Blockbuster Drugs Research Articles

Computational approaches to therapeutic antibody design: established methods and emerging trends.

Antibodies are proteins that recognize the molecular surfaces of potentially noxious molecules to mount an adaptive immune response or, in the case of autoimmune diseases, molecules that are part of healthy cells and tissues. Due to their binding versatility, antibodies are currently the largest class of biotherapeutics, with five monoclonal antibodies ranked in the top 10 blockbuster drugs. Computational advances in protein modelling and design can have a tangible impact on antibody-based therapeutic development. Antibody-specific computational protocols currently benefit from an increasing volume of data provided by next generation sequencing and application to related drug modalities based on traditional antibodies, such as nanobodies. Here we present a structured overview of available databases, methods and emerging trends in computational antibody analysis and contextualize them towards the engineering of candidate antibody therapeutics.

Big assets, major risks

Drug services providers began acquiring drug companies’ manufacturing sites 20 years ago as, one by one, big pharma firms pared back in-house production. Acquisitions often appeared to be win-wins: the drugmakers continued to be served by the plants, and contractors got to bring in new customers. But converting large factories, some built to produce one blockbuster drug, to multiclient ventures has proved a huge undertaking. While many service providers have built stable businesses at sites acquired from drug firms, ventures continue to fail when the owners aren’t able to bring in new clients. News 5 years ago that a little-known Chinese company, UniTao Pharmaceuticals, had bought a Boehringer Ingelheim drug plant in Petersburg, Virginia, for $22.5 million raised eyebrows in the pharmaceutical services industry. Few had heard of the company or its parent, Shanghai Tenry Pharmaceutical. But UniTao seemed ready to rescue the 240 jobs the German drugmaker had said

The Influence of a Firm’s Capability and Dyadic Relationship of the Knowledge Base on Ambidextrous Innovation in Biopharmaceutical M&As

In recent years, technological mergers and acquisitions (M&As) have become important strategic tools for enterprises to access and utilize new external knowledge. In particular, in the biopharmaceutical industry, M&A activities are actively being progressed due to an increase in new drug development costs, a decrease in R&D productivity, and the patent expiration of blockbuster drugs. However, there is a lack of research on the integrated view of (1) the acquirer’s capability and (2) the dyadic relationship of the knowledge base between the acquirer and target on the innovation performance of the acquirer. Furthermore, there are few empirical studies on the impact of these factors on ambidextrous innovation; that is, exploitative and explorative innovation. Therefore, with this integrated view in mind, this study analyzed the effect of each factor on the exploitative and exploratory innovation performance of the acquirer. A negative binomial regression was conducted using patent data to measure the innovation outcome of the acquirer after M&A. The findings suggest that (1) the acquisition experience of the acquirer and (2) the technological commonness between the acquirer and the target both had a significant impact on the exploitation and exploration innovation performance.

PastCast: Monoclonal antibodies, from basic science to blockbuster drugs

In the Nature PastCast series, we delve into the archives to tell the stories behind some of Nature’s biggest papers. We delve into the archives to tell the stories behind some of Nature’s biggest papers.

Environmental Effects on the Molecular Mobility of Ranitidine Hydrochloride: Crystalline State versus Drug Loaded into the Silica Matrix

The internal molecular mobility of a blockbuster antiulcer drug, ranitidine hydrochloride, was extensively studied by referring to the most-stable crystalline form (polymorph II) and the form loade...

Fluorine-Containing Drugs Approved by the FDA in 2018.

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine-containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3 , as well as aliphatic (CF2 ) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

Solution versus Crystal Hydration: The Case of γ-Amino Acid Pregabalin

Understanding the link between solution chemistry and nucleation is essential to control crystallization processes, in particular regarding pharmaceutical compounds. In the present work, the link between the solution hydration state and crystallization of the γ-amino acid pregabalin is presented. Pregabalin is a blockbuster pharmaceutical drug having broad therapeutic effects. Using induction time experiments in combination with the classical nucleation theory, we show that the ease of nucleation increases with solubility and water fraction of the solvent. Water was found to enhance both the kinetic and thermodynamic processes of forming a nuclei. As a result, larger clusters which represent the hydrate form were measured using dynamic light scattering in pure water. Once in the solid state, the hydrate form of pregabalin was found to be physically unstable, as it rapidly converted back into its anhydrate form, as rationalized using in-line Raman spectroscopy. Thus, the hydration and nucleation of pregaba...

Open science precision medicine in Canada: Points to consider

Open science can significantly influence the development and translational process of precision medicine in Canada. Precision medicine presents a unique opportunity to improve disease prevention and healthcare, as well as to reduce health-related expenditures. However, the development of precision medicine also brings about economic challenges, such as costly development, high failure rates, and reduced market size in comparison with the traditional blockbuster drug development model. Open science, characterized by principles of open data sharing, fast dissemination of knowledge, cumulative research, and cooperation, presents a unique opportunity to address these economic challenges while also promoting the public good. The Centre of Genomics and Policy at McGill University organized a stakeholders’ workshop in Montreal in March 2018. The workshop entitled “Could Open be the Yellow Brick Road to Precision Medicine?” provided a forum for stakeholders to share experiences and identify common objectives, challenges, and needs to be addressed to promote open science initiatives in precision medicine. The rich presentations and exchanges that took place during the meeting resulted in this consensus paper containing key considerations for open science precision medicine in Canada. Stakeholders would benefit from addressing these considerations as to promote a more coherent and dynamic open science ecosystem for precision medicine.

Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification.

Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting solvent exchanges or intermediate purification. Linezolid was obtained in 73 % isolated yield in a total residence time of 27 minutes, corresponding to a throughput of 816 mg h-1 .

Fungal Bioactive Compounds in Pharmaceutical Research and Development

Background:Exploration of antibiotics from microorganisms became widespread in the academia and the industry with the serendipitous discovery of Penicillin from Penicillium notatum by Sir Alexander Fleming. This embarked the golden era of antibiotics which lasted for over 60 years. However, the traditional phenotypic screening was replaced with more rational and smarter methods of exploration of bioactive compounds from fungi and microorganisms. Fungi have been responsible for providing a variety of bioactive compounds with diverse activities which have been developed into blockbuster drugs such as Cyclosporine, Caspofungin, Lovastatin and Fingolimod etc. It has been reported that ca. 40% of the 1453 New Chemical Entities (NCE’s) approved by USFDA are natural products, natural product inspired or mimics many of which have their origins from fungi. Hence fungal compounds are playing a very important role in drug discovery and development in the pharmaceutical industry.Methods:We undertook structured searches of bibliographic databases of peer-reviewed research literature which pertained to natural products, medicinal chemistry of natural products and drug discovery from fungi. With the strategic improvement in screening and identification methods, fungi are still a potential resource for novel chemistries. Thus the searches also comprised of bioactive agents from fungi isolated or derived from special ecological groups and lineages. To find different molecules derived or isolated from fungi under clinical studies, clinical trial data from the NIH as well as from pharmaceutical companies were also explored. This comprised of data wherein the pharmaceutical industries have acquired or licensed a fungal bioactive compound for clinical study or a trial.Results:Natural product chemistry and medicinal chemistry continue to play an important role in converting a bioactive compound into therapeutic moieties or pharmacophores for new drug development.Conclusion:Thus one can say fungal bioactive compounds are alive and well for development into new drugs as novel ecological groups of fungi as well as novel chemistries are being uncovered. This review further emphasizes the collaboration of fungal biologists with chemists, pharmacologists and biochemists towards the development of newer drugs for taking them into the drug development pipeline.

Navigating around Patented Routes by Preserving Specific Motifs along Computer-Planned Retrosynthetic Pathways

Summary By keeping track of lists of specific bonds one wishes to preserve, a computer program is able to identify the key disconnections used in the patented syntheses and design synthetic routes that circumvent these approaches. Here, we provide examples of computer-designed syntheses relevant to medicinal chemistry, in which the machine avoids “strategic” disconnections common to industrial patents and is forced to use different starting materials. The ability of modern retrosynthetic planners to navigate around patented solutions may have significant implications for the ways in which intellectual property related to multistep syntheses is protected and/or challenged.

Use of bacteriophage for discovery of therapeutically relevant antibodies against infectious diseases

Scientists George P Smith and Gregory Winter were recently awarded half of the 2018 Nobel Prize for Chemistry for developing a technology to display exogenous peptides and proteins on the surface of bacteriophage. ‘Phage display' has revolutionised the development of monoclonal antibodies, allowing fully human-derived antibodies to be isolated from large antibody libraries. It has been used for the discovery of many blockbuster drugs, including Humira (adalimumab), the highest selling drug yearly since 2012, with US$18.4b in sales globally in 20171. Phage display can be used to isolate antibodies to almost any antigen for a wide range of applications including clinical use (for cancer, inflammatory conditions and infectious diseases), diagnostic use or as research tools. The technology is accessible to any laboratory equipped for molecular biology and bacteria culture.

Synthesis of α-Substituted Primary Benzylamines through Copper-Catalyzed Cross-Dehydrogenative Coupling.

A copper-catalyzed route to α-substituted, primary benzylamines by C-H functionalization of alkylarenes is described. The method directly affords the amine hydrochloride salt. Catalyst loadings down to 0.1 mol % in combination with scalability, insensitivity to air and moisture, and no need for column chromatography makes the procedure highly practical. The facile synthesis of the racemate of a blockbuster drug highlights the relevance for the development of pharmaceuticals. Preliminary mechanistic data are also included.

May your drug price be evergreen.

ABSTRACTPresenting the first comprehensive study of evergreening, this article examines the extent to which evergreening behavior—which can be defined as artificially extending the protection cliff—may contribute to the problem. The author analyses all drugs on the market between 2005 and 2015, combing through 60,000 data points to examine every instance in which a company added a new patent or exclusivity. The results show a startling departure from the classic conceptualization of intellectual property protection for pharmaceuticals. Rather than creating new medicines, pharmaceutical companies are largely recycling and repurposing old ones. Specifically, 78% of the drugs associated with new patents were not new drugs, but existing ones, and extending protection is particularly pronounced among blockbuster drugs. Once companies start down the road of extending protection, they show a tendency to return to the well, with the majority adding more than one extension and 50% becoming serial offenders. The problem is growing across time.

Biosimilars Striving for US Uptake

Though biosimilars have to go through an abbreviated regulatory pathway for approval, it is quite challenging given the scientific and technical complexities associated with these products. As an increasing number of biologics face patent expiration, biosimilars offer an attractive opportunity. While companies would be desiring to have a footing in the developed markets like US and EU, considerable opportunities exist in developing/emerging markets. With more number of biosimilars making their commercial foray, starting to gain acceptance across formularies, the leading biologic players have started taking a hit on price, volume and market share of their blockbuster drugs. The pace of sales erosion due to biosimilars is expected to be gradual yet relentless. Since the enactment of Biologics Price Competition and Innovation (BPCI) Act, 12 biosimilars have been approved by the US Food and Drug Administration (FDA) till September 2018. However, only a small percentage have seen the light of the day in terms of commercial launches. These are primarily driven by legal challenges and hesitancy from insurers and healthcare providers. While originators have been trying all the means at their disposal to thwart competition by posing challenges, the biosimilar players are striving to take them head on with the anticipated revenues in mind. Stakeholders have made key recommendations to increase the uptake of biosimilars in US market. Regulatory agencies have to play a key role in promoting confidence in biosimilars among healthcare practitioners and patients. The FDAs much awaited Biosimilars Action Plan (BAP) is expected to revive the sedentary biosimilar market in the US. The medical community, payers, and the FDA should work together for ensuring the approved biosimilars are adopted and prescribed in a manner to bring down overall healthcare costs.

Purity by design: Reducing impurities in bioproduction by stimulus-controlled global translational downregulation of non-product proteins

Capitalizing on the ability of mammalian cells to conduct complex post-translational modifications, most protein therapeutics are currently produced in cell culture systems. Addition of a signal peptide to the product protein enables its accumulation in the cell culture supernatant, but separation of the product from endogenously secreted proteins remains costly and labor-intensive. We considered that global downregulation of translation of non-product proteins would be an efficient strategy to minimize downstream processing requirements. Therefore, taking advantage of the ability of mammalian protein kinase R (PKR) to switch off most cellular translation processes in response to infection by viruses, we fused a caffeine-inducible dimerization domain to the catalytic domain of PKR. Addition of caffeine to this construct results in homodimerization and activation of PKR, effectively rewiring rapid global translational downregulation to the addition of the stimulus in a dose-dependent manner. Then, to protect translation of the target therapeutic, we screened viral and cellular internal ribosomal entry sites (IRESes) known or suspected to be resistant to PKR-induced translational stress. After choosing the best-in-class Seneca valley virus (SVV) IRES, we additionally screened for IRES transactivation factors (ITAFs) as well as for supplementary small molecules to further boost the production titer of the product protein under conditions of global translational downregulation. Importantly, the residual global translation activity of roughly 10% under maximal downregulation is sufficient to maintain cellular viability during a production timeframe of at least five days. Standard industrially used adherent as well as suspension-adapted cell lines transfected with this synthetic biology-inspired Protein Kinase R-Enhanced Protein Production (PREPP) system could produce several medicinally relevant protein therapeutics, such as the blockbuster drug rituximab, in substantial quantities and with significantly higher purity than previous culture technologies. We believe incorporation of such purity-by-design technology in the production process will alleviate downstream processing bottlenecks in future biopharmaceutical manufacturing.

Next-generation flexible formats of VNAR domains expand the drug platform's utility and developability.

Therapeutic mAbs have delivered several blockbuster drugs in oncology and autoimmune inflammatory disease. Revenue for mAbs continues to rise, even in the face of competition from a growing portfolio of biosimilars. Despite this success, there are still limitations associated with the use of mAbs as therapeutic molecules. With a molecular mass of 150 kDa, a two-chain structure and complex glycosylation these challenges include a high cost of goods, limited delivery options, and poor solid tumour penetration. There remains an urgency to create alternatives to antibody scaffolds in a bid to circumvent these limitations, while maintaining or improving the therapeutic success of conventional mAb formats. Smaller, less complex binders, with increased domain valency, multi-specific/paratopic targeting, tuneable serum half-life and low inherent immunogenicity are a few of the characteristics being explored by the next generation of biologic molecules. One novel 'antibody-like' binder that has naturally evolved over 450 million years is the variable new antigen receptor (VNAR) identified as a key component of the adaptive immune system of sharks. At only 11 kDa, these single-domain structures are the smallest IgG-like proteins in the animal kingdom and provide an excellent platform for molecular engineering and biologics drug discovery. VNAR attributes include high affinity for target, ease of expression, stability, solubility, multi-specificity, and increased potential for solid tissue penetration. This review article documents the recent drug developmental milestones achieved for therapeutic VNARs and highlights the first reported evidence of the efficacy of these domains in clinically relevant models of disease.

The impact of policy on the growth of precision medicine

ObjectivesAlthough precision medicine is a rapidly-emerging field in healthcare, its growth for the next few decades depends on a number of scientific and economic factors. Policy will play a major role in addressing these factors. In this study, we dynamically simulated the impact of policies related to the two factors—'knowledge sharing and accumulation’ and ‘reimbursement’—foregrounded in the literature as having the most significant influence on the growth of precision medicine. MethodsTo analyze the impact of specific policies, we used system dynamics methodology. This allowed us to analyze multiple interaction processes, feedback loops, time delays, and other nonlinear effects. ResultsAccording to our results, strengthening the knowledge sharing and accumulation policy greatly contributes to the growth of precision medicine by significantly increasing its market share through a complex route. Conversely, strengthening the reimbursement policy only slightly increases precision medicine's market share and is therefore unable to change an industry based on blockbuster drugs. ConclusionsWe conclude that it is preferable to prioritize and actively implement a knowledge sharing and accumulation policy rather than a reimbursement policy. However, knowledge sharing and accumulation policies must be carefully handled in order to avoid individual privacy issues. To prevent such issues, there must be joint cooperation and efforts not only within one country but also among any related countries. Additionally, although reimbursement funding is often scarce and the policy's effects might be limited, a reimbursement policy is needed throughout the development cycle for drug treatments, devices, and supporting diagnostics.

Sterol inhibitor “Fluconazole” enhance the Taxol yield and molecular expression of its encoding genes cluster from Aspergillus flavipes

Taxol is a blockbuster anticancer drug that commercially synthesized from 10-decaetylbaccatin III intermediate of Taxus baccata, however, this technology has been challenged by reproducibility and association of unwanted compounds. Recently, endophytic fungi with fast growing and feasibility of molecular engineering raise the hope for sustainable production of Taxol, unfortunately the loss of their productivity with multiple subculturing is the main challenge to authenticate this approach industrially. Thus, searching for novel fungal isolates with molecular and metabolic functional stability for Taxol production was the objective of this work. Among the experimented fungal isolates, Aspergillus flavipes, a soil-dwelling saprophyte, gave the highest Taxol yield (185 μg/l). Metabolically, A. flavipes had a strong stability for Taxol production till the 10th subcultures (185-160 μg/l) on the same cultural conditions. The yield of Taxol by A. flavipes was increased by 5 folds (850 μg/ L) with fluconazole (1.0 μg/ml) addition to 5 days old culture. The expression of Taxol biosynthetic genes ts, dbat, bapt and transcriptional factor pbcR was significantly increased by 8–10 folds upon fluconazole addition that correlates with Taxol yield. HSP70 was induced by 13 folds with addition of fluconazole to cultures of A. flavipes. Thus, Taxol biosynthesis could be transcriptionally regulated by pbcR and post-translationally modified by HSP70 chaperones. To the best of knowledge, this is the first report exploring the potency of saprophytic A. flavipes for Taxol production with metabolic stability with multiple subculturing.

How do healthcare professionals working in accountable care organisations understand patient activation and engagement? Qualitative interviews across two time points

ObjectiveIf patient engagement is the new ‘blockbuster drug’ why are we not seeing spectacular effects? Studies have shown that activated patients have improved health outcomes, and patient engagement has become...