Laronidase 500units/5ml solution for infusion vials

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease caused by deficient activity of alpha-L-iduronidase. Intravenous (IV) enzyme replacement therapy (ERT) with laronidase is currently used for treating patients with MPS I. Objective To evaluate the efficacy and safety of IV laronidase for MPS I. Methods A systematic literature review was performed by searching the ClinicalTrials.gov, MEDLINE/PubMed, EMBASE, LILACS, and Cochrane Library databases, limited to clinical trials published until December 31, 2016. The first inclusion criterion was being a randomized controlled trial (RCT). If < five RCTs were identified, open-label and nonrandomized trials, controlled or uncontrolled (quasi-experimental), including ≥ five patients, and evaluating relevant outcomes defined a priori, would also be included. For meta-analysis, primary inferences were based on random-effects models. Assessment of article quality was performed in accordance with the GRADE criteria. The Cochrane Risk of Bias tool was used to examine the risk of bias for RCTs. Results The selection phase retrieved 632 articles. During the first phase of selection, 158 had the abstract or full text read for assessment of eligibility, of which nine (two RCTs) were included for qualitative synthesis. Four papers were included in the meta-analysis, which was performed for the following outcomes: occurrence of treatment-emergent or infusion-related adverse events (65%; 95%CI 53, 76), mild in most cases; development of IgG antibodies to laronidase (88%; 95%CI 67, 100); apnea-hypopnea index (not significant—NS), urinary glycosaminoglycans (GAGs) [mean change -65.5 μg/mg creatinine (95%CI -68.8, -62.3)], liver size [mean change -31.03% (95%CI -36.1, -25.9)], left ventricular mass index (LVMI) [mean change -1.8 (95%CI -2.32, -0.25)], and distance covered in the 6-minute walk test (NS). Among the outcomes not included in meta-analysis, we found evidence for benefit of laronidase only on shoulder flexion. Conclusions Our findings suggest that IV laronidase effectively reduces urinary GAGs excretion, hepatomegaly and LVMI, and can improve shoulder flexion in MPS I patients. Laronidase appears to be safe in the studied population.

Abstract licence: CC BY 4.0

Orphan medicinal products (OMPs) are often authorized based on pivotal phase II and III trials that do not always meet high quality criteria. Laronidase is an example of an OMP used for treatment of mucopolysaccharidosis I (MPS I). One randomized controlled trial demonstrated efficacy on several somatic symptoms. However, effectiveness in the real-world setting remains to be determined. We performed a systematic review to evaluate the effectiveness of enzyme replacement therapy (ERT) on clinically relevant outcomes in MPS I. A search in OVID MEDLINE and OVID EMBASE was performed. Postmarketing studies including MPS I patients treated with ERT and reporting data on any of 19 predefined clinical outcome measures obtained before the start of ERT and at follow-up were eligible. Three scenarios were used to define effectiveness of ERT. The first scenario (A) assumes that improvement is essential, while the second scenario (B) also includes stabilization of signs and symptoms. The third scenario (C) defines failure of therapy. Twenty case series were included. The criteria indicating effectiveness (A), were met for four of 19 outcome measures while the criteria, indicating unclear effectiveness (B) were met for five of 19. For one of 19 nonverifiable data were reported and for nine of 19 no overall conclusions could be drawn (ambiguous results). Real-world effectiveness of laronidase is extremely difficult to assess, 15 years after marketing authorization. This is partially due to insufficient natural history data. We recommend the conduct of rigorous and independent postmarketing studies including core outcome sets for OMPs, enforced by marketing and/or reimbursing authorities aiming to demonstrate real-world effectiveness within a reasonable time frame.

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An orphan disease is defined in the EU as a disorder affecting less than 1 in 2 000 individuals. The concept of ultra-orphan has been proposed for diseases with a prevalence of less than 1:50 000. Drugs for ultra-orphan diseases are amongst the most expensive medicines on a cost-per-patient basis. The extremely high prices have prompted initiatives to evaluate cost-effectiveness and cost-utility in EU-member states. The objective of this review was to evaluate the quality of cost-effectiveness and cost-utility studies on ultra-orphan drugs. We searched 2 databases and the reference lists of relevant systematic reviews. Studies reporting on full economic evaluations, or at least aiming at such evaluation, were eligible for inclusion. Quality was assessed with the use of the Consensus on Health Economic Criteria (CHEC)-list. Two-hundred-fifty-one studies were identified. Of these, 16 fitted our inclusion criteria. A study on enzyme replacement and substrate reduction therapies for lysosomal storage disorders did not perform a full economic evaluation due to the high drug costs and the lack of a measurable effect on either clinical or health-related quality of life outcomes. Likewise, a cost-effectiveness analysis of laronidase for mucopolysaccharidosis type 1 was considered unfeasible due to lack of clinical effectiveness data, while in the same study a crude model was used to estimate cost-utility of enzyme replacement therapy (ERT) for Fabry disease. Three additional studies, one on ERT for Fabry disease, one on ERT for Gaucher disease and one on eculizumab for paroxysmal nocturnal haemoglobinuria, used an approach that was too simplistic to lead to a realistic estimate of the incremental cost-effectiveness (ICER) or cost-utility ratio (ICUR). In all other studies (N = 11) more sophisticated pharmacoeconomic models were used to estimate cost-effectiveness and cost-utility of the specific drug, mostly ERT or drugs indicated for pulmonary arterial hypertension (PAH). Seven studies used a Markov-state-transition model. Other models used were patient-level simulation models (N = 3) and decision trees (N = 1). Only 4 studies adopted a societal perspective. All but 2 studies discounted costs and effects appropriately. Drugs for metabolic diseases appeared to be significantly less cost-effective than drugs indicated for PAH, with ICERs ranging from €43 532 (Gaucher disease) to €3 282 252 (Fabry disease). Quality of studies using a Markov-state-transition or patient-level simulation model is in general good with 14-19 points on the CHEC-list. We therefore conclude that economic evaluations of ultra-orphan drugs are feasible if pharmacoeconomic modelling is used. Considering the need for modelling of several disease states and the small patient groups, a Markov-state-transition model seems to be most suitable type of model. However, it should be realised that ultra-orphan drugs will usually not meet the conventional criteria for cost-effectiveness. Nevertheless, ultra-orphan drugs are often reimbursed. Further discussion on the use of economic evaluations and their consequences in case of ultra-orphan drugs is therefore warrante

Abstract licence: CC BY