Blockbuster Drugs Research Articles

The impact of researchers loyal to Big Pharma on the ethics and quality of clinical trials in Latin America

This article explains the difficulties innovative pharmaceutical firms have in repaying shareholders with attractive dividends. The problem is the result of the expiration of the patents of blockbuster drugs and the difficulties that the firms have in bringing new blockbuster drugs to the market. One of the solutions companies have found has been to accelerate the implementation of clinical trials in order to expedite the commercialization of new drugs. Doing so increases the period in which they can sell drugs at monopoly prices. We therefore discuss how innovative pharmaceutical firms shorten the implementation time of clinical trials in Latin America and the consequences such actions have on the quality of the collected data, the protection of human rights of the subjects of experimentation, and compliance with the ethical principles approved in international declarations.

Strategies to make protein serine/threonine (PP1, calcineurin) and tyrosine phosphatases (PTP1B) druggable: Achieving specificity by targeting substrate and regulatory protein interaction sites

The established dogma is that protein serine/threonine (PSPs) and tyrosine (PTPs) phosphatases are unattainable drug targets. This is because natural product inhibitors of PSP active sites are lethal, while the active sites of PTPs are exceptionally conserved and charged, making it nearly impossible to develop PTP inhibitors that are selective. However, due to a series of recent structural and functional studies, this view of phosphatases is about to undergo a radical change. Rather than target active sites, these studies have demonstrated that targeting PSP/PTP protein (substrate/regulatory) interaction sites, which are distal from the active sites, are highly viable and suitable drugs targets. This is especially true for calcineurin (CN), in which the blockbuster immunosuppressant drugs FK506 and cyclosporin A were recently demonstrated to bind and block one of the key CN substrate interaction sites, the LxVP site. Additional studies show that this approach—targeting substrate and/or regulatory protein interaction sites—also holds incredible promise for protein phosphatase 1 (PP1)-related diseases. Finally, domains outside PTP catalytic domains have also recently been demonstrated to directly alter PTP activity. Collectively, these novel insights offer new, transformative perspectives for the therapeutic targeting of PSPs by interfering with the binding of PIPs or substrates and PTPs by targeting allosteric sites outside their catalytic domains.

Determinants of generic vs. brand drug choice: Evidence from population-wide Danish data

We investigate if demand for branded prescription medications in post-patent markets is patient- or doctor driven. When drugs go off-patent the brand medication often maintains non-negligible market shares. We use population-wide Danish data including all prescriptions for seven blockbuster drugs from 1998 to 2008, which amounts to 13,415,012 prescriptions. At the outset, descriptive statistics suggest large variation in drug choice over doctors. Nonetheless, using a two-way fixed effects model we find that the primary determinants of brand drug use are unobserved patient characteristics and price effects.

Insight into the conformational polymorph transformation of a block-buster multiple sclerosis drug fingolimod hydrochloride (FTY 720)

Single-crystal structures of fingolimod hydrochloride (FTY 720), a block-buster multiple sclerosis drug, were revealed for the first time in this study. Three different conformational polymorphs (designated as forms I–III) were characterized using a variety of analytical techniques, including single-crystal XRD, VT-PXRD, DSC, HSM, and VT-confocal Raman spectroscopy. A temperature-dependent solid–solid transformation between different conformational polymorphs was observed to be reversible, and the transition process was studied using both VT-PXRD and VT-Raman techniques. Structural analysis revealed that the FTY 720 molecules adopt distinctive conformations in different polymorphs. Single-crystal to single-crystal transformation from form I to II was observed and was closely monitored by X-ray diffraction.

Single-step fermentative production of the cholesterol-lowering drug pravastatin via reprogramming of Penicillium chrysogenum

The cholesterol-lowering blockbuster drug pravastatin can be produced by stereoselective hydroxylation of the natural product compactin. We report here the metabolic reprogramming of the antibiotics producer Penicillium chrysogenum toward an industrial pravastatin production process. Following the successful introduction of the compactin pathway into the β-lactam-negative P. chrysogenum DS50662, a new cytochrome P450 (P450 or CYP) from Amycolatopsis orientalis (CYP105AS1) was isolated to catalyze the final compactin hydroxylation step. Structural and biochemical characterization of the WT CYP105AS1 reveals that this CYP is an efficient compactin hydroxylase, but that predominant compactin binding modes lead mainly to the ineffective epimer 6-epi-pravastatin. To avoid costly fractionation of the epimer, the enzyme was evolved to invert stereoselectivity, producing the pharmacologically active pravastatin form. Crystal structures of the optimized mutant P450(Prava) bound to compactin demonstrate how the selected combination of mutations enhance compactin binding and enable positioning of the substrate for stereo-specific oxidation. Expression of P450(Prava) fused to a redox partner in compactin-producing P. chrysogenum yielded more than 6 g/L pravastatin at a pilot production scale, providing an effective new route to industrial scale production of an important drug.

Anxious wait for patients and big pharma

Anxious wait for patients and big pharma

Bioreductive production of enantiopure (S)-duloxetine intermediates catalyzed with ketoreductase ChKRED15

The blockbuster antidepressant drug duloxetine contains one stereo-center derived from chiral alcohol intermediates. The stereoselective bioreductive production of five of such intermediates could be achieved using the recombinant ketoreductase ChKRED15, yielding the enantiopure (S)-alcohols with >99% ee. Sequence alignment indicated that ChKRED15 lacks the conserved G-rich motif, which was then amended by a single mutation of S12G. The resulting S12G mutant displayed significantly improved catalytic activity and protein stability. When coupled with a cofactor recycling system, the S12G mutant was able to catalyze the complete conversion of ethyl 3-oxo-3-(thiophen-2-yl)propanoate within 6h and N-methyl-3-oxo-3-(thiophen-2-yl)propanamide within 24h at substrate concentrations of 10 and 50g/l, respectively, without the compromise of enantioselectivity.

Analysts predict surge in ‘blockbuster drugs’ entering the market in 2015

Analysts predict surge in ‘blockbuster drugs’ entering the market in 2015

Ethnopharmacology-A Novel Approach for Drug Discovery

The era of blockbuster drugs is now ending, the pharmaceutical industry is not as innovative due to shortage of new lead structures. Ethnopharmacology and natural product drug discovery remains a significant hope in the current scenario. Ethno pharmacology provides a divergent approach involving indigenous knowledge with current technology for drug development using new approaches. Natural products have been the source of active ingredients of many medicines from 1981 till date. Aspirin, artimesinin, colchicine, digoxin, ephedrine are few important drugs that were developed from medicinal plants in the past. Hurdles like lack of trials, safety and efficacy records, gap between old concepts and modern understanding, malpractice due to intense competition in drug research, carelessly carried out bioassays and biopiracy stop this knowledge from becoming mainstream. Physician can play an important role in overcoming some of these hurdles and strict guidelines are required for ethnoergogenics. A sincere effort needs to be made to prevent the loss of this rich traditional knowledge which can help drug discovery for many years to come.

SMi'S 4th Annual Orphan Drugs and Rare Diseases Conference (October 19-20, 2015--London, UK).

The story of rare diseases is a story of people. Often very young, and usually with little hope of treatment, it is often a desperately sad and tragic story, but increasingly a story of hope. Statistics are inescapable when discussing the subject: small numbers of patients in huge populations, the massively disproportionate contribution to pediatric mortality, and the necessarily high prices for rare drugs. Almost every speaker at the SMi's Fourth Orphan Drugs and Rare Diseases conference provided figures that illustrated just how different this area is to the macro-world of the blockbuster drug.

Natural Bioenhancers: Current Outlook

Pharmaceutical companies around the globe have always been in the urge of discovering innovative blockbuster drugs for various ailments by spending billions of dollars for the drug discovery programmes. Although identification of new chemical entities (NCEs) with alternate mode of actions for diseases is a primary concern for the pharmaceutical companies, application of innovative techniques and technologies to increase the bioavailability, efficacy and safety of the already existing drugs are of no less concern as well. In fact, enhancing bioavailability of therapeutically potent but poorly bioavailable molecules has always been a crucial aspect of drug development programmes, as it reduces the drug dosage and frequency resulting in reduced toxicity and cost for the patients [1]. Among the various factors responsible for poor bioavailability of drugs, physiochemical properties of the drug itself and biological barriers are two predominant factors [2]. While physicochemical properties of the drug include poor aqueous solubility, poor intestinal membrane permeability, and poor stability of drug in gastrointestinal tract (GIT), biological barrier constitutes hepatic and intestinal drug metabolizing enzymes (DMEs) and efflux drug transporters (EDTs). The metabolism of drugs by cytochrome P450 (CYP) DMEs in the gut wall and in the liver is the major contributors of reduced bioavailability of drugs that are substrate to these DMEs [3]. In addition to this, EDTs such as P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), multidrug resistant-associated protein (MRP) are also responsible for reduced bioavailability of the therapeutically active drugs, especially anticancer drugs [3].

R&D Productivity in the Pharmaceutical Industry

The pharmaceutical industry is in a R&D productivity crisis. Rapidly increasing development costs, decreasing profitability of new medical entities and missing breakthrough innovations are negatively affecting the future of the pharmaceutical industry. This complex problem requires a systems thinking approach to find effective solutions. In this study, a general pharmaceutical R&D productivity system has been modeled as a Bayesian Belief Network (BBN). This model is based on a literature review and the mental model of experts in the pharmaceutical field. The model does not only support users to understand the system but is also able to simulate different future scenarios. A blockbuster drug scenario, a generic drug scenario, and a personalized drug scenario has been modeled with three different corresponding outcomes. These simulations enables decision makers to identify the leverage points of the pharmaceutical R&D productivity system. These leverage points could be the foundation of any further strategy development. The R&D productivity system archetype is potentially applicable for other R&D intensive industries.

Drug Firms Prevail In Antitrust Trial

A deal between AstraZeneca and Ranbaxy Laboratories that resolved a patent dispute involving the launch of a cheaper, generic version of the blockbuster heartburn drug Nexium did not violate federa...

Chemical assembly systems: layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients.

While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels--choice of starting material, reagent, or order of reaction modules--enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49-75%).

Strategic approaches to optimizing peptide ADME properties.

Development of peptide drugs is challenging but also quite rewarding. Five blockbuster peptide drugs are currently on the market, and six new peptides received first marketing approval as new molecular entities in 2012. Although peptides only represent 2% of the drug market, the market is growing twice as quickly and might soon occupy a larger niche. Natural peptides typically have poor absorption, distribution, metabolism, and excretion (ADME) properties with rapid clearance, short half-life, low permeability, and sometimes low solubility. Strategies have been developed to improve peptide drugability through enhancing permeability, reducing proteolysis and renal clearance, and prolonging half-life. In vivo, in vitro, and in silico tools are available to evaluate ADME properties of peptides, and structural modification strategies are in place to improve peptide developability.

Histamine H4 receptor ligands: future applications and state of art.

Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs.

Assesing the Impact of Patent Loss on Overall Revenues and Stocks Price of Pharmaceutical Companies.

With the pre-tax R&D cost of bringing a biopharmaceutical product to market estimated at $1.2 billion, revenues from blockbuster drugs may need to cover the development cost of multiple drugs. We analyzed four major blockbuster products that lost patent between 2011 and 2012 and the associated change in sales it had on the company. We identified four major products (atorvastatin, clopidogrel, quetiapine, and montelukast) that lost patent protection between 2011 and 2012. Then, we retrieved sales data for the drug, total revenue, and stock price for the company from Q1 2011 to Q4 2013. Sales data was from IMS Health via drugs. com. Total company revenue per quarter was provided by Charles Schwab & Co. and historical stock data was taken from Yahoo! Finance. During the time the drugs were under patent, they made up an average of 16.8% of total revenues per quarter. Total sales for the four drugs were down an average of 78.8% by Q4 2013 while total revenues for the companies were only down on average 11.9%. Stock prices over the same period increased an average of 72.5%. During the time the product had patent protection, the stock prices of those four companies increased at an average of 3.7% per quarter, as opposed to the 5.8% increase per quarter when the patent expired. During patent protection, average company revenue grew at an average of 1.52% per quarter; when the patent expired, revenue declined at an average of 1.9%. Overall these blockbuster drugs do not seem to significantly decrease revenues and do not influence stock prices when their patent protection is up. Large pharmaceuticals may reinvest profits to bolster their pipelines and find replacements for these large-revenue drugs. Investors seem to appropriately price in patent expiration into stock prices long before the actual event.

Blockbuster drugs: the rise and decline of the pharmaceutical industry

Table of Contents Chapter 1 Before the Age of Blockbuster Drugs Chapter 2 The Beginning of an Era - The First Blockbuster Drug Tagamet Chapter 3 More Blockbuster Drugs for Ulcer Chapter 4 Antihistamines as Allergy Medicines Chapter 5 Blood Thinners, From Heparin to Plavix Chapter 6 Conquest of Pain-Analgesics: from Morphine to Lyrica Chapter 7 Lessons Bibliography Appendix Index

Here Comes the Sun: Medical Professionalism and the Implications of the Sunshine Act for Gastroenterology Practice

The Affordable Care Act, passed in 2010, contained a number of regulations that directly affect physician practices, behavior, and relationships with others in the health care industry. One such provision is the “Physician Payment Sunshine Act,” which is the subject of this month’s Practice Management: The Road Ahead column. The authors have provided us with a detailed and enlightening review of how our relationships with pharmaceutical and medical device companies have become transparent and public. It will be important for you to understand this law and take the time to review your own data through CMS’s Enterprise Portal (http://www.cms.gov/Regulations-andGuidance/Legislation/National-Physician-Payment-Transp arency-Program/Physicians.html).

Mechanisms to provide safe and effective drugs for children.

* Abbreviation: FDA — : Food and Drug Administration Children are therapeutic orphans. The majority of drugs used in children are “off label”; that is, the data regarding dose, safety, or efficacy (and often all 3) are not deemed sufficient by the US Food and Drug Administration (FDA) for inclusion on the product label. Not surprisingly, off-label drug use increases the risk of adverse events. To address the knowledge gap leading to such use, the US government has enacted multiple laws to stimulate increased drug research and labeling for children. One such law is known as “pediatric exclusivity,” first passed in 1997 and most recently made permanent in 2012 under the FDA Safety and Innovation Act. Pediatric exclusivity grants pharmaceutical companies a 6-month patent extension if they study a product under a written request from the FDA. For so-called blockbuster drugs, those with ≥$1 billion in sales per year, the incentive is substantial. In this issue of Pediatrics , Wharton et al1 review the labeling changes related to pediatric exclusivity. These 3 items are worth additional consideration. First, although the FDA issued 401 written requests, pharmaceutical companies chose to respond to fewer than … Address correspondence to Daniel K. Benjamin Jr, MD, PhD, MPH, Duke University, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. E-mail: danny.benjamin{at}duke.edu