Comment
Diagnosis and trials of clinically isolated syndrome Published Online September 3, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70202-9 See Articles page 977
962
Clinically isolated syndrome is often described as a first single clinical episode that is consistent with demyelination, and typically presents as optic neuritis, myelitis, or a brainstem syndrome. Most patients with a clinically isolated syndrome and an abnormal brain MRI will develop clinically definite multiple sclerosis within 20 years of follow-up.1 The benefits of reducing the percentage of patients who will develop clinically definite multiple sclerosis are obvious, and trials of patients with clinically isolated syndrome that have used interferons, glatiramer acetate, and cladribine have had some success.2–7 In The Lancet Neurology, Aaron Miller and colleagues now present the results of a trial of the first oral drug that has been approved for use in multiple sclerosis and show its a beneficial effect on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome.8 In the TOPIC trial,8 teriflunomide was administered in two different doses—7 mg (205 patients) and 14 mg (216 patients)—and was compared against placebo (197 patients) for up to 108 weeks. Compared with placebo, teriflunomide at both doses significantly reduced the risk of relapse that defined conversion to clinically definite multiple sclerosis, by 42·6% with the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379–0·869]; p=0·0087) and by 37·2% with the 7 mg dose (HR 0·628 [0·416–0·949]; p=0·0271), with an acceptable safety profile. The sponsor decided to stop the trial in August, 2012, after publication of the 2010 version (third revision) of the McDonald multiple sclerosis diagnostic criteria9 and the consequent change in the medical environment for clinically isolated syndrome and multiple sclerosis that might have affected the availability of people eligible to participate in the trial. The number of patients planned to be included was 780, but the actual number recruited at trial stoppage was 618. Fortunately, the trial was positive despite this substantial decrease in the sample size. The diagnosis of multiple sclerosis can be a complicated matter. The present criteria used to diagnose multiple sclerosis are the 2010 McDonald criteria.9 In these criteria, MRI has an important role, and the simultaneous presence of gadolinium-enhancing and non-gadoliniumenhancing lesions on MRI scans (indicating both current and past disease activity, and therefore evidence of
dissemination in time) in specific locations in the CNS (indicating involvement of more than one part of the CNS typically affected in multiple sclerosis, and therefore evidence of dissemination in space) suggests a diagnosis of multiple sclerosis, even at the onset of clinically isolated syndrome.10 About half of patients who present with this syndrome fulfil the 2010 McDonald criteria for multiple sclerosis, which is the most important improvement introduced by the new criteria; previous versions of these criteria required longer times from onset to achieve a diagnosis of multiple sclerosis. Until now, the gold standard used to assess the diagnostic properties of any new revisions to diagnostic criteria for multiple sclerosis has been the conversion to clinically definite multiple sclerosis after clinically isolated syndrome (ie, the occurrence of a second attack); the occurrence of a second event was the basis of the Poser criteria—the most widely used for many years.11 Multiple sclerosis diagnostic criteria are not useful for the classification of individual patients into different clinical phenotypes (including relapsingremitting, primary progressive and secondary progressive classical phenotypes)—a classification that has recently been revised.12 Moreover, clinically isolated syndrome is an inappropriate name for the first episode suggestive of demyelinating disease, specifically multiple sclerosis: if we adhere strictly to semantics, headache, seizure, or stroke could be considered clinically isolated syndrome, and also lumbar pain, jaundice, or chest pain. Several attempts to change this name have failed to gain acceptance by neurologists, and the multiple sclerosis community seems to have reached a point of resignation. This ambiguous definition of clinically isolated syndrome means that neurologists—including those who specialise in multiple sclerosis—have differing views (some incorrect) of the same diagnostic criteria. To stop the TOPIC trial was probably not necessary, since interferons and glatiramer acetate are indicated by the European Medicines Agency in ambulatory patients with relapsing multiple sclerosis with at least two recurrent attacks during the preceding 2–3 years13 and also for the treatment of patients who have experienced a single demyelinating event if they are judged to be at high risk of developing clinically definite www.thelancet.com/neurology Vol 13 October 2014
Comment
multiple sclerosis (ie, they have a sufficiently abnormal MRI). The BENEFIT study of interferon beta-1b in patients with clinically isolated syndrome3 could have been used as a precedent, since trial recruitment and conduct was not affected by the licensing of intramuscular interferon beta-1a for patients with clinically isolated syndrome. Therefore, the release of a new version of the diagnostic criteria is unlikely to have affected the clinical management of these patients. In fact the baseline characteristics of patients in TOPIC are similar to those in other trials of clinically isolated syndrome,2–7 except for a lower percentage of baseline MRI scans with gadolinium-enhancing lesions in TOPIC than in the previous trials in patients with clinically isolated syndrome. The results of the TOPIC trial support the notion based on findings of previous studies that the treatment of patients with first episodes suggestive of multiple sclerosis produces at least a similar and probably a more beneficial effect than does the treatment of patients with relapsing–remitting multiple sclerosis. One might wonder whether trials in patients with clinically isolated syndrome are still necessary, given that the results of such trials seem to be similar to those in trials of multiple sclerosis. The most intriguing issue is whether the higher percentage of patients who do not develop multiple sclerosis with active treatment compared with placebo represents a cure for the disease or if this is just a transitory finding.
XM has received compensation for consulting services and speaking honoraria from Neurotec, Novartis, Roche, Sanofi-Genzyme, TEVA, Geneuro, Genentech, Merck, EMD, Biogen-Idec, Bayer and Almirall. JS-G has received compensation for consulting services and speaking honoraria from Merck-Serono, Almirall, Genzyme, Roche, Biogen-Idec, Teva, and Novartis, and has received a grant from Genzyme. 1
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Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131: 808–17. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Eng J Med 2000; 343: 898–904. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67: 1242–49. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374: 1503–11. Comi G, Filippi M, Barkhof F, et al; Early Treatment of Multiple Sclerosis Study Group. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357: 1576–82. Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012; 11: 33–41. Leist TP, Comi G, Cree BA, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol 2014; 13: 257–67. Miller AE, Wolinsky JS, Kappos L, et al, for the TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; published online Sept 3. http://dx.doi.org/10.1016/S1474-4422(14)70191-7. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Ann Neurol 2011; 69: 292–302. Montalban X, Tintoré M, Swanton J, et al. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 2010; 74: 427–34. Poser CM, Paty DW, Sceinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–31. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 15: 278–86. European Medicines Agency. http://www.ema.europa.eu/ema/ (accessed Aug 29, 2014).
*Xavier Montalban, Jaume Sastre-Garriga Department of Neurology/Neuroimmunology, Centre d’Esclerosi Multiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119-129, Barcelona 08035, Spain [email protected]
A rebirth for drisapersen in Duchenne muscular dystrophy? Duchenne muscular dystrophy is one of the most common and best studied inherited disorders, with an incidence of about one in 5000 boys worldwide. The disease was a proving ground for population genetics in the 1950s, molecular genetics and gene identification methods in the 1980s, and genetargeted therapeutic approaches in the 2010s. The exon-skipping approach—in which small nucleic acid drugs are delivered systemically, enter muscle www.thelancet.com/neurology Vol 13 October 2014
cells, and modulate the RNA splicing to skip over the patient’s mutation—has received great interest, owing to both its novelty and impressive biochemical rescue and phenotype improvement seen in mouse and dog models of Duchenne muscular dystrophy.1–5 In The Lancet Neurology, Thomas Voit and colleagues6 report results from their 6 month, randomised, masked, phase 2 study of exon skipping with drisapersen in 53 boys with Duchenne muscular dystrophy.
Published Online September 8, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70158-9 See Articles page 987 For more on the partnership see http://www.reuters.com/ article/2014/01/13/us-gskprosensaidUSBREA0C0S420140113
963
Diagnosis and trials of clinically isolated syndrome Published Online September 3, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70202-9 See Articles page 977
962
Clinically isolated syndrome is often described as a first single clinical episode that is consistent with demyelination, and typically presents as optic neuritis, myelitis, or a brainstem syndrome. Most patients with a clinically isolated syndrome and an abnormal brain MRI will develop clinically definite multiple sclerosis within 20 years of follow-up.1 The benefits of reducing the percentage of patients who will develop clinically definite multiple sclerosis are obvious, and trials of patients with clinically isolated syndrome that have used interferons, glatiramer acetate, and cladribine have had some success.2–7 In The Lancet Neurology, Aaron Miller and colleagues now present the results of a trial of the first oral drug that has been approved for use in multiple sclerosis and show its a beneficial effect on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome.8 In the TOPIC trial,8 teriflunomide was administered in two different doses—7 mg (205 patients) and 14 mg (216 patients)—and was compared against placebo (197 patients) for up to 108 weeks. Compared with placebo, teriflunomide at both doses significantly reduced the risk of relapse that defined conversion to clinically definite multiple sclerosis, by 42·6% with the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379–0·869]; p=0·0087) and by 37·2% with the 7 mg dose (HR 0·628 [0·416–0·949]; p=0·0271), with an acceptable safety profile. The sponsor decided to stop the trial in August, 2012, after publication of the 2010 version (third revision) of the McDonald multiple sclerosis diagnostic criteria9 and the consequent change in the medical environment for clinically isolated syndrome and multiple sclerosis that might have affected the availability of people eligible to participate in the trial. The number of patients planned to be included was 780, but the actual number recruited at trial stoppage was 618. Fortunately, the trial was positive despite this substantial decrease in the sample size. The diagnosis of multiple sclerosis can be a complicated matter. The present criteria used to diagnose multiple sclerosis are the 2010 McDonald criteria.9 In these criteria, MRI has an important role, and the simultaneous presence of gadolinium-enhancing and non-gadoliniumenhancing lesions on MRI scans (indicating both current and past disease activity, and therefore evidence of
dissemination in time) in specific locations in the CNS (indicating involvement of more than one part of the CNS typically affected in multiple sclerosis, and therefore evidence of dissemination in space) suggests a diagnosis of multiple sclerosis, even at the onset of clinically isolated syndrome.10 About half of patients who present with this syndrome fulfil the 2010 McDonald criteria for multiple sclerosis, which is the most important improvement introduced by the new criteria; previous versions of these criteria required longer times from onset to achieve a diagnosis of multiple sclerosis. Until now, the gold standard used to assess the diagnostic properties of any new revisions to diagnostic criteria for multiple sclerosis has been the conversion to clinically definite multiple sclerosis after clinically isolated syndrome (ie, the occurrence of a second attack); the occurrence of a second event was the basis of the Poser criteria—the most widely used for many years.11 Multiple sclerosis diagnostic criteria are not useful for the classification of individual patients into different clinical phenotypes (including relapsingremitting, primary progressive and secondary progressive classical phenotypes)—a classification that has recently been revised.12 Moreover, clinically isolated syndrome is an inappropriate name for the first episode suggestive of demyelinating disease, specifically multiple sclerosis: if we adhere strictly to semantics, headache, seizure, or stroke could be considered clinically isolated syndrome, and also lumbar pain, jaundice, or chest pain. Several attempts to change this name have failed to gain acceptance by neurologists, and the multiple sclerosis community seems to have reached a point of resignation. This ambiguous definition of clinically isolated syndrome means that neurologists—including those who specialise in multiple sclerosis—have differing views (some incorrect) of the same diagnostic criteria. To stop the TOPIC trial was probably not necessary, since interferons and glatiramer acetate are indicated by the European Medicines Agency in ambulatory patients with relapsing multiple sclerosis with at least two recurrent attacks during the preceding 2–3 years13 and also for the treatment of patients who have experienced a single demyelinating event if they are judged to be at high risk of developing clinically definite www.thelancet.com/neurology Vol 13 October 2014
Comment
multiple sclerosis (ie, they have a sufficiently abnormal MRI). The BENEFIT study of interferon beta-1b in patients with clinically isolated syndrome3 could have been used as a precedent, since trial recruitment and conduct was not affected by the licensing of intramuscular interferon beta-1a for patients with clinically isolated syndrome. Therefore, the release of a new version of the diagnostic criteria is unlikely to have affected the clinical management of these patients. In fact the baseline characteristics of patients in TOPIC are similar to those in other trials of clinically isolated syndrome,2–7 except for a lower percentage of baseline MRI scans with gadolinium-enhancing lesions in TOPIC than in the previous trials in patients with clinically isolated syndrome. The results of the TOPIC trial support the notion based on findings of previous studies that the treatment of patients with first episodes suggestive of multiple sclerosis produces at least a similar and probably a more beneficial effect than does the treatment of patients with relapsing–remitting multiple sclerosis. One might wonder whether trials in patients with clinically isolated syndrome are still necessary, given that the results of such trials seem to be similar to those in trials of multiple sclerosis. The most intriguing issue is whether the higher percentage of patients who do not develop multiple sclerosis with active treatment compared with placebo represents a cure for the disease or if this is just a transitory finding.
XM has received compensation for consulting services and speaking honoraria from Neurotec, Novartis, Roche, Sanofi-Genzyme, TEVA, Geneuro, Genentech, Merck, EMD, Biogen-Idec, Bayer and Almirall. JS-G has received compensation for consulting services and speaking honoraria from Merck-Serono, Almirall, Genzyme, Roche, Biogen-Idec, Teva, and Novartis, and has received a grant from Genzyme. 1
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10 11 12 13
Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008; 131: 808–17. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Eng J Med 2000; 343: 898–904. Kappos L, Polman CH, Freedman MS, et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67: 1242–49. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 2009; 374: 1503–11. Comi G, Filippi M, Barkhof F, et al; Early Treatment of Multiple Sclerosis Study Group. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 2001; 357: 1576–82. Comi G, De Stefano N, Freedman MS, et al. Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial. Lancet Neurol 2012; 11: 33–41. Leist TP, Comi G, Cree BA, et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol 2014; 13: 257–67. Miller AE, Wolinsky JS, Kappos L, et al, for the TOPIC Study Group. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol 2014; published online Sept 3. http://dx.doi.org/10.1016/S1474-4422(14)70191-7. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald Criteria. Ann Neurol 2011; 69: 292–302. Montalban X, Tintoré M, Swanton J, et al. MRI criteria for MS in patients with clinically isolated syndromes. Neurology 2010; 74: 427–34. Poser CM, Paty DW, Sceinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–31. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 15: 278–86. European Medicines Agency. http://www.ema.europa.eu/ema/ (accessed Aug 29, 2014).
*Xavier Montalban, Jaume Sastre-Garriga Department of Neurology/Neuroimmunology, Centre d’Esclerosi Multiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Passeig Vall d’Hebron 119-129, Barcelona 08035, Spain [email protected]
A rebirth for drisapersen in Duchenne muscular dystrophy? Duchenne muscular dystrophy is one of the most common and best studied inherited disorders, with an incidence of about one in 5000 boys worldwide. The disease was a proving ground for population genetics in the 1950s, molecular genetics and gene identification methods in the 1980s, and genetargeted therapeutic approaches in the 2010s. The exon-skipping approach—in which small nucleic acid drugs are delivered systemically, enter muscle www.thelancet.com/neurology Vol 13 October 2014
cells, and modulate the RNA splicing to skip over the patient’s mutation—has received great interest, owing to both its novelty and impressive biochemical rescue and phenotype improvement seen in mouse and dog models of Duchenne muscular dystrophy.1–5 In The Lancet Neurology, Thomas Voit and colleagues6 report results from their 6 month, randomised, masked, phase 2 study of exon skipping with drisapersen in 53 boys with Duchenne muscular dystrophy.
Published Online September 8, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70158-9 See Articles page 987 For more on the partnership see http://www.reuters.com/ article/2014/01/13/us-gskprosensaidUSBREA0C0S420140113
963
