Blockbuster Drugs Research Articles

Discovery of the RANKL/RANK/OPG system.

Almost a quarter century has passed since discovery of receptor activator of NF-κB ligand (RANKL). This discovery had a major impact on identification of mechanisms regulating osteoclast differentiation and function, establishment of a research field bridging bone and the immune system (osteoimmunology), and development of a fully human anti-RANKL neutralizing antibody (denosumab). Denosumab is now clinically available for treatment of osteoporosis and cancer-induced bone diseases in the US, Europe and many other countries, including Japan. Denosumab is a so-called blockbuster drug, with sales of 5.0 billion US dollars in 2019. This is a real success story from bench to bedside. In this review, the pivotal roles of the RANKL/RANK/OPG system in osteoclast differentiation and function are shown. RANKL is a ligand required for osteoclast generation, RANK is the receptor for RANKL, and osteoprotegerin (OPG) is a decoy receptor for RANKL. The review covers recent results showing the importance of RANKL on osteoblasts in regulation of osteogenesis and the role of RANKL-RANK dual signaling in coupling of bone resorption and formation, including demonstration of RANKL reverse signaling that we had previously hypothesized. Possible applications of anti-RANKL antibody in treatment of cancer are also discussed.

Fungal natural products galaxy: Biochemistry and molecular genetics toward blockbuster drugs discovery.

Secondary metabolites synthesized by fungi have become a precious source of inspiration for the design of novel drugs. Indeed, fungi are prolific producers of fascinating, diverse, structurally complex, and low-molecular-mass natural products with high therapeutic leads, such as novel antimicrobial compounds, anticancer compounds, immunosuppressive agents, among others. Given that these microorganisms possess the extraordinary capacity to secrete diverse chemical scaffolds, they have been highly exploited by the giant pharma companies to generate small molecules. This has been made possible because the isolation of metabolites from fungal natural sources is feasible and surpasses the organic synthesis of compounds, which otherwise remains a significant bottleneck in the drug discovery process. Here in this comprehensive review, we have discussed recent studies on different fungi (pathogenic, non-pathogenic, commensal, and endophytic/symbiotic) from different habitats (terrestrial and marines), the specialized metabolites they biosynthesize, and the drugs derived from these specialized metabolites. Moreover, we have unveiled the logic behind the biosynthesis of vital chemical scaffolds, such as NRPS, PKS, PKS-NRPS hybrid, RiPPS, terpenoids, indole alkaloids, and their genetic mechanisms. Besides, we have provided a glimpse of the concept behind mycotoxins, virulence factor, and host immune response based on fungal infections.

Improved, gram-scale synthesis of sildenafil in water using arylacetic acid as the acyl source in the pyrazolo[4,3-d]pyrimidin-7-one ring formation

An improved, gram-scale synthesis of the blockbuster drug sildenafil, used for the treatment of male erectile dysfunction, has been developed.

Topological network measures for drug repositioning.

Drug repositioning has received increased attention since the past decade as several blockbuster drugs have come out of repositioning. Computational approaches are significantly contributing to these efforts, of which, network-based methods play a key role. Various structural (topological) network measures have thereby contributed to uncovering unintuitive functional relationships and repositioning candidates in drug-disease and other networks. This review gives a broad overview of the topic, and offers perspectives on the application of topological measures for network analysis. It also discusses unexplored measures, and draws attention to a wider scope of application efforts, especially in drug repositioning.

Research on Pharmaceutical Product Life Cycle Patterns for Sustainable Growth

An important agenda of pharmaceutical companies is the establishment of therapeutic area strategies, drug modality, and geographic strategies for research and development. It is worthwhile to understand the changes in therapeutic area, modality and internationalization of the top-selling pharmaceutical drugs over the past. Hence, the purposes of this study are to investigate changes in therapeutic area, modality and internationalization of the top-selling drugs and to identify their life cycle patterns. We compared the top-selling drugs between 2011 and 2017, and found that the percentages of nichebuster cancer drugs and home region-oriented drugs have increased whereas the proportions of traditional blockbuster cardiovascular drugs and global drugs have decreased. We compared product life cycle patterns via a Kruskal–Wallis test, and identified the features of product life cycle patterns per therapeutic area and modality. We performed a case study on drugs in the same class with the same pharmacological mechanism but found no differences across cases. Our results provide insights into therapeutic area strategies that consider life cycle patterns and geographic strategies that consider the competitive advantages of home region-oriented drugs. Finally, we presented new and simple models of life cycle patterns. This approach may help such enterprises establish and maintain sustainable growth.

Optimizing the biosynthesis of oxygenated and acetylated Taxol precursors in Saccharomyces cerevisiae using advanced bioprocessing strategies.

Taxadien-5α-hydroxylase and taxadien-5α-ol O-acetyltransferase catalyze the oxidation of taxadiene to taxadien-5α-ol and subsequent acetylation to taxadien-5α-yl-acetate in the biosynthesis of the blockbuster anticancer drug, paclitaxel (Taxol®). Despite decades of research, the promiscuous and multispecific CYP725A4 enzyme remains a major bottleneck in microbial biosynthetic pathway development. In this study, an interdisciplinary approach was applied for the construction and optimization of the early pathway in Saccharomyces cerevisiae, across a range of bioreactor scales. High-throughput microscale optimization enhanced total oxygenated taxane titer to 39.0 ± 5.7 mg/L and total taxane product titers were comparable at micro and minibioreactor scale at 95.4 ± 18.0 and 98.9 mg/L, respectively. The introduction of pH control successfully mitigated a reduction of oxygenated taxane production, enhancing the potential taxadien-5α-ol isomer titer to 19.2 mg/L, comparable with the 23.8 ± 3.7 mg/L achieved at microscale. A combination of bioprocess optimization and increased gas chromatography-mass spectrometry resolution at 1 L bioreactor scale facilitated taxadien-5α-yl-acetate detection with a final titer of 3.7 mg/L. Total oxygenated taxane titers were improved 2.7-fold at this scale to 78 mg/L, the highest reported titer in yeast. Critical parameters affecting the productivity of the engineered strain were identified across a range of scales, providing a foundation for the development of robust integrated bioprocess control systems.

Are We Dropping the Crystal Ball? Understanding Nascent & Potential Competition in Antitrust

We root for the underdog, and nascent and potential competitors are the antitrust version of underdogs. They introduce a promising product and innovation with the hopes of challenging the incumbent for supremacy in a market. Yet, are those hopes cancelled before they even begin with powerful incumbents acquiring these nascent and potential competitors? Some even refer to these acquisitions as “killer.” However, is this the full story? Assessments of nascent and potential competition are ultimately about “what if.” What if the upstart competitor grows into the next dominant platform or develops the next blockbuster drug? What if the incumbent knows its market position has a weakness that the entrant will exploit so the incumbent must end the competition before it even begins? On the other hand, what if the nascent competitor never fully develops its potential and engages in a series of missteps? What if the nascent competitor’s innovation can be improved upon and reach the market faster and more widely through the well-oiled machinery of the incumbent? These are all possible scenarios. The problem is that the counterfactual world is never actually observable. Thus, speculative “what ifs” cannot guide antitrust policy—whether in an overly permissive or aggressive manner. What are we left with? What should agencies and courts do in face of such uncertainty? This Article offers a number of propositions to address these concerns and questions in regard to competition that has not been fully realized. First, the Article offers a clear legal and analytical delineation between the doctrines of nascent and potential competition—as there has recently been a degree of “semantic satiation” between these two concepts. Second, some have argued that the acquisition of nascent competitors should be adjudicated using legal standards developed under the Sherman Act, Section 2, which covers monopolization, rather than under the traditional Clayton Act, Section 7, which governs mergers and acquisitions. Yet, the counterfactual exercise is fundamentally different between ex ante merger evaluations (Section 7) and ex post monopolization claims (Section 2). Consequently, based on this fact alone, courts should be cautious to adopt Section 2 approaches to Section 7 issues. Third, when evaluating the wider set of proposals to address the nascent and potential competition problem, which the Article comments on, we must ask whether there is a problem in the first place. To that end, the Article examines a number of recent merger retrospectives. Finally, while using the past to predict the future can be a difficult and uncertain exercise even within mature markets, these hinderances can be overstated. Economic tools are available to frame our approach, and agencies and courts should focus particularly on whether the characteristics and nature of the acquired nascent competitor are sufficiently differentiated from the remaining competitors to warrant increased scrutiny.

Impact of the Medicare Part D Coverage Gap Closure and Generic Entry on Medication Use

The Affordable Care Act included a provision to eliminate the Medicare prescription drug coverage gap. The policy was phased in by gradually diminishing the gap each year between 2011-2020. This provides a natural experiment to conduct an in-depth study of how the policy affected medication use, which has implications for other benefit designs that vary cost sharing throughout the year. Using 2007-2016 Medicare claims data, we estimate the effects of closing-the-gap policy with a difference-in-differences approach that compares changes in medication use before and after policy between non-subsidized beneficiaries and a subset of Medicare beneficiaries who have not been affected by the policy. To account for the gradual phase-in of policy changes and possible learning effects, we examine the dynamic effects using an event study difference-in-differences model. Importantly, around the same time as the coverage gap closure, several blockbuster drugs that are commonly used by the Medicare population experienced patent expiration and began to see generic entry. To isolate the effect of coverage gap closure from patent expirations, we further use monthly prescription drug event data to more accurately track initial generic entry by therapeutic class. We find that filling the gap significantly reduced individuals’ out-of-pocket spending on branded drugs and increased the number of prescriptions filled for branded drugs. Consistent with the policy design, people who fell in the gap, were at older ages, or had coexisting chronic conditions saw a larger reduction in the amount they paid for prescription drugs. Without controlling for generic entry, the effect of the policy on utilization is underestimated for branded drugs and overestimated for generic drugs.

Overcoming inefficiencies in the development of personalized medicine

The pharmaceutical industry faces a radical change in its business model. Whereas one-size-fits-all blockbuster drugs dominated in the past, today technological breakthroughs like the decoding of the human genome allow pharmaceutical firms to develop more customized products. This so-called personalized medicine can only work if a product tandem of specialized drug and companion diagnostic test exists, making new product development processes interdependent. We consider a pharmaceutical firm and a diagnostic firm that develop such a product tandem for personalized medicine. We show that the dependence on each other and the diagnostic firm’s option to postpone R&D activities lead to systematic inefficiencies in the development of personalized medicine. In practice, revenue-sharing and cost-sharing contracts are used to address such inefficiencies by better balancing and aligning the financial interests of drug and diagnostic manufacturers. We show that simple revenue-sharing and cost-sharing contracts can often, but not always, solve problems related to postponed or reduced investment, and we characterize settings where the pharmaceutical firm prefers revenue sharing over cost sharing. To account for different existing market structures, we compare the pharmaceutical firm’s contract preferences under regulated and free pharmaceutical pricing.

Indian Pharma—Some Challenges and Acceptances

Business enterprises are an important organ of society. The impact of a business enterprise’s motive will directly affect society, which includes environment, consumers, employees, suppliers, and other stakeholders. Big pharma companies face a huge drop in revenue from blockbuster drugs coming off patent. Without generating revenues through sales, these companies will struggle to fund the development of new life-saving drugs. Artificial intelligence (AI) can be a powerful tool in the pharmaceutical industry’s research and development. So with the help of modern technologies, pharmaceutical companies should aim for quality but cheap products for common people and serve society better.

Market Exclusivity for Drugs with Multiple Orphan Approvals (1983-2017) and Associated Budget Impact in the US.

The Orphan Drug Act extends exclusivity of branded drugs by 7years for each rare disease approval. By extending market exclusivity, manufacturers can forestall generic competition. We determined the prevalence of drugs with multiple orphan approvals, the duration for which manufacturers are able to maintain exclusivity using this mechanism, and the budget impact of these additional exclusivity periods on US spending on orphan drugs. We analyzed a retrospective cohort of US orphan drug approvals filed between 1983 and 2017. Drug costs throughout this time period were measured using IQVIA claims data. We estimated additional years of exclusivity per drug per orphan approval using mixed-effects negative binomial regression. The budget impact analyzed potential cost-savings for exclusivity periods greater than 7years after the initial orphan approval based on potential price reductions from the introduction of biosimilar/generic competition. A total of 432 branded drugs were approved for 615 orphan indications, of which 108 had multiple indications. Market exclusivity, beyond the initial 7years, increased by 4.7years with two orphan approvals, and there were 3.1-, 2.7-, and 2.9-year extensions for three, four, and five approvals, respectively (p < 0.05). Drugs with five approvals averaged 13.4 additional years of exclusivity. Sixteen drugs had exclusivity periods extending at least 1 decade beyond the original exclusivity period. The potential budget impact of additional exclusivity was estimated at US$591 billion for 7years following the end of the first approval. Multiple blockbuster drugs have received exclusivity of > 10years through the Orphan Drug Act, thereby delaying rare disease cohorts' access to generic/biosimilar equivalents.

Developing blockbuster drugs: both nature and nurture.

Developing blockbuster drugs: both nature and nurture.

A Bio-logical Approach to Catalysis in the Pharmaceutical Industry.

Enzymes have the potential to catalyse complex chemical reactions with unprecedented selectivity, under mild conditions in aqueous media. Accordingly, there is serious interest from the pharmaceutical industry to utilize enzymes as biocatalysts to produce medicines in an environmentally sustainable and economic manner. Prominent advances in the field of biotechnology have transformed this potential into a reality. Using modern protein engineering techniques, in a matter of months it is possible to evolve an enzyme, which fits the demands of a chemical process, or even to catalyse entirely novel chemistry. Consequently, biocatalysis is routinely applied throughout the pharmaceutical industry for a variety of applications, ranging from the manufacture of large volumes of high value blockbuster drugs to expanding the chemical space available for drug discovery.

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

Hypertension is a diverse illness interlinked with cerebral, cardiovascular (CVS) and renal abnormalities. Presently, the malady is being treated by focusing on Renin- angiotensin system (RAS), voltage-gated calcium channels, peripheral vasodilators, renal and sympathetic nervous systems. Cardiovascular and renal abnormalities are associated with the overactivation of RAS, which can be constrained by angiotensin- converting enzyme inhibitors (ACEIs), angiotensin II (Ang-II) -AT1 receptor blockers (ARBs) and renin inhibitors. The latter is a new player in the old system. The renin catalyzes the conversion of angiotensinogen to Angiotensin I (Ang-I). This can be overcome by inhibiting renin, a preliminary step, eventually hinders the occurrence of the cascade of events in the RAS. Various peptidomimetics, the first-generation renin inhibitors developed six decades ago have limited drug-like properties as they suffered from poor intestinal absorption, high liver first-pass metabolism and low oral bioavailability. The development of chemically diverse molecules from peptides to nonpeptides expanded the horizon to achieving direct renin inhibition. Aliskiren, a blockbuster drug that emerged as a clinical candidate and got approved by the US FDA in 2007 was developed by molecular modeling studies. Aliskiren indicated superior to average efficacy and with minor adverse effects relative to other RAS inhibitors. However, its therapeutic use is limited by poor oral bioavailability of less than 2% that is similar to first-generation peptidic compounds. In this review, we present the development of direct renin inhibitors (DRIs) from peptidic to nonpeptidics that lead to the birth of aliskiren, its place in the treatment of cardiovascular diseases and its limitations.

Marketing and Pricing Strategies of Blockbuster Drugs in the South Korean Market: A 15-Year Retrospective Cohort Study for Choline Alfoscerate.

IntroductionUnderstanding marketing strategies and price competition among manufacturers is essential to manage health care expenditures, particularly those related to blockbuster drugs.ObjectivesTo assess marketing and pricing strategies of blockbuster drugs in South Korea.MethodsBaseline information on manufacturers who were granted marketing approval for choline alfoscerate in various forms was retrieved. Accumulation of manufacturers in the market was also identified, and manufacturers were categorized into first movers and latecomers based on their marketing time. Then, an event history analysis and a regression analysis were applied to estimate the duration of marketing and their price competition.ResultsCurrently, 109, 83, and 26 manufacturers produce choline alfoscerate in capsule, tablet, or syrup form, respectively, indicating that many manufacturers have marketed generics and the majority of the generics are categorized as latecomers. The size of the manufacturer was a significant factor in marketing new medicines, while the variable was not related to the marketing of modified drugs. Furthermore, price competition in the market was rare and only a few major firms initiated price competition.ConclusionThe Korean market appears to be an example of perfect competition when we focus on the number of manufacturers. However, the market is near-monopolistic when examining the price of generic drugs. While product competition between different forms of drugs is effective in lowering price, product competition within the same form of a drug does not exist in the market.

Recent Advances of Pharmaceutical Process Chemistry and Its Innovation in China: Part 1

AbstractThis review article summarizes recent developments and innovations in China's pharmaceutical process chemistry over the last several decades. Case studies of dozens of blockbuster drug processes are presented, including bulk drugs, such as the over-the-counter medicine biotin, demonstrating China's substantial effort to green its pharmaceutical processes. Owing to the increasing stringent environmental regulations, Chinese chemists have invented several cutting-edge and eco-friendly synthetic methods that are beneficial to environmental protection. Applied to large-scale industrial production, these processes have a greatly reduced environmental footprint, promoting the sustainable development of global economy and health.

Combination of multicomponent KA2 and Pauson-Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones.

The Cu-catalyzed multicomponent ketone–amine–alkyne (KA2) reaction was combined with a Pauson–Khand cycloaddition to give access of unprecedented constrained spirocyclic pyrrolocyclopentenone derivatives following a DOS couple-pair approach. The polyfunctional molecular scaffolds were tested on the cyclopentenone reactivity to further expand the skeletal diversity, demonstrating the utility of this combined approach in generating novel spiro compounds as starting material for the generation of chemical libraries. The chemoinformatics characterization of the newly-synthesized molecules gave evidence about structural and physicochemical properties with respect to a set of blockbuster drugs, and showed that such scaffolds are drug-like but more spherical and three-dimensional in character than the drugs.

Insight into Biosimilars: Short Description, Analytical Assessment and Market

The World Health Organization (WHO) defines a similar biotherapeutic product, i.e. a biosimilar as a biotherapeutic product that is similar in terms of quality, safety and efficacy to an already licensed reference product on the market (termed as originator or innovator). To ensure similar efficacy and safety, comparability studies for biosimilars should be carried out at quality, preclinical and clinical level.Glycosylation profiles of biosimilars are getting an additional critical quality attribute. The portfolio required for regulatory comparison of identity and release testing has to be assessed with a large number of analytical tests, which are presented here in detail for the example of adalimumab.Adalimumab, as one of the blockbuster drugs and the best-sellingpharmaceutical product world-wide, is analyzed additionally with a competitive field presenting the marketed products or such in development. This competitive field is not surprisingly very crowded. Furthermore, general information about the currently marketed biosimilars includingModeofAction (MoA), clinical indication(s), patent situation, and market situation are shortly summarized for each of the respective originator/biosimilar molecules.As there are not only markets in developed and highly regulated countries, but also in other regions, examples for companies and products in Asia, South and Middle America, and even in Africa are highlighted as well.

Co-pay cards in Canada: Improving choice or institutionalizing bribes?

[See related article at [www.cmaj.ca/lookup/doi/10.1503/cmaj.190098][2]][2] KEY POINTS Between 2010 and 2015, many patents for blockbuster drugs expired, and pharmaceutical companies were faced with competition from the makers of generic versions (“generics”). It was called the “patent cliff

Conceptual frameworks and degrees of patient engagement in the planning and designing of health services: A scoping review of qualitative studies

Increasingly, patients are being recognized as essential partners in the solutions to healthcare system problems. Patient engagement has been referred to as the “holy grail” and next “blockbuster drug” of health care because it may be revolutionary for transforming the design, delivery, and responsiveness of health services. Patients engage in a variety of healthcare activities, and there are multiple frameworks that depict the degrees of patient engagement in these activities. The literature also uses a variety of terms and concepts to depict the degrees of patient engagement. Moreover, meaningful patient engagement is a concept widely utilized in the literature without a clear definition. The conceptual boundaries and differences between degrees of engagement are unclear. This scoping review summarizes the descriptive characteristics, the degrees of engagement, and examines the terms used to depict meaningful engagement as conceptualized by studies on planning and designing of administrative or health services and interventions. The research questions for this study are: What are the descriptive and study characteristics of studies where patients engage in planning and designing activities? What terms do studies use to depict meaningful patient engagement? This review found a variety of terms used by the literature to depict meaningful engagement: collaboration, cooperation, co-production, active involvement, partnership, and consumer and peer leadership. This review also found that studies seldom use patient engagement frameworks to identify the degree of engagement. The implications of these findings are discussed in light of the literature on patient engagement and recommendations for future practice are provided.