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Key Points This Analysis article describes the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality. Safety and toxicology are the largest sources of failure within the data set. The link between calculated physicochemical properties and frequent causes of attrition (preclinical toxicology, clinical safety and human pharmacokinetics) is assessed. Analysis of this data set shows that none of the physicochemical descriptors we examined correlates with preclinical toxicology outcomes. This work is the first to indicate a link between lipophilicity and clinical failure owing to safety issues. The utility of this finding in a prospective sense is discussed. Although control of physicochemical properties is clearly important, this analysis suggests that further stringency in this respect is unlikely to have a significant effect on attrition in development and that additional work is required to address safety-related failures. Attempts to reduce the number of efficacy- and safety-related failures that may be linked to the physicochemical properties of small-molecule drug candidates have been inconclusive owing to the limited size of data sets from individual companies. Waring and colleagues analyse the largest data set compiled so far on the causes of attrition for oral, small-molecule drug candidates, derived from a pioneering data-sharing effort by AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers — systemic, microenvironmental and cellular — that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.Advances in nanoparticle design could make substantial contributions to personalized and non-personalized medicine. In this Review, Langer, Mitchell, Peppas and colleagues discuss advances in nanoparticle design that overcome heterogeneous barriers to delivery, as well as the challenges in translating these design improvements into personalized medicine approaches.

Key Points Biopharmaceutical drugs such as antibodies, peptides and recombinant proteins have high specificity and potency compared to small molecules. These features arise from their macromolecular composition, which provides the structural complexity that is often required for specificity. However, this structural complexity means that biopharmaceutical drugs are large and susceptible to degradation, which makes it challenging to formulate and deliver them. These drugs also have reduced permeation across biological barriers, which complicates their delivery to specific sites or intracellular targets. In this Review we highlight recent advances in formulation and delivery strategies that have facilitated the transformation of product portfolios and development pipelines by this class of compounds. These advances include the use of microsphere-based sustained-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, as well as genetic manipulation of biopharmaceutical drugs such as Fc- and albumin-fusions. We also highlight current and emerging delivery routes that provide alternatives to injection, including transdermal, oral and pulmonary delivery. Current areas of formulation and delivery research show promise for the application of biopharmaceutical drugs to tumour immunotherapy using nanoparticle technology, tissue engineering and enhanced approaches to cell-based therapy. These delivery methods could be used for the targeted delivery of proteins to the brain, which could have implications in the treatment of a wide range of central nervous system disorders. These technologies could potentially increase the effectiveness of conventional approaches that have not yet translated to the clinic, although they have had promising preclinical results. Intracellular delivery of proteins and peptides is a new frontier in delivery research, which could dramatically augment the breadth of targets amenable to biopharmaceutical drug therapy. Biological drugs offer high specificity and potency, but their formulation and delivery pose substantial challenges. Here, the authors highlight recent advances in formulation strategies, describe current and emerging delivery routes and review the potential of targeted and intracellular delivery of biologics. The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies — such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs — and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.

The success of protein, peptide and antibody based therapies is evident - the biopharmaceuticals market is predicted to reach $388 billion by 2024 [1], and more than half of the current top 20 blockbuster drugs are biopharmaceuticals. However, the intrinsic properties of biopharmaceuticals has restricted the routes available for successful drug delivery. While providing 100% bioavailability, the intravenous route is often associated with pain and needle phobia from a patient perspective, which may translate as a reluctance to receive necessary treatment. Several non-invasive strategies have since emerged to overcome these limitations. One such strategy involves the use of microneedles (MNs), which are able to painlessly penetrate the stratum corneum barrier to dramatically increase transdermal drug delivery of numerous drugs. This review reports the wealth of studies that aim to enhance transdermal delivery of biopharmaceutics using MNs. The true potential of MNs as a drug delivery device for biopharmaceuticals will not only rely on acceptance from prescribers, patients and the regulatory authorities, but the ability to upscale MN manufacture in a cost-effective manner and the long term safety of MN application. Thus, the current barriers to clinical translation of MNs, and how these barriers may be overcome are also discussed.

Retinoids regulate a wide spectrum of cellular functions from the embryo throughout adulthood, including cell differentiation, metabolic regulation, and inflammation. These traits make retinoids very attractive molecules for medical purposes. In light of some of the physicochemical limitations of retinoids, the development of drug delivery systems offers several advantages for clinical translation of retinoid-based therapies, including improved solubilization, prolonged circulation, reduced toxicity, sustained release, and improved efficacy. In this Review, we discuss advances in preclinical and clinical tests regarding retinoid formulations, specifically the ones based in natural retinoids, evaluated in the context of regenerative medicine, brain, cancer, skin, and immune diseases. Advantages and limitations of retinoid formulations, as well as prospects to push the field forward, will be presented. Retinoids are involved in a wide range of cellular functions; as such, delivery systems for retinoids are of significant clinical interest. Here the authors review the advances in preclinical and clinical testing regarding retinoid formulations in the context of regenerative medicine, brain, cancer, skin and immune diseases.

Background The treat-to-target (T2T) approach to the care of patients with rheumatoid arthritis involves using validated metrics to measure disease activity, frequent follow-up visits for patients with moderate to high disease activity, and escalation of therapy when patients have inadequate therapeutic response as assessed by standard disease activity scores. The study described is a newly launched cluster-randomized behavioral intervention to assess the feasibility and effectiveness of the T2T approach in US rheumatology practices. It is designed to identify patient and provider barriers to implementing T2T management. This initial paper focuses on the novel study design and methods created to provide these insights. Methods/Design This trial cluster-randomizes rheumatology practices from the existing Corrona network of private and academic sites rather than patients within sites or individual investigators to provide either T2T or usual care (UC) for qualified patients who meet the 2010 revised American College of Rheumatology criteria for the diagnosis of rheumatoid arthritis and have moderate to high disease activity. Specific medication choices are left to the investigator and patient, rather than being specified in the protocol. Enrollment is expected to be completed by the end of 2013, with 30 practices randomized and enrolling a minimum of 530 patients. During the 12-month follow-up, visits are mandated as frequently as monthly in patients with active disease in the T2T group and every 3 months for the UC group. Safety data are collected at each visit. The coprimary endpoints include a comparison of the proportion of patients achieving low disease activity in the T2T and UC groups and assessment of the feasibility of implementing T2T in rheumatology practices, specifically assessment of the rates of treatment acceleration, frequency of visits, time to next visit conditional on disease activity, and probability of acceleration conditional on disease activity in the 2 groups. Discussion This cluster-randomized behavioral intervention study will provide valuable insights on the outcomes and feasibility of employing a T2T treatment approach in clinical practice in the United States. Trial registration NCT01407419

Over the past decade, the drug–target residence time model has been broadly applied to drug discovery programmes across multiple therapeutic areas. To mark the 10 year anniversary of this model, Copeland discusses the benefits of assessing residence time, highlighting some of the advances in its theory and application. The drug–target residence time model was first introduced in 2006 and has been broadly adopted across the chemical biology, biotechnology and pharmaceutical communities. While traditional in vitro methods view drug–target interactions exclusively in terms of equilibrium affinity, the residence time model takes into account the conformational dynamics of target macromolecules that affect drug binding and dissociation. The key tenet of this model is that the lifetime (or residence time) of the binary drug–target complex, and not the binding affinity per se , dictates much of the in vivo pharmacological activity. Here, this model is revisited and key applications of it over the past 10 years are highlighted.

The complement system consists of a network of plasma and membrane proteins that modulate tissue homeostasis and contribute to immune surveillance by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement components contribute to the pathogenesis of some autoimmune neurological disorders and could even contribute to neurodegenerative diseases. In this Review, we summarize current knowledge about the main functions of the complement pathways and the involvement of complement in neurological disorders. We describe the complex network of complement proteins that target muscle, the neuromuscular junction, peripheral nerves, the spinal cord or the brain and discuss the autoimmune mechanisms of complement-mediated myopathies, myasthenia, peripheral neuropathies, neuromyelitis and other CNS disorders. We also consider the emerging role of complement in some neurodegenerative diseases, such as Alzheimer disease, amyotrophic lateral sclerosis and even schizophrenia. Finally, we provide an overview of the latest complement-targeted immunotherapies including monoclonal antibodies, fusion proteins and peptidomimetics that have been approved, that are undergoing phase I–III clinical trials or that show promise for the treatment of neurological conditions that respond poorly to existing immunotherapies.In this Review, Dalakas et al. discuss the complement system, the role it plays in autoimmune neurological disease and neurodegenerative disease, and provide an overview of the latest therapeutics that target complement and that can be used for or have potential in neurological disorders.

The number of new drugs approved per billion US dollars spent on research and development (R&D) has fallen around 80-fold in inflation-adjusted terms since 1950, despite advances in many of the scientific and technological inputs into the R&D process. Given the apparent lack of impact of proposed solutions to declining R&D efficiency so far, Scannell and colleagues ask whether the underlying problems have been correctly diagnosed and discuss factors that they consider to be the primary causes. The past 60 years have seen huge advances in many of the scientific, technological and managerial factors that should tend to raise the efficiency of commercial drug research and development (R&D). Yet the number of new drugs approved per billion US dollars spent on R&D has halved roughly every 9 years since 1950, falling around 80-fold in inflation-adjusted terms. There have been many proposed solutions to the problem of declining R&D efficiency. However, their apparent lack of impact so far and the contrast between improving inputs and declining output in terms of the number of new drugs make it sensible to ask whether the underlying problems have been correctly diagnosed. Here, we discuss four factors that we consider to be primary causes, which we call the 'better than the Beatles' problem; the 'cautious regulator' problem; the 'throw money at it' tendency; and the 'basic research–brute force' bias. Our aim is to provoke a more systematic analysis of the causes of the decline in R&D efficiency.