Accelerating access to treatments for rare diseases

Dunoyer, Marc

doi:10.1038/nrd3493

Cited by 52 publications

(44 citation statements)

References 2 publications

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“…Although sirolimus has no clear effect on neuronal firing patterns in vitro (24), reduction of mTOR activation has been linked to reduced seizures in animal models of TSC as well as in TSC patients. This translational approach has been previously suggested for rare and devastating diseases for which large-scale clinical trials are not feasible (25). …”

Section: Resultsmentioning

confidence: 99%

Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder

et al. 2013

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A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heterotopic neurons in subcortical white matter and subependymal regions. PMSE is caused by a homozygous deletion of exons 9 to 13 of the LYK5/STRADA gene, which encodes the pseudokinase STRADA, an upstream inhibitor of mammalian target of rapamycin complex 1 (mTORC1). We show that disrupted pathfinding in migrating mouse neural progenitor cells in vitro caused by STRADA depletion is prevented by mTORC1 inhibition with rapamycin or inhibition of its downstream effector p70 S6 kinase (p70S6K) with the drug PF-4708671 (p70S6Ki). We demonstrate that rapamycin can rescue aberrant cortical lamination and heterotopia associated with STRADA depletion in the mouse cerebral cortex. Constitutive mTORC1 signaling and a migration defect observed in fibroblasts from patients with PMSE were also prevented by mTORC1 inhibition. On the basis of these preclinical findings, we treated five PMSE patients with sirolimus (rapamycin) without complication and observed a reduction in seizure frequency and an improvement in receptive language. Our findings demonstrate a mechanistic link between STRADA loss and mTORC1 hyperactivity in PMSE, and suggest that mTORC1 inhibition may be a potential treatment for PMSE as well as other mTOR-associated neurodevelopmental disorders.

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Section: Resultsmentioning

confidence: 99%

Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder

et al. 2013

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“…While rare diseases exhibit considerable diversity in etiology and clinical presentation, most are severely disabling with serious effects on life expectancy and physical and mental abilities [11]. Further, rare diseases constitute a major economic burden independent of a country’s size and demographics; these costs arise from increased healthcare spending and lost productivity [1, 12–14]. …”

Section: Introductionmentioning

confidence: 99%

Review of 11 national policies for rare diseases in the context of key patient needs

Dharssi

Wong‐Rieger²,

Harold

et al. 2017

Orphanet J Rare Dis

144

149

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Rare diseases collectively exert a global public health burden in the severity of their manifestations and the total number of people they afflict. For many patients, considerable barriers exist in terms of access to appropriate care, delayed diagnosis and limited or non-existing treatment options. Motivated by these challenges, the rare disease patient community has played a critical role, elevating the patient voice and mobilizing legislation to support the development of programs that address the needs of patients with rare diseases.The US Orphan Drug Act of 1983 served as a key milestone in this journey, providing a roadmap for other countries to introduce and implement similar orphan drug legislation; more recently, the European Union (EU) has gone further to encourage the widespread adoption and implementation of rare disease plans or strategies designed to more adequately address the comprehensive needs of patients with rare diseases. Despite these legislative efforts and the growing contributions of patient advocacy groups in moving forward implementation and adoption of rare disease programs, gaps still exist across the policy landscape for several countries. To gain deeper insights into the challenges and opportunities to address key needs of rare disease patients, it is critical to define the current status of rare disease legislation and policy across a geographically and economically diverse selection of countries. We analyzed the rare disease policy landscape across 11 countries: Germany, France, the United Kingdom, Canada, Bulgaria, Turkey, Argentina, Mexico, Brazil, China, and Taiwan. The status and implementation of policy was evaluated for each country in the context of key patient needs across 5 dimensions: improving coordination of care, diagnostic resources, access to treatments, patient awareness and support, and promoting innovative research. Our findings highlight the continuing role of the patient community in driving the establishment and adoption of legislation and programs to improve rare disease care. Further, we found that while national rare disease plans provide important guidance for improving care, implementation of plans is uneven across countries. More research is needed to demonstrate the effect of specific elements of rare disease plans on patient outcomes.

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“…As a result, there are now a greater number of products available for treating rare diseases than were available two decades ago [3]. For example, more than 400 products have been developed and marketed in the US since 1983 compared with fewer than ten in the previous decade [4].…”

Section: Introductionmentioning

confidence: 99%

Value-Based Reimbursement Decisions for Orphan Drugs: A Scoping Review and Decision Framework

et al. 2014

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BackgroundThe rate of development of new orphan drugs continues to grow. As a result, reimbursing orphan drugs on an exceptional basis is increasingly difficult to sustain from a health system perspective. An understanding of the value that societies attach to providing orphan drugs at the expense of other health technologies is now recognised as an important input to policy debates.ObjectivesThe aim of this work was to scope the social value arguments that have been advanced relating to the reimbursement of orphan drugs, and to locate these within a coherent decision-making framework to aid reimbursement decisions in the presence of limited healthcare resources.MethodsA scoping review of the peer reviewed and grey literature was undertaken, consisting of seven phases: (1) identifying the research question; (2) searching for relevant studies; (3) selecting studies; (4) charting, extracting and tabulating data; (5) analyzing data; (6) consulting relevant experts; and (7) presenting results. The points within decision processes where the identified value arguments would be incorporated were then located. This mapping was used to construct a framework characterising the distinct role of each value in informing decision making.ResultsThe scoping review identified 19 candidate decision factors, most of which can be characterised as either value-bearing or ‘opportunity cost’-determining, and also a number of value propositions and pertinent sources of preference information. We were able to synthesize these into a coherent decision-making framework.ConclusionOur framework may be used to structure policy discussions and to aid transparency about the values underlying reimbursement decisions for orphan drugs. These values ought to be consistently applied to all technologies and populations affected by the decision.Electronic supplementary materialThe online version of this article (doi:10.1007/s40273-014-0235-x) contains supplementary material, which is available to authorized users.

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Accelerating access to treatments for rare diseases

Cited by 52 publications

References 2 publications

Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder

Rapamycin Prevents Seizures After Depletion of STRADA in a Rare Neurodevelopmental Disorder

Review of 11 national policies for rare diseases in the context of key patient needs

Value-Based Reimbursement Decisions for Orphan Drugs: A Scoping Review and Decision Framework

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