Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products

Objectives: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs. Methods: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs. Results: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients. Conclusions: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs

Three Families with Autosomal Dominant Nephrogenic Diabetes Insipidus Caused by Aquaporin-2 Mutations in the C-Terminus

The vasopressin-regulated water channel aquaporin-2 (AQP2) is known to tetramerize in the apical membrane of the renal tubular cells and contributes to urine concentration. We identified three novel mutations, each in a single allele of exon 4 of the AQP2 gene, in three families showing autosomal dominant nephrogenic diabetes insipidus (NDI). These mutations were found in the C-terminus of AQP2: a deletion of G at nucleotide 721 (721 delG), a deletion of 10 nucleotides starting at nucleotide 763 (763–772del), and a deletion of 7 nucleotides starting at nucleotide 812 (812–818del). The wild-type AQP2 is predicted to be a 271–amino acid protein, whereas these mutant genes are predicted to encode proteins that are 330–333 amino acids in length, because of the frameshift mutations. Interestingly, these three mutant AQP2s shared the same C-terminal tail of 61 amino acids. In Xenopus oocytes injected with mutant AQP2 cRNAs, the osmotic water permeability (Pf) was much smaller than that of oocytes with the AQP2 wild-type (14%–17%). Immunoblot analysis of the lysates of the oocytes expressing the mutant AQP2s detected a band at 34 kD, whereas the immunoblot of the plasma-membrane fractions of the oocytes and immunocytochemistry failed to show a significant surface expression, suggesting a defect in trafficking of these mutant proteins. Furthermore, coinjection of wild-type cRNAs with mutant cRNAs markedly decreased the oocyte Pf in parallel with the surface expression of the wild-type AQP2. Immunoprecipitation with antibodies against wild-type and mutant AQP2 indicated the formation of mixed oligomers composed of wild-type and mutant AQP2 monomers. Our results suggest that the trafficking of mutant AQP2 is impaired because of elongation of the C-terminal tail, and the dominant-negative effect is attributed to oligomerization of the wild-type and mutant AQP2s. Segregation of the mutations in the C-terminus of AQP2 with dominant-type NDI underlies the importance of this domain in the intracellular trafficking of AQP2

Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats

Aims/hypothesis High plasma copeptin, a marker of vasopressin (VP) secretion, has been shown to be associated with the metabolic syndrome and development of type 2 diabetes in humans. The present study was designed to determine the long-term influence of plasma VP concentration in a rodent model prone to metabolic dysfunction. Methods Obese Zucker rats and their lean counterparts were submitted for 4 weeks to one of three protocols inducing different levels of VP. Circulating VP was either reduced by increasing the daily water intake (low-VP), or increased by a chronic i.p. infusion of VP (high-VP). The control rats had normal VP levels that depended on their own regulation of water intake and VP secretion. Results Compared with controls with normal VP, lean rats with high-VP had a higher fasting glycaemia after 4 weeks. In obese rats, high-VP promoted hyperinsulinaemia, glucose intolerance, assessed by glucose and insulin tolerance tests, and an impaired response to a pyruvate challenge. Conversely, treatment with a selective arginine vasopressin receptor 1A (V1aR) antagonist reduced glucose intolerance. Low-VP obese rats had unchanged glucose tolerance but exhibited a drastic decrease in liver steatosis compared with control obese rats, associated with low hepatic triacylglycerol and cholesterol content, and reduced expression of hepatic lipogenic genes. These effects were independent of changes in body adiposity, and plasma sodium and osmolality did not differ among groups. Conclusion/interpretation These findings show a causal relationship between the VP-hydration axis and the metabolic risk. Therapeutic perspectives include diet recommendations regarding hydration, but also potential pharmacological interventions targeting the VP V1aR