Correspondence
General Hospital Braunau, Cardiology and Intensive Care, Braunau A-5280, Austria 1
2
3
4
5
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. SEARCH Study Collaborative Group. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J 2007; 154: 815–23. Auer J, Lamm G, Eber B. Intensive lipid lowering with atorvastatin in coronary disease. N Engl J Med 2005; 353: 93–96. FDA Drug Safety Communication. New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. http://www.fda. gov/Drugs/DrugSafety/ucm256581.htm (accessed July 3, 2014). Schulz KF, Grimes DA. Sample size calculations in randomised trials: mandatory and mystical. Lancet 2005; 365: 1348–53.
We wish to congratulate Jeremy Chataway and colleagues for successfully completing the high-dose simvastatin in secondary progressive multiple sclerosis (MS-STAT) trial.1 The detected delay in disease progression in this phase 2 study now calls for phase 3 trial evidence. However, we are concerned such evidence will never be produced, simply because simvastatin costs about £0·06 per day in the UK. Which industrial partner will be prepared to fund a phase 3 development programme, let alone the costs to apply for (and maintain) a license should further trials confirm the efficacy of simvastatin in progressive multiple sclerosis? Or is there an alternative pathway to repurposing beyond the stage at which MS-STAT has arrived—ie, to the point where the drugs can be made available to patients with secondary progressive multiple sclerosis? If it is not feasible to develop licensed drugs to the stage they can actually be prescribed for a new indication, can we justify, ethically and economically, proof-of-concept studies such as MS-STAT? One might argue such trials become little more than academic exercises creating false hopes for people in desperate need of treatments. 952
We declare no competing interests.
*Gavin Giovannoni, David Baker, Klaus Schmierer [email protected] Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK 1
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21.
Authors’ reply We thank Johann Auer and Robert Berent for their Correspondence regarding our phase 2 trial of simvastatin in secondary progressive multiple sclerosis (MS-STAT). 1 In this trial, simvastatin (80 mg) was well-tolerated with no difference in adverse events between the two groups. The same dose was also used in the largest trial in relapsing-remitting multiple sclerosis (SIMCOMBIN), 2 which included 307 patients, and also in the Danish acute optic neuritis trial (64 patients);3 again, there was no difference in serious adverse events between placebo and active arms, in either trial.2,3 As Auer and Berent state, the US FDA has recommended that this dose is to be used with particular care in the treatment of vascular disease. We agree with that. However, the risk–benefit ratio is different in secondary progressive multiple sclerosis, for which no treatment exists for a devastating, progressively disabling disease. Although we recognise that infrequent adverse effects might require a larger sample size, we believe that if monitored carefully, as in our study,1 this dose of simvastatin can be safely used perhaps with additional pharmacogenomic information (eg, the SLCO1B1 risk allele for simvastatin-induced myopathy4). Indeed, in multiple sclerosis, we are familiar with using drugs such natalizumab and alemtuzumab, which have their own uncommon, but serious safety issues. For example, the risk of progressive multifocal
leukoencephalopathy (a potentially fatal viral disease) approaches 0·5% after 2 years of treatment with natalizumab in JC virus positive patients. Regarding the use of other statins, we were originally excited by the potential of simvastatin in multiple sclerosis by the study of Vollmer and colleagues,5 which again used simvastatin at a dose of 80 mg. One of our central reasons for using simvastatin was that we considered it to have a favourable combination of brain penetrance and potency. Gavin Giovannoni and colleagues raise the general issue of off-patent repurposed drugs and the subsequent licensing process. This is a crucial issue, which is a challenge for the current regulatory structure and one where guidance is evolving with the authorities. An effective resolution is needed, as there are an increasing number of compounds for which this process might apply—eg, the use of aspirin in cancer prevention.6 However without positive (investigator-led) phase 2 data such as ours, the opportunity or the grounds will not exist to challenge what is clearly an unsatisfactory and increasingly problematic situation. We declare no competing interests.
Jeremy Chataway on behalf of the MS-STAT investigators1 [email protected] National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK 1
2
3
4
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. Sorensen P, Lycke J, Eralinna JP, et al. Simvastatin as add-on to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol 2011; 10: 691–701. Tsakiri A, Kallenbach K, Fuglo D, Wanscher B, Larsson H, Frederiksen J. Simvastatin improves final visual outcome in acute optic neuritis: a randomized study. Mult Scler J 2012; 18: 72–81. Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 update. Clin Pharmacol Ther 2014; published online June 11. DOI:10.1038/clpt.2014.125.
www.thelancet.com Vol 384 September 13, 2014
General Hospital Braunau, Cardiology and Intensive Care, Braunau A-5280, Austria 1
2
3
4
5
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. SEARCH Study Collaborative Group. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J 2007; 154: 815–23. Auer J, Lamm G, Eber B. Intensive lipid lowering with atorvastatin in coronary disease. N Engl J Med 2005; 353: 93–96. FDA Drug Safety Communication. New restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. http://www.fda. gov/Drugs/DrugSafety/ucm256581.htm (accessed July 3, 2014). Schulz KF, Grimes DA. Sample size calculations in randomised trials: mandatory and mystical. Lancet 2005; 365: 1348–53.
We wish to congratulate Jeremy Chataway and colleagues for successfully completing the high-dose simvastatin in secondary progressive multiple sclerosis (MS-STAT) trial.1 The detected delay in disease progression in this phase 2 study now calls for phase 3 trial evidence. However, we are concerned such evidence will never be produced, simply because simvastatin costs about £0·06 per day in the UK. Which industrial partner will be prepared to fund a phase 3 development programme, let alone the costs to apply for (and maintain) a license should further trials confirm the efficacy of simvastatin in progressive multiple sclerosis? Or is there an alternative pathway to repurposing beyond the stage at which MS-STAT has arrived—ie, to the point where the drugs can be made available to patients with secondary progressive multiple sclerosis? If it is not feasible to develop licensed drugs to the stage they can actually be prescribed for a new indication, can we justify, ethically and economically, proof-of-concept studies such as MS-STAT? One might argue such trials become little more than academic exercises creating false hopes for people in desperate need of treatments. 952
We declare no competing interests.
*Gavin Giovannoni, David Baker, Klaus Schmierer [email protected] Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London E1 2AT, UK 1
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21.
Authors’ reply We thank Johann Auer and Robert Berent for their Correspondence regarding our phase 2 trial of simvastatin in secondary progressive multiple sclerosis (MS-STAT). 1 In this trial, simvastatin (80 mg) was well-tolerated with no difference in adverse events between the two groups. The same dose was also used in the largest trial in relapsing-remitting multiple sclerosis (SIMCOMBIN), 2 which included 307 patients, and also in the Danish acute optic neuritis trial (64 patients);3 again, there was no difference in serious adverse events between placebo and active arms, in either trial.2,3 As Auer and Berent state, the US FDA has recommended that this dose is to be used with particular care in the treatment of vascular disease. We agree with that. However, the risk–benefit ratio is different in secondary progressive multiple sclerosis, for which no treatment exists for a devastating, progressively disabling disease. Although we recognise that infrequent adverse effects might require a larger sample size, we believe that if monitored carefully, as in our study,1 this dose of simvastatin can be safely used perhaps with additional pharmacogenomic information (eg, the SLCO1B1 risk allele for simvastatin-induced myopathy4). Indeed, in multiple sclerosis, we are familiar with using drugs such natalizumab and alemtuzumab, which have their own uncommon, but serious safety issues. For example, the risk of progressive multifocal
leukoencephalopathy (a potentially fatal viral disease) approaches 0·5% after 2 years of treatment with natalizumab in JC virus positive patients. Regarding the use of other statins, we were originally excited by the potential of simvastatin in multiple sclerosis by the study of Vollmer and colleagues,5 which again used simvastatin at a dose of 80 mg. One of our central reasons for using simvastatin was that we considered it to have a favourable combination of brain penetrance and potency. Gavin Giovannoni and colleagues raise the general issue of off-patent repurposed drugs and the subsequent licensing process. This is a crucial issue, which is a challenge for the current regulatory structure and one where guidance is evolving with the authorities. An effective resolution is needed, as there are an increasing number of compounds for which this process might apply—eg, the use of aspirin in cancer prevention.6 However without positive (investigator-led) phase 2 data such as ours, the opportunity or the grounds will not exist to challenge what is clearly an unsatisfactory and increasingly problematic situation. We declare no competing interests.
Jeremy Chataway on behalf of the MS-STAT investigators1 [email protected] National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK 1
2
3
4
Chataway J, Schuerer N, Alsanousi A, et al. Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial. Lancet 2014; 383: 2213–21. Sorensen P, Lycke J, Eralinna JP, et al. Simvastatin as add-on to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol 2011; 10: 691–701. Tsakiri A, Kallenbach K, Fuglo D, Wanscher B, Larsson H, Frederiksen J. Simvastatin improves final visual outcome in acute optic neuritis: a randomized study. Mult Scler J 2012; 18: 72–81. Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 update. Clin Pharmacol Ther 2014; published online June 11. DOI:10.1038/clpt.2014.125.
www.thelancet.com Vol 384 September 13, 2014
