Clinical trial summary from ECTRIMS

A board to discuss future MS therapies in early stage (Phase I or II) trials.

Clinical trial summary from ECTRIMS

Postby dignan » Mon Nov 27, 2006 8:22 am

Interesting, long summary of clinical trials from ECTRIMS conference in September (hope it hasn't already been posted).

ECTRIMS 2006 - New Advances in Clinical Trial Design and in the Treatment of Multiple Sclerosis

Barry A. Singer, MD

Advances in clinical trial design and in the treatment of multiple sclerosis (MS) were presented during the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 27-30, 2006, in Madrid, Spain. The highlights of new findings are reviewed, and implications for clinical practice are discussed.

Clinical Trial Design
Is it ethical to continue to have placebo arms in MS treatment clinical trials? Because therapies exist for relapsing-remitting and secondary progressive MS, randomizing patients to placebo for 2 years has become more controversial. The placebo arm has been critical in measuring the placebo effect. Relapse rates of the placebo group can be reduced by 30% to 50% as patients transition from prestudy to the active placebo phase. Without information of patients on placebo, treatment effects would be overestimated.[1]

Options to avoid a placebo trial include designs that employ add-on therapy, an external placebo group, and an active comparator. The Safety and Efficacy of Natalizumab in Combination with Avonex (interferon beta-1a) (SENTINEL) trial is an example of add-on therapy because natalizumab was added to interferon beta-1a intramuscularly in half of the trial patients. With an external placebo group, such as the Sylvia Lawry data set, all patients can also be on active treatment in a clinical trial. However, historical control groups can have very different outcomes with the same inclusion criteria. For example, patients in different secondary progressive trials of interferon beta-1b had very different disease progression results, although patients were selected with the same inclusion criteria. Active comparator trials are another option in which one treatment is compared with an existing treatment.[2] For example, the Betaferon Efficacy Yielding Outcomes of a New Dose (BEYOND) trial compares 2 doses of interferon beta-1b with glatiramer.

Criteria to ethically perform placebo trials in MS patients must start with informed consent, including the option of being randomized to not receive treatment. Patients should not have tolerated, failed, or refused current treatments. The trial design should be of short duration and have surrogate markers. Rules for patients to drop out of the trial for worsening disease should be clearly delineated. Equipoise is paramount in which the investigator is uncertain of the outcomes before placing patients on placebo.[1]

An important outcomes measure of the pivotal phase 3 MS trials has been confirmed progression of disability. Patients are considered to have confirmed progression with a documented Extended Disability Status Scale (EDSS) increase of greater than 1.0 point on 2 examinations 3-6 months apart. Butzkueven and colleagues[3] assessed whether the trial definition of "confirmed disability progression" equates with "long-term sustained" EDSS progression with the prospectively acquired global MSBase dataset. In their analysis of 4043 relapsing-remitting and secondary progressive patients from 33 contributing MS clinics, 981 had confirmed progression of disability on neurologic exams at least 3 months apart. After 2 years of confirmed disability progression in relapsing-remitting disease, 25% of patients' EDSS scores returned to baseline. After 5 years, 50% of relapsing-remitting patients with confirmed progression returned to baseline level of disability. Fifteen percent of patients with secondary progressive disease returned to baseline level of disability.

Early evaluation of new treatments frequently relies on MRI endpoints. Many trials, such as the 20-mg vs 40-mg glatiramer acetate phase 2 trial, have screened patients for enhancing lesions to assist in determining efficacy with fewer patients. Zhao and colleagues[4] examined the short-term changes in monthly gadolinium-enhancing lesion activity in patients with different initial activity levels. In the 65 placebo patients studied, 49% had no enhancing lesions at baseline. Of this group, 75% developed new lesions over 9 months. All patients with enhancing lesions at baseline had at least 2 more enhancing lesions over 9 months with monthly MRI scans.

New Therapies in Clinical Trials

MRI results for oral fingolimod (FTY720) were presented from the placebo-controlled, phase II study with active drug extension.[5] At 6 months, the median cumulative number of new and persistent enhancing lesions was 5 for placebo, 1 for fingolimod 1.25 mg (P < .001 vs placebo), and 3 for fingolimod 5 mg (P = .006 vs placebo). The mean number of cumulative enhancing lesions was 14.8 with placebo, 8.4 with fingolimod 1.25 mg, and 5.7 with fingolimod 5 mg. A statistically significant effect on T2 lesions was seen early between months 1 and 2 (P < .003 for both doses). Crossover from placebo to active fingolimod treatment at month 6 resulted in a significant reduction in enhancing and T2 lesions at month 12 on both doses.

Oral BG00012, a fumaric acid ester, was studied in 257 patients who were randomized into 4 arms by Kappos and colleagues.[6] The 240-mg thrice-daily dose resulted in a 69% reduction in the total number of enhancing MRI lesions at weeks 12-24 (P < .001). The number of new and enlarging T2-hyperintense lesions with treatment at week 24 was 4.2 ± 5.4 compared with 2.2 ± 5.4 with placebo (P < .001). The number of T1-hypointense lesions was also lower with oral fumarate therapy (1.7 ± 2.5 vs 0.8 ± 2.0; P = .014). A 32% reduction in relapse rate was a trend, but it was not statistically significant.

Oral cladribine is currently being investigated in a phase 3, multicenter international trial for MS. Although the results of this trial are pending, Martinez-Rodriguez and colleagues[7] used the intravenous form of cladribine in 6 patients with aggressive relapsing-remitting disease. These patients were treated with intravenous cladribine 0.07 mg/kg/day for 5 days monthly in 2-4 courses. The EDSS decreased from 5.5 to 7.0 at baseline to 1.5-5.0 at 12 months. The mean annualized relapse rate dropped to 0.71 ± 0.55 from 2.67 ± 0.75 at baseline. After 1 year, cladribine was infused again in 4 patients due to new severe relapses. No significant side effects were seen.

O'Connor and colleagues[8] reported on a 144-week open-label extension study of the phase 2, randomized, double-blind, placebo-controlled teriflunomide trial. Teriflunomide demonstrated more than a 61% reduction in the number of combined unique active lesions on MRI compared with placebo over 36 weeks of treatment. In the extension phase, the 55 placebo patients were randomized to receive either 7 mg or 14 mg teriflunomide a day, and a total of 147 patients entered this phase. The placebo patients who switched to 7 mg teriflunomide had a 65% reduction in the number of combined unique active lesions (P = .02). Those placebo patients who switched to 14 mg teriflunomide a day had an 85% reduction in the number of combined unique active lesions (P = .02). Annual relapses were similar between arms at approximately 0.4 relapses per year.

Alemtuzumab is a humanized monoclonal antibody that targets the CD52 antigen and is administered intravenously over 3-5 days annually. In a multicenter, rater-blinded trial of 334 relapsing-remitting patients, patients on alemtuzumab had a 75% reduction in relapse rate (P < .003) and a 60% reduction in the risk for sustained accumulation of disability (P < .05) compared with patients on interferon beta-1a 44 micrograms (mcg) subcutaneously thrice weekly.[9] Four patients developed immune thrombocytopenic purpura from 1.5 to 14 months after their last infusion. One patient died from cerebral hemorrhage after 2 weeks of unrecognized symptoms of immune thrombocytopenic purpura. The other patients were successfully treated with steroids ± rituximab. Compston and colleagues[10] presented thyroid-related findings from the year 2 interim safety analysis. With 2.2 years of median follow-up, 11.1% of patients on alemtuzumab had a thyroid-related clinical adverse event compared with 1.9% of patients on interferon beta-1a. Both hyperthyroid and hypothyroid adverse events were reported, including the development of Graves' disease in 3 patients. Antithyroid-stimulating hormone receptor antibodies and antithyroid peroxidase antibodies without clinical thyroid adverse events were seen in 16.7% of alemtuzumab-treated patients and in 11.3% of interferon-treated patients.

Daclizumab, a humanized monoclonal antibody, binds to the alpha chain of the interleukin (IL)-2 receptor. Rose and colleagues[11] described results from a phase 1/2 trial of daclizumab in patients with relapsing-remitting MS. Eight patients on interferon therapy were treated with the combination of daclizumab and interferon. One patient developed a severe relapse prior to daclizumab and only received 2 doses at baseline and in 2 weeks. The other 7 patients received daclizumab infusions at 1 mg/kg every 2 weeks for the first month and then monthly for 5.5 months. Five patients were found to have no contrast-enhancing lesions on MRI at 6 months, so interferon was discontinued, and daclizumab was continued at 1.5 mg/kg monthly for a total of 27.5 months of treatment. Two patients had contrast-enhancing lesions at 6 months, so interferon was continued with daclizumab at 1.5 mg/kg monthly. A significant reduction of total contrast-enhancing lesions (P < .05-.001) and new contrast-enhancing lesions (P < .001) was seen compared with pretreatment scans and subsequent scans in 3-month intervals. A significant reduction in relapses also occurred (P < .001).

Anti-CD154 Antibody
Blockage of CD154 prevents costimulation of CD4+ T cells, which disrupt T-cell activation. Kasper and colleagues[12] assessed clinical and MRI progression in subjects with relapsing MS following blockade of CD154. Four cohorts of 3 relapsing MS patients each received 1, 5, 10, or 15 mg/kg of fully humanized monoclonal anti-CD154 antibody every other week for 8 weeks. After 5 years of follow-up, no statistically significant change in disability was found on the EDSS (baseline 2.3 ± 0.5, and 5 years 2.5 ± 1.6; P = .622). Higher doses of anti-CD154 significantly correlated with less disability at 5 years (P < .05). The average annual relapse rate over 5 years was 0.125, whereas the pretreatment rate was 1.0.

Combination Therapy
To assess the benefit of add-on therapy with azathioprine and prednisone, a randomized, double-blind, placebo-controlled study of 181 relapsing patients on intramuscular weekly interferon beta-1a was conducted.[13] Over 2 years, the annualized relapse rate was 1.19 for patients only on interferon. The relapse rate was 1.06 for those on azathioprine 50 mg daily and interferon. Lastly, the relapse rate was 0.80 for patients on azathioprine, interferon, and prednisone 10 mg every other day. The differences in the relapse rate and in the cumulative proportion of patients with sustained disability progression at 2 years were not significant. Triple-combination therapy was superior to monotherapy with interferon on T2 lesion volume (P = .015). Combination therapy was safe and well tolerated with similar rates of infection among the groups. Perhaps greater efficacy would have been derived had the investigators used higher doses of azathioprine.

Induction with mitoxantrone prior to glatiramer therapy was investigated in a randomized trial of 40 relapsing-remitting patients with at least 1 gadolinium-enhancing lesion at baseline.[14] The patients received either daily glatiramer acetate 20 mg subcutaneously for 15 months or monthly intravenous mitoxantrone for 3 months and then glatiramer acetate for 12 months. Mitoxantrone induction produced an 89% greater reduction in enhancing lesions at 9 months (P = .0001) than glatiramer alone. Patients who received glatiramer alone had a 47% reduction in enhancing lesion frequency at 9 months and an 87% reduction at 15 months. The relapse rate over 15 months was 0.16 for the mitoxantrone induction group and 0.32 for the glatiramer-only group. The relapse rates over 24 months were 0.24 for patients who received glatiramer acetate after mitoxantrone induction and 0.62 for patients who received glatiramer acetate alone. The reduction in relapse rate was a trend in favor of the combination therapy, but the trial design does not allow one to determine whether this result is superior to that observed by administering mitoxantrone alone.

Updates on Current Therapies

New Interferon beta-1a Formulation
A new formulation of subcutaneous interferon beta-1a without human serum albumin was studied in 260 patients in a single-arm, open-label, multicenter trial.[15] At 48 weeks, neutralizing antibodies greater then 20 neutralizing units/mL were detected in 13.9% of patients compared with 24.4% in the Evidence for Interferon Dose Response: European-North American Comparative Efficacy (EVIDENCE) trial. Persistently positive antibody incidence at 48 weeks was 2.5% compared with 14.3% in the EVIDENCE trial. The incidence of injection site reactions was 29.6% with the new formulation compared with 83.3% in the EVIDENCE trial. Flulike symptoms were higher at 70.8% compared with 48.1% in the EVIDENCE trial. Only 38% of patients who received the new formulation were taking anti-inflammatory medications or anilides at study day 1, which likely contributed to the higher incidence of flu symptoms. The lower incidence of neutralizing antibodies may be potentially clinically beneficial. The study is ongoing to assess the persistently positive neutralizing antibody incidence at 96 weeks because these antibodies generally form over the first 18 months of therapy.

Glatiramer Acetate
Double-dose (40 mg) glatiramer acetate was compared with the standard 20-mg dose by Cohen and colleagues[16] in a randomized, double-blind trial. Of the 229 patients screened, only 90 had 1-15 enhancing MRI lesions at baseline and were randomized to receive 20 or 40 mg of daily subcutaneous glatiramer acetate. The higher dose resulted in a 38% reduction of total enhancing lesions over months 7-9, but this primary endpoint was not statistically significant (P = .09). Seventy-six percent of patients on the 40-mg dose and 52% on the 20-mg dose were relapse-free, which was a significant benefit. There was a trend in favor of the higher dose in the relapse rate; the rate was 0.43 with 40 mg and 0.57 with 20 mg (P = .12). The rates of immediate postinjection reactions were 22.7% with 20 mg and 32.6% with 40 mg. Further study of higher dose glatiramer is being pursued in a phase 3 clinical trial.

Interferon beta-1b
Goodin and colleagues[17] examined the rates of neutralizing antibody-positive titers in 2 cohorts of patients with a poor clinical response to interferon beta-1b therapy and 1 cohort of patients unselected for response to therapy. This analysis of 6698 patients was conducted to gain an understanding of the clinical impact of these antibodies. Out of the 1998 patients in the North American cohort, 94% had neutralizing antibody testing for disease worsening. Sixty-seven percent had disease progression for at least 6 months, and 34% had at least 3 exacerbations that required steroids and/or hospitalizations per year. Of interest, only 21.3% of patients in the North American cohort were neutralizing antibody-positive with a mean duration of interferon treatment of 3.32 years. Compulsory testing was performed in the Australian cohort of 2271 patients regardless of their clinical response. If neutralizing antibody-positive status was a principal cause for worsening disease, the incidence of positive neutralizing antibodies would be expected to be lower in the Australian cohort with routine testing than in the North American cohort with testing for worsening disease. However, in the Australian cohort, 37% of patients had at least 20 neutralizing units/mL of neutralizing antibodies. Therefore, these results suggest that antibody positivity does not appear to be the major etiology for worsening MS.

O'Connor and colleagues[18] presented the pivotal trial extension results after natalizumab dosing was suspended. The annualized relapse rate for 1866 patients increased monthly after treatment cessation and peaked at 0.64 at 7 months. Data from 341 patients who had MRI results greater than 60 days after natalizumab discontinuation also experienced a rise in enhancing lesions over 6 months. No new cases of progressive multifocal leukoencephalopathy were reported.

Le Page and colleagues[19] presented the long-term safety data for mitoxantrone in a French cohort of 802 patients. All patients had at least 5 years of follow-up. One patient developed acute congestive heart failure. Thirty-nine patients (4.9%) developed an asymptomatic reduction of their left ventricular ejection fraction below 50%, but it was only transitory in 26 patients. Two patients (0.25%) developed therapy-related acute myeloblastic leukemia 20 and 22 months after the initiation of treatment. One of the 2 patients died regardless of receiving specific chemotherapy. Persistent amenorrhea occurred in 5.4% of women less than 35 and in 31% of women 35 and older. With up to 15 years of follow-up, 51 patients had died but only the leukemia patient's death was considered treatment-related. Thirty-three patients' deaths were considered complications of severe MS.

Therapeutic Development in Experimental Models

IL-17, a proinflammatory cytokine, can be blocked with a monoclonal antibody. Smith and colleagues[20] tested the hypothesis that IL-17 was responsible for driving relapses in the spontaneous chronic-relapsing experimental allergic encephalomyelitis model in the mouse, with an antimouse IL-17 monoclonal immunoglobulin antibody. Ten milligrams per kilogram of anti-IL-17 antibody were administered weekly subcutaneously during remission. The anti-IL-17 antibody significantly reduced the relapse incidence and the inhibited neurologic deficit formation. Treatment with the antibody prior to the acute phase delayed disease, but failed to reduce the clinical score. Because IL-17 may be playing an important role in driving relapses, anti-IL-17 therapies may prove to be effective treatment options for relapsing-remitting disease.

c-Jun N-terminal Kinase Inhibition
The c-Jun N-terminal kinase (JNK) pathway, which can be induced in activated T cells, affects gene expression, cellular survival, and cellular proliferation in response to cytokines. These events are associated with the pathogenesis of autoimmune diseases, such as MS. Ferrandi and colleagues[21] investigated the potential role of the JNK pathway in MS. The JNK2 isoform was upregulated in peripheral blood mononuclear cells of patients with relapsing-remitting disease. In vitro administration of a JNK inhibitor resulted in a significant reduction in cell proliferation with triggering of T-cell apoptosis and c-Jun dephosphorylation. The JNK inhibitor, given in daily oral doses, reduced the severity of pathology and delayed the onset of disease in experimental allergic encephalomyelitis. These results support the hypothesis that the inhibition of the JNK pathway could have a role in the treatment of relapsing-remitting MS.

Tyrosine Kinase Inhibition
C-1311 (Symadex), a tyrosine kinase inhibitor, disrupts trafficking of autoreactive cells and concomitant angiogenic processes. Karlik and Ajami[22] presented results showing that treatment initiated in the chronic phase of guinea pig experimental allergic encephalomyelitis showed reversal of clinical and pathologic signs. Treatment with C-1311 was associated with remyelination and modulation of vascular changes.

Arundic Acid
Arundic acid (ONO-2506) is a compound that modulates the function of astrocytes. Studies are examining its use in stroke, Parkinson's disease, and Alzheimer's disease. Arundic acid may enhance the uptake of the neurotransmitter glutamate by activation of astrocytic glutamate transporter receptors in ischemia models. With less extracellular glutamate, neurons are more protected from glutamate influx and cell death. Arundic acid was studied by Takizawa and colleagues[23] in chronic progressive and relapsing-remitting experimental allergic encephalomyelitis. Treatment resulted in milder neurologic symptoms and fewer demyelinating lesions in the brain and spinal cord.

Sphingosine-1-phosphate Receptors and Extracellular Receptor Regulated Kinase Phosphorylation
FTY-720 (fingolimod) also may modulate astrocyte function, which could be beneficial in MS. FTY-720 can activate subtypes 1 and 3 of sphingosine-1-phosphate (S1P) receptors on astrocytes. Osinde and Dev[24] determined which receptor subtype is involved in extracellular receptor regulated kinase (ERK) phosphorylation in astrocytes. Activation of these receptors was measured with downstream signaling via adenylyl cyclase, phospholipase C, and ERK. The study authors found that the S1P receptor subtype-1 mediates ERK phosphorylation in astrocytes. Potential astrocytic functions that are beneficial in MS are those that promote neuronal survival and remyelination and strengthen the contact sites between endothelial cells at the blood-brain barrier.

Understanding Axonal and Myelin Injury and New Opportunities for Treatment

Obtaining a deeper understanding of mechanisms of axonal and myelin injury in MS is leading to opportunities for targeted treatment. Matute[25] presented current knowledge about the mechanisms leading to oligodendrocyte cell death and demyelination as a consequence of alterations in glutamate signaling, and the clinical relevance to MS. Glutamate excitotoxicity can cause injury to neurons, myelin, and oligodendrocytes. The mechanisms of action are either from sustained activation of glutamate receptors or independent influx of glutamate. Treatments directed at glutamate receptor types, such as NMDA, AMPA, or kainate, may prevent downstream events that lead to cell death from DNA fragmentation. Clinically, plasma glutamate levels of MS patients are higher than control patient levels, especially in relapse. The P2X7 receptor is expressed on oligodendrocytes, and in vitro activation leads to oligodendrocyte cell death. P2X7 receptor expression is higher in the white matter of MS brains that appears normal on MRI than the white matter of controls. BBG, a P2X7 antagonist, has been shown to ameliorate disease in chronic experimental allergic encephalomyelitis.

Smith[26] discussed partial blockade of sodium channels and axonal protection. At sites of inflammation, sodium influx occurs along the axon via sodium channels. The calcium/sodium exchanger fails, resulting in further sodium accumulation plus calcium influx. The resultant high intracellular concentration of sodium and calcium leads to axonal injury. In experimental allergic encephalomyelitis, sodium channel blockers, such as flecainide and lamotrigine, can block this influx and reduce disease severity. Furby and colleagues[27] are recruiting patients for a phase 2 trial of lamotrigine in secondary progressive disease. In total, 120 patients are being randomized to receive either lamotrigine or placebo. The primary outcome of this trial will be brain atrophy.

A critical question in MS is whether early treatment of inflammation prevents axonal degeneration. A partial answer comes from the results of a pathologic brain study of 5 MS patients who died after autologous stem cell transplantation.[28] The patients had died 20 days to 1.5 years after transplantation. Of the 53 total white matter lesions examined, 41 had demyelinating features and 20 had remyelinating features. Sixteen lesions demonstrated chronic active features with macrophages at the edge or rim of the lesions. Inflammation of T cells, B cells, and plasma cells was profoundly suppressed. However, microglia and macrophage activation were ongoing. In addition, axonal degeneration and demyelination continued regardless of the transplant. These results parallel those from the phase 1/2 clinical studies,[29] which showed continued disease progression in patients with high Expanded Disability Status Scale (EDSS) scores despite autologous stem cell transplantation.

Comi[30] described progress in MS research in Europe, including research on disease injury. Early inflammatory changes in MS may lead to axonal injury and/or oligodendrocyte cell death. An alternative hypothesis is that the inflammation is actually secondary to axonal loss and/or oligodendrocyte cell death. Possible triggers for oligodendrocyte apoptosis are nitrous oxide, excitotoxicity, and hypoxia. Noninflammatory oligodendrocyte injury (pattern III lesions) may precede inflammatory pathologic changes (pattern II lesions). Radiologic evidence for this alternative hypothesis is increased diffusion restriction and decreased magnetic transfer ratios prior to lesion formation on MRI. Therefore, focal inflammation may be a reaction to axonal damage.

Mesenchymal stem cells are a subset of adult stem cells that may have the potential to repair damage in the central nervous system in MS. Derived from the bone marrow stroma, mesenchymal stem cells can differentiate into 3 germ cell layers. In addition, these cells can directly inhibit T cells and B cells. Intravenous injection of mesenchymal stem cells into a tail vein can ameliorate both relapsing-remitting (proteolipid protein-induced) and chronic progressive (myelin-oligodendrocyte-glycoprotein-induced) experimental allergic encephalomyelitis. Reduction in disease occurs when the mesenchymal stem cells are added either before or after disease onset. Gerdoni and colleagues[31] showed that intravenously injected mesenchymal stem cells can ameliorate relapsing-remitting and chronic progressive experimental autoimmune encephalomyelitis before and after disease onset. Injection with mesenchymal stem cells led to reduced inflammatory infiltrates, demyelination, and axonal loss within the central nervous system. Neurons, astrocytes, and oligodendrocytes were spared, which could suggest a neuroprotective role of the stem cells. The mesenchymal stem cells had migrated to the central nervous system in 30 days, but no differentiation to neural cells was seen.

Neurofascin, a cell-surface glycoprotein, may be a target for antibody-mediated axonal injury in MS. Mathey and colleagues[32] performed a proteomics-based analysis of autoantibody specificities in patients with MS and controls that identified a prominent disease associated antibody response to neurofascin, a cell-surface glycoprotein that exists in 2 isoforms. The study authors found that neurofascin-specific monoclonal antibodies rapidly exacerbated disease severity in experimental allergic encephalomyelitis. Marked acute axonal injury was seen in the absence of demyelination and any significant local inflammatory response. Confocal microscopy demonstrated that the antineurofascin monoclonal antibody colocalizes with voltage-gated sodium channels at the nodes of Ranvier. These results suggest that blocking this autoantibody may prevent axonal injury.

Baker[33] investigated the protection of axonal damage by cannabinoids in experimental autoimmune encephalomyelitis. Cannabinoids in cannabis and synthetic cannabinoid receptor agonists can help spare axonal damage in experimental allergic encephalomyelitis. Cannabinoids can inhibit mononuclear cells from invading the central nervous system. Stimulation of the cannabinoid CB1 receptor in the brain in experimental allergic encephalomyelitis caused the release of immunosuppressive molecules that downregulate proinflammatory TH1 responses. However, cannabinoids may also protect axons via a direct neuroprotective role in the central nervous system. Animals deficient in cannabinoid receptors exhibit exaggerated nerve loss to autoimmune attacks and increased neurodegeneration in experimental allergic encephalomyelitis. Cannabinoid receptor stimulation slowed neurodegeneration in a manner independent of inhibition of autoimmunity in animal models of MS, uveitis, and amyotrophic lateral sclerosis. These results suggest that the cannabinoid system may be able to slow progression of disease by preventing nerve loss in addition to symptom control.

Placebo-controlled trials can still be ethically performed if patients have not tolerated, failed, or refused current treatments. Such trials should have informed consent, be of short duration, and allow dropping out of the trial for worsening disease. Potential new treatments being studied are oral agents (BG00012, cladribine, fingolimod, and teriflunomide) and monoclonal therapies (alemtuzumab, daclizumab, and anti-CD154 antibody). Additional advances in treatment include a new formulation of interferon beta-1a that produces fewer neutralizing antibodies and the use of double-dose glatiramer acetate. Ongoing research may yield further discovery, leading to targeted treatments to prevent axonal and myelin injury.
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