Jonathan C.P. Roos

Orphan drug pricing may warrant a competition law investigation.

EU legislation offers an exclusive marketing period as an incentive for companies to develop drugs for rare diseases. But pricing for orphan drugs hinders access and may warrant a competition law investigation, say Jonathan C P Roos, Hanna I Hyry, and Timothy M Cox

A series of pregnancies in women with inherited metabolic disease

In this case series we report 12 pregnancies, in women treated at four centres, illustrating some of the issues that may be encountered during pregnancy by women with inherited metabolic disease. We discuss how specific pregnancy, labour and delivery issues for mothers with methylmalonic acidemia, homocystinuria, propionic acidemia, glutaric acidemia type 1, ornithine transcarbamylase (OTC) deficiency and 3-hydroxy-3-methylglutaric(HMG)-CoA lyase deficiency were managed and the outcome for the mother and child in each case. Eight of the 12 pregnancies resulted in the successful delivery of a liveborn infant. Several women experienced decompensation of their condition during pregnancy or the post-partum period. There was one maternal death in a women with 3-hydroxy-3-methylglutaric(HMG)-CoA lyase deficiency. Pre-pregnancy counselling and co-management of high risk medical patients by obstetricians and specialist physicians with an understanding of the relationship between pregnancy and inherited metabolic disease is essential.

Metabolic myopathies: a guide and update for clinicians.

Purpose of reviewThe present review will focus on the clinical features, and recent advances in the investigation and treatment, of metabolic muscle disease. The aim is to present a summary of this vast and complex topic emphasizing key points of relevance to nonspecialists in the field. Salient examples from each category will be highlighted to illustrate characteristic features and potential sources of diagnostic confusion. The general approach to management will then be outlined. Recent findingsAwareness of these diseases has grown over recent years, as has appreciation of their variable clinical presentation. Many of the precise genetic and biochemical abnormalities underlying these conditions have been elucidated and novel enzyme defects continue to be discovered. Perhaps the greatest progress, however, has been made in the management of disease. Advances in tandem mass spectrometry techniques have facilitated the introduction of nationwide neonatal screening programmes for a large number of metabolic disorders. Enzyme replacement in Pompe disease has proved successful, improving outcome in a hitherto untreatable condition. Progress towards gene therapy, perhaps the ultimate goal, has been made in animal models. SummaryAlthough individually rare, the metabolic myopathies together constitute a significant group of disabling and potentially life-threatening disorders. Appropriate investigations, timely treatment and genetic counselling are paramount to ameliorate the short and long-term consequences of disease.

A single mechanism for the timing of spontaneous and evoked saccades

The study of saccadic latency—the reaction time between presenting a visual stimulus and initiating an eye movement to look at it—has led to a better understanding of decision mechanisms in general, through the development of quantitative models such as LATER. But outside the laboratory, evoked saccades of this kind are rare. Most saccades are made spontaneously while viewing static scenes. Can their initiation be explained by the same decision mechanism? We suggest that in a series of spontaneous saccades, each can be considered to be evoked by the new retinal image generated by its predecessor, so that the intersaccadic interval (ISI) can be regarded as equivalent to latency. We measured ISIs in subjects spontaneously viewing static scenes, and found their distributions to be qualitatively similar to those of evoked saccades, differing quantitatively in just two respects: (1) the main part of the distribution is slower; and (2) there is an increased number of very early responses. By using novel saccadic tasks we show that (1) can be accounted for by lateral inhibition between multiple, suddenly presented image elements, and (2) by the fact that the stimulus is necessarily extremely predictable. Adding these two factors to an evoked saccadic task produced latency distributions indistinguishable from those of spontaneous ones. This suggests that the mechanisms generating evoked and spontaneous movements may be less functionally distinct than is commonly assumed. Both clinically and scientifically, a common, unified framework for explaining both spontaneous and evoked movements is an exciting prospect.

The legal imperative for treating rare disorders.

BackgroundLife-saving orphan drugs are some of the most expensive medicines. European Union governments aim to accommodate their provision within stretched healthcare budgets but face pressure to reduce funding of such treatments. Patients struggle to retain or gain access to them as their special status is questioned, causing distress and in some cases, fears of premature death. In the UK and EU reimbursement and pricing model of drugs, and orphan drugs in particular, is being re-evaluated.MethodsUsing the United Kingdom as a case study we present, for the first time, legal arguments which compel governments to provide orphan medicinal products. These include (i) disability legislation, (ii) national and organisational constitutions, (iii) judicial review, (iv) tort law and (v) human rights legislation. We then address directly potential objections to our analysis and counter arguments which aim to limit provision of orphan drugs to the intended patient recipients.ResultsWe demonstrate that a compelling case can be made that the law demands the treatment of orphan diseases.ConclusionsOur legal framework will assist doctors and patients in ensuring the continued provision of treatments despite significant economic pressure to reduce funding. These legal avenues will empower stakeholders in drafting funding guidelines throughout the EU. The legal right to treatment extends beyond rare diseases and our analysis may therefore affect allocation of healthcare budgets throughout the EU.

Necrotizing group A streptococcal periorbital infection following adalimumab therapy for rheumatoid arthritis

Objective: (1) To describe a case of necrotizing group A streptococcal periorbital infection in a patient receiving treatment with adalimumab (Humira, Abbott)— a fully humanized monoclonal anti-TNF-α agent. (2) To identify bacterial species responsible for infection with different forms of biological therapy. Design: Single interventional case report and literature review. Case: A 57-year-old woman developed severe right-sided necrotizing periorbital infection whilst receiving treatment with adalimumab for rheumatoid arthritis (RA). Cultures grew Lancefield Group A Streptococcus pyogenes. An extensive literature search for reports of ocular infections associated with biological therapy was conducted. Results: Adalimumab therapy was discontinued and the patient was admitted to an intensive care unit. The patient made a complete recovery after receiving appropriate antibiotic therapy. Overall Gram-positive cocci are the most common infection associated with use of biological therapy. Conclusions: Anti-TNF-α agents are powerful immune-modulating drugs with potentially serious side effects. This case is the first to link adalimumab to necrotizing periorbital infection. Resolved infection does not preclude reintroduction of anti-TNF therapy however, careful assessment of the risks versus benefits of therapy is required at the individual patient level.

Saving orphan drug legislations: misconceptions and clarifications.

Orphan-drug sales are rocketing, with revenue expected to total

Objective Assessment of the Hemisphere-Specific Neurological Outcome of Carotid Endarterectomy: A Quantitative Saccadometric Analysis

176 billion annually by 2020. As a share of the industry, orphan drugs now account for close to 15% of all prescription revenue globally (excluding generics) and the sector is set to grow at more than twice the rate (10.5%) of the overall prescription market (4.3%). But this success also equates to costs – borne by individual patients and cash-strapped health systems. Prices for orphan drugs can be 19 times higher than for other medications, hampering access for patients, many of whom are children. With ever more such expensive drugs reaching the market, the situation is becoming unsustainable and putting the survival of the orphan drug legislation itself at risk. Here the authors consider why there has been an increase in orphan drug designations, how orphan drug prices are set and regulated, before discussing proposals for how changes which could save the legislation.

Heterogeneity in a large pedigree with Danon disease: Implications for pathogenesis and management

BACKGROUND: Carotid endarterectomy (CEA) improves the cerebrovascular prognosis of patients with carotid stenosis but carries a risk of causing postoperative neurological deterioration. OBJECTIVE: We assessed hemisphere-specific changes in saccadic eye movements to determine the utility of saccadometry as a quantitative neurosurgical outcome measure. METHODS: Visually evoked saccades were recorded at the bedside before and 2 days after surgery from 30 patients undergoing CEA for symptomatic carotid stenosis. Hemisphere-specific latency distributions were compared using Kolmogorov-Smirnov statistics. Latency distributions were fitted using the Linear Approach to Threshold with Ergodic Rate model and compared with binomial logistic regression. RESULTS: There were 21 males and mean age at surgery was 71 ± 7 years. Following CEA, the distribution of saccades initiated by the cerebral hemisphere distal to the operated artery significantly changed in 25 patients. By contrast, there were 14 significant contralateral-hemisphere saccadic changes (P < .001). Significant contralateral saccadic changes always co-occurred with significant ipsilateral changes and 10 of 14 patients with contralateral saccadic change had contralateral carotid stenosis. There was a significantly greater postoperative reduction in early saccades generated by the ipsilateral hemisphere than by the contralateral hemisphere (P < .02) CONCLUSION: CEA leads to significant hemisphere-specific subclinical changes in saccadic performance and, in particular, differentially affects the proportion of early saccades, a measure of the ability of the frontal cortex to successfully inhibit lower centers, generated by the 2 hemispheres. Saccadometry, a bedside test, provides data that can be statistically compared for individual and groups of patients. It could allow the neurological outcome of carotid surgery to be objectively quantified.

Outrageous prices of orphan drugs: a call for collaboration

BACKGROUND Danon disease is an X-linked disturbance of autophagy manifesting with cognitive impairment and disordered heart and skeletal muscle. After a period of relative stability, patients deteriorate rapidly and may quickly become ineligible for elective heart transplantation - the only life-saving therapy. METHODS We report a large pedigree with diverse manifestations of Danon disease in hemizygotes and female heterozygotes. RESULTS Malignant cardiac arrhythmias requiring amiodarone treatment induced thyroid disease in two patients; intractable thyrotoxicosis, which enhances autophagy, caused the death of a 21year-old man. Our patients also had striking elevation of serum troponin I during the accelerated phase of their illness (p<0.01) and rising concentrations heralded cardiac decompensation. We argue for changes to cardiac transplantation eligibility criteria. CONCLUSION Danon disease causes hypertrophic cardiomyopathy - here we propose a common pathophysiological basis for the metabolic and structural effects of this descriptive class of heart disorders. We also contend that troponin I may have prognostic value and merits exploration for clinical decision-making including health warning bracelets. Rapamycin (Sirolimus®), an approved immunosuppressant which also influences autophagy, may prove beneficial. In the interim, while new treatments are developed, a revaluation of cardiac transplantation eligibility criteria is warranted.