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Treatments for rare diseases: molybdenum cofactor deficiency
Comment
Treatments for rare diseases: molybdenum cofactor deficiency blood–brain barrier otherwise prevents enzyme reaching the brain.4 One could argue that a treatment needing frequent infusions for life is risky and interferes too much with quality of life to be in the best interests of the child. And then there is cost. Cost is a major problem in many therapies, especially when patient numbers are small. Dietary therapy needing special aminoacid supplements for phenylketonuria costs up to around £15 000 per year for an adult, but a new and much more convenient therapy suited to some patients might cost five to ten times that much.5 Enzyme replacement therapies can cost hundreds of thousands of pounds per life-year gained.6 Very large expenditure must be considered from an ethical viewpoint—could the money be better spent to support health outcomes in some other arena? The costs of treatment for MoCD are not yet clear, but are likely to be very high. For many rare disorders the long-term outcomes with new treatments are as yet unknown. The signs for some are not good. Krabbe’s disease is a severe neurometabolic disorder usually fatal in the first year or two of life. Haemopoietic stem-cell transplantation certainly prolongs life, but in the long term the disorder seems to remain progressive, converted from one lethal in early infancy to a degenerative disorder, probably fatal later in life.7 In Krabbe’s disease, like MoCD, therapy must be instituted very soon after birth. But, unlike MoCD, the treatment is risky
www.thelancet.com Published online September 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00125-7
Published Online September 4, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00125-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)00124-5
1suisse.ch
In The Lancet, Bernd Schwahn and colleagues1 report on the follow-up of a cohort of infants with molybdenum cofactor deficiency (MoCD), some of whom benefited greatly from a novel therapy. A very rare metabolic disorder is perhaps an unlikely subject for a general medical journal, but new treatments for rare metabolic diseases have problems in common that need much thought. MoCD causes loss of function of the enzyme sulphite oxidase, and is clinically characterised by severe and progressive neurological damage and intractable seizures; symptoms are usually apparent within the first hours or days of life.2 No treatment has been effective until recently, when studies in a mouse model showed the benefit of replacement of cyclic pyranopterin monophosphate, a precursor of the cofactor lacking in two-thirds of patients with MoCD.2 In Schwahn and colleagues’ report,1 11 patients with MoCD type A were first treated from 0 to 68 days of life. Of eight who showed initial improvement and clear biochemical response, three did well in the longer term, having started treatment by day 7. The treatment has proved very safe. The report1 is immensely encouraging for those who manage patients with genetic metabolic disorders, so often seemingly untreatable. The investigation of long-term outcome in treated patients has been done in a model way, involving 12 centres spread across five countries, a standardised protocol, and great attention to detail. Too often, in the case of a rare disease, formal long-term outcome studies have not been undertaken, mainly because of the small number of available patients. One aspect requiring further discussion is the burdensome nature of this particular treatment—daily intravenous infusions, for life.1 Although the authors hope for development of safer and more convenient administration than the present form, new treatments now being used for several other rare disorders also necessitate frequent infusions. Enzyme replacement therapy for lysosomal storage disorders is one example, with life-long infusions every week or fortnight, often complicated by immune reactions.3 Some of these enzyme replacement therapies are now being given intrathecally, with the attendant risks, because the
1
Comment
and which patients have infantile disease needing urgent treatment, and which do not have clinically significant disease, is not yet always clear. Certainly treatment for many lysosomal storage disorders and other rare enzymopathies has been encouraging and life-changing, but long-term outcomes remain uncertain and there is also uncertainty, if diagnosis is made by newborn screening, about which patients need immediate treatment. Pompe’s disease is one example.8 For MoCD, as for some other rare disorders, the window of opportunity to start treatment is very short. Diagnosis needs to be both swift and sure. Unfortunately there is not at present a test suitable for newborn screening, as there is for some lysosomal storage disorders.9 However, babies presenting with seizures could all be tested quickly and easily10 (in our hands the simple bedside urine sulphite test is unreliable) and MoCD suspected or ruled out. Schwahn and colleagues are to be congratulated on this exciting and effective new treatment for a previously untreatable disease,1 but the likely problems in assessing new treatments for rare diseases must be borne in mind, and well designed long-term surveillance provided for treated patients.
2
Bridget Wilcken Sydney Children’s Hospitals Network and University of Sydney, Sydney, NSW 2145, Australia [email protected] I declare no competing interests. 1
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Schwahn BC, Van Spronsen FJ, Belaidi AA, et al. Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet 2015; published online Sept 4. http://dx.doi.org/10.1016/S0140-6736(15)00124-5. Johnson JL, Duran M. Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The metabolic and molecular bases of inherited disease, 8th edn. New York: McGraw-Hill, 2001: 3163–77. Desnick RJ, Schuchman EH. Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet 2012; 13: 307–35. Augustine EF, Mink JW. Enzyme replacement in neuronal storage disorders in the pediatric population. Curr Treat Options Neurol 2013; 15: 634–51. Harding CO. New era in treatment for phenylketonuria: pharmacologic therapy with sapropterin dihydrochloride. Biologics 2010; 4: 231–36. Kanters TA, Hoogenboom-Plug I, Rutten-Van Mölken MP, Redekop WK, van der Ploeg AT, Hakkaart L. Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in classic-infantile patients with Pompe disease. Orphanet J Rare Dis 2014; 9: 75. Kemper AR, Knapp AA, Green NS, Comeau AM, Metterville DR, Perrin JM. Weighing the evidence for newborn screening for early-infantile Krabbe disease. Genet Med 2010; 12: 539–43. Kishnani PS, Beckemeyer AA. New therapeutic approaches for Pompe disease: enzyme replacement therapy and beyond. Pediatr Endocrinol Rev 2014; 12 (suppl 1): 114–24. Matern D, Gavrilov D, Oglesbee D, Raymond K, Rinaldo P, Tortorelli S. Newborn screening for lysosomal disorders. Semin Perinatol 2015; 39: 2206–16. Pitt JJ, Eggington M, Kahler SG. Comprehensive screening of urine samples for inborn errors of metabolism by electrospray tandem mass spectrometry. Clin Chem 2002; 48: 1970–80.
www.thelancet.com Published online September 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00125-7
Treatments for rare diseases: molybdenum cofactor deficiency blood–brain barrier otherwise prevents enzyme reaching the brain.4 One could argue that a treatment needing frequent infusions for life is risky and interferes too much with quality of life to be in the best interests of the child. And then there is cost. Cost is a major problem in many therapies, especially when patient numbers are small. Dietary therapy needing special aminoacid supplements for phenylketonuria costs up to around £15 000 per year for an adult, but a new and much more convenient therapy suited to some patients might cost five to ten times that much.5 Enzyme replacement therapies can cost hundreds of thousands of pounds per life-year gained.6 Very large expenditure must be considered from an ethical viewpoint—could the money be better spent to support health outcomes in some other arena? The costs of treatment for MoCD are not yet clear, but are likely to be very high. For many rare disorders the long-term outcomes with new treatments are as yet unknown. The signs for some are not good. Krabbe’s disease is a severe neurometabolic disorder usually fatal in the first year or two of life. Haemopoietic stem-cell transplantation certainly prolongs life, but in the long term the disorder seems to remain progressive, converted from one lethal in early infancy to a degenerative disorder, probably fatal later in life.7 In Krabbe’s disease, like MoCD, therapy must be instituted very soon after birth. But, unlike MoCD, the treatment is risky
www.thelancet.com Published online September 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00125-7
Published Online September 4, 2015 http://dx.doi.org/10.1016/ S0140-6736(15)00125-7 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(15)00124-5
1suisse.ch
In The Lancet, Bernd Schwahn and colleagues1 report on the follow-up of a cohort of infants with molybdenum cofactor deficiency (MoCD), some of whom benefited greatly from a novel therapy. A very rare metabolic disorder is perhaps an unlikely subject for a general medical journal, but new treatments for rare metabolic diseases have problems in common that need much thought. MoCD causes loss of function of the enzyme sulphite oxidase, and is clinically characterised by severe and progressive neurological damage and intractable seizures; symptoms are usually apparent within the first hours or days of life.2 No treatment has been effective until recently, when studies in a mouse model showed the benefit of replacement of cyclic pyranopterin monophosphate, a precursor of the cofactor lacking in two-thirds of patients with MoCD.2 In Schwahn and colleagues’ report,1 11 patients with MoCD type A were first treated from 0 to 68 days of life. Of eight who showed initial improvement and clear biochemical response, three did well in the longer term, having started treatment by day 7. The treatment has proved very safe. The report1 is immensely encouraging for those who manage patients with genetic metabolic disorders, so often seemingly untreatable. The investigation of long-term outcome in treated patients has been done in a model way, involving 12 centres spread across five countries, a standardised protocol, and great attention to detail. Too often, in the case of a rare disease, formal long-term outcome studies have not been undertaken, mainly because of the small number of available patients. One aspect requiring further discussion is the burdensome nature of this particular treatment—daily intravenous infusions, for life.1 Although the authors hope for development of safer and more convenient administration than the present form, new treatments now being used for several other rare disorders also necessitate frequent infusions. Enzyme replacement therapy for lysosomal storage disorders is one example, with life-long infusions every week or fortnight, often complicated by immune reactions.3 Some of these enzyme replacement therapies are now being given intrathecally, with the attendant risks, because the
1
Comment
and which patients have infantile disease needing urgent treatment, and which do not have clinically significant disease, is not yet always clear. Certainly treatment for many lysosomal storage disorders and other rare enzymopathies has been encouraging and life-changing, but long-term outcomes remain uncertain and there is also uncertainty, if diagnosis is made by newborn screening, about which patients need immediate treatment. Pompe’s disease is one example.8 For MoCD, as for some other rare disorders, the window of opportunity to start treatment is very short. Diagnosis needs to be both swift and sure. Unfortunately there is not at present a test suitable for newborn screening, as there is for some lysosomal storage disorders.9 However, babies presenting with seizures could all be tested quickly and easily10 (in our hands the simple bedside urine sulphite test is unreliable) and MoCD suspected or ruled out. Schwahn and colleagues are to be congratulated on this exciting and effective new treatment for a previously untreatable disease,1 but the likely problems in assessing new treatments for rare diseases must be borne in mind, and well designed long-term surveillance provided for treated patients.
2
Bridget Wilcken Sydney Children’s Hospitals Network and University of Sydney, Sydney, NSW 2145, Australia [email protected] I declare no competing interests. 1
2
3
4 5 6
7
8
9
10
Schwahn BC, Van Spronsen FJ, Belaidi AA, et al. Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet 2015; published online Sept 4. http://dx.doi.org/10.1016/S0140-6736(15)00124-5. Johnson JL, Duran M. Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. In: Scriver C, Beaudet A, Sly W, Valle D, eds. The metabolic and molecular bases of inherited disease, 8th edn. New York: McGraw-Hill, 2001: 3163–77. Desnick RJ, Schuchman EH. Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet 2012; 13: 307–35. Augustine EF, Mink JW. Enzyme replacement in neuronal storage disorders in the pediatric population. Curr Treat Options Neurol 2013; 15: 634–51. Harding CO. New era in treatment for phenylketonuria: pharmacologic therapy with sapropterin dihydrochloride. Biologics 2010; 4: 231–36. Kanters TA, Hoogenboom-Plug I, Rutten-Van Mölken MP, Redekop WK, van der Ploeg AT, Hakkaart L. Cost-effectiveness of enzyme replacement therapy with alglucosidase alfa in classic-infantile patients with Pompe disease. Orphanet J Rare Dis 2014; 9: 75. Kemper AR, Knapp AA, Green NS, Comeau AM, Metterville DR, Perrin JM. Weighing the evidence for newborn screening for early-infantile Krabbe disease. Genet Med 2010; 12: 539–43. Kishnani PS, Beckemeyer AA. New therapeutic approaches for Pompe disease: enzyme replacement therapy and beyond. Pediatr Endocrinol Rev 2014; 12 (suppl 1): 114–24. Matern D, Gavrilov D, Oglesbee D, Raymond K, Rinaldo P, Tortorelli S. Newborn screening for lysosomal disorders. Semin Perinatol 2015; 39: 2206–16. Pitt JJ, Eggington M, Kahler SG. Comprehensive screening of urine samples for inborn errors of metabolism by electrospray tandem mass spectrometry. Clin Chem 2002; 48: 1970–80.
www.thelancet.com Published online September 4, 2015 http://dx.doi.org/10.1016/S0140-6736(15)00125-7