Oncologic orphan drugs approved in the EU - do clinical trial data correspond with real-world effectiveness?

Background: Evaluation of evidence for efficacy of orphan medicinal products (OMPs) for rare malignancies may be hampered by the use of tumor measurements instead of clinical endpoints. This may cause efficacy data to not always match effectiveness in the real-world. We investigated whether an efficacy-effectiveness gap exists for oncologic OMPs and aimed to identify which factors contribute to it.

Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: an international cohort study.

Background: Two recombinant enzymes (agalsidase alfa 0.2 mg/kg/every other week and agalsidase beta 1.0 mg/kg/every other week) have been registered for the treatment of Fabry disease (FD), at equal high costs.

Phenotype, disease severity and pain are major determinants of quality of life in Fabry disease: results from a large multicenter cohort study.

Quality of life (QoL) is decreased in patients with Fabry disease (FD). To improve QoL, it is important to understand the influence of FD related characteristics, symptoms, and complications. In this retrospective cohort study we explored the effect of pain (measured by the Brief Pain Inventory), phenotype, treatment, and FD-related complications on QoL.

Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors.

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence.

Factors Contributing to the Efficacy-Effectiveness Gap in the Case of Orphan Drugs for Metabolic Diseases.

Introduction: Authorization of orphan medicinal products (OMPs) is often based on studies with several methodological shortcomings. Hence, data are difficult to interpret and efficacy does not always correspond to real-world effectiveness. We investigated to what extent an efficacy-effectiveness gap exists for OMPs for metabolic diseases and set out to explore which factors contribute to it.

Hearing loss in children with Fabry disease.

Background: Hearing loss (HL) is a well-known feature of Fabry disease (FD). Its presence and characteristics have mainly been studied in adult patients, while only limited data are available on the presence and degree of HL in children with FD. This prompted us to study hearing sensitivity in pediatric FD patients.

Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease.

Background: The level of plasma globotriaosylsphingosine (lysoGb3) is an indication of disease severity in Fabry disease (FD) and its decrease during enzyme replacement therapy could be a reflection of treatment efficacy. Early treatment of FD may improve clinical outcome, but data to support this hypothesis are scarce. In this study we compared lysoGb3 decrease after ERT initiation in men with classical FD who started ERT before the age of 25 (early-treatment) with those who started later in life (late-treatment).

Biceps Rerouting after Forearm Osteotomy: An Effective Treatment Strategy for Severe Supination Deformity in Obstetric Plexus Palsy.

 Retrospective cohort study.  Supination deformity in obstetric brachial plexus injury can have debilitating consequences for the functionality of the hand. Surgical treatment by a forearm osteotomy has a recurrence rate of 20 to 42%.

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment.

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence.

Pain management strategies for neuropathic pain in Fabry disease--a systematic review.

Background: Neuropathic pain is one of the key features of (classical) Fabry disease (FD). No randomized clinical trials comparing effectiveness of different pain management strategies have been performed. This review aims to give an overview of existing pain management strategies.

Position statement on the role of healthcare professionals, patient organizations and industry in European Reference Networks.

A call from the EU for the set-up of European Reference Networks (ERNs) is expected to be launched in the first quarter of 2016. ERNs are intended to improve the care for patients with low prevalent or rare diseases throughout the EU by, among other things, facilitating the pooling and exchange of experience and knowledge and the development of protocols and guidelines. In the past, for example where costly orphan drugs have been concerned, industry has played an important role in facilitating consensus meetings and publication of guidelines.

Discontinuation of enzyme replacement therapy in Fabry disease in the Dutch cohort.

Fabry disease (FD) is a progressive, multi-organ, lysosomal storage disease. Enzyme replacement therapy (ERT) is available for the treatment of the disease. While the reasons to initiate ERT have been frequently discussed, discontinuation of ERT is rarely reported.

In Patients with an α-Galactosidase A Variant, Small Nerve Fibre Assessment Cannot Confirm a Diagnosis of Fabry Disease.

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by an α-galactosidase A enzyme deficiency due to pathogenic variants in the α-galactosidase A gene (GLA). An increasing number of individuals with a GLA variant, but without characteristic FD features, are identified. A definite diagnosis of FD has important consequences for treatment and counselling.

The quality of economic evaluations of ultra-orphan drugs in Europe - a systematic review.

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.

Quality of life in patients with Fabry disease: a systematic review of the literature.

Fabry disease (FD), caused by deficiency of the lysosomal enzyme α-galactosidase-A, is a progressive multisystem disease. The disease is X-linked with generally more severe manifestations in males, but can impact on quality of life (QoL) of both male and female patients. The purpose of this literature review is to analyse the currently available data concerning QoL measurement, specifically which questionnaires have been used to measure QoL, how patients with FD score compared to the general population, and the effects of enzyme replacement therapy (ERT) on QoL.

Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.

Introduction: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory.

Cornea verticillata supports a diagnosis of Fabry disease in non-classical phenotypes: results from the Dutch cohort and a systematic review.

Background: Screening for Fabry disease (FD) increasingly reveals individuals without characteristic features and with a variant of unknown significance in the α-galactosidase A (GLA) gene. Cornea verticillata (CV) assessment, as a characteristic sign of FD, may be a valuable diagnostic tool to assess whether these individuals have a non-classical phenotype or no FD at all.

Methods: We performed a systematic review to estimate the prevalence of CV in FD.

Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease.

Background: Fabry disease (FD), a lysosomal storage disorder caused by α-galactosidase A (GLA) gene variants, has a heterogeneous phenotype. GLA variants can lead to classical FD, an attenuated non-classical phenotype, or no disease at all. This study investigates the value of plasma globotriaosylsphingosine (lysoGb3) to distinguish between these groups.

Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance.

Background: Screening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the α-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment.

Hearing loss in adult patients with Fabry disease treated with enzyme replacement therapy.

Introduction: Data on prevalence, natural history, and effect of enzyme replacement therapy (ERT) on hearing loss (HL) in Fabry disease (FD) are scarce.

Methods: This is a retrospective study with cross-sectional and longitudinal analyses. Low and high-frequency HL in the Dutch FD cohort was studied in four groups: classical and non-classical FD patients with or without ERT.

Uncertain diagnosis of fabry disease in patients with neuropathic pain, angiokeratoma or cornea verticillata: consensus on the approach to diagnosis and follow-up.

Introduction: Individuals with neuropathic pain, angiokeratoma (AK) and/or cornea verticillata (CV) may be tested for Fabry disease (FD). Classical FD is characterised by a specific pattern of these features. When a patient presents with a non-specific pattern, the pathogenicity of a variant in the α-galactosidase A (GLA) gene may be unclear.

Chronic kidney disease and an uncertain diagnosis of Fabry disease: approach to a correct diagnosis.

Background And Objectives: Screening for Fabry disease (FD), an X-linked lysosomal storage disorder, reveals a significant number of individuals with a genetic variant of unknown significance without classical FD manifestations; these variants in the α-galactosidase A gene often result in a high residual leukocyte α-galactosidase A and it is unclear whether these individuals suffer from FD. Therefore, a structured diagnostic approach is warranted. We present a diagnostic algorithm on how to approach adults with chronic kidney disease and an uncertain diagnosis of FD nephropathy.