefits. “On the basis of the correlation between the Th2 and disease activity on MRI, we believe that a shift in the balance of Th2 to Th1 is an essential part of GA’s effect,” Dr. Sellebjerg reported.

However, a more detailed understanding of mechanisms of the DMTs continues to be generated by experimental work. In a study evaluating B-cell cytokine and growth factor expression in experimental autoimmune encephalomyelitis (EAE), one of the most commonly used MS models, GA was found to induce an increase in B2-processing CD5+ B-cells while downregulating expression of two receptors for pro-inflammatory cytokines, BAFF and APRIL. “These findings suggest that in addition to the known effect on Th2 polarization and the T-cell regulatory response, GA may have a direct effect on both the activating pathway and the response of B-cells in MS,” reported Dr. Sakhina Begun-Haque, Dartmouth Medical School, Lebanon, New Hampshire. This activity is considered important because of growing appreciation of the involvement of B-cells in the pathogenesis of MS.

Renewed Focus on MAB Treatment

More focus on B-cells is being driven by the activity of newer therapies, including several MABs, such as rituximab, that appear to act primarily within this area of immune regulation.

The number of MABs being tested in the treatment of MS is expanding quickly, with new data presented on rituximab, daclizumab and alemtuzumab in RRMS patients. In the study of rituximab, eight RRMS patients who had been previously treated with natalizumab received a single dose of rituximab 100 mg. The treatment was associated with a significant depletion of CD19+ B-cells. Although relapses occurred in two of the eight patients within six weeks, a co-author of the study, Dr. Revere P. Kinkel, Beth Israel Deaconess Medical Center, Boston, Massachusetts, characterized the results as promising and suggested an expansion of clinical studies seeking a dose that is both effective and well tolerated.

New or updated results of clinical trials with daclizumab and alemtuzumab also show promising activity even though long-term safety remains an issue. In the daclizumab study, 230 RRMS patients were randomized to one of two doses (2 mg/kg or 1 mg/kg) or placebo and were followed for up to 42 weeks. In the previously presented but updated phase II study of alemtuzumab, 334 RRMS patients were randomized to one of two doses (24 mg or 12 mg) administered at month 0 and month 12, or to standard dosing of IFNß-1a. In both cases, substantial reductions in target immune functions correlated with protection against progressive disability. The authors concluded in both cases that further efficacy and safety analyses are warranted.

Progress with Oral Agents

Recent progress with oral agents may represent a potentially interesting clinical advance. In a latebreaker presented here at the AAN, the phase III CLARITY study associated cladribine tablets with 33% reduction in the risk of disability progression (HR 0.67; P=0.026) and more than double the odds of remaining relapse-free (OR 2.13; P<0.001) relative to placebo. According to senior author Dr. Gavin Giovannoni, London School of Medicine and Dentistry, UK, “Highly significant reductions in brain lesion activity were seen in all three pre-specified MRI measures.” The major adverse events were reversible cytopenias with about 90% of cladribine patients completing their course. However, lymphopenia was seen in 22% of patients with low-dose cladribine and in 33% of those receiving high-dose vs. 2% in the placebo cohort. Four malignancies were reported, including cervical, melanoma, ovarian and pancreatic.

Another oral agent at an earlier stage of development, laquinimod, also continues to advance. Rather than an immunosuppressant, laquinimod is an immunomodulator. While its encouraging safety and efficacy was already documented in a phase IIb study published last year, new data from an experimental study indicate that laquinimod inhibits T-cell adherence to endothelial cells, which is considered a critical step for destructive autoimmune activity in the CNS (Keegan BM, Weinshenker BG. Lancet 2008;371(9630):2059-60).

Researchers from the FTY720D2201 Study Group presented their findings from their four-year phase II extension study of oral fingolimod. The first in a new class of sphingosine 1-phosphate receptor modulators, fingolimod significantly reduced the annualized relapse rate and evidence of inflammatory activity on MRI imaging at the end of six months in the previously published results (Kappos et al. N Engl J Med 2006;355(11):1124-40). Of the 281 initial patients, 250 opted to participate in the extension study, with 155 patients (62%) still on study drug at the end of 48 months. Over this period, the reduction in the annualized relapse rate observed at six months relative to placebo was maintained. Moreover, 79% to 88% of patients (depending on initial randomization group) had no new inflammatory MRI lesion activity at month 48, and the majority of patients remained relapse-free. However, there were seven cases of skin cancer and 16% of patients developed liver enzyme levels three times the upper limit of normal.

Data were also made available for another experimental agent, ATL 1102, which provides antisense to the mRNA for VLA-4, a mediator of T-cell adhesion. In a phase IIa trial, 77 patients were randomized to a 200-mg dose of ATL 1102 or placebo administered twice weekly. MRI scans were performed monthly over the 16-week trial. According to the senior author, Dr. Volker Limmroth, Cologne City Hospital, University of Cologne, Germany, the cumulative number of new T1 Gd-enhancing lesions was reduced by 66.7% relative to placebo. He called the activity a “proof-of-concept” that should generate the next phase of clinical development.

With any agent active against autoimmune disease, the relative safety over the long term must be evaluated as closely as the relative efficacy. Although long-term safety is essential for any chronically administered therapy, it can often be assumed that risks are low when treatments have remained well tolerated over six months or more. Even though there are many instances when rare side effects of new agents are not immediately recognized, the complexity of immune function suggests that risks must be evaluated over an exceptionally long time frame. Relative safety in the context of efficacy is one of the major advantages of the established agents.

Summary

The proliferation of new strategies for the control of MS is encouraging not only for the promise of new treatment options but for the potential for newer targets to expand the understanding of the pathophysiological events in the autoimmune cascade. While the specific mechanisms of action of even the most widely used MS therapies, GA and the IFNßs, are still not completely understood, they have provided a framework for achieving an acceptable balance of efficacy, tolerability and safety. The development of newer agents is important for expanding treatment options and providing new clues for understanding the disease process. Even as the efficacy and safety of current first-line therapies ensures their contribution to disease control, new drug development has a role to play in evaluating a complex disease.