Top-selling Drugs Research Articles

Introduction of the Trifluoropropionate Moiety into Aromatic Rings via Rhodium-Catalyzed Coupling of Arylboronic Acids with Diazoesters.

A catalytic method for the introduction of pharmaceutically meaningful fluorinated propionic acid side chains into aromatic compounds is presented. In the presence of rhodium catalyst [RhCp*Cl2]2, various arylboronic acids are efficiently coupled with an easy-to-access diazoester reagent to give perfluorinated derivatives of phenylpropionic acids, including top-selling profen drugs. The key advantage of this approach is that the pharmacophore is introduced as a whole and is compatible with various functionalities and drug discovery.

Patent Portfolios Protecting 10 Top-Selling Prescription Drugs

Brand-name drugs are sold at high prices in the US during market exclusivity periods protected by patents. Multiple overlapping patents protecting a drug are known as patent thickets and can effectively delay the emergence of price-lowering generic competition for many years. To evaluate the composition of patent thickets of 10 top-selling prescription drugs in the US and compare the characteristics of drug patents filed during development with those filed on these products after US Food and Drug Administration (FDA) approval. This cross-sectional study examined US patent thickets of the 10 prescription drugs with the highest US net sales revenue in 2021 using information on issued patents and patent applications as of June 30, 2022, obtained from a public database by the Initiative for Medicines, Access, and Knowledge. Data were analyzed from September 2022 to June 2023. Prevalence of patents filed before and after FDA approval; types of claims present in issued patents (ie, chemical composition, method of use, process or synthesis, formulation, and delivery device); and patent thicket density (number of active patents at a given time). The 10 top-selling prescription drugs in the US for 2021 included 4 small-molecule drugs and 6 biologics. These 10 drugs were linked to 1429 patents and patent applications: 742 (52%) issued patents, 218 (15%) pending applications, and 469 (33%) abandoned applications. Almost three-quarters of patent applications (1028 [72%]) were filed after FDA approval. The postapproval proportion was higher for biologics (80%) than for small-molecule drugs (58%). Postapproval filing of patent applications peaked in the first 5 years after FDA approval for small-molecule drugs and 12 years after FDA approval for biologics. Of 465 patents issued for applications filed after FDA approval, 189 (41%) had method of use claims, 127 (27%) had formulation claims, and 103 (22%) had process or synthesis claims, while 86 (19%) had chemical composition claims and 46 (10%) had device claims. Patent thicket density peaked 13 years after FDA approval, at which time these 10 drugs were protected by a median (IQR) of 42 (18-83) active patents, 66% of which were filed after FDA approval. This study found that among the 10 top-selling prescription drugs in the US in 2021, patents filed after FDA approval and containing claims covering aspects other than the active ingredient of the drug contributed to patent thickets. Scrutiny of patent applications and of patents filed after FDA approval is needed to facilitate timely generic or biosimilar competition.

The use of tracker technologies on branded prescription drug websites: privacy, data acquisition and programmatic advertising

PurposeThe purpose of this study was to examine consumer data acquired by branded prescription drug websites and the ethics of privacy related to the interconnected web of personal information accessed, packaged and resold by tracker technologies.Design/methodology/approachThe research used the DMI Tracker Tool to collect data on the top 17 branded prescription drug websites, with a specific interest in the tracker technologies embedded in those websites. That data was analyzed using Gephi, an open-source data visualization tool, to map the network of trackers embedded in those branded prescription drug websites.FindingsFindings visualize the interconnections between tracker technologies and prescription drug websites that undergird a system of personal data acquisition and programmatic advertising vehicles that serve the interests of prescription drug marketers and Big Tech. Based on the theory of platform ethics, the study demonstrated the presence of a technostructural ecosystem dominated by Big Tech, a system that goes unseen by consumers and serves the interests of advertisers and resellers of consumer data.Research limitations/implicationsThe 17 websites used in this study were limited to the top-selling prescription drugs or those with the highest ad expenditures. As such this study is not based on a random sampling of branded prescription drug websites. The popularity of these prescription drugs or the expanse of advertising associated with the drugs makes them appropriate to study the presence of tracking devices that collect data from consumers and serve advertising to them. It is also noted that websites are dynamic spaces, and some trackers within their infrastructures are apt to change over time.Practical implicationsBranded prescription drug information has over the past three decades become part of consumers’ routine search for information regarding what ails them. As drug promotion moved from print to TV and the Web, searching for drug information has become a part of everyday life. The implications of embedded trackers on branded prescription drug websites are the subject of this research.Social implicationsThis study has significant social implications as consumers who are searching for information regarding prescription medications may not want drug companies tracking them in a way that many perceive to be an invasion of privacy. Yet, as the Web is dominated by Big Tech, web developers have little choice but to remain a part of this technostructural ecosystem.Originality/valueThis study sheds light on branded prescription drug websites, exploring the imbalance between the websites under study, Big Tech and consumers who lack awareness of the system that operates backstage.

Medicare price negotiation and pharmaceutical innovation following the Inflation Reduction Act.

The Inflation Reduction Act (IRA) requires Medicare to negotiate lower prices for some medicines with high Medicare spending. Using historical data from public and proprietary sources to apply the IRA's negotiation criteria retrospectively, we identify all drugs that met the eligibility criteria from 2012 to 2021 to classify drugs that would have had a negotiated price in effect in 2022 and to calculate associated decreases in industry revenues. Our results suggest that the IRA's reduction in overall industry revenue will be modest, will not affect most top-selling drugs and will not likely result in large-scale defunding of research and development. Changes in the net present value of drug-development projects will be concentrated in medicines where Medicare is a notable purchaser and where the ratio between expected revenue and development costs was only marginally positive before the IRA. Policymakers considering narrowing or expanding the scope of Medicare negotiation should carefully consider the tradeoffs across medicines with diverse characteristics.

Prescription drug spending by payer: Implications for managed care

BackgroundBrand-name prescription drugs are an important driver of prescription drug spending, but different payers may bear these costs differentially necessitating different policy goals for each payer. But little is known about how the top 10 selling drugs in the U.S. impact spending across payers. ObjectiveTo estimate the differential spending burden of top prescription drugs on Medicaid, Medicare, commercial coverage, and out-of-pocket (OOP) spending. MethodsThe percentage of total prescription drug spending, total spending, total prescriptions, and average cost per prescription overall and for each of the following payers – Medicaid, Medicare, private insurance, and OOP – was calculated for each of the top 10 selling prescription drugs using 2017–2019 Medical Expenditure Panel Survey data. ResultsThese 10 prescription drugs accounted for average annual spending of $83.4 billion and 19.0% of all prescription drug spending. Medicare tended to contribute the highest fraction of spending. The average annual cost per prescription ranged from $500 for Advair to $7400 for Tecfidera. Significant variation in the average annual number of prescriptions filled was observed, ranging from 1.4 million for Tecfidera to 13.6 million for Lantus. ConclusionsThe findings highlight the significant impact of the top 10 selling prescription drugs on U.S. prescription drug spending. The wide variation in per prescription cost as well as contribution to each payer's prescription drug burden emphasizes how policies targeting top-selling drugs may differentially impact payers as well as how payer-specific policies may differ substantially even for top selling drugs.

Orphan Drug Label Expansions: Analysis Of Subsequent Rare And Common Indication Approvals.

The Orphan Drug Act of 1983 was enacted to provide financial incentives to stimulate drug development for rare diseases. In recent years, concerns have been raised regarding these orphan drugs, including how many are being approved for both rare and common diseases and the number of subsequent indication approvals. Policy makers have suggested modifications to the Orphan Drug Act's incentives to address these concerns. In this study we investigated the approval "family trees" of orphan drugs. We found that 491 novel orphan drugs were approved between 1990 and 2022. To date, 65percent have been approved for a single rare disease, 15percent have been approved for multiple rare diseases, and 20percent have been approved for both rare and common diseases. Ten percent of orphan drugs received a subsequent indication approval for a pediatric population of an orphan disease. Revenue estimates from 2021 show that one-third of the drugs approved for both rare and common indications and 6percent of rare-only drugs were among the 200 top-selling drugs worldwide. The results have implications for the possible externalities of modifying the incentives of the Orphan Drug Act, such as a potential decrease in the initiation of programs to develop pediatric rare disease drugs.

Enantioselective Synthesis of Arylglycines via Pd-Catalyzed Coupling of Schöllkopf Bis-Lactim Ethers with Aryl Chlorides.

Arylglycines are important pharmacophores present in several top-selling drugs. This compound class has now been made accessible from abundant aryl chlorides by a Pd-catalyzed Schöllkopf-type amino acid synthesis. In the presence of the catalyst methylnaphthyl(XPhos)-palladium bromide, the base lithium 2,2,6,6-tetramethylpyrrolidide and the additive ZnCl2 , tert-leucine-derived bis-lactim ethers were efficiently arylated at room temperature, reaching yields of 95 % and diastereoselectivities of 98 : 2. Hydrolysis gave the corresponding arylglycines in high enantiomeric excess.

Spending on and Use of Clinician-Administered Drugs in Medicare

Medicare Part B drug expenditures have increased in recent years. This trend is likely to persist given the increased use and availability of biologics. To assess the extent to which Medicare Part B spending growth was associated with changes in price vs quantity, and how these trends interacted with entry of new drugs into the marketplace. This cross-sectional study quantified the degree of spending concentration and the association between price and use of Part B drugs among fee-for-service Medicare beneficiaries. Data on use and spending for separately payable Part B drugs were included. Source data were aggregated to the drug-year level and reported from 2016 to 2020. Descriptive decomposition and index analyses quantified the relative association of price and use changes separately for existing single-source drugs, existing drugs that faced competition, and new drugs that entered the market. Data analysis was performed from June to December 2022. Part B drug spending by the fee-for-service Medicare program and beneficiaries, as well as use, defined as dosage units and beneficiaries using the drugs. The study included 535 unique Part B drug products. From 2016 to 2020, 15 or fewer products comprised half of all Part B drug expenditures. The set of 7 drugs that comprised the top 25% of spending was very consistent over time, and all were biologics. Part B drug products that cost $1.85 or less per administration accounted for more than half of the doses administered in 2020. Spending on Part B drugs increased by $15 billion from 2016 to 2020. The entry of new, nonbiosimilar drugs during this period accounted for $12 billion of this increased spending (80%), while shifts in use and price increases among existing single-source brand drugs accounted for the remaining increase in spending. Part B spending decreased among the subset of existing drugs facing generic or biosimilar competition. Among single-source drugs on the market in 2016, the index that varied dosage units exceeded the index that varied price in all years, confirming that changes in use were associated more with spending growth for those drugs. In this cross-sectional study of Medicare Part B drug expenditures, spending was found to be concentrated among a small number of drugs. The entry of new products was a key factor associated with recent increases in Part B drug spending. These findings suggest that policies targeting top-selling drugs may have greater potential to curb Part B drug spending than those targeting price growth.

Estimated Savings From Using Added Therapeutic Benefit and Therapeutic Reference Pricing in United States Medicare Drug Price Negotiations

ObjectivesUS Medicare will begin negotiating prices for top-selling drugs in 2023. This study describes and estimates potential savings from a therapeutic reference pricing approach, linking comparative effectiveness with the costs of existing therapeutic alternatives, that Medicare could use to adjust the starting point for price negotiations. MethodsFirst, we identified target drugs likely to be selected for Medicare negotiation. Second, we identified comparative effectiveness ratings for target drugs based on French Haute Autorité de Santé reports. For target drugs with minor or no added benefit, we identified therapeutic alternatives based on the French reports and US clinical guidelines. For each target drug with minor or no added benefit, we computed the difference between spending based on the drug’s estimated statutory ceiling price and spending based on the weighted average cost of therapeutic alternatives or the lowest cost therapeutic alternative. Finally, we calculated potential annual savings from using a starting point in negotiations based on costs of therapeutic alternatives. ResultsPotential drug-level savings to Medicare from using a starting point in negotiations based on average spending across therapeutic alternatives, compared with using the statutory ceiling price alone, ranged from $186 541 340 to $2 173 441 197. Potential savings from using a starting point based on the lowest cost alternative ranged from $199 872 163 to $3 605 904 765. ConclusionsAlthough we do not expect Medicare to rely on French comparative effectiveness assessments, this study demonstrates the potential for additional savings when using comparative effectiveness and costs of therapeutic alternatives to inform the starting price for negotiations.

Photo-Induced C1 Substitution Using Methanol as a C1 Source.

The development of sustainable and efficient C1 substitution methods is of central interest for organic synthesis and pharmaceuticals production, the methylation motifs bound to a carbon, nitrogen, or oxygen atom widely exist in natural products and top-selling drugs. In the past decades, a number of methods involving green and inexpensive methanol have already been disclosed to replace industrial hazardous and waste-generating C1 source. Among the various efforts, photochemical strategy is considered as a "renewable" alternative that shows great potential to selectively activate methanol to achieve a series of C1 substitutions at mild conditions, typically C/N-methylation, methoxylation, hydroxymethylation, and formylation. Herein the recent advances in selective transformation of methanol to various C1 functional groups via well-designed photochemical systems involving different types of catalysts or not is systematically reviewed. Both the mechanism and corresponding photocatalytic system were discussed and classified on specific methanol activation models. Finally, the major challenges and perspectives are proposed.

Added Therapeutic Benefit of Top-Selling Brand-name Drugs in Medicare

The Inflation Reduction Act of 2022 authorizes Medicare to negotiate prices of top-selling drugs based on several factors, including therapeutic benefit compared with existing treatment options. To determine the added therapeutic benefit of the 50 top-selling brand-name drugs in Medicare in 2020, as assessed by health technology assessment (HTA) organizations in Canada, France, and Germany. In this cross-sectional study, publicly available therapeutic benefit ratings, US Food and Drug Administration documents, and the Medicare Part B and Part D prescription drug spending dashboards were used to determine the 50 top-selling single-source drugs used in Medicare in 2020 and to assess their added therapeutic benefit ratings through 2021. Ratings from HTA bodies in Canada, France, and Germany were categorized as high (moderate or greater) or low (minor or no) added benefit. Each drug was rated based on its most favorable rating across countries, indications, subpopulations, and dosage forms. We compared the use and prerebate and postrebate (ie, net) Medicare spending between drugs with high vs low added benefit. Forty-nine drugs (98%) received an HTA rating by at least 1 country; 22 of 36 drugs (61%) received a low added benefit rating in Canada, 34 of 47 in France (72%), and 17 of 29 in Germany (59%). Across countries, 27 drugs (55%) had a low added therapeutic rating, accounting for $19.3 billion in annual estimated net spending, or 35% of Medicare net spending on the 50 top-selling single-source drugs and 11% of total Medicare net prescription drug spending in 2020. Compared with those with high added benefit, drugs with a low added therapeutic rating were used by more Medicare beneficiaries (median 387 149 vs 44 869) and had lower net spending per beneficiary (median $992 vs $32 287). Many top-selling Medicare drugs received low added benefit ratings by the national HTA organizations of Canada, France, and Germany. When negotiating prices for these drugs, Medicare should ensure they are not priced higher than reasonable therapeutic alternatives.

Global Analysis of Aggregation Profiles of Three Kinds of Immuno-Oncology mAb Drug Products Using Flow Cytometry.

Accurately quantifying the protein particles in both subvisible (1-100 μm) and submicron (≤1 μm) ranges remains a prominent challenge in the development and manufacturing of protein drugs. Due to the limitation of the sensitivity, resolution, or quantification level of various measurement systems, some instruments may not provide count information, while others can only count particles in a limited size range. Moreover, the reported concentrations of protein particles commonly have significant discrepancies owing to different methodological dynamic ranges and the detection efficiency of these analytical tools. Therefore, it is extremely difficult to accurately and comparably quantify protein particles within the desired size range at one time. To develop an efficient protein aggregation measurement method that can span the entire range of interest, we established, in this study, a single particle-sizing/counting method based on our highly sensitive lab-built flow cytometry (FCM) system. The performance of this method was assessed, and its capability of identifying and counting microspheres between 0.2 and 25 μm was demonstrated. It was also used to characterize and quantify both subvisible and submicron particles in three kinds of top-selling immuno-oncology antibody drugs and their lab-produced counterparts. These assessment and measurement results suggest that there may be a role for an enhanced FCM system as an efficient investigative tool for characterizing and learning the molecular aggregation behavior, stability, or safety risk of protein products.

Association Between Drug Characteristics and Manufacturer Spending on Direct-to-Consumer Advertising

Some drugs are heavily marketed through direct-to-consumer advertising. To identify drug characteristics associated with a greater share of promotional spending on advertising directly to consumers. Exploratory cross-sectional analysis of drug characteristics and promotional spending for the 150 top-selling branded prescription drugs in the US in 2020 as identified from IQVIA National Sales Perspectives data. Promotional spending data were provided by IQVIA ChannelDynamics. Drug characteristics (total 2020 sales; total 2020 promotional spending; clinical benefit ratings; number of indications, off-label use; molecule type; nature of condition treated; administration type; generic availability; US Food and Drug Administration [FDA] approval year, World Health Organization anatomical therapeutic chemical classification; Medicare annual mean spending per beneficiary; percent sales attributable to the drug; market size; market competitiveness) assessed from health technology assessment agencies (France's Haute Autorité de Santé and Canada's Patented Medicine Prices Review Board) and drug data sources (Drugs@FDA, the FDA Purple Book, Lexicomp, Merative Marketscan Research Databases, and Medicare Spending by Drug data). Proportion of total promotional spending allocated to direct-to-consumer-advertising for each drug. The 2020 median proportion of promotional spending allocated to direct-to-consumer advertising was 13.5% (IQR, 1.96%-36.6%); median promotional spending, $20.9 million (IQR, $2.72-$131 million); and median total sales, $1.51 billion (IQR, $0.97-$2.26 billion). Of the 150 best-selling drugs, 16 were missing data and key covariates; therefore, the primary study sample comprised 134 drugs. After adjustment for multiple drug characteristics, the mean proportion of total promotional spending allocated to direct-to-consumer advertising for the remaining 134 drugs was an absolute 14.3% (95% CI, 1.43%-27.2%; P = .03) higher for those with low added clinical benefit than for those with high added clinical benefit and an absolute 1.5% (95% CI, 0.44%-2.56%; P = .005) higher for each 10% increase in total sales. Among top-selling US drugs in 2020, a rating of lower added benefit and higher total drug sales were associated with a higher proportion of manufacturer total promotional spending allocated to direct-to-consumer advertising. Further research is needed to understand the implications of these findings.

Estimates of Medicaid and Non-Medicaid Net Prices of Top-Selling Brand-name Drugs Incorporating Best Price Rebates, 2015 to 2019

The US spends far more on brand-name prescription drugs than other comparable countries. However, studies of prescription drug spending in the US are often limited because there can be substantial differences in the confidential rebates that drug manufacturers pay to Medicaid vs other payers. To demonstrate an approach for improved estimation of Medicaid rebates through case studies of 18 top-selling drugs to better understand trends in net Medicaid and non-Medicaid spending and prices for brand-name drugs. This was a cross-sectional study of US pricing data from 2015 to 2019 derived from Medicaid State Drug Utilization data SSR Health, Medi-Span, the Federal Supply Schedule, and IQVIA. Pricing data for 18 top-selling brand-name drugs measured consistently in both SSR Health, which captures US sales reported by publicly traded companies, and IQVIA's top US prescription drugs by nondiscounted spending in 2015 to 2019. Data were accessed and analyzed from January 2019 to June 2021. Gross and net Medicaid and non-Medicaid drug spending for the sample of 18 drugs and prices corresponding to a 30-day supply of medication. Medicaid aggregate gross spending for the 18 drugs in the sample increased 173%, from $3.6 billion in 2015 to $9.9 billion in 2019, and estimated net spending after discounts increased by 119%, from $1.4 billion to $3.0 billion. Medicaid inflation-linked rebates reduced average gross price per 30-day supply by an estimated 43% in 2019, and up to 67% for individual drugs. In addition to the basic rebate, the best price provision reduced the average gross price per 30-day supply by an estimated 3% in 2019 and up to 54% for individual drugs. Between 2015 and 2019 across all study drugs, estimated average non-Medicaid net 30-day prices were between 1.9 and 2.6 times higher than Medicaid net prices. Excluding adalimumab-a spending anomaly because of the entry of a new high-cost formulation-net prices weighted by average gross spending decreased annually by 1% from 2015 through 2019 for Medicaid, while increasing by 2% for non-Medicaid payers. In this cross-sectional study of 18 top-selling brand-name drugs, excluding 1 anomaly, Medicaid average net prices declined from 2015 to 2019. Simultaneously, for non-Medicaid payers, net price increased more than previously published marketwide growth rates, raising the importance of restraining drug price growth in non-Medicaid markets. Rigorous and transparent methods to estimate Medicaid discounts are imperative to understand patterns in Medicaid and non-Medicaid prices and develop policies that better align drug prices with clinical benefits.

Small biotechs versus large pharma: Who drives first-in-class innovation in oncology?

There is a narrative that large pharma relies on biotech and academia for drug innovation. We tested this thesis by identifying the originators of all 50 first-in-class (FIC) oncology drugs that were approved by the FDA from 2010 through 2020. Overall, the numbers support the narrative: large pharma was the sole originator of only 14% of FIC cancer drugs, whereas small biotechs originated 46%, and academic labs 14%. However, origins tell an incomplete story: large pharma companies launched or were involved in launching 76% of FIC cancer drugs. Moreover, three of the five top-selling FIC oncology drugs had large pharma origins. Thus, although biotechs and academia do originate more drugs, large pharma remains important in shepherding drugs through clinical development and approval, and in originating high-impact novel therapies.

Drug Likeness Screening and Evaluation of Physicochemical Properties of Selected Medicinal Agents by Computer Aided Drug Design Tools

The current drug research techniques, combinatorial synthesis and high throughput screening, help in obtaining and pre-evaluating thousands of compounds in a short duration of time. Among the selected compounds, the best hit molecule becomes the lead, and the drug likeness property helps to optimize the selection. Lipinski's Rule of five is the most widely used filter in pre-evaluation of compounds, according to Lipinski's Rule of five the molecule with poor oral absorption and low permeation has the molecular weight >500, ClogP >5, hydrogen bond acceptor more than 10 and hydrogen bond donor more than 5. To evaluate the Rule of Five, the top selling drugs of 2018-19 were selected. Among the selected 56 drugs, 12 drugs (tenofovir disoproxil, sofosbuvir and ledipasvir, sofosbuvir/velpatasvir, trastuzumab, glecaprevir, pegtilgrastion, Lumacaftor/ ivacaftor, fluticasone propionate and salmetarol, elbasvir, darunavir ethanolate, Linagliptin, metformin, fluticasone furoate and vilanterol) did not fulfill the rule. The rule is very useful in selecting the better compound in chemolibraries, but should be used carefully and with certain criterion due to possible exclusion of promising compounds.

Improving recombinant protein production by yeast through genome-scale modeling using proteome constraints

Eukaryotic cells are used as cell factories to produce and secrete multitudes of recombinant pharmaceutical proteins, including several of the current top-selling drugs. Due to the essential role and complexity of the secretory pathway, improvement for recombinant protein production through metabolic engineering has traditionally been relatively ad-hoc; and a more systematic approach is required to generate novel design principles. Here, we present the proteome-constrained genome-scale protein secretory model of yeast Saccharomyces cerevisiae (pcSecYeast), which enables us to simulate and explain phenotypes caused by limited secretory capacity. We further apply the pcSecYeast model to predict overexpression targets for the production of several recombinant proteins. We experimentally validate many of the predicted targets for α-amylase production to demonstrate pcSecYeast application as a computational tool in guiding yeast engineering and improving recombinant protein production.

Accuracy of Google Translate in translating the directions and counseling points for top-selling drugs from English to Arabic, Chinese, and Spanish.

A study was conducted to evaluate the accuracy of Google Translate (Google LLC, Mountain View, CA) when used to translate directions for use and counseling points for the top 100 drugs used in the United States into Arabic, Chinese (simplified), and Spanish. Directions for use and common counseling points for the top 100 drugs were identified by 2 clinicians. This information was translated from English to Arabic, Chinese (simplified), and Spanish using Google Translate. Two nonclinician, bilingual native speakers of each language back-translated the Google Translate translation into English and determined if the sentence made sense in their native language. Two clinicians reviewed the back-translations to determine the clinical significance of each inaccurate translation. For the top 100 drugs, 38 unique directions for use and 170 unique counseling points were identified for translation. For the 38 directions for use, 29 (76.3%) of the Arabic translations were accurate, 34 (89.5%) of the Chinese (simplified) translations were accurate, and 27 (71%) of the Spanish translations were accurate. For the 170 counseling points, 92 (54.1%) of the Arabic translations were accurate, 130 (76.5%) of the Chinese (simplified) translations were accurate, and 65 (38.2%) of the Spanish translations were accurate. Of the 247 inaccurate translations, 72 (29.1%) were classified as highly clinically significant or potentially life-threatening. Certified translators should be used to translate directions for use and common counseling points for prescription medications into Arabic, Chinese (simplified), and Spanish. Clinicians should be aware of the risk of inaccurate translation when Google Translate is used.

The Chemistry of Nonclassical Taxane Diterpene.

The taxane diterpenes are a pharmaceutically vital family of natural products, consisting of more than 550 congeners. All taxane diterpenes are isolated from slow growing evergreen shrubs (genus Taxus) commonly known as "yews" and have a history of over 50 years as potent anticancer compounds. The most prominent congener, taxol (paclitaxel = PTX), has been used in clinics for more than 25 years and is one of the top-selling anticancer drugs worldwide, with annual sales reaching 1.5 billion USD in 1999. Within the taxane diterpene family 11 different scaffolds originating from rearrangements, fragmentations, or transannular C-C bond formations of the "classical taxane core" are known. Among them, five different scaffolds alone belong to the so-called complex or cyclotaxane subfamily, their signature structural feature bearing different types and numbers of transannular C-C bonds across the classical taxane backbone. For synthetic chemists, these five scaffolds represent by far the most challenging of all and have thus evaded total synthesis as well as detailed pharmaceutical evaluation-the latter due to extremely poor sourcing from natural producers. The cousinship of complex taxanes to taxol renders them potentially interesting compounds for drug research in the fight against cancer.This Account specifically summarizes the work on nonclassical taxanes from a biosynthetic, as well as a synthetic, point and provides a synthetic perspective on complex taxanes. Special attention is given to the biosynthetic relationship of complex taxanes and their biological emergence from classical taxanes. The transannular C-C bond forming events in the biosynthesis leading to the five individual scaffolds within this subfamily are structured on the basis of the exact type and number of these specific C-C bond formations. Since functionalization of the classical taxane core in the "oxidase phase" of the biosynthesis precedes the formation of complex taxanes, and is in part prerequisite for these transannular cyclization events, a detailed discussion of these oxidations of the classical taxane backbone is provided. Synthetic efforts toward nonclassical taxanes are scarce in literature and are thus presented in a comprehensive manner for abeotaxanes and complex taxanes. The last part of this Account deals with a synthetic perspective on the synthesis of complex taxanes (cyclotaxanes) and how these most intricate scaffolds can potentially be obtained via a deconvolution strategy. This discussion involves in part unpublished results by our group and is based upon synthetic studies in the literature. The deconvolution strategy we advocate aims for selective fragmentations of the signature transannular C-C bonds of the most intricate scaffold represented by the natural product canataxpropellane, which has recently been synthesized by our group. This strategy represents the converse process of the biosynthesis of complex taxanes (e.g., transannular cyclizations) and is enabled and feasible due to our approach to the canataxpropellane scaffold. We show that, by following this deconvolution strategy, all five scaffolds of complex taxanes can thereby be accessed.

Efficacy and Safety of Adalimumab Biosimilars: Current Critical Clinical Data in Rheumatoid Arthritis.

Adalimumab, as a TNF inhibitor biologic for the treatment of rheumatoid arthritis, is one of the top-selling drugs worldwide. As its various patents have gradually expired, experiments on its biosimilars are constantly being implemented. In this review, we summarized clinical trials of seven biosimilars currently approved by the FDA and/or EMA for the treatment of rheumatoid arthritis, namely: ABP 501 (Amjevita/Amgevita/Solymbic), BI 695501 (Cyltezo), SB5 (Imraldi/Hadlima), GP2017 (Hyrimoz/Hefiya/Halimatoz), MSB11022 (Idacio), FKB327 (Hulio), and PF-06410293 (Abrilada). Overall, these biosimilars showed similar efficacy, safety, and immunogenicity to adalimumab. All biosimilar switching trials indicated that switching from adalimumab to a biosimilar does not have a significant impact on efficacy, safety, and immunogenicity.