Anti-angiogenic drug discovery: lessons from the past and thoughts for the future

Introduction: Since the pioneering work of Judah Folkman, the discovery of bevacizumab has introduced the use of anti-angiogenic agents as a new modality for the treatment of cancer. Currently, hundreds of clinical trials involving anti-angiogenic agents, targeting different elements of the tumour angiogenesis pathway, are underway. However, thus far, the benefits of anti-angiogenic therapy in unselected patient populations are often marginal with harmful side effects.

Areas covered: This article presents a detailed discussion of the lessons learnt from the use of bevacizumab and other VEGF pathway inhibitors in the clinical setting. Specifically, this article provides a review of the literature on anti-VEGF agents and other angiogenesis inhibitors used in pre-clinical and clinical trials for cancer treatment.

Expert opinion: Future anti-angiogenic drug design centres on multiple protein targets and combinations including: growth factors, hypoxia-inducible factor and tumour endothelial cell markers unique to the tumour vasculature. Furthermore, treatment dosing, scheduling and combination with radiation and chemotherapy require further investigation, as does the potential of treating early disease, and the development of biomarkers which accurately predict response to therapy. These are essential for the future development of these drugs with individualised therapy likely to be the ultimate goal.     

Anti-TNF antibodies: lessons from the past, roadmap for the future

Tumor necrosis factor alpha (TNF) is an important cell-signaling component of the immune system. Since its discovery over 20 years ago, much has been learned about its functions under normal and disease conditions. Nonclinical studies suggested a role for TNF in chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and psoriasis, and therefore neutralizing monoclonal antibodies specific to human TNF were developed for clinical evaluation. Treatment with anti-TNF monoclonal antibodies (infliximab, adalimumab, and certolizumab pegol) has been shown to provide substantial benefit to patients through reductions in both localized and systemic expression of markers associated with inflammation. In addition, there are beneficial effects of anti-TNF treatment on markers of bone and cartilage turnover. Further exploration of changes in these markers and their correlation with clinical measures of efficacy will be required to allow accurate prediction of those patients most in need of these treatments. Both the clinical and commercial experience with these anti-TNF antibodies provide a wealth of information regarding their pharmacological effects in humans.     

The past, present and future of antiviral drug discovery

A review of the history, development and current status of antiviral chemotherapy is presented from its origins in the 1960s until the present day. Key issues in the development of novel antivirals are the emergence of resistant virus, safety and side effects. This review describes the current therapeutic status of the herpes viruses, HIV, hepatitis viruses and respiratory viruses, and outlines the current limitations in the field together with the future compounds likely to emerge to address these needs. The future of antiviral research is assessed in relation to the impact of potential 'emerging viruses' and biological weapons, and the potential of combination therapies involving antivirals and disease modification.     

Polypharmacology: drug discovery for the future

In recent years, even with remarkable scientific advancements and a significant increase of global research and development spending, drugs are frequently withdrawn from markets. This is primarily due to their side effects or toxicities. Drug molecules often interact with multiple targets, coined as polypharmacology, and the unintended drug–target interactions could cause side effects. Polypharmacology remains one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective, but less toxic, therapeutic agents. This review outlines the latest progress and challenges in polypharmacology studies.     

Drug discovery and development: lessons from an undeveloped drug

In this article, drug discovery and preclinical development paradigms, as employed in today's pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients. Implementation of systems pharmacology, disease progression and pharmacokinetic/pharmacodynamic models are proposed. These models offer a superior approach in selecting the best drug candidates with the highest chance of success of entry into the market.     

Drug discovery and development: lessons from an undeveloped drug

In this article, drug discovery and preclinical development paradigms, as employed in today’s pharmaceutical companies, are discussed. The antimalarial drug, artemisinin, is given as an example of a compound that is unlikely to be developed by a modern pharmaceutical company, yet is a safe and effective drug for the treatment of a deadly disease. It is argued that the use of prespecified charts, listing undesired properties to deselect molecules may lead to missed opportunities in bringing best-in-class medications to patients. Implementation of systems pharmacology, disease progression and pharmacokinetic/pharmacodynamic models are proposed. These models offer a superior approach in selecting the best drug candidates with the highest chance of success of entry into the market.     

Magnetic resonance imaging in drug discovery: lessons from disease areas

Imaging technologies are presently receiving considerable attention in the pharmaceutical area owing to their potential to accelerate the drug discovery and development process. One of the principal imaging modalities is magnetic resonance imaging (MRI). The multiparametric nature of MRI enables anatomical, functional and even molecular information to be obtained non-invasively from intact organisms at high spatial resolution, thereby enabling a comprehensive characterization of a disease state and the corresponding drug intervention. The non-invasiveness of MRI strengthens the link between pre-clinical and clinical drug studies, making the technique attractive for pharmaceutical research.     

Applying pharmaceutical lessons: learning lessons from the past

Systematic evaluation of a project, product or other successes, and failures, is an important method for improving the performance of a company, as well as that of an individual. One should evaluate and determine if lessons learned can be applied to the systems and procedures being used in the company. Even if the company does not have to adjust its strategies, procedures, portfolio or systems as a result of lessons it has learned, there may be pointers to communicate to staff. It is easy for many aspects of a system to become outdated, particularly in an organization that is growing or changing rapidly. It is therefore generally appropriate to evaluate the company's regulatory compliance, toxicology compliance, clinical auditing practices and other appropriate systems on an annual or biannual basis. Most lessons of success or failure are specific to a single situation because of the combination of people, drug, competition, priorities and many other factors involved, and cannot be extrapolated to other situations. Some general lessons and principles are presented that will facilitate drug discovery, development and marketing.     

Learnings from past failures: Future routes of antimicrobial drug discovery

Despite the unprecedented unmet need to discover new antibiotics, only a few molecules have been registered for clinical use. This shortage is primarily based on the scientific failure in the postgenomic era of drug discovery. It appears counterintuitive that knowledge of the bacterial genome was followed by the failure to produce new antibiotics using the paradigm of target-driven drug discovery. Here, I discuss the causes of the failures and also describe how small biotech is mitigating these risks and moving forward using new strategies to identify new antibiotics.     

Shared care in the UK: failings of the past and lessons for the future

Aims —To explore and evaluate the implementation of shared care in the UK, to identify failings and to make recommendations for successful implementation of shared care in the future. Methods —The study utilised a triangulation approach, employing three different methods to explore the production and format of shared care protocols (SCPs) and the perceived use and future trends of shared care. A postal survey of hospital pharmacists and pharmaceutical and medical advisers in health authorities and interviews with health care professionals provided insight into perceptions of shared care and recommendations for the future. A content analysis of a sample of SCPs in current use assessed the utility of SCPs in practice. Results — A total of 321 SCPs were identified that described 99 different drugs and treatments. The protocols varied considerably with no apparent standard either within or between regions, but there was a correlation between the patient‐related information available, information across the health care interface (r=0.355, P=0.05) and pharmaceutical information (r=0.401, P=0.05). There were expressions of uncertainty about the benefit of such protocols to patients. Health authority staff in particular expressed predominantly negative attitudes in the questionnaire whereas the pharmacists were more positive. The transfer of prescribing and associated costs from hospital to community (described as “cost shifting”) was repeatedly identified as a barrier, together with competing professional interests and reluctance to change with the times. General practitioners (GPs) were most commonly excluded from the production of SCPs, which may enforce negative feelings around implementation of SCPs across the health care interface. Improved information technology and better use of evidence‐based guidelines and protocols were seen as ways forward in developing shared care. Conclusions — Since 1991, a large number of SCPs have been produced in the UK but the benefits to patients are not clear. There is a general perception of cynicism about their use; “cost‐shifting” is perceived as their main purpose. There appears to have been no formal evaluation of their use or mechanisms for their implementation, and distribution has been erratic. This study highlights that, with greater involvement of health care professionals, better communication systems and the removal of identified barriers, shared care is a concept essential in the evolving NHS.     

Pharmacogenomics of primary hypertension--the lessons from the past to look toward the future

A number of recent reviews have addressed the issue of the pharmacogenomics of primary hypertension and related complications by considering the data on the genotype-drug response relationship. Here we mainly discuss the methodological aspects of this issue, trying to integrate 'traditional' clinical and experimental pathophysiology and therapy-pharmacology with the 'new' genetics. Such integration is indispensable to: a). define the appropriate 'context' (genetic background, environment, age, gender, phase of hypertension, previous therapy etc.) in which a given genotype-drug response relationship should be tested (it is indeed likely that many discrepancies among published data originate from context's interference); b). assign the correct clinical meaning to the results obtained by statistics and functional genetics methodologies; c). define a novel clinical entity caused by a disease favoring allele, alone or in combination with other alleles, with a consistent clinical picture, prognosis and responsiveness to the appropriate drug; d). estimate the size of the population target amenable to benefit from a therapeutic intervention developed according to the pharmacogenomics' principles; e). develop a novel drug that selectively interferes with the sequence of events triggered by the genetic mechanism(s) underlying the clinical entity. Peculiar to this strategy is to look for consistency among findings gathered from different 'contexts' after having properly accounted for the context's dependency of the results.