Early treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibships

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by deficient α-L-iduronidase activity, a lysosomal enzyme involved in degradation of the glycosaminoglycans (GAGs) heparan and dermatan sulfate. Enzyme deficiency leads to accumulation of GAGs in multiple tissues resulting in a progressive and multisystem disease. MPS I includes a spectrum of clinical presentations ranging from severe (Hurler syndrome) to attenuated (Hurler-Scheie, [H/S] and Scheie syndromes) [1]. Patients with Hurler syndrome develop coarse facial features, debilitating skeletal disease, organomegaly, cognitive impairment, and cardiac and respiratory disease shortly after birth. Patients with H/S have mild or no cognitive impairment; however somatic symptoms result in significant disease morbidity and reduce life expectancy to the second or third decade of life. Disease progression is slowest in patients affected with Scheie syndrome.

Treatment options include hematopoietic stem cell transplant (HSCT) recommended before 2.5 years of age for patients with the most severe phenotype, and enzyme replacement therapy (ERT) with laronidase (recombinant human α-L-iduronidase; Aldurazyme®) indicated as the primary treatment option for patients with attenuated MPS I [2]. Laronidase administration is safe and effective, and improvements in clinical manifestations and stabilization of disease progression are achieved in patients with varying degrees of disease severity [3‐6]. The long-term clinical benefits achieved with ERT appear to be largely dependent on early diagnosis and treatment [7]. Clinical features such as cardiac valve disease, corneal clouding, and skeletal changes do not respond as well to ERT since irreversible pathology may be established by the time symptoms appear [8].

Due to the large phenotypic heterogeneity seen in MPS I, correlating ERT timing to the effect on the clinical course and progression of symptoms can be challenging. However, it is evident from assessing treatment outcomes in siblings with similar genetic backgrounds and expected rates of disease progression that pre-symptomatic initiation of ERT drastically alters the clinical course of MPS I [9, 10]. In two sets of siblings, more serious clinical findings were well documented for older siblings initiating ERT later in life after the onset of symptoms compared with their younger counterparts who commenced treatment before disease manifestations were apparent. In both cases, early ERT prevented the development of many clinical features of MPS I in the younger sibling [9, 10].

Here, we present the largest compilation of sibling data to date for patients with the H/S phenotype. This case series examines data from sibling pairs/sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings, the majority of whom initiated laronidase before significant symptomatology.

This multinational, retrospective, chart review case series was conducted at the authors’ institutions. All patients with MPS I diagnosed by enzyme biochemical determination and/or molecular analysis were treated with laronidase according to prescribing information (weekly intravenous infusions of 100 U/kg of body weight). Sibships were identified where younger siblings initiated ERT at an earlier age than older siblings. In general, older siblings initiated treatment with laronidase after the onset of MPS I symptoms while younger siblings initiated ERT before onset of significant physical and clinical symptoms. Written informed consent was provided by the legal guardians/parents of all patients.

Treating physicians completed questionnaires assessing signs and symptoms of MPS I prior to and following ERT. Data from patient records, medical histories and neurological, cardiovascular, pulmonary, gastroenterology, musculoskeletal, ophthalmologic, audiologic, and psychomotor developmental examinations were abstracted including:

Height/length (absolute); Description of facial features observed during physical examination; Presence of corneal opacity, hearing loss/use of hearing aids, sleep apnea, hernia; Results of pulmonary function tests (PFT); Liver and spleen size determined by palpation and/or imaging studies; Cardiac disease description/severity determined from echocardiogram; Joint and skeletal disease observed during physical examination and/or radiographic imaging; Presence/severity of dysostosis multiplex, joint contractures and affected joints; Motor development assessed during physical examination; Cognitive and language development assessed by formal evaluation or by investigator impression; and Ability to perform activities of daily living (ADL).

Data were abstracted at a time point just prior to initiating ERT (Time point 1, T1) and follow-up data were collected after at least 3 years of ERT (Time point 2, T2).

Twenty patients within nine sibships (seven sibling pairs and two sets of three siblings) were identified from nine centers in Argentina (two sites), Brazil, France, Spain, Saudi Arabia, UK, and the US (two sites). Median age (range) at diagnosis was 5.6 years (1, 9) for older siblings (n = 10) and 0.5 years (0, 6.7) for younger siblings (n = 10). All older siblings initiated laronidase by 14 years of age, while younger siblings initiated therapy before 4 years of age (with one exception). Five younger siblings (sibships 1–5a) were diagnosed at less than 1 year of age and initiated treatment by 1.3 years of age. For analysis of responses to treatment, these patients are presented together as Group A. A second group of younger siblings (Group B, sibships 5b–8) began laronidase treatment after age 2. Age at diagnosis, treatment, and duration of treatment for each patient, and median data by group are presented in Table 1. Older and younger siblings within a sibship had similar ERT duration.

Figure 1 summarizes the percentages of signs and symptoms present at T1 (out of the total number of signs/symptoms assessed per patient) for all patients by sibship. Younger siblings (blue bars) generally had fewer symptoms than older siblings (red bars) at T1, particularly in Group A. All older siblings were symptomatic at T1.

The data collected from this multinational case series demonstrate the benefit of early ERT initiation in patients with attenuated MPS I. Laronidase is believed to stabilize but not improve cardiac and skeletal/connective tissue disease when pathological changes are already present at the start of treatment, and early ERT may help prevent the onset of disease features [8]. However, there are limited studies in young patients with clinically significant somatic symptoms prior to initiation of ERT. The pivotal laronidase clinical trial for MPS I enrolled patients 5 years of age and older [6]. A subsequent trial enrolled patients younger than 5 years of age and reported improved clinical status after 1 year of treatment with no safety concerns [5]. Previously-published single case studies in siblings with MPS I support the pre-symptomatic initiation of ERT to prevent or delay many clinical manifestations of the disease [9, 10]. The alteration of clinical disease progression has also been described in sibling pairs with MPS VI where early, pre-symptomatic initiation of ERT in the younger sibling resulted in prevention of symptoms, including bone deformities, and sustained benefits over 10 years of treatment [11‐13]. Studies in animal models of MPS I also support early initiation of ERT. Laronidase treatment initiated soon after birth in affected dogs and mice improves outcomes and prevents cardiac and skeletal disease [14, 15]. Our comparison of disease progression following laronidase treatment in a series of older and younger siblings with MPS I lends additional support to the value of early ERT initiation.

Grouping sibships based on the age of ERT initiation in the younger sibling provided additional insight into the benefits of early treatment and the development of clinical features. In Group A (younger sibling initiated treatment ≤1.3 years of age), mild to severe symptoms were noted before treatment initiation in older siblings while symptoms were absent to mild in younger siblings. Most striking is the continued absence of clinical symptoms in the younger sibling from sibship 1 after nearly 5 years of ERT contrasted to the stabilization, but not reversal, of symptoms in the older sibling. Prominent differences were seen within other sibships in Group A for corneal opacity, organomegaly, dysostosis multiplex, and joint contractures. The extent of cardiac involvement was variable amongst siblings; however, improvement or stabilization of symptoms was noted following ERT. Younger siblings in Group A also tended to have fewer delays in motor and cognitive function, and less restriction in ADL.

For Group B (younger sibling initiated treatment between 2 and 4 years, with the exception of sibship 9), symptoms present in older siblings at T1 ranged from mild to severe. In younger siblings, symptoms generally ranged from absent to moderate, largely depending on the age treatment was initiated. At T2, symptoms noted in younger siblings at the time of ERT initiation either improved or stabilized, and only one developed symptoms classified as severe (sibship 6; joint contractures). Clinical differences were noted between older and younger siblings in Group B for organomegaly and dysostosis multiplex. Following treatment initiation, older siblings experienced improvements (especially in symptoms that were severe at baseline) or stabilization while younger siblings in this group experienced slower and less severe disease progression.

Short stature is a key clinical feature of MPS I. The rate of growth in children with MPS I is slower than in the healthy population, and differences in height between healthy and affected children increase with age [16]. Some studies have not found early ERT therapy to be associated with improved growth patterns in children with attenuated MPS I [16, 17]. However, a case study of three siblings reported stabilized or improved growth in two of three siblings who initiated laronidase therapy before 5 years of age [10]. In contrast, growth was further from the normal population mean in the third sibling who initiated laronidase therapy at age 6. Our data support the findings that ERT does not lead to improvement in growth. However, younger siblings remained taller than their older counterparts at a comparable age.

As a retrospective study, our analyses were limited by lack of control over the primary data collection, missing data, and issues with objective data analysis. While we recognize that the assessment of symptoms severity by physicians was subjective and could be influenced by sociocultural differences in medical practice, it is important to note that the patients were followed for most of their lives by the same physicians, who were able to compare symptoms in the siblings for a number of years and through various developmental stages. We believe this factor can limit the bias in assessing severity between siblings. Given the difficulties in conducting randomized controlled trials in the setting of a rare disease, and the geographical dispersion of patients with MPS I, we believe that comparing data between the siblings rather than across patients is an effective retrospective design. While comparing siblings is an insightful model to better understand the benefits of early treatment initiation in MPS I due to similar genetic backgrounds, there are a number of factors to consider. Phenotypic variability resulting from the effects of modifying polymorphisms is known to occur with some mutations [18], including the p.P533R homozygous mutation present in sibships 1 and 2. In general, the phenotypes between siblings within these sibships were similar. While we cannot totally exclude phenotypic differences as playing a role in the different clinical outcomes between siblings, in general we believe that there is a tendency for family group clusters for disease presentation in affected siblings, and that phenotypic differences are more pronounced between, rather than within, families.

Compliance with ERT is important in order to achieve maximal clinical effect [19]. In our case series, both siblings in sibship 4 had a reported ERT compliance rate of 60 %, and the younger sibling experienced progressive joint contractures and cognitive delays similar to the older sibling despite initiating therapy at an earlier age While cognitive function is not believed to be directly affected by ERT in patients with MPS I since laronidase does not cross the blood brain barrier, improvements in somatic disease following ERT may impact results of cognitive testing. Likewise, interventions including hearing aids, speech t herapy and physical therapy, as well as psychosocial assistance can optimize patient’s capacities and quality of life. Improvements in treatment outcomes were augmented in patients, such as those in sibship 7, who received supportive care along with ERT. The available data support the role of early or pre-symptomatic ERT initiation in slowing disease progression in patients with attenuated MPS I. Especially for disease manifestations that may be irreversible despite laronidase therapy, such as cardiac and musculoskeletal symptoms, early treatment is believed to be key in slowing the progression of these symptoms [7].

These findings support early initiation of ERT with laronidase prior to the onset of symptoms in patients with attenuated MPS I in order to delay disease progression and/or prevent the development of severe clinical manifestations.