Efficiency of antisense oligonucleotide drug discovery

The costs for discovering and developing new drugs continue to escalate, with current estimates that the average cost is more than $800 million for each new drug brought to the market. Pharmaceutical companies are under enormous pressure to increase their efficiency for bringing new drugs to the market by third-party payers, shareholders, and their patients, and at the same time regulators are placing increased demands on the industry. To be successful in the future, pharmaceutical companies must change how they discover and develop new drugs. So far, new technologies have done little to increase overall efficiency of the industry and have added additional costs. Platform technologies such as monoclonal antibodies and antisense oligonucleotides have the potential of reducing costs for discovery of new drugs, in that many of the steps required for traditional small molecules can be skipped or streamlined. Additionally the success of identifying a drug candidate is much higher with platform technologies compared to small molecule drugs. This review will highlight some of the efficiencies of antisense oligonucleotide drug discovery compared to traditional drugs and will point out some of the current limitations of the technology.     

Unlocking the potential of natural products in drug discovery

The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Despite their historical importance, few pharmaceutical companies currently emphasize their exploitation in new drug discovery and instead favour synthetic compounds as more tractable alternatives. Ironically, we are in a Golden Age of understanding of natural product biosynthesis, biochemistry and engineering. These advances have the potential to usher in a new era of natural product exploration and development taking full advantage of the unique and favourable properties of natural products compounds in drug discovery.     

Paediatric Drug Development and Formulation Design—a European Perspective

The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize “better” medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the “Guideline on the Pharmaceutical Development of Medicines for Paediatric Use.” Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline’s key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.     

Antibiotic bill doesn't GAIN enough ground

With an eye to tackling the growing problem of antimicrobial drug resistance, uS lawmakers last month proposed new incentives to jump-start the ailing antibiotic industry. but the legislation as written is not likely to have the intended consequences, as it fails to adequately shield companies from competition with generic drugs. To truly entice investment and research from the drug industry, the bill needs to simplify the path to regulatory approval, provide greater protection from generic competition and aid drug companies with intellectual property extensions, tax relief and guaranteed market commitments.     

Structure-directed combinatorial library design

In recent years pharmaceutical companies have utilized structure-based drug design and combinatorial library design techniques to speed up their drug discovery efforts. Both approaches are routinely used in the lead discovery and lead optimization stages of the drug discovery process. Fragment-based drug design, a new power tool in the drug design toolbox, is also gaining acceptance across the pharmaceutical industry. This review will focus on the interplay between these three design techniques and recent developments in computational methodologies that enhance their integration. Examples of successful synergistic applications of these three techniques will be highlighted. Opinion regarding possible future directions of the field will be given.     

虚拟筛选与新药发现

虚拟筛选是创新药物研究的新方法和新技术,近年来引起了研究机构和制药公司的高度重视,并且已经成为一种与高通量筛选互补的实用化工具,加入到了创新药物研究的工作流程(pipeline)中。本文介绍国际上虚拟筛选及其在创新药物发现中应用的研究进展,特别介绍了我国这方面研究的状况。     

New aspects of natural products in drug discovery

During the past 15 years, most large pharmaceutical companies have decreased the screening of natural products for drug discovery in favor of synthetic compound libraries. Main reasons for this include the incompatibility of natural product libraries with high-throughput screening and the marginal improvement in core technologies for natural product screening in the late 1980s and early 1990 s. Recently, the development of new technologies has revolutionized the screening of natural products. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. Examples of these new advances and technologies are described in this review.     

Effect of generic drug competition on the price of prescription drugs in Ontario.

OBJECTIVE: To analyse the potential effect of generic drug competition on prices in Ontario to assess the costs and benefits associated with Bill C-22 (An Act to amend the Patent Act). DESIGN: Comparison of the cost of the least and most expensive versions of all products sold by more than one manufacturer in 1991. The number of brand-name and generic drug companies marketing each of the products was recorded. RESULTS: Of 1599 products 437 (27.3%) were made by more than one company. Almost half (44.6%) of the 437 were sold by two companies. The more companies that sold a drug the greater the difference in price between the least and most expensive versions. Similarly, as the proportion of generic drug companies in competition increased, the greater the price difference. When competition was between generic drug companies only, the price spread was smaller than when it was between brand-name drug companies only. CONCLUSIONS: Generic drug competition can result in savings to the Ontario Drug Benefit Plan. A more in-depth analysis of the potential savings is necessary to fully assess the costs and benefits associated with Bill C-22.     

The next generation of PPAR drugs: do we have the tools to find them?

Agonists of PPARalpha and PPARgamma are currently approved for use in treating, respectively, dyslipidemia and type 2 diabetes. Agonists of PPARbeta/delta are currently in development by several pharmaceutical companies. Despite their therapeutic importance, there are dose limiting side effects associated with PPAR drug treatments, thus a new generation of safer PPAR drugs are being actively sought after. In this review we will discuss the side effects associated the PPARs, how the current drugs in clinical development were discovered and new concepts in how to screen for PPAR drugs.     

High-throughput screening: update on practices and success

High-throughput screening (HTS) has become an important part of drug discovery at most pharmaceutical and many biotechnology companies worldwide, and use of HTS technologies is expanding into new areas. Target validation, assay development, secondary screening, ADME/Tox, and lead optimization are among the areas in which there is an increasing use of HTS technologies. It is becoming fully integrated within drug discovery, both upstream and downstream, which includes increasing use of cell-based assays and high-content screening (HCS) technologies to achieve more physiologically relevant results and to find higher quality leads. In addition, HTS laboratories are continually evaluating new technologies as they struggle to increase their success rate for finding drug candidates. The material in this article is based on a 900-page HTS industry report involving 54 HTS directors representing 58 HTS laboratories and 34 suppliers.     

我国创新药研发模式与价值评估(I)

创新药研发对企业研发能力要求高,目前我国大部分药企仍然处于仿创阶段,但随着政策环境的改善,国家不断释放鼓励创新信号, 创新型药企不断涌现,传统药企积极布局,创新药物迎来发展机遇。借鉴国外创新药研发经验,探讨我国创新药的 3 种研发模式及估值方法, 解析创新药研发的机遇与风险。     

Human embryonic stem cell technologies and drug discovery

Development of new drugs is costly and takes huge resources into consideration. The big pharmaceutical companies are currently facing increasing developmental costs and a lower success‐rate of bringing new compounds to the market. Therefore, it is now of outmost importance that the drug‐hunting companies minimize late attritions due to sub‐optimal pharmacokinetic properties or unexpected toxicity when entering the clinical programs. To achieve this, a strong need to test new candidate drugs in assays of high human relevance in vitro as early as possible has been identified. The traditionally used cell systems are however remarkably limited in this sense, and new improved technologies are of greatest importance. The human embryonic stem cells (hESC) is one of the most powerful cell types known. They have not only the possibility to divide indefinitely; these cells can also differentiate into all mature cell types of the human body. This makes them potentially very valuable for pharmaceutical development, spanning from use as tools in early target studies, DMPK or safety assessment, as screening models to find new chemical entities modulating adult stem cell fate, or as the direct use in cell therapies. This review illustrates the use of hESC in the drug discovery process, today, as well as in a future perspective. This will specifically be exemplified with the most important cell type for pharmaceutical development—the hepatocyte. We discuss how hESC‐derived hepatocyte‐like cells could improve this process, and how these cells should be cultured if optimized functionality and usefulness should be achieved. J. Cell. Physiol. 219: 513–519, 2009. © 2009 Wiley‐Liss, Inc.     

·我国创新药研发模式与价值评估(II)

创新药研发对企业研发能力要求高,目前我国大部分药企仍然处于仿创阶段,但随着政策环境的改善,国家不断释放鼓励创新信号, 临前所未有的挑战,呼唤历史发展的转折点。 3.1 由仿到创的大型创新药企——1.0模式 2015 年临床数据自查、仿制药一致性评价、化学药 国内当下的政策环境和市场环境,使得我国创新 品注册分类改革工作方案、上市许可人制度试点、药监市 朱迅 创新型药企不断涌现,传统药企积极布局,创新药物迎来发展机遇。借鉴国外创新药研发经验,探讨我国创新药的 3 种研发模式及估值方法, 解析创新药研发的机遇与风险。     

Combination drugs, an emerging option for antibacterial therapy

The emerging and sustained resistance to antibiotics and the poor pipeline of new antibacterials is creating a major health issue worldwide. Bacterial pathogens are increasingly becoming resistant even to the most recently approved antibiotics. Few antibiotics are being approved by regulatory organizations, which reflects both the difficulty of developing such agents and the fact that antibiotic discovery programs have been terminated at several major pharmaceutical companies in the past decade. As a result, the output of the drug pipelines is simply not well positioned to control the growing army of resistant pathogens, although academic institutions and smaller companies are trying to fill that gap. An emerging option to fight such pathogens is combination therapy. Combinations of two antibiotics or antibiotics with adjuvants are emerging as a promising therapeutic approach. This article provides and discusses clinical and scientific challenges to support the development of combination therapy to treat bacterial infections.     

Who will develop new antibacterial agents?

The golden age of antimicrobial drug development is a distant memory, and the likelihood of there being another seems slim. In part, this is because the pharmaceutical industry, which has now adopted an unsustainable business model, abandoned the anti-infective sector, and the pipeline is almost empty. The contribution to this crisis of national governments, health agencies and funders also merits discussion. Much of the basis for drug discovery is funded by the public sector, thereby generating intellectual property and leads for drug development that are often not pursued owing to funding gaps. In particular, the cost of testing drug efficacy in clinical trials is beyond the means of most companies and organizations. Lack of a concerted international effort to develop new antimicrobials is particularly alarming at a time when multidrug-resistant bacteria threaten all areas of human medicine globally. Here, the steps that led to this situation are retraced, and some possible solutions to the dilemma are proposed.     

Overcoming obstacles to developing new analgesics

Despite substantial investment by the pharmaceutical industry over several decades, there has been little progress in developing new, efficacious and safe analgesics. As a result, many large pharmaceutical companies are leaving the area of pain medication. Nevertheless, the chances of success could increase if analgesic drug development strategy changed. To achieve such a paradigm shift we must understand why development of drugs for pain relief is so challenging.     

Internet Resources Related to Drug Action and Human Response: A Review

It has been demonstrated that numerous proteins interact with drugs or their metabolites. Knowledge of these proteins is necessary to understand the mechanisms of drug action and human response. Progress in modern genetics, molecular biology, biochemistry and pharmacology is generating a comprehensive mechanistic understanding of drug-target interaction on the molecular level. This is valuable for researchers and pharmaceutical companies in their efforts to improve the efficacy of existing drugs and to discover new ones. Most recently, the integration of a systems biology approach into drug discovery processes calls for more holistic knowledge and easily accessible resources of the proteins that are important in drug action and human response. We have reviewed many publicly accessible internet resources of these proteins, according to their roles in drug action and human response, such as therapeutic effect, adverse reaction, absorption, distribution, metabolism and excretion.     

Cytomics and drug discovery.

Pharmaceutical companies try to develop new drugs that have a high success rate of reaching the market. However, current disease models lack a strong correlation to clinical reality, because of the underestimation of the complexity and variability of clinical disease processes. This leads to high attrition rates late in drug development and soaring costs. Improvement of disease models is an important issue to reduce the high attrition rates in drug development. Using cell-based disease models, which should take into account the molecular diversity of the human cytome, will improve the predictive value of drug discovery.     

治疗耐甲氧西林金黄色葡萄球菌感染的抗体药物

耐甲氧西林金黄色葡萄球菌(methicillin-resistant staphylococcus aureus, MRSA) 作为超级细菌的典型代表,严重威胁人民群众的健康。目前经典的抗生素治疗和疫苗主动预防都无法有效控制MRSA的感染。近年来,随着抗体药物产业的兴起,诸多药物研发公司和研究人员致力于研究治疗性抗体,以期控制MRSA的感染并已经取得了很多突破。就治疗MRSA感染的抗体药物研究进展作一简要综述。     

Patents Associated with High-Cost Drugs in Australia

Australia, like most countries, faces high and rapidly-rising drug costs. There are longstanding concerns about pharmaceutical companies inappropriately extending their monopoly position by “evergreening” blockbuster drugs, through misuse of the patent system. There is, however, very little empirical information about this behaviour. We fill the gap by analysing all of the patents associated with 15 of the costliest drugs in Australia over the last 20 years. Specifically, we search the patent register to identify all the granted patents that cover the active pharmaceutical ingredient of the high-cost drugs. Then, we classify the patents by type, and identify their owners. We find a mean of 49 patents associated with each drug. Three-quarters of these patents are owned by companies other than the drug''s originator. Surprisingly, the majority of all patents are owned by companies that do not have a record of developing top-selling drugs. Our findings show that a multitude of players seek monopoly control over innovations to blockbuster drugs. Consequently, attempts to control drug costs by mitigating misuse of the patent system are likely to miss the mark if they focus only on the patenting activities of originators.