Reports

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58th Annual Meeting of the American Academy of Neurology

San Diego, California / April 1-8, 2006

New Mechanisms of Interferon Resistance

Dr. Jan Hillert, Professor of Neurology, Karolinska Institutet, Stockholm, Sweden, and his team set out to determine the influence of increasing neutralizing antibody titres on the pharmacodynamic effects of interferon beta (IFNß). According to Dr. Hillert, “The concern is that prolonged repeated injections of proteins can result in immune reactions and development of neutralizing antibodies [NAbs].” His group enrolled 66 patients who developed NAbs against IFNß. Their NAb levels were measured with an in vitro MxA protein induction test. Dr. Hillert indicated his studies “support the increasing evidence that NAbs diminish all efficacy after a certain titre level.” He and colleagues found that screening of TRAIL in multiple sclerosis (MS) patients seemed “to offer little advantage over MxA in separating those patients with a full or partial loss of pharmacodynamic response.”

The phenomenon of IFNß neutralization due to antibodies developed by patients to IFNß, also known as “antibody resistance,” highlights the need for alternative therapeutic options, particularly for those patients who may now be refractive to this therapeutic option.

New findings in MS research presented here at the AAN suggest additional mechanisms at work in addition to the already known blocking effects of NAbs to IFNß therapy. One of these possible mechanisms has been described by Dr. Antonio Bertolotto, Centro Riferimento Regionale Sclerosi Multipla (CReSM) and Neurobiologia Clinica, Ospedale Universitario San Luigi Gonzaga, Orbassano, Turin, Italy, and colleagues. He and co-investigators noted that “a subset of MS patients treated with IFNß present a non-antibody-mediated neutralization, which inhibits both in vivo and in vitro biological activity of IFNß.” An additional rationale for their study was to characterize the prevalence of this phenomenon, noting that it likely involves “a significant percentage of subjects.”

Dr. Bertolotto and colleagues collected a total of 354 samples from 256 MS patients. In what the researchers described as a surprising finding, they demonstrated that 5.4% of the sample (n=19) “showed a significant inhibition of IFNß activity,” without any measurable anti-IFNß-binding antibodies (BAbs), and could be classified as BAb-negative patients.

The researchers posited that the therapeutic effects of IFNß are not hampered by the presence of antibodies only. The high levels of polypeptide sequence of the human IFN a/ss receptor (sIFNAR) found in over 5% of sera demonstrate that there is a need for further investigation regarding its role, possibly as a competitive inhibitor of IFNß.

Echoing the significance of these findings, a presentation by Dr. Bianca Weinstock-Guttman, Assistant Professor and Director, Baird Multiple Sclerosis Center, Jacobs Neurological Institute, State University of New York, Buffalo, and colleagues reinforced the need to better understand the role of sIFNAR in IFN inhibitory activity (IIA). “The molecular mechanisms of IFNß non-responsiveness are not well understood,” she told delegates. “Our group first hypothesized and later confirmed that IFN non-responsiveness in malignancies was associated with circulating IIA.”

Dr. Weinstock-Guttman and colleagues obtained blood and serum samples from 38 relapsing-remitting (RR) MS patients who were NAb-negative and from 16 healthy control patients. The results showed that IIA and sIFNAR levels were higher in MS patients when compared to the control group. Dr. Weinstock-Guttman summarized the work by saying, “Circulating IIA is significantly associated with [compromised efficacy of] clinical and MRI measures of disease activity in IFNß-treated patients who are NAb-negative.”

Therapeutic Options for Neurogenesis and Slowing Neurodegeneration

Dr. Ines Siglienti, University of Gottingen, Germany, and colleagues presented the results of their latest study to better understand the effect of glatiramer acetate (GA) treatment on brain-derived neurotrophic factor (BDNF) expression by immune cells in recombinant mice. The study made use of recombinant mice with a conditional deletion of BDNF in the T-cell (IckCre BDNFflox/-) or macrophage/microglia (lysMCre BDNF flox/-) lineage. The recombinant mice, along with the control wild-type (WT) mice, were then challenged by myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 to induce experimental autoimmune encephalomyelitis (EAE) followed by GA treatment.

The results demonstrated a protective effect of GA administration. “Treated mice were completely protected from disease by GA,” reported Dr. Siglienti. She added, “No infiltrating cells were found in the treated groups. Our findings suggest a role of T-cell-derived BDNF in EAE and support a maintained therapeutic effect of GA even in the setting of BDNF deficiency in different subsets of immune cells.” Further studies will provide a better understanding of the immunological and neurobiological mechanisms.

A presentation by Dr. Rina Aharoni, Department of Immunology, Weizmann Institute of Science, Rehovot, Israel, sought to determine whether GA affects the expression of BDNF, neurotrophin 3 (NT3) and neurotrophin 4 (NT4) in the central nervous system (CNS). While previous studies have shown that GA enhances neurogenesis in EAE, MS in mice, this particular study examined the effects of daily GA injections on neurotrophin expression.

One of the most important results that the researchers identified was that in GA-treated mice, intense BDNF expression within the CNS caused the migration of neuronal progenitors into lesions of injured areas. This finding led Dr. Aharoni and her team to conclude, “GA exerts not only an anti-inflammatory effect, but also enhances the secretion of neurotrophins, leading to neuroprotection and regeneration of neural cells in the diseased brain.” These trends provide new lines of inquiry for future research and for the development of additional MS therapies.

Using a murine experiment, Dr. Viktor Skihar, University of Calgary, Alberta, and colleagues sought to generate highly enriched GA-specific murine Th2 lines, as well as determine if they could produce insulin-like growth factor-1 (IGF-1), which regulates oligodendrocyte maturation. A final goal was to ascertain if GA-Th2 cells could promote remyelination of the injured spinal cord tissue. The researchers observed that while Th1 response might be considered neurotoxic, anti-inflammatory Th2 cells, by contrast, might in fact confer neuroprotection. GA treatment is known to produce GA-specific Th2 cells.

Qualitative determinations from the study suggested that there was improved remyelination in mice with GA-Th2-injected cells compared to non-injected demyelinated controls, and quantitative assessments are ongoing. This research focuses on a potential role for beneficial neuroinflammation.

Another study focused on the role of myo-inositol (Ins), since elevated Ins levels within the CNS may represent accumulation of myelin breakdown products. “We wanted to study the effect of GA on Ins in RRMS patients,” explained researcher Megan MacKenzie, Department of Neurology, Wayne State University, Detroit, Michigan. To that end, the researchers enrolled 11 patients on GA therapy, two untreated patients, and four healthy individuals as part of a substudy to monitor Ins intensities using magnetic resonance spectroscopy of the brain over a two-year period. Mean Ins/creatinine (Cr) of the GA-treated group decreased from 0.87 at baseline to 0.82 at two years. In contrast, in the two untreated patients, the Ins/Cr increased from 0.89 at baseline to 0.95 at year 2. The decrease in the Ins/Cr in the treated cohort was associated with an increase in the N-acetylaspartate (NAA):Cr ratio, which has previously been shown to be a marker of axonal injury and memory functions (Staffen et al. J Neuropsychiatry Clin Neurosci 2005;17(3):357-63).

Remarking on the findings, Ms. MacKenzie suggested that GA limits axonal injury as well as potentially decreases inflammatory tissue destruction.

MRI and Imaging

Imaging tools are useful for assessing MS disease severity and progression, and the ongoing development of new imaging techniques provides tools in the therapy of MS. Magnetic resonance imaging (MRI) is a common tool for MS imaging.

Dr. Jerry Wolinsky, Bartels Family Professor of Neurology, University of Texas Health Science Center, Houston, and colleagues presented the findings of their work to develop a composite MRI-derived metric (Z4) as a potential predictor of future accumulation of clinical disability, measured by the expanded disability status score (EDSS). The Z4-composite score takes into account a variety of mesures of gadolinium (Gd)-enhanced tissue, including hyperintense lesions on T2-weighted images, hypointense lesions on T1-weighted images and cerebrospinal fluid volume. Dr. Wolinsky pointed out that their previous study of 135 RRMS patients on long-term GA therapy studied by MRI at a mean of 2447 days after randomization demonstrated that “Z4 highly correlated with whether patients had improved, were unchanged or worsened over the open-label phase of the extension study.”

Dr. Wolinsky and researchers examined data from 135 patients and continuing data on 101 of the same individuals, as well as 15 participants who agreed to a long-term follow-up visit at 10 years since randomization. EDSS determinations were at six-month intervals, at which time researchers grouped the patients into quartiles based on their Z4 scores derived from MRI taken at 2447 days after randomization. EDSS findings were assessed at the start of GA therapy, at time of MRI, and at the last follow-up visit. Time from MRI to last available EDSS was 4.5±0.93 years. The last EDSS results by Z4 quartiles were significant: 3.09±1.91, 3.19±1.96, 3.09±1.73 and 4.87±2.12, respectively (P=0.0005).

These findings imply that Z4 scores assessed at regular intervals may serve as a predictor for future MS-related disability. “Our findings suggest the potential of Z4 as a surrogate outcome measure for [future] accumulated disability,” Dr. Wolinsky concluded.

A study by Dr. Anthony Traboulsee, Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, and colleagues discussed another use of composite MRI score as a biomarker in clinical trials. In a study cohort of 357 patients, Dr. Traboulsee’s team used a three-value composite MRI score with the following breakdown: 0=zero to six active T2 lesions in one year and burden of disease (BOD) <280 mm2 volume change; 1=either T2 lesions or BOD volume change was high; and 2=both T2 lesions and BOD volume changes were high.

The scores were evaluated with respect to time to disability progression, defined as a one-point change in EDSS in 90 days over a two-year period. In the placebo group, 51% (n=90) had a score of 0, 24% (n=43) had a score of 1 and 25% (n=44) had a score of 2. In the high-dose IFNß-1a (subcutaneous [s.c.] 44 µg t.i.w.) cohort, 86% (n=155) had a score of 0, 8% (n=14) had a score of 1 and 6% (n=11) had a score of 2. Building on the findings of the PRISMS (Prevention of Relapses and Disability by Interferon Subcutaneously in MS) study, investigators determined that the effects of treatment can be visualized on MRI. “We have proven that there is a treatment effect on these MRI outcome measures,” Dr. Traboulsee indicated.

Combination Options and New Developments

Among the therapies that showed promise was a study demonstrating the use of mitoxantrone for MS. The results of a five-year longitudinal study of 97 RRMS patients showed that inductive mitoxantrone therapy was effective in those patients with aggressive RRMS. Patients received mitoxantrone 20 mg monthly along with methylprednisone 1 g (mean cumulative dose 65 mg/m2). For the study duration, relapses and EDSS scores were recorded. After the initial induction therapy, 73 patients received a maintenance therapy with mitoxantrone every three months (n=21), IFNß (n=25), azathioprine (n=15), methotrexate (n=7) and GA (n=5).

Researchers found that during the 12 months following mitoxantrone initiation, annualized relapse rates dropped by 91%, 78% of patients were relapse-free and MRI activity was reduced by 89%. They concluded that not only did mitoxantrone confer strong, immediate impact, but that it also affected long-term disability progression, especially in combination with other therapies, such as GA. Dr. Jeffrey Cohen, Department of Neurology, Cleveland Clinic Foundation, Ohio, reported results from a trial with a new, higher dose of GA involving RRMS patients. Ninety eligible patients were enrolled in the study designed to evaluate the safety and efficacy of GA 40 mg s.c. administered daily for nine months when compared to the standard 20-mg dosage given with the same frequency. The efficacy was to be evaluated based on the number of Gd-enhancing lesions on serial T1-weighted MRI at months 7, 8 and 9.

In comparing the patient groups, the researchers found a 38% risk reduction (P=0.0898) in favour of 40 mg vs. 20 mg in the mean cumulative number of Gd-enhancing lesions at months 7, 8 and 9. Indeed, the effects of the higher dosage regimen were apparent as early as month 3 (1.33±1.58 vs. 2.6±4.22 lesions for the 40- and 20-mg groups, respectively; P=0.005). Other findings demonstrated that of the 20% of patients who experienced a relapse during the trial, time to the first relapse was prolonged from 80 days in the 20-mg group to 213 days in the 40-mg group (P=0.0367, log rank test). The higher dosage was well tolerated with a similar profile to the 20-mg dosage. This led Dr. Cohen and his colleagues to conclude, “The 40-mg dose of GA is more effective than the currently approved 20-mg dose in reducing MRI activity and clinical relapse.”

A new compound on the horizon known as FTY720 targets the lysophospholipid (LP) receptor. It has been shown to reduce mRNA expression of Th1 cytokines interleukin (IL)-2 and IL-6, mediators of the inflammatory response. The compound is part of a growing group of sphingosine 1-phosphate (S1P) receptor agonists that can inhibit T-cell response and may prove to be an additional target in MS therapy (Chun J, Rosen H. Curr Pharm Des 2006;12(2):161-71).

Dr. Paul O’Connor, Chief, Division of Neurology, St. Michael’s Hospital, and Associate Professor, Department of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto, Ontario, reported on data from a continuing phase II study of FTY720 in relapsing MS patients. According to Dr. O’Connor and colleagues, it has already demonstrated clinical and MRI efficacy in 281 relapsing MS patients randomized to either active treatment or placebo in a six-month study. The study was then further extended with patients in the treatment arm continuing on the medication, while those in the placebo cohort were randomized to either FTY720 1.25 or 5 mg.

At an additional six months of study participation, of the 250 patients who continued to participate, 91% (n=227) completed 12 months of the study. Of those receiving 1.25 mg after placebo, the annualized relapse rate was reduced by 70%, and for those receiving 5 mg after placebo, the annualized relapse rate was reduced by 86%. Among the original cohort who started and continued on treatment, the relapse rates remained low throughout the 12-month study period. The MRI findings confirmed these trends. Among patients receiving 1.25 mg subsequent to placebo, there were significant reductions of Gd-enhancing lesions (P<0.001), as was also the case for those on the 5-mg regimen subsequent to placebo (P=0.004). Researchers did find that there was a higher incidence of adverse events reported among the 5-mg cohort compared to the 1.25-mg group. The researchers suggested that the agent be further evaluated in phase III studies.

Vision Disturbances

Dr. Fiona Costello, Assistant Professor, Department of Ophthalmology, University of Ottawa Eye Institute, Ontario, compared the retinal nerve fibre layer (RNFL) measurements among RRMS patients. Because optic neuritis (ON) demyelination of the visual pathway commonly occurs among MS patients, injuries and thinning of the structures can be measured with optical coherence tomography (OCT). Examining cross-sectional OCT data of 82 MS patients, Dr. Costello found that lower RNFL is usually indicative of a decrease in visual acuity and visual field function. “The use of OCT testing can be used to demonstrate different RNFL values among subsets of MS patients,” Dr. Costello noted.

Another study designed to examine the visual consequences of MS was described by Dr. Benjamin Osborne, Birmingham, Alabama, and colleagues, who examined the relationship between macular volume, RNFL thickness and visual function. Dr. Osborne and his team made use of OCT to examine macular volume, using OCT-3 to assess MS patients. When compared to the control group, both total macular volume and RNFL thickness were lower in MS (6.86 mm3 vs. 6.48 mm3 for macular volume; 98 mm vs. 88 mm for RNFL thickness, P<0.0005). The reduced tissue integrity was correlated with lower vision scores. “As markers of axonal and ganglion cell integrity, RNFL thickness and macular volume are complementary in their capacity to identify anterior visual pathway disease in MS,” Dr. Osborne told delegates.

A study by Dr. James Kirk Roberts, Assistant Professor of Clinical Neurology, Division of Clinical Neurology, Columbia University Medical Center, New York, and colleagues reported on two cases of retinopathy associated with IFNß therapy. Patient 1 received IFNß-1b 0.25 mg every other day and Patient 2 received 44 µg IFNß-1a three times per week. The patients had no other serious morbidities. Four to six months after treatment was initiated, both patients developed what the authors described as “cotton wool spots” indicative of retinopathy. Patient 1 on IFNß-1b was switched to GA therapy, resulting in the resolution of retinal findings. Patient 2, who continued on IFNß-1a therapy, did not report any vision loss. Since IFNß therapy is associated with ischemic retinopathy, Dr. Roberts and his team concluded, “Retinopathy, if discovered in a patient being treated with one of the IFNßs, needs to be monitored and may necessitate a change in therapy.”