Blockbuster Drugs Research Articles

ChemInform Abstract: Advances in Exploring Alternative Taxol Sources

AbstractReview: 75 refs.

Protective gene offers hope for next blockbuster heart drug

Protective gene offers hope for next blockbuster heart drug

Potential and Challenges for Start-ups in Japan’s Biotech Industry

Although Japan has both a globally rare national mandated healthcare program and one of the most extensive life science research capabilities in the world, there is a future risk of their divergence due to Japan’s aging citizenry and the patent cliff of blockbuster drugs in domestic pharmaceutical industry. In order to bridge the gap between the research findings and the healthcare welfare with innovative new drugs under a prolonged drug development period and diminishing grace period before generic drug introduction, we will examine the potential of flexible risk management methods in biotech start-ups from real options, game theory, and start-up ecosystems perspectives. One of the reasons of this article’s focus on the biotech start-ups reflects the trend of the government 2015 policy as ‘Comprehensive reform of social security and tax’ for the global drug discovery and start-up founding.

Restructuring of the Pharmaceutical Industry

The pharmaceutical companies face serious challenges in the coming future when several of the blockbuster drugs run out of patents and a growing political pressure to stop the fast increase in health care expenditures has emerged. The recent wave of merger and acquisitions within the industry can be seen as an effective means to reduce costs and compensate for the educed earnings from patented drugs. The paper examines the main development in the expenditure to research and development (R&D) and number of patents in the industry with a focus on the role of company size. The analysis builds on a data set containing information of both patents and R&D expenditure for the world’s top 90 largest pharmaceutical companies, as well as their sales revenue, earning, and total asset from 2002 to 2013. The empirical part estimate the firm size effect on R&D efficiency and the amount of investment allocated to R&D, and the regression models control differences in firm characteristics by using fixed effects estimations. We find significant higher innovation activities in small companies with a higher innovation productivity as well. The restructuring of the pharmaceutical industry through a merger and acquisitions strategy may have been the large pharmaceutical company move to catch up in new drugs and revenues.

Single-Component Phosphinous Acid Ruthenium(II) Catalysts for Versatile C-H Activation by Metal-Ligand Cooperation.

Well-defined ruthenium(II) phosphinous acid (PA) complexes enabled chemo-, site-, and diastereoselective C-H functionalization of arenes and alkenes with ample scope. The outstanding catalytic activity was reflected by catalyst loadings as low as 0.75 mol %, and the most step-economical access reported to date to angiotensin II receptor antagonist blockbuster drugs. Mechanistic studies indicated a kinetically relevant C-X cleavage by a single-electron transfer (SET)-type elementary process, and provided evidence for a PA-assisted C-H ruthenation step.

Classroom Enters the Courtroom: Stereochemistry of SN1 and SN2 Reactions in Enantiomer Patent Litigations of the Antidepressant Escitalopram.

The role of elementary stereochemistry is illustrated in the patent litigations of the blockbuster antidepressant drug escitalopram oxalate. An undergraduate student of organic chemistry would recognize the stereochemical courses of the intramolecular SN 2 and SN 1 reactions of the single-enantiomer (S)-diol intermediate in the synthesis of the blockbuster antidepressant drug escitalopram oxalate: retention of configuration of the chiral carbon atom under basic conditions and racemization under acidic conditions, respectively. He/she, in searching for a stereoselective ring-closure reaction of the enantiomeric diol, will think of an SN 2 reaction in a basic medium. From these points of view, the process claim in the enantiomer patents of escitalopram is obvious/lacks an inventive step. An organic chemistry examination problem based on this scenario is offered.

Abstract IA06: Designing immunostimulatory antibodies for cancer treatment

Abstract Immunomodulatory mAb, led by the checkpoint blockers against CTLA-4 and PD-1/PD-L1, are changing the outlook for a number of difficult to manage cancers, such as melanoma and non-small cell lung cancer, and look set to become blockbuster drugs in the near future. While there is still some uncertainty concerning how these reagents work, it is generally agreed that they target exhausted effector T cells and Tregs within the tumour tissue. An alternative way to regulate anti-cancer T cells is using immunostimulatory mAb which trigger activatory T-cell co-receptors, often of the TNF receptor superfamily. Interestingly, most preclinical models show that immunostimulatory mAb are as good if not better than checkpoint blockers in terms of therapeutic potency. However, other than some limited success with anti-CD40 mAb in pancreatic cancer, immunostimulatory mAb have yet to display the level of clinical success seen with the checkpoint blockers. In this lecture we will discuss the mechanisms of action of these two groups of reagents and explore how differences in the rodent and human antibody effector functions might explain why immunostimulatory mAb have not performed as well in patients. We will show how the mouse inhibitory Fc gamma Receptor (FcγR), FcγRIIB, plays a critical role in hyper-crosslinking agonistic anti-TNFR mAb, yet in humans the equivalent receptor is less available to perform this function. We will also discuss how this knowledge is being used to engineer new immunostimulatory mAb which can exploit human FcγR effectively, or even mAb which can operate independently of FcγR with the opportunity of potent agonistic function regardless of bio-availability of FcγR. Citation Format: Martin J. Glennie, Aymen Al-Shamkhani, Stephen A. Beers, Ann L. White, Peter W. Johnson, Ruth R. French, Mark S. Cragg. Designing immunostimulatory antibodies for cancer treatment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr IA06.

Plant Bioactive Metabolites and Drugs Produced by Endophytic Fungi of Spermatophyta

It is known that plant-based ethnomedicine represented the foundation of modern pharmacology and that many pharmaceuticals are derived from compounds occurring in plant extracts. This track still stimulates a worldwide investigational activity aimed at identifying novel bioactive products of plant origin. However, the discovery that endophytic fungi are able to produce many plant-derived drugs has disclosed new horizons for their availability and production on a large scale by the pharmaceutical industry. In fact, following the path traced by the blockbuster drug taxol, an increasing number of valuable compounds originally characterized as secondary metabolites of plant species belonging to the Spermatophyta have been reported as fermentation products of endophytic fungal strains. Aspects concerning sources and bioactive properties of these compounds are reviewed in this paper.

The patent price of market access in the AUSFTA

New generation trade agreements reach far behind borders, affecting many areas of domestic policy not previously associated closely with trade. One of the most uneasy of these areas is intellectual property, particularly patent monopolies. The USA has been a major force behind the extended reach of patent monopolies using preferential trade agreements. The patent and data exclusivity provisions of the AUSFTA were proposed by the USA. This paper provides detailed evidence about how such ‘TRIPS+’ policies compare to a balanced patent policy—one equally favouring creators and users of technology. Australia has never had an active patent agenda, but since AUSFTA has been willing to accept in its bilateral and regional trade deals highly prescriptive rules that tie the hands of future governments. The overall trend has thus been toward increasing imbalance, with Australian patent policy now having a very broad reach and very low eligibility standards. This particularly affects the cost of medicines, where large numbers of relatively uninventive patents surround a blockbuster drug and delay the market entry of generic alternatives. In addition to outlining the costs of Australia’s current patent policy approach, the paper concludes by highlighting a more balanced and less costly way forward.

Synthesis of an advanced precursor of Rivastigmine: Cinchona-derived quaternary ammonium salts as organocatalysts for stereoselective imine reductions

The enantioselective reduction of ketoimines has been successfully realized, using trichlorosilane as the stoichiometric reducing agent in the presence of catalytic amounts of a Lewis base, specifically a Cinchona derivative. For the first time, a novel class of derivatives was studied, featuring a picolinamide unit bound to the alkaloid scaffold, further functionalized as quaternary ammonium salt at the quinuclidine ring. Excellent yields and from good to high enantioselectivities (up to 92% ee) were obtained in the reduction of ketoimines. The novel catalysts were successfully employed in the synthesis of an enantiomerically pure advanced precursor of the blockbuster drug Rivastigmine.

Pharma Bets Big On New Products

For three-and-a-half years, the big pharmaceutical firms tracked by C&EN have struggled to show sales and earnings gains. Their difficulties are perhaps not surprising since, in that time, they have faced the steepest part of the patent cliff plus predictions that the days of blockbuster drugs are over. However, eight of the top 10 new drugs approved in 2014 should achieve annual sales of well over $1 billion—so-called blockbuster status—within five years of their launch, according to EvaluatePharma, a London-based market research firm. And several drugs approved so far in 2015 are predicted to join those ranks as well. As sales of these products ramp up, pharma is expected to enter a new period of growth. “Continued confidence in the sector is being driven by a number of positive fundamentals, including the recent increase in R&D productivity, which has resulted in a big hike in drug approvals, and the emergence ...

Emerging Nanonisation Technologies: Tailoring Crystalline Versus Amorphous Nanomaterials.

The overall pharmaceutical market is changing. A more personalised medicine approach is replacing the concept of blockbuster drugs and the "one size fits all" model. The two main forces that fuel the growth of nano-enabled drug technologies are the low aqueous solubility of new chemical entities and the pharmaceutical market itself, as the development of novel drug delivery systems can extend the drug patent lifetime. Classical solubilisation techniques, such as salt formation and the use of cyclodextrins can only be applied to drugs with ionisable groups or specific molecular weight ranges in order to fit in the cavity of the cyclodextrin. However, drug nanonisation, or particle size reduction into the nanosize range, is a versatile technique that can be applied to a wide range of pharmaceutical compounds. Nano-drugs exhibit higher surface area per unit of volume, which leads to faster dissolution kinetics and hence potentially improved bioavailability. Marketed nano-drugs are mostly crystalline due to the improved physical stability afforded by the crystalline state whereas amorphous nano-drugs have been largely neglected in spite of generating higher saturation solubility compared to their crystalline counterparts. Due to the vast potential in the global pharmaceutical market, many technologies have been licensed to produce nano-drugs. Among them, the most successful by far is Nanocrystal(®); Technology based on wet milling methods. In this review, the main methods to generate and characterise nano-drugs are covered and also, the biopharmaceutical characteristics of the marketed nano-drugs are discussed.

Patents and R&D expenditure effects on equity returns in pharmaceutical industry

ABSTRACTAs costs of pharmaceutical R&D soar and productivity falls, the role of research pipelines in firm valuations is changing. To date, surprisingly little work has been published on the effects of R&D pipeline performance on equity returns, while controlling for coincident factors, such as legacy patents and presence of blockbuster drugs in production. Using 1996–2013 data for nine largest pharmaceutical companies in the world, this article assesses the role of the above factors on returns to pharmaceutical companies equity. We show significant positive link between changes in the number of blockbusters on patent six months prior and returns in excess of pharmaceutical equity index. The number of patents granted by United States Patent and Trademark Office in a quarter is also a significant factor. On the other hand, we find that increases in R&D expenditure in large-cap pharmaceutical companies are viewed negatively by investors in the short term.

Strategic Patenting in the Pharmaceutical Industry

While the roles of the pharmaceutical industry remain pivotal to human welfare and longevity, the industry is characterized by huge Research and Development (R&D) cost of new drugs and enormous uncertainties on whether or not the drugs make it into the market. Corollary, originator companies involve in strategic behaviors to maximize profit. Recently, this has intensified due to the patent expiry of their blockbuster drugs which, accounts for a substantial part of their sales and profits. This paper analyses the impact of these strategic behaviors of pharmaceutical firms on innovation, price and social welfare.

Lansoprazole is an antituberculous prodrug targeting cytochrome bc1.

Better antibiotics capable of killing multi-drug-resistant Mycobacterium tuberculosis are urgently needed. Despite extensive drug discovery efforts, only a few promising candidates are on the horizon and alternative screening protocols are required. Here, by testing a panel of FDA-approved drugs in a host cell-based assay, we show that the blockbuster drug lansoprazole (Prevacid), a gastric proton-pump inhibitor, has intracellular activity against M. tuberculosis. Ex vivo pharmacokinetics and target identification studies reveal that lansoprazole kills M. tuberculosis by targeting its cytochrome bc1 complex through intracellular sulfoxide reduction to lansoprazole sulfide. This novel class of cytochrome bc1 inhibitors is highly active against drug-resistant clinical isolates and spares the human H+K+-ATPase thus providing excellent opportunities for targeting the major pathogen M. tuberculosis. Our finding provides proof of concept for hit expansion by metabolic activation, a powerful tool for antibiotic screens.

Integrated Biocatalysis in Multistep Drug Synthesis without Intermediate Isolation: A de Novo Approach toward a Rosuvastatin Key Building Block

In this contribution, we report the chemoenzymatic preparation of a key building block for the active pharmaceutical ingredient rosuvastatin, one of the “top 5 blockbuster drugs” with a worldwide market value of 6.25 billion USD in 2012, via a seven-step synthesis without isolation of intermediates and with incorporation of two highly efficient biotransformations. This chemoenzymatic process reaches excellent space-time yields by using high substrate concentrations (several hundred grams per liter), emphasizing the potential of biocatalysis for industrial processes related to pharmaceutical drug synthesis and the compatibility of enzyme chemistry with classical organic synthesis.

Assessing protein kinase target similarity: Comparing sequence, structure, and cheminformatics approaches

In just over two decades, structure based protein kinase inhibitor discovery has grown from trial and error approaches, using individual target structures, to structure and data driven approaches that may aim to optimize inhibition properties across several targets. This is increasingly enabled by the growing availability of potent compounds and kinome-wide binding data. Assessing the prospects for adapting known compounds to new therapeutic uses is thus a key priority for current drug discovery efforts. Tools that can successfully link the diverse information regarding target sequence, structure, and ligand binding properties now accompany a transformation of protein kinase inhibitor research, away from single, block-buster drug models, and toward “personalized medicine” with niche applications and highly specialized research groups. Major hurdles for the transformation to data driven drug discovery include mismatches in data types, and disparities of methods and molecules used; at the core remains the problem that ligand binding energies cannot be predicted precisely from individual structures. However, there is a growing body of experimental data for increasingly successful focussing of efforts: focussed chemical libraries, drug repurposing, polypharmacological design, to name a few.Protein kinase target similarity is easily quantified by sequence, and its relevance to ligand design includes broad classification by key binding sites, evaluation of resistance mutations, and the use of surrogate proteins. Although structural evaluation offers more information, the flexibility of protein kinases, and differences between the crystal and physiological environments may make the use of crystal structures misleading when structures are considered individually. Cheminformatics may enable the “calibration” of sequence and crystal structure information, with statistical methods able to identify key correlates to activity but also here, “the devil is in the details.” Examples from specific repurposing and polypharmacology applications illustrate these points. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.

To monitor dabigatran or not: a matter of patient safety.

In October 2010, the US Food and Drug Administration (FDA)2 approved dabigatran etexilate (Pradaxa), a new oral, direct thrombin inhibitor, for prevention of stroke and thrombosis in patients with nonvalvular atrial fibrillation (AF). This marked a new era in the development of fixed-dose novel oral anticoagulants (NOACs) with the hope of achieving improved safety and clinical outcomes compared with warfarin. The concept of a fixed-dose anticoagulant that requires no monitoring quickly made the transition from concept to practice, helped partially by the FDA's new approach to innovative therapies. This new approach gave the manufacturer, Boehringer Ingelheim, access to priority reviews and a shorter approval process for its blockbuster drug, dabigatran. Rather than the conventional requirement of at least 2 pivotal trials, only a single large clinical trial was necessary for approval. Fixed-dose dabigatran demonstrated noninferior performance compared with dose-optimized warfarin therapy in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial for prevention of stroke and thrombosis in patients with nonvalvular AF, thus providing the bulk of support for FDA approval. After approval by the FDA in 2010 and the European Medicines Agency (EMA) a year later, dabigatran's popularity grew quickly, and by the end of 2013 sales approached $2 billion. However, amid litigation in US courts that centered on claims that dabigatran caused severe and fatal bleeding in patients, an investigation by the British Medical Journal revealed that as far back as 2010 Boehringer Ingelheim had knowledge that adjusting the dose of dabigatran might provide patients with superior efficacy and safety compared with a fixed dose (1, 2). This raised serious concerns about what the manufacturer chose not to disclose as it sought regulatory approval. The clinical impetus to explore novel anticoagulants originated from the difficulty in managing anticoagulation in patients receiving the standard-of-care treatment, warfarin. Anticoagulation …

Incorporating Virtual Reactions into a Logic-based Ligand-based Virtual Screening Method to Discover New Leads.

The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21×1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs.

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.