The Price of Progress: Funding and Financing Alzheimer\u27s Disease Drug Development

Introduction Advancing research and treatment for Alzheimer\u27s disease (AD) and the search for effective treatments depend on a complex financial ecosystem involving federal, state, industry, advocacy, venture capital, and philanthropy funding approaches. Methods We conducted an expert review of the literature pertaining to funding and financing of translational research and drug development for AD. Results The federal government is the largest public funder of research in AD. The National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, and National Center for Advancing Translational Science all fund aspects of research in AD drug development. Non-National Institutes of Health federal funding comes from the National Science Foundation, Veterans Administration, Food and Drug Administration, and the Center for Medicare and Medicaid Services. Academic Medical Centers host much of the federally funded basic science research and are increasingly involved in drug development. Funding of the “Valley of Death” involves philanthropy and federal funding through small business programs and private equity from seed capital, angel investors, and venture capital companies. Advocacy groups fund both basic science and clinical trials. The Alzheimer Association is the advocacy organization with the largest research support portfolio relevant to AD drug development. Pharmaceutical companies are the largest supporters of biomedical research worldwide; companies are most interested in late stage de-risked drugs. Drugs progressing into phase II and III are candidates for pharmaceutical industry support through licensing, mergers and acquisitions, and co-development collaborations. Discussion Together, the funding and financing entities involved in supporting AD drug development comprise a complex, interactive, dynamic financial ecosystem. Funding source interaction is largely unstructured and available funding is insufficient to meet all demands for new therapies. Novel approaches to funding such as mega-funds have been proposed and more integration of component parts would assist in accelerating drug development

Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial

Carboplatin/taxane combination is first-line therapy for ovarian cancer. However, patients can encounter treatment delays, impaired quality of life, even death because of chemotherapy-induced gastrointestinal (GI) toxicity. A candidate gene study was conducted to assess potential association of genetic variants with GI toxicity in 808 patients who received carboplatin/taxane in the Scottish Randomized Trial in Ovarian Cancer 1 (SCOTROC1). Patients were randomized into discovery and validation cohorts consisting of 404 patients each. Clinical covariates and genetic variants associated with grade III/IV GI toxicity in discovery cohort were evaluated in replication cohort. Chemotherapy-induced GI toxicity was significantly associated with seven single-nucleotide polymorphisms in the ATP7B, GSR, VEGFA and SCN10A genes. Patients with risk genotypes were at 1.53 to 18.01 higher odds to develop carboplatin/taxane-induced GI toxicity (P<0.01). Variants in the VEGF gene were marginally associated with survival time. Our data provide potential targets for modulation/inhibition of GI toxicity in ovarian cancer patients

The UK National Health Service’s 'innovation agenda': lessons on commercialization and trust

The UK National Health Service (the 'NHS'), encouraged by the 2011 report Innovation Health and Wealth, Accelerating Adoption and Diffusion in the NHS, and empowered by the Health and Social Care Act 2012, is in the process of adopting a new agenda for stimulating innovation in healthcare. For this, the bodies, body materials, and confidential health information of NHS patients may be co-opted. We explain why this brings the NHS into a moral conflict with its basic goal of providing a universal healthcare service. Putting NHS databases at the disposal of industry, without addressing ethical concerns regarding the privacy, autonomy, and moral integrity of patients and without requiring a 'kick-back' to enhance the service that the NHS provides, is inappropriate. As this article shows, with reference to the commercial arena of direct-to-consumer genetic testing, it is crucial that patient and public trust in the NHS is not eroded

Phenotype standardization for statin-induced myotoxicity

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.</p

Preformed metal crowns for decayed primary molar teeth

BackgroundPreformed metal crowns (PMCs) are recommended by the British Society of Paediatric Dentistry (BSPD) for restoring badly broken down primary molar teeth. However, few dental practitioners adopt this technique in clinical practice, citing cost and clinical difficulty as reasons for this. Whilst there is a subjective impression by clinical academics that PMCs provide a more durable restoration than filling materials, there appears to be little evidence within the literature to support this.ObjectivesThe primary aim of this systematic review was to compare clinical outcomes for primary molar teeth restored using PMCs compared to those restored with filling materials.Search methodsThe literature was searched using: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 3); MEDLINE (1966 to August 2005); EMBASE (1980 to August 2005); System for Information on Grey Literature in Europe (SIGLE) (1976 to August 2005). Relevant publications' reference lists were reviewed for relevant articles. The most recent search was carried out on 24 August 2005.Selection criteriaRandomised controlled trials (RCTs) that assessed the effectiveness of PMCs compared with filling materials or where there had been no treatment in children with untreated tooth decay in one or more primary molar teeth.Data collection and analysisTwo review authors independently assessed the title and abstracts for each article from the search results to decide whether it was likely to be relevant. Full papers were obtained for relevant articles and all three review authors studied these.Main resultsForty‐seven records were retrieved by the search strategies of which some were duplicates. Of these, 14 studies were scrutinised. No studies met the inclusion criteria and six studies were excluded from the review as they were either retrospective in design or reported as prospective outcomes but not randomised. No data were available for extraction and analysis and therefore, no conclusion could be made as to whether PMCs were more successful than filling materials for restoring primary molar teeth.Authors' conclusionsNo RCTs were available for appraisal. Whilst this technique is recommended by the BSPD for use in clinical practice, the evidence to support this is not strong, consisting mainly of case reports and uncontrolled studies. It is important that the absence of evidence for PMCs is not misinterpreted as evidence for their lack of efficacy.There is a strong need for prospective RCTs comparing PMCs and fillings for managing decayed primary molar teeth. The lower levels of evidence that have been produced, however, have strength in that the clinical outcomes are consistently in favour of PMCs, despite many of the studies placing PMCs on the most damaged of the pair of teeth being analysed

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome.

Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by developmental delay, impaired communication, motor deficits and ataxia, intellectual disabilities, microcephaly, and seizures. The genetic cause of AS is the loss of expression of UBE3A (ubiquitin protein ligase E6-AP) in the brain, typically due to a deletion of the maternal 15q11-q13 region. Previous studies have been performed using a mouse model with a deletion of a single exon of Ube3a. Since three splice variants of Ube3a exist, this has led to a lack of consistent reports and the theory that perhaps not all mouse studies were assessing the effects of an absence of all functional UBE3A. Herein, we report the generation and functional characterization of a novel model of Angelman syndrome by deleting the entire Ube3a gene in the rat. We validated that this resulted in the first comprehensive gene deletion rodent model. Ultrasonic vocalizations from newborn Ube3am-/p+ were reduced in the maternal inherited deletion group with no observable change in the Ube3am+/p- paternal transmission cohort. We also discovered Ube3am-/p+ exhibited delayed reflex development, motor deficits in rearing and fine motor skills, aberrant social communication, and impaired touchscreen learning and memory in young adults. These behavioral deficits were large in effect size and easily apparent in the larger rodent species. Low social communication was detected using a playback task that is unique to rats. Structural imaging illustrated decreased brain volume in Ube3am-/p+ and a variety of intriguing neuroanatomical phenotypes while Ube3am+/p- did not exhibit altered neuroanatomy. Our report identifies, for the first time, unique AS relevant functional phenotypes and anatomical markers as preclinical outcomes to test various strategies for gene and molecular therapies in AS

How Can Network-Pharmacology Contribute to Antiepileptic Drug Development?

Network-pharmacology is a field of pharmacology emerging from the observation that most clinical drugs have multiple targets, contrasting with the previously dominant magic bullet paradigm which proposed the search of exquisitely selective drugs. What is more, drug targets are often involved in multiple diseases and frequently present co-expression patterns. Therefore, useful therapeutic information can be drawn from network representations of drug targets. Here, we discuss potential applications of drug-target networks in the field of antiepileptic drug development.Fil: Di Ianni, Mauricio Emiliano. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Ciencias Biológicas. Cátedra de Química Medicinal; Argentin