Advances in the treatment of hereditary transthyretin amyloidosis: A review

Introduction: Amyloid transthyretin amyloidosis (ATTR) is a progressive and often fatal disease caused by the buildup of mutated (hereditary ATTR [hATTR]; also known as ATTR variant [ATTRv]) or normal transthyretin (wild-type ATTR) throughout the body. Two new therapies-inotersen, an antisense oligonucleotide therapy, and patisiran, an RNA interference therapy-received marketing authorization and represent a significant advance in the treatment of amyloidosis. Herein, we describe the clinical presentation of ATTR, commonly used procedures in its diagnosis, and current treatment landscape for ATTR, with a focus on hATTR. Methods: A PubMed search from 2008 to September 2018 was conducted to review the literature on ATTR. Results: Until recently, there have been few treatment options for polyneuropathy of hATTR. Inotersen and patisiran substantially reduce the amyloidogenic precursor protein transthyretin and have demonstrated efficacy in patients with early- and late-stage disease and in slowing or improving neuropathy progression. In contrast, established therapies, such as liver transplantation, typically reserved for patients with early-stage disease, and tafamidis, indicated for the treatment of early-stage disease in Europe, or diflunisal, a nonsteroidal anti-inflammatory drug that is used off-label, are associated with side effects and/or unclear efficacy in certain patient populations. Thus, inotersen and patisiran are positioned to be the preferred therapeutic modalities. Conclusions: Important differences between inotersen and patisiran, including formulation, dosing, requirements for premedications, and safety monitoring, require an understanding and knowledge of each treatment for informed decision making.info:eu-repo/semantics/publishedVersio

Akathisia and Newer Second‐Generation Antipsychotic Drugs: A Review of Current Evidence

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/1/phar2404_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/2/phar2404.pd

Adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people: systematic review and economic evaluation

Background: Psoriasis is a chronic inflammatory disease that predominantly affects the skin. Adalimumab (HUMIRA®, AbbVie, Maidenhead, UK), etanercept (Enbrel®, Pfizer, New York, NY, USA) and ustekinumab (STELARA®, Janssen Biotech, Inc., Titusville, NJ, USA) are the three biological treatments currently licensed for psoriasis in children. Objective: To determine the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and ustekinumab within their respective licensed indications for the treatment of plaque psoriasis in children and young people. Data sources: Searches of the literature and regulatory sources, contact with European psoriasis registries, company submissions and clinical study reports from manufacturers, and previous National Institute for Health and Care Excellence (NICE) technology appraisal documentation. Review methods: Included studies were summarised and subjected to detailed critical appraisal. A network meta-analysis incorporating adult data was developed to connect the effectiveness data in children and young people and populate a de novo decision-analytic model. The model estimated the cost-effectiveness of adalimumab, etanercept and ustekinumab compared with each other and with either methotrexate or best supportive care (BSC), depending on the position of the intervention in the management pathway. Results: Of the 2386 non-duplicate records identified, nine studies (one randomised controlled trial for each drug plus six observational studies) were included in the review of clinical effectiveness and safety. Etanercept and ustekinumab resulted in significantly greater improvements in psoriasis symptoms than placebo at 12 weeks’ follow-up. The magnitude and persistence of the effects beyond 12 weeks is less certain. Adalimumab resulted in significantly greater improvements in psoriasis symptoms than methotrexate for some but not all measures at 16 weeks. Quality-of-life benefits were inconsistent across different measures. There was limited evidence of excess short-term adverse events; however, the possibility of rare events cannot be excluded. The majority of the incremental cost-effectiveness ratios for the use of biologics in children and young people exceeded NICE’s usual threshold for cost-effectiveness and were reduced significantly only when combined assumptions that align with those made in the management of psoriasis in adults were adopted. Limitations: The clinical evidence base for short- and long-term outcomes was limited in terms of total participant numbers, length of follow-up and the absence of young children. Conclusions: The paucity of clinical and economic evidence to inform the cost-effectiveness of biological treatments in children and young people imposed a number of strong assumptions and uncertainties. Health-related quality-of-life (HRQoL) gains associated with treatment and the number of hospitalisations in children and young people are areas of considerable uncertainty. The findings suggest that biological treatments may not be cost-effective for the management of psoriasis in children and young people at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year, unless a number of strong assumptions about HRQoL and the costs of BSC are combined. Registry data on biological treatments would help determine safety, patterns of treatment switching, impact on comorbidities and long-term withdrawal rates. Further research is also needed into the resource use and costs associated with BSC. Adequately powered randomised controlled trials (including comparisons against placebo) could substantially reduce the uncertainty surrounding the effectiveness of biological treatments in biologic-experienced populations of children and young people, particularly in younger children. Such trials should establish the impact of biological therapies on HRQoL in this population, ideally by collecting direct estimates of EuroQol-5 Dimensions for Youth (EQ-5D-Y) utilities. Study registration: This study is registered as PROSPERO CRD42016039494. Funding: The National Institute for Health Research Health Technology Assessment programme

The potential savings of using thiazides as the first choice antihypertensive drug: cost-minimisation analysis

BACKGROUND: All clinical practice guidelines recommend thiazides as a first-choice drug for the management of uncomplicated hypertension. Thiazides are also the lowest priced antihypertensive drugs. Despite this, the use of thiazides is much lower than that of other drug-classes. We wanted to estimate the potential for savings if thiazides were used as the first choice drug for the management of uncomplicated hypertension. METHODS: For six countries (Canada, France, Germany, Norway, the UK and the US) we estimated the number of people that are being treated for hypertension, and the proportion of them that are suitable candidates for thiazide-therapy. By comparing this estimate with thiazide prescribing, we calculated the number of people that could switch from more expensive medication to thiazides. This enabled us to estimate the potential drug-cost savings. The analysis was based on findings from epidemiological studies and drug trials, and data on sales and prescribing provided by IMS for the year 2000. RESULTS: For Canada, France, Germany, Norway, the UK and the US the estimated potential annual savings were US$13.8 million, US$37.4 million, US$72.2 million, US$10.7 million, US$119.7 million and US$433.6 million, respectively. CONCLUSIONS: Millions of dollars could be saved each year if thiazides were prescribed for hypertension in place of more expensive drugs. Our calculations are based on conservative assumptions. The potential for savings is likely considerably higher and may be more than US$1 billion per year in the US