- Email: [email protected]
Where to go next with neuroprotection in multiple sclerosis?
Reflection and Reaction
with a higher number of adverse events than in earlier studies,3,4 which had less frequent dose administration. The high rate of early treatment discontinuation in the methylprednisolone group than in the placebo group suggests that this steroid regimen was poorly tolerated. The results of the MECOMBIN trial indicate that, after 1 year, there was a better treatment effect of the combination therapy on the relapse-rate reduction in the 144 patients with T1-gadolinium-enhancing lesions (relative reduction 0·64; p=0·0068) than in the 181 patients without these lesions (relative reduction 0·51; p=0·66), at baseline. Nevertheless, the size of the study meant that no conclusive recommendation could be made about which patients might benefit most from such treatment. In conclusion, the article by Ravnborg and colleagues7 is an important reminder of the need for a more careful approach to combination therapy trials. A much better study design, through a large and well controlled sample size and a long follow-up, was adopted in the MECOMBIN trial than had been used in previous studies. The results from this trial provide a welcome addition to the evidence for a range of treatment options for patients with relapsing-remitting multiple sclerosis. However, large comparison studies are needed to provide definitive data on which dosage of corticosteroids in combination therapy will have the best efficacy and tolerability. Future studies should also establish whether
a combination of corticosteroids and interferon beta therapy is more efficacious than interferon beta alone for preventing the development of long-term confirmed disability,8 which is ultimately the most important goal for treatment of multiple sclerosis. Maria Trojano Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy [email protected] I have received consultancy or speaker honoraria from Biogen, Sanofi-Aventis, Merck Serono, and Bayer-Schering, and have received research grants from Merck Serono, Biogen, and Novartis. 1 2 3
4
5
6
7
8
Berger JR, Houff S. Opportunistic infections and other risks with newer multiple sclerosis therapies. Ann Neurol 2009; 65: 367–77. Conway D, Cohen JA. Combination therapy in multiple sclerosis. Lancet Neurol 2010; 9: 299–308. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 2001; 57: 1239–47. Cohen JA, Imrey PB, Calabresi PA, et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology 2009; 72: 535–41. Havrdova E, Zivadinov R, Krasensky J, et al. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler 2009; 15: 965–76. Sorensen PS, Mellgren SI, Svenningsson A, et al. NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol 2009; 8: 519–29. Ravnborg M, Soelberg Sørensen P, Andersson M, et al. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial. Lancet Neurol 2010; published online June 8. DOI:10.1016/S14744422(10)70132-0. Trojano M, Pellegrini F, Fuiani A, et al. New natural history of interferon-β-treated relapsing multiple sclerosis. Ann Neurol 2007; 61: 300–06.
Where to go next with neuroprotection in multiple sclerosis? An increasing number of immunomodulatory and immunosuppressive treatments are available for patients with relapsing-remitting multiple sclerosis. However, the benefit of these treatment options for patients with secondary progressive multiple sclerosis is much more doubtful. This suggests that these treatments can efficiently modulate the inflammatory component of multiple sclerosis—which occurs predominantly in the early stages of the disease—but that other still poorly defined processes continue to cause tissue destruction and contribute to the accumulation of disability despite suppression of inflammation. These processes are often referred to as the degenerative component of multiple sclerosis. www.thelancet.com/neurology Vol 9 July 2010
Protecting tissue, particularly axons, from such degeneration is thus an important alternative strategy to ameliorate the course of multiple sclerosis and might also help patients with more advanced stages of the disease.1 Partial blockade of voltage-gated sodium channels has protected axons from inflammatory injury in an animal model of multiple sclerosis.2 In this issue of The Lancet Neurology, Kapoor and colleagues3 tested whether such neuroprotection also occurred in people with secondary progressive multiple sclerosis in a phase 2 clinical trial. 120 patients were treated for 2 years with lamotrigine (target dose 400 mg/day) or placebo. Patients had a mean age of about 50 years,
Published Online June 7, 2010 DOI:10.1016/S14744422(10)70133-2 See Articles page 681
647
Reflection and Reaction
mean disease duration of about 20 years, and median expanded disability status scale (EDSS) score of 6·0. Neuroprotection is assumed to slow down tissue loss in the CNS,4,5 and therefore the rate of change of partial (central) cerebral volume was chosen as the primary outcome of this trial.3 Unfortunately, treatment with lamotrigine neither altered cerebral volume loss in the expected manner nor had a beneficial effect on five of six clinical outcomes. Only the rate of deterioration of the timed 25-foot walk was markedly lower in patients treated with lamotrigine. This outcome is disappointing but nevertheless the trial provides important insights and intriguing results. Although a slowing of brain volume loss was expected, partial (central) cerebral volume decreased more steeply in the lamotrigine group than in the placebo group, particularly in the first 12 months. Also, after treatment was discontinued, an increase in brain volume was noted in the lamotrigine group. These volume changes seemed to occur mainly in the white matter compartment. Also, treatment with lamotrigine was not as well tolerated as had been expected or as was seen with other indications for lamotrigine in multiple sclerosis.6 An interesting finding was that patients with a higher EDSS score at baseline were especially susceptible to treatmentrelated side-effects—that is, they tolerated only lower lamotrigine concentrations. These results raise a few questions. First, they show that longitudinal changes in brain volume are complex. Many factors can affect brain volume measurements and the modes of action of these factors are often difficult to predict or even to control, as has been seen with other treatment trials.7 This complicates the interpretation of brain volume as an outcome variable and thus it should be used with caution, especially when examining potential new drugs. In patients treated with lamotrigine, channel blockade might reduce cell volumes by lowering the entry of sodium ions and water. This could also explain the rapid reversal of volume loss after treatment was stopped. Such interaction might obscure potentially positive effects of slowing axonal degeneration but could also mimic beneficial effects. The fact that different tissue compartments might respond differently to treatment should also be considered when using atrophy as a surrogate endpoint, as was done in this trial. 648
Second, lamotrigine was less well tolerated by patients with a higher EDSS score, which suggests that detrimental effects of sodium-channel blockade are occurring in patients with advanced disease. Conversely, this observation also seems to support ion-channel modulation as a valuable strategy for symptomatic treatment of multiple sclerosis.8 Furthermore, having measured the serum concentrations of lamotrigine, the investigators have given an excellent example of how this approach could be used to monitor patient adherence in an objective manner, which clearly should be done whenever possible. In summary, although the trial by Kapoor and colleagues3 provides no new hope for patients with secondary progressive multiple sclerosis, the observations made in this study take us further towards understanding the complexity of brain volume changes and multiple sclerosis pathophysiology. The results will inform the design of future studies in patients with secondary progressive multiple sclerosis and strongly suggest that—similar to immunomodulatory treatment—we probably should not delay efforts of neuroprotection to the advanced stages of multiple sclerosis but rather explore this strategy early on in the disease course. Franz Fazekas Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, A - 8036 Graz, Austria [email protected] I serve on advisory boards and have received honoraria for lecturing and the organisation of workshops and symposia from the following companies that market or develop multiple sclerosis treatments: Biogen Idec, Bayer Schering, Merck Serono, Novartis, Teva, and Sanofi-Aventis. 1 2
3
4
5 6
7
8
Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol 2009; 65: 239–48. Bechtold DA, Miller SJ, Dawson AC, et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol 2006; 253: 1542–51. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 2010; published online June 7. DOI:10.1016/S1474-4422(10)70131-9. Fazekas F, Soelberg-Sorensen P, Comi G, Filippi M. MRI to monitor treatment efficacy in multiple sclerosis. J Neuroimaging 2007; 17 (suppl 1): 50S–55S. Barkhof F, Filippi M. MRI—the perfect surrogate marker for multiple sclerosis? Nat Rev Neurol 2009; 5: 182–83. Leandri M, Lundardi G, Inglese M, et al. Lamotrigine in trigeminal neuralgia secondary to multiple sclerosis. J Neurol 2000; 247: 556–58. Zivadinov R, Reder AT, Filippi M, et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 2008; 71: 136–44. Thompson A, Polman C. Improving function: a new treatment era for multiple sclerosis? Lancet 2009; 373: 697–98.
www.thelancet.com/neurology Vol 9 July 2010
with a higher number of adverse events than in earlier studies,3,4 which had less frequent dose administration. The high rate of early treatment discontinuation in the methylprednisolone group than in the placebo group suggests that this steroid regimen was poorly tolerated. The results of the MECOMBIN trial indicate that, after 1 year, there was a better treatment effect of the combination therapy on the relapse-rate reduction in the 144 patients with T1-gadolinium-enhancing lesions (relative reduction 0·64; p=0·0068) than in the 181 patients without these lesions (relative reduction 0·51; p=0·66), at baseline. Nevertheless, the size of the study meant that no conclusive recommendation could be made about which patients might benefit most from such treatment. In conclusion, the article by Ravnborg and colleagues7 is an important reminder of the need for a more careful approach to combination therapy trials. A much better study design, through a large and well controlled sample size and a long follow-up, was adopted in the MECOMBIN trial than had been used in previous studies. The results from this trial provide a welcome addition to the evidence for a range of treatment options for patients with relapsing-remitting multiple sclerosis. However, large comparison studies are needed to provide definitive data on which dosage of corticosteroids in combination therapy will have the best efficacy and tolerability. Future studies should also establish whether
a combination of corticosteroids and interferon beta therapy is more efficacious than interferon beta alone for preventing the development of long-term confirmed disability,8 which is ultimately the most important goal for treatment of multiple sclerosis. Maria Trojano Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy [email protected] I have received consultancy or speaker honoraria from Biogen, Sanofi-Aventis, Merck Serono, and Bayer-Schering, and have received research grants from Merck Serono, Biogen, and Novartis. 1 2 3
4
5
6
7
8
Berger JR, Houff S. Opportunistic infections and other risks with newer multiple sclerosis therapies. Ann Neurol 2009; 65: 367–77. Conway D, Cohen JA. Combination therapy in multiple sclerosis. Lancet Neurol 2010; 9: 299–308. Zivadinov R, Rudick RA, De Masi R, et al. Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 2001; 57: 1239–47. Cohen JA, Imrey PB, Calabresi PA, et al. Results of the Avonex Combination Trial (ACT) in relapsing-remitting MS. Neurology 2009; 72: 535–41. Havrdova E, Zivadinov R, Krasensky J, et al. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler 2009; 15: 965–76. Sorensen PS, Mellgren SI, Svenningsson A, et al. NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial. Lancet Neurol 2009; 8: 519–29. Ravnborg M, Soelberg Sørensen P, Andersson M, et al. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial. Lancet Neurol 2010; published online June 8. DOI:10.1016/S14744422(10)70132-0. Trojano M, Pellegrini F, Fuiani A, et al. New natural history of interferon-β-treated relapsing multiple sclerosis. Ann Neurol 2007; 61: 300–06.
Where to go next with neuroprotection in multiple sclerosis? An increasing number of immunomodulatory and immunosuppressive treatments are available for patients with relapsing-remitting multiple sclerosis. However, the benefit of these treatment options for patients with secondary progressive multiple sclerosis is much more doubtful. This suggests that these treatments can efficiently modulate the inflammatory component of multiple sclerosis—which occurs predominantly in the early stages of the disease—but that other still poorly defined processes continue to cause tissue destruction and contribute to the accumulation of disability despite suppression of inflammation. These processes are often referred to as the degenerative component of multiple sclerosis. www.thelancet.com/neurology Vol 9 July 2010
Protecting tissue, particularly axons, from such degeneration is thus an important alternative strategy to ameliorate the course of multiple sclerosis and might also help patients with more advanced stages of the disease.1 Partial blockade of voltage-gated sodium channels has protected axons from inflammatory injury in an animal model of multiple sclerosis.2 In this issue of The Lancet Neurology, Kapoor and colleagues3 tested whether such neuroprotection also occurred in people with secondary progressive multiple sclerosis in a phase 2 clinical trial. 120 patients were treated for 2 years with lamotrigine (target dose 400 mg/day) or placebo. Patients had a mean age of about 50 years,
Published Online June 7, 2010 DOI:10.1016/S14744422(10)70133-2 See Articles page 681
647
Reflection and Reaction
mean disease duration of about 20 years, and median expanded disability status scale (EDSS) score of 6·0. Neuroprotection is assumed to slow down tissue loss in the CNS,4,5 and therefore the rate of change of partial (central) cerebral volume was chosen as the primary outcome of this trial.3 Unfortunately, treatment with lamotrigine neither altered cerebral volume loss in the expected manner nor had a beneficial effect on five of six clinical outcomes. Only the rate of deterioration of the timed 25-foot walk was markedly lower in patients treated with lamotrigine. This outcome is disappointing but nevertheless the trial provides important insights and intriguing results. Although a slowing of brain volume loss was expected, partial (central) cerebral volume decreased more steeply in the lamotrigine group than in the placebo group, particularly in the first 12 months. Also, after treatment was discontinued, an increase in brain volume was noted in the lamotrigine group. These volume changes seemed to occur mainly in the white matter compartment. Also, treatment with lamotrigine was not as well tolerated as had been expected or as was seen with other indications for lamotrigine in multiple sclerosis.6 An interesting finding was that patients with a higher EDSS score at baseline were especially susceptible to treatmentrelated side-effects—that is, they tolerated only lower lamotrigine concentrations. These results raise a few questions. First, they show that longitudinal changes in brain volume are complex. Many factors can affect brain volume measurements and the modes of action of these factors are often difficult to predict or even to control, as has been seen with other treatment trials.7 This complicates the interpretation of brain volume as an outcome variable and thus it should be used with caution, especially when examining potential new drugs. In patients treated with lamotrigine, channel blockade might reduce cell volumes by lowering the entry of sodium ions and water. This could also explain the rapid reversal of volume loss after treatment was stopped. Such interaction might obscure potentially positive effects of slowing axonal degeneration but could also mimic beneficial effects. The fact that different tissue compartments might respond differently to treatment should also be considered when using atrophy as a surrogate endpoint, as was done in this trial. 648
Second, lamotrigine was less well tolerated by patients with a higher EDSS score, which suggests that detrimental effects of sodium-channel blockade are occurring in patients with advanced disease. Conversely, this observation also seems to support ion-channel modulation as a valuable strategy for symptomatic treatment of multiple sclerosis.8 Furthermore, having measured the serum concentrations of lamotrigine, the investigators have given an excellent example of how this approach could be used to monitor patient adherence in an objective manner, which clearly should be done whenever possible. In summary, although the trial by Kapoor and colleagues3 provides no new hope for patients with secondary progressive multiple sclerosis, the observations made in this study take us further towards understanding the complexity of brain volume changes and multiple sclerosis pathophysiology. The results will inform the design of future studies in patients with secondary progressive multiple sclerosis and strongly suggest that—similar to immunomodulatory treatment—we probably should not delay efforts of neuroprotection to the advanced stages of multiple sclerosis but rather explore this strategy early on in the disease course. Franz Fazekas Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, A - 8036 Graz, Austria [email protected] I serve on advisory boards and have received honoraria for lecturing and the organisation of workshops and symposia from the following companies that market or develop multiple sclerosis treatments: Biogen Idec, Bayer Schering, Merck Serono, Novartis, Teva, and Sanofi-Aventis. 1 2
3
4
5 6
7
8
Weiner HL. The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol 2009; 65: 239–48. Bechtold DA, Miller SJ, Dawson AC, et al. Axonal protection achieved in a model of multiple sclerosis using lamotrigine. J Neurol 2006; 253: 1542–51. Kapoor R, Furby J, Hayton T, et al. Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Neurol 2010; published online June 7. DOI:10.1016/S1474-4422(10)70131-9. Fazekas F, Soelberg-Sorensen P, Comi G, Filippi M. MRI to monitor treatment efficacy in multiple sclerosis. J Neuroimaging 2007; 17 (suppl 1): 50S–55S. Barkhof F, Filippi M. MRI—the perfect surrogate marker for multiple sclerosis? Nat Rev Neurol 2009; 5: 182–83. Leandri M, Lundardi G, Inglese M, et al. Lamotrigine in trigeminal neuralgia secondary to multiple sclerosis. J Neurol 2000; 247: 556–58. Zivadinov R, Reder AT, Filippi M, et al. Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis. Neurology 2008; 71: 136–44. Thompson A, Polman C. Improving function: a new treatment era for multiple sclerosis? Lancet 2009; 373: 697–98.
www.thelancet.com/neurology Vol 9 July 2010