ARCHIVE # 4: 554 ARTICLES (NOV -SEPT 2006)

New Therapies in Clinical Trials [Medscape-Med Students November
Fingolimod

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.

BG00012

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.

Cladribine

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.

Teriflunomide

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

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

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.

Natalizumab

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.

Mitoxantrone

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

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.

Wednesday, November 22, 2006