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Sunday
Current Research on Existing and Emerging Therapies for the Treatment of MS
Current Research on Existing and Emerging Therapies for the Treatment of MS
ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis
Introduction
The ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, held in Prague, Czech Republic, from October 11 to 14, 2007, discussed the current research and treatment in multiple sclerosis (MS). Scientists and clinicians addressed key issues in the pathogenesis, diagnosis, and treatment of MS. Currently, there are 6 US Food and Drug Administration (FDA)-approved disease-modifying treatments: interferon beta-1a (intramuscular or subcutaneous), interferon beta-1b, glatiramer acetate, mitoxantrone, and natalizumab. This summary discusses the new data presented about these current treatment options and new potential treatments for MS.
New Treatments in Development
Daclizumab, a treatment for renal allograft transplant, is a humanized anti-CD25 monoclonal antibody that blocks the alpha chain of the interleukin-2 receptor. In the CHOICE trial, 230 actively relapsing patients on interferon beta were randomized to treatment with either placebo or 1 mg/kg or 2 mg/kg of daclizumab subcutaneously every 2 weeks for 24 weeks. The mean number of new or enlarging contrast-enhancing lesions at weeks 8-24 were 72% reduced in the 2-mg/kg treated arm compared with placebo (P = .004). A 25% reduction in enhancing lesions was seen on the lower dose, but was not statistically significant. Relapse rate reduction was 33% on the high dose, but was not statistically significant. Serious infections were more common in the patients who were treated with the higher dose, which was reported by Montalban and colleagues.[1]
FTY720 (fingolimod), an important potential oral treatment for MS, is in multiple phase 3 clinical trials. As a potent agonist on sphingosine 1-phosphate (S1P) receptors, FTY720 prevents the egress of activated lymphocytes from peripheral lymphoid tissue. Because S1P receptors are also expressed on astrocytes, oligodendrocytes, microglia, and neurons, other potential mechanisms of action are being explored in new research. FTY720 in cell culture studies has been shown to increase both mature and immature oligodendrocyte lineages, raising the possibility of remyelination.[2] Intraventricular administration of FTY720 reduced the degree of experimental allergic encephalomyelitis (EAE) without decreasing the peripheral lymphocyte count.[3] S1P receptor type 1 knockout mice developed attenuated EAE independent of FTY720 administration.[4]
BHT-3009 is a DNA plasmid vaccine that encodes the full-length myelin basic protein. In a phase 2b trial, 289 patients were randomized to placebo, 0.5 mg of BHT-3009 intramuscular injections, or 1.5 mg of BHT-3009 intramuscular injections. The median rate of contrast-enhancing lesions between weeks 24 and 28 was reduced 50% on the 0.5-mg BHT-3009 dose (P = .07). The 1.5-mg BHT-3009 has no significant effect on contrast-enhancing lesions. In addition, no significant effect was seen either on the relapse rate or T2 lesions, as described in the oral presentation by Garren and colleagues.[5]
MN-166 (ibudilast) is an oral agent with anti-inflammatory and neuroprotectant properties. Two hundred ninety-seven relapsing patients were randomized to placebo, 30 mg/day or 60 mg/day. More patients were relapse-free on 60 mg than on placebo (56.1% vs 41.0%, P = .03). In addition, time to first relapse was greater than 1 year on MN-166 60 mg/day and 244 days on placebo (P = .04). A lower mean cumulative active lesion count was seen on 60 mg/day compared with placebo, but this primary endpoint result was not statistically significant. MN-166 60 mg/day did significantly attenuate the percentage of brain volume loss (P = .04).[6]
Fluoxetine may have beneficial effects in MS because it can reduce lymphocyte proliferation, suppress interferon-gamma, and increase production of neurotrophic factors. Forty relapsing nondepressed patients were randomized to 20 mg of fluoxetine daily or placebo. The mean cumulative number of enhancing lesions during the 24 weeks of treatment was 1.84 on fluoxetine and 5.16 on placebo (P = .15). A significantly lower number of scans had new enhancing lesions on fluoxetine than on placebo (25% vs 41%; P = .04).[7]
Updates on Existing Treatments
The Rebif vs Glatiramer Acetate in Relapsing MS Disease (REGARD) trial examined the efficacy and safety of interferon beta-1a 44 micrograms (mcg) subcutaneously thrice weekly and glatiramer acetate in a randomized assessor-blind trial of 764 patients over 96 weeks. The time to the first relapse for the 30th percentile of patients was 495 days on interferon beta-1a and 432 days on glatiramer acetate. This primary endpoint measure was not statistically significant (P = .643). In the prespecified subgroup analysis of the patients with a score less than or equal to the median Expanded Disability Status Scale (EDSS), a significant difference was seen in the primary outcome measure (P = .022). The overall on-treatment annualized relapse rate was only 0.3, which was much less than planned to demonstrate a 30% difference between the 2 treatments on time to first relapse.
The number of lesions per patient per scan for interferon beta-1a and glatiramer acetate, respectively, was 0.7 vs 0.8 for T2-active lesions (P = .178), 0.2 vs 0.4 for T1-enhancing lesions (P < .001), and 0.9 vs 1.2 for combined unique lesions (P = .010).[8] The effect on T2-active lesions was not statistically significant, but the benefit of interferon beta-1a on T1-enhancing lesions was significant. A similar number of adverse events were seen with both treatments. Discontinuations due to adverse events were 8.1 % on interferon beta-1a (1.6% for flulike symptoms) and 6.4% on glatiramer acetate (1.3% for immediate postinjection reactions). At last assessment at 96 weeks, 27.3% of the patients were neutralizing antibody-positive on interferon therapy.[9]
The BECOME trial is a single-center, 2-year study of 75 patients randomized to interferon beta-1b or glatiramer acetate. The confirmed annualized relapse rate was 0.28 on interferon and 0.32 on glatiramer acetate, which was not statistically significant (P = .80). No difference was seen on the EDSS or Multiple Sclerosis Functional Composite (MFSC).[10] The median number of combined active lesions over 24 months was 0.60 on interferon and 0.38 on glatiramer acetate, which was also not statistically significant (P = .24). The median reduction in contrast-enhancing lesions from baseline to on-treatment was 1.19 on interferon beta-1b (P < .001) and 0 on glatiramer acetate (P = .14), which statistically favored interferon beta-1b treatment.[11]
Interferon beta-1a (new formulation) 96-week data revealed a last observation prevalence of neutralizing antibodies of 17%. This preparation of interferon beta-1a lacks human serum albumin. The injection site reactions were only 30.8% compared with 85.8% in the EVIDENCE trial.[12] The COGIMUS trial interim 2-year data demonstrated a significant dose-dependent benefit of interferon beta-1a thrice weekly subcutaneously on neuropsychological testing. Twenty-eight percent of patients on 44 mcg and 39% of patients on 22 mcg had impairment in at least 2 cognitive tests (P = .035).[13]
Further analysis of the BENEFIT trial elucidated the role of interferon beta-1b in patients treated with clinically isolated syndrome. Treatment initiation after the first attack reduced the risk for confirmed EDSS progression by 40% compared with delayed treatment (P = .022). In the early treatment group, 31.8% of patients were neutralizing antibody-positive at any time over 3 years, but 46.6% became antibody-negative by 3 years. Neutralizing antibody positivity did not affect the time to clinically definite MS or time to confirmed disability progression.[14] On the basis of 393 patient MRI studies from the European secondary progressive trial, cerebral brain volume dropped significantly more on interferon beta-1b than placebo on the first year of treatment and less than placebo from years 1 to 3.[15]
Several glatiramer-specific T-cell lines were generated from the cerebrospinal fluid of glatiramer acetate-treated MS patients. Eleven out of 12 of the T-cell lines were of the TH2 phenotype and secreted brain-derived neurotrophic factor.[16]
The STRATA study is examining redosing of natalizumab in patients who participated in the AFFIRM, SENTINEL, and GLANCE trials after voluntary suspension of natalizumab. Of the 1076 patients, 40 (3.7%) developed hypersensitivity reactions. These reactions occurred most frequently in those patients receiving only 1 or 2 doses prior to redosing. No new cases of progressive multifocal leukoencephalopathy have been reported.[17] Khatri and colleagues[18] demonstrated that plasma exchange reduced the serum concentration of natalizumab, which potentially could be a strategy to help restore immunocompetence if progressive multifocal leukoencephalopathy occurs. Interim data of an ongoing trial demonstrated statistically significant improvement on the Fatigue Severity Scale and the Modified Fatigue Impact Scale in 19 patients treated with natalizumab. In addition, improvement was also seen in Beck's Depression Inventory.[19] Oral treatment with a different alpha-4 integrin-blocking agent, AJM300, was effective in reducing the severity of EAE in the Lewis rat.[20]
Combination or Induction Therapy
Mitoxantrone induction therapy followed by interferon beta-1b was compared with interferon beta-1b therapy alone over 3 years in 109 active MS patients. The induction protocol consisted of methylprednisolone 1 g and mitoxantrone 20-mg monthly infusions for 6 months. Nine percent of induction-treated patients and 26% of interferon-only patients had worsening disability of greater than 1 EDSS point (65% benefit). The annualized relapse rate with induction was 0.44 compared with 1.14 on interferon only (56% benefit; P < .007).[21] The risks for mitoxantrone were highlighted in a study in Spain that calculated a leukemia incidence of 2.83% (95% confidence interval 1.2-4.4) in exposed patients.[22] This rate was much higher than previously recorded, including the 0.25% prevalence in a French cohort of 802 patients.[23]
Use of statin medications in MS was reexamined. An earlier pilot trial had demonstrated increased relapses and MRI-enhancing lesions on the combination of atorvastatin (40 or 80 mg) and interferon beta-1a subcutaneously.[24] In a separate randomized trial in Naples, Italy, using only 20 mg of atorvastatin, no significant differences were seen with combination therapy. Twenty-eight percent of patients on interferon beta-1a subcutaneously thrice weekly and 25% of patients on both interferon beta-1a and atorvastatin 20 mg daily had MRI-enhancing lesions.[25] Interim safety analysis of 47 patients in the SIMCOMBIN trial on 80 mg of simvastatin or placebo in addition to interferon beta-1a 30 mcg intramuscularly demonstrated no antagonistic effects of the combination therapy.[26] In a pilot study with MRI imaging, 12 clinically isolated syndrome patients were randomized to placebo or simvastatin 80 mg daily plus interferon beta-1a intramuscularly. The addition of simvastatin was safe and well tolerated.[27]
From:
ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis
Introduction
The ECTRIMS 2007: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, held in Prague, Czech Republic, from October 11 to 14, 2007, discussed the current research and treatment in multiple sclerosis (MS). Scientists and clinicians addressed key issues in the pathogenesis, diagnosis, and treatment of MS. Currently, there are 6 US Food and Drug Administration (FDA)-approved disease-modifying treatments: interferon beta-1a (intramuscular or subcutaneous), interferon beta-1b, glatiramer acetate, mitoxantrone, and natalizumab. This summary discusses the new data presented about these current treatment options and new potential treatments for MS.
New Treatments in Development
Daclizumab, a treatment for renal allograft transplant, is a humanized anti-CD25 monoclonal antibody that blocks the alpha chain of the interleukin-2 receptor. In the CHOICE trial, 230 actively relapsing patients on interferon beta were randomized to treatment with either placebo or 1 mg/kg or 2 mg/kg of daclizumab subcutaneously every 2 weeks for 24 weeks. The mean number of new or enlarging contrast-enhancing lesions at weeks 8-24 were 72% reduced in the 2-mg/kg treated arm compared with placebo (P = .004). A 25% reduction in enhancing lesions was seen on the lower dose, but was not statistically significant. Relapse rate reduction was 33% on the high dose, but was not statistically significant. Serious infections were more common in the patients who were treated with the higher dose, which was reported by Montalban and colleagues.[1]
FTY720 (fingolimod), an important potential oral treatment for MS, is in multiple phase 3 clinical trials. As a potent agonist on sphingosine 1-phosphate (S1P) receptors, FTY720 prevents the egress of activated lymphocytes from peripheral lymphoid tissue. Because S1P receptors are also expressed on astrocytes, oligodendrocytes, microglia, and neurons, other potential mechanisms of action are being explored in new research. FTY720 in cell culture studies has been shown to increase both mature and immature oligodendrocyte lineages, raising the possibility of remyelination.[2] Intraventricular administration of FTY720 reduced the degree of experimental allergic encephalomyelitis (EAE) without decreasing the peripheral lymphocyte count.[3] S1P receptor type 1 knockout mice developed attenuated EAE independent of FTY720 administration.[4]
BHT-3009 is a DNA plasmid vaccine that encodes the full-length myelin basic protein. In a phase 2b trial, 289 patients were randomized to placebo, 0.5 mg of BHT-3009 intramuscular injections, or 1.5 mg of BHT-3009 intramuscular injections. The median rate of contrast-enhancing lesions between weeks 24 and 28 was reduced 50% on the 0.5-mg BHT-3009 dose (P = .07). The 1.5-mg BHT-3009 has no significant effect on contrast-enhancing lesions. In addition, no significant effect was seen either on the relapse rate or T2 lesions, as described in the oral presentation by Garren and colleagues.[5]
MN-166 (ibudilast) is an oral agent with anti-inflammatory and neuroprotectant properties. Two hundred ninety-seven relapsing patients were randomized to placebo, 30 mg/day or 60 mg/day. More patients were relapse-free on 60 mg than on placebo (56.1% vs 41.0%, P = .03). In addition, time to first relapse was greater than 1 year on MN-166 60 mg/day and 244 days on placebo (P = .04). A lower mean cumulative active lesion count was seen on 60 mg/day compared with placebo, but this primary endpoint result was not statistically significant. MN-166 60 mg/day did significantly attenuate the percentage of brain volume loss (P = .04).[6]
Fluoxetine may have beneficial effects in MS because it can reduce lymphocyte proliferation, suppress interferon-gamma, and increase production of neurotrophic factors. Forty relapsing nondepressed patients were randomized to 20 mg of fluoxetine daily or placebo. The mean cumulative number of enhancing lesions during the 24 weeks of treatment was 1.84 on fluoxetine and 5.16 on placebo (P = .15). A significantly lower number of scans had new enhancing lesions on fluoxetine than on placebo (25% vs 41%; P = .04).[7]
Updates on Existing Treatments
The Rebif vs Glatiramer Acetate in Relapsing MS Disease (REGARD) trial examined the efficacy and safety of interferon beta-1a 44 micrograms (mcg) subcutaneously thrice weekly and glatiramer acetate in a randomized assessor-blind trial of 764 patients over 96 weeks. The time to the first relapse for the 30th percentile of patients was 495 days on interferon beta-1a and 432 days on glatiramer acetate. This primary endpoint measure was not statistically significant (P = .643). In the prespecified subgroup analysis of the patients with a score less than or equal to the median Expanded Disability Status Scale (EDSS), a significant difference was seen in the primary outcome measure (P = .022). The overall on-treatment annualized relapse rate was only 0.3, which was much less than planned to demonstrate a 30% difference between the 2 treatments on time to first relapse.
The number of lesions per patient per scan for interferon beta-1a and glatiramer acetate, respectively, was 0.7 vs 0.8 for T2-active lesions (P = .178), 0.2 vs 0.4 for T1-enhancing lesions (P < .001), and 0.9 vs 1.2 for combined unique lesions (P = .010).[8] The effect on T2-active lesions was not statistically significant, but the benefit of interferon beta-1a on T1-enhancing lesions was significant. A similar number of adverse events were seen with both treatments. Discontinuations due to adverse events were 8.1 % on interferon beta-1a (1.6% for flulike symptoms) and 6.4% on glatiramer acetate (1.3% for immediate postinjection reactions). At last assessment at 96 weeks, 27.3% of the patients were neutralizing antibody-positive on interferon therapy.[9]
The BECOME trial is a single-center, 2-year study of 75 patients randomized to interferon beta-1b or glatiramer acetate. The confirmed annualized relapse rate was 0.28 on interferon and 0.32 on glatiramer acetate, which was not statistically significant (P = .80). No difference was seen on the EDSS or Multiple Sclerosis Functional Composite (MFSC).[10] The median number of combined active lesions over 24 months was 0.60 on interferon and 0.38 on glatiramer acetate, which was also not statistically significant (P = .24). The median reduction in contrast-enhancing lesions from baseline to on-treatment was 1.19 on interferon beta-1b (P < .001) and 0 on glatiramer acetate (P = .14), which statistically favored interferon beta-1b treatment.[11]
Interferon beta-1a (new formulation) 96-week data revealed a last observation prevalence of neutralizing antibodies of 17%. This preparation of interferon beta-1a lacks human serum albumin. The injection site reactions were only 30.8% compared with 85.8% in the EVIDENCE trial.[12] The COGIMUS trial interim 2-year data demonstrated a significant dose-dependent benefit of interferon beta-1a thrice weekly subcutaneously on neuropsychological testing. Twenty-eight percent of patients on 44 mcg and 39% of patients on 22 mcg had impairment in at least 2 cognitive tests (P = .035).[13]
Further analysis of the BENEFIT trial elucidated the role of interferon beta-1b in patients treated with clinically isolated syndrome. Treatment initiation after the first attack reduced the risk for confirmed EDSS progression by 40% compared with delayed treatment (P = .022). In the early treatment group, 31.8% of patients were neutralizing antibody-positive at any time over 3 years, but 46.6% became antibody-negative by 3 years. Neutralizing antibody positivity did not affect the time to clinically definite MS or time to confirmed disability progression.[14] On the basis of 393 patient MRI studies from the European secondary progressive trial, cerebral brain volume dropped significantly more on interferon beta-1b than placebo on the first year of treatment and less than placebo from years 1 to 3.[15]
Several glatiramer-specific T-cell lines were generated from the cerebrospinal fluid of glatiramer acetate-treated MS patients. Eleven out of 12 of the T-cell lines were of the TH2 phenotype and secreted brain-derived neurotrophic factor.[16]
The STRATA study is examining redosing of natalizumab in patients who participated in the AFFIRM, SENTINEL, and GLANCE trials after voluntary suspension of natalizumab. Of the 1076 patients, 40 (3.7%) developed hypersensitivity reactions. These reactions occurred most frequently in those patients receiving only 1 or 2 doses prior to redosing. No new cases of progressive multifocal leukoencephalopathy have been reported.[17] Khatri and colleagues[18] demonstrated that plasma exchange reduced the serum concentration of natalizumab, which potentially could be a strategy to help restore immunocompetence if progressive multifocal leukoencephalopathy occurs. Interim data of an ongoing trial demonstrated statistically significant improvement on the Fatigue Severity Scale and the Modified Fatigue Impact Scale in 19 patients treated with natalizumab. In addition, improvement was also seen in Beck's Depression Inventory.[19] Oral treatment with a different alpha-4 integrin-blocking agent, AJM300, was effective in reducing the severity of EAE in the Lewis rat.[20]
Combination or Induction Therapy
Mitoxantrone induction therapy followed by interferon beta-1b was compared with interferon beta-1b therapy alone over 3 years in 109 active MS patients. The induction protocol consisted of methylprednisolone 1 g and mitoxantrone 20-mg monthly infusions for 6 months. Nine percent of induction-treated patients and 26% of interferon-only patients had worsening disability of greater than 1 EDSS point (65% benefit). The annualized relapse rate with induction was 0.44 compared with 1.14 on interferon only (56% benefit; P < .007).[21] The risks for mitoxantrone were highlighted in a study in Spain that calculated a leukemia incidence of 2.83% (95% confidence interval 1.2-4.4) in exposed patients.[22] This rate was much higher than previously recorded, including the 0.25% prevalence in a French cohort of 802 patients.[23]
Use of statin medications in MS was reexamined. An earlier pilot trial had demonstrated increased relapses and MRI-enhancing lesions on the combination of atorvastatin (40 or 80 mg) and interferon beta-1a subcutaneously.[24] In a separate randomized trial in Naples, Italy, using only 20 mg of atorvastatin, no significant differences were seen with combination therapy. Twenty-eight percent of patients on interferon beta-1a subcutaneously thrice weekly and 25% of patients on both interferon beta-1a and atorvastatin 20 mg daily had MRI-enhancing lesions.[25] Interim safety analysis of 47 patients in the SIMCOMBIN trial on 80 mg of simvastatin or placebo in addition to interferon beta-1a 30 mcg intramuscularly demonstrated no antagonistic effects of the combination therapy.[26] In a pilot study with MRI imaging, 12 clinically isolated syndrome patients were randomized to placebo or simvastatin 80 mg daily plus interferon beta-1a intramuscularly. The addition of simvastatin was safe and well tolerated.[27]
Labels: 500 BEST PML STORIES & STUDIES, PML (Progressive Multifocal Leukoencephalopathy)