We reviewed the evidence about the effect and safety of enzyme replacement therapy with laronidase for people with mucopolysaccharidosis type I (MPS I) who do not undergo haemopoietic stem cell transplantation and in people with MPS I who receive enzyme replacement therapy prior to haemopoietic stem cell transplantation. This is an updated version of the original Cochrane Review published in 2013 and previously updated in 2015.
Hurler syndrome or mucopolysaccharidosis type I is a rare genetic disorder that occurs when an enzyme that the body needs is missing or not working well enough. This leads to the build up of a number of complex molecules in certain cells and tissues. If untreated, this results in a classic picture of dwarfism, enlargement of body organs and a reduction in thinking ability. It occurs when a person inherits two copies of the defective gene (one from each parent) and is just as common in males as in females. It classically presents in infancy, however milder versions can present in adulthood. Enzyme replacement therapy with laronidase aims to replace the missing enzyme; however, given its high cost, it is essential to assess how effective and safe this treatment is.
The evidence is current to: 30 January 2019.
One 26-week randomised controlled study (45 participants) was included in the review. Participants were aged between six and 43 years old. The study was carried out in several centres around the world. Participants either received an intravenous infusion of laronidase 0.58 mg/kg or a placebo ('dummy' infusion).
Current evidence is limited because we only found one randomised clinical trial in the medical literature, which did not include very many participants. Compared with placebo, enzyme replacement therapy improved lung function, the individuals’ ability to walk, reduced the excretion of abnormal glycosaminoglycans (a type of carbohydrate molecule) in the urine and also reduced the stopping of breathing related to sleep. Adverse reactions in relation to the infusions occurred in both groups but all were mild and none required medical intervention or for the infusions to be stopped. Enzyme replacement therapy can be used before and around the time of stem cell transplant, which is now the gold standard treatment for Hurler syndrome in individuals diagnosed before the age of two and a half years. More studies are needed to look at the long-term effects of this treatment and also to see the effects on the quality of life of these individuals. We do not anticipate any further trials to be undertaken and therefore do not plan to update this review.
Quality of the evidence
The included study was small and of low quality.
The current evidence demonstrates that laronidase is effective when compared to placebo in the treatment of mucopolysaccharidosis type I. The included study was comprehensive, with few participants and of low quality. The study included all of the key outcome measures we wished to look at. It demonstrated that laronidase is efficacious in relation to reducing biochemical parameters (reduced urine glycosaminoglycan excretion) and improved functional capacity as assessed by forced vital capacity and the six-minute-walk test. In addition glycosaminoglycan storage was reduced as ascertained by a reduction in liver volume. Laronidase appeared to be safe and, while antibodies were generated, these titres were reducing by the end of the study. More studies are required to determine long-term effectiveness and safety and to assess the impact upon quality of life. Enzyme replacement therapy with laronidase can be used pre- and peri-haemopoietic stem cell transplant, which is now the gold standard treatment in those individuals diagnosed under 2.5 years of age. We do not anticipate any further trials to be undertaken and therefore do not plan to update this review.
Mucopolysaccharidosis type I can be classified as three clinical sub-types; Hurler syndrome, Hurler-Scheie syndrome and Scheie syndrome, with the scale of severity being such that Hurler syndrome is the most severe and Scheie syndrome the least severe. It is a rare, autosomal recessive disorder caused by a deficiency of alpha-L-iduronidase. Deficiency of this enzyme results in the accumulation of glycosaminoglycans within the tissues. The clinical manifestations are facial dysmorphism, hepatosplenomegaly, upper airway obstruction, skeletal deformity and cardiomyopathy. If Hurler syndrome is left untreated, death ensues by adolescence. There are more attenuated variants termed Hurler-Scheie or Scheie syndrome, with those affected potentially not presenting until adulthood. Enzyme replacement therapy has been used for a number of years in the treatment of Hurler syndrome, although the current gold standard would be a haemopoietic stem cell transplant in those diagnosed by 2.5 years of age. This is an updated version of the original Cochrane Review published in 2013 and previously updated in 2015.
To evaluate the effectiveness and safety of treating mucopolysaccharidosis type I with laronidase enzyme replacement therapy as compared to placebo.
We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register, MEDLINE via OVID and Embase.
Date of most recent search: 30 January 2019.
Randomised and quasi-randomised controlled studies of laronidase enzyme replacement therapy compared to placebo.
Two authors independently screened the identified studies. The authors then appraised and extracted data. The quality of the evidence was assessed using GRADE.
One study (45 participants) met the inclusion criteria. This double-blind, placebo-controlled, randomised, multinational study looked at laronidase at a dose of 0.58 mg/kg/week versus placebo in people with mucopolysaccharidosis type I. All primary outcomes listed in this review were studied in this study. The laronidase group achieved statistically significant improvements in per cent predicted forced vital capacity compared to placebo, MD 5.60 (95% confidence intervals 1.24 to 9.96) (low-quality evidence) and in the six-minute-walk test (mean improvement of 38.1 metres in the laronidase group; P = 0.039, when using a prospectively planned analysis of covariance) (low-quality evidence). The levels of urinary glycoaminoglycans were also significantly reduced (low-quality evidence). In addition, there were improvements in hepatomegaly, sleep apnoea and hypopnoea. Laronidase antibodies were detected in nearly all participants in the treatment group with no apparent clinical effect and titres were reducing by the end of the study (very low-quality evidence). Infusion-related adverse reactions occurred in both groups but all were mild and none necessitated medical intervention or infusion cessation (low-quality evidence). As assessed by questionnaires,changes in a 'Disability Index' after treatment were small and did not differ between groups (low-quality evidence). There were no deaths in either group (low-quality evidence).