FDA Breakthrough Therapy Designation Reduced Late-Stage Drug Development Time.

The Food and Drug Administration's (FDA's) breakthrough therapy designation (BTD) program was created to increase patient access to safe and effective therapies by supporting the efficient clinical development of qualifying, clinically meaningful therapies. Using a new data set of key development milestones for drugs approved between 2006 and 2020, including both BTD drugs and a set of comparator drugs identified by FDA experts, we estimated the BTD program's impact on time spent in late-stage clinical development, measured as the elapsed time between a drug's end-of-Phase-II meeting with regulators and its approval for marketing. Our analysis suggests that the BTD program lowers late-stage clinical development time by 30 percent. Our findings provide insight into future regulatory and innovation policies aimed at driving efficiency in medical product development to ensure timely patient access to the most clinically meaningful therapies.

The history and potential future of monoclonal antibody therapeutics development and manufacturing in four eras.

Therapeutic monoclonal antibody (mAb) development and the processes for manufacturing drug substance have evolved since the first approval of the mAb in 1986. As the past is often the prologue to the future, the history of these technologies has been classified here into three eras, leading to speculation about what the next era may hold with regard to development and manufacturing strategies, as well as the potential impacts to patients. The substantial increase in production culture titers and bioreactor production volumes and the availability of large-scale contract manufacturing facilities could translate into improved global access for these therapies and an expansion of indications for therapeutic antibodies.

Drug screening and development cascade for Chagas disease: an update of in vitro and in vivo experimental models.

Chagas disease is a tropical neglected disease that affects millions of people worldwide, still demanding a more effective and safer therapy, especially in its chronic phase which lacks a treatment that promotes substantial parasitological cure. The technical note of Romanha and collaborators published in 2010 aimed establish a guideline with the set of minimum criteria and decision gates for the development of new agents against Trypanosoma cruzi with the focus on developing new antichagasic drugs. In this sense, the present review aims to update this technical note, bringing the state of the art and new advances on this topic in recent years.

Editorial: The Global Threats of Increasing Antimicrobial Resistance Require New Approaches to Drug Development, Including Molecular Antimicrobial Adjuvants.

Antimicrobial resistance and the associated morbidity and mortality from untreatable common infectious organisms is an increasing threat to global public health. In 2019, the Antimicrobial Resistance Collaborators identified that antimicrobial resistance was directly responsible for up to 1.27 million deaths worldwide and was associated with up to 4.95 million deaths, with low-income and middle-income countries being the most severely affected. In 2019, before the COVID-19 pandemic began, they predicted that antimicrobial resistance could result in 10 million deaths per year by 2050, overtaking cancer as a leading cause of death worldwide. Therefore, there is an urgent need for new approaches to antimicrobial treatment. In June 2024, the findings from researchers at the Ineos Oxford Institute for Antimicrobial Research (IOI) and the Oxford University Department of Pharmacology in the UK reported the use of a small molecule that can work alongside antibiotics to suppress the development of antimicrobial resistance in bacteria. The SOS inhibitor molecule has been called OXF-077. This editorial aims to highlight the global threats from increasing antimicrobial resistance and the urgent need for new molecules that function through novel mechanisms of action, including molecular antimicrobial adjuvants.

Development and therapeutic potential of DNA-dependent protein kinase inhibitors.

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

Making new drugs the hard way.

A new drug can have its origin in either pharma, biotech or academia. In general, discovery scientists working in pharma and biotech are advantaged over their academic counterparts and the relative advantages and disadvantages associated are discussed in depth. Against all odds, an increasing number of important drugs have had their origins in academia. This article reports three case studies from the Liotta Research Group (LRG), which explores the special circumstances that allowed these drug development campaigns to be successful. The first involves the antiretroviral agent, emtricitabine. In this case efficient synthetic methodology, developed in the LRG, coupled with some key university and commercial sector partnerships, enabled a group of academic collaborators to discover and develop a highly effective HIV reverse transcriptase inhibitor. The second case study involves the discovery and development of the breakthrough hepatitis C drug, sofosbuvir. Based on key input from Professors Schinazi and Liotta at Emory University, scientists at the Emory startup, Pharmasset, identified the nucleoside core of the drug that would become sofosbuvir. Subsequent analysis of its phosphorylation profile by Pharmasset scientists suggested that converting it to its corresponding monophosphate prodrug would circumvent a kinase block and enable it to be an effective hepatitis C polymerase inhibitor. The third case study describes the formation of DRIVE (Drug Innovation Ventures at Emory)/EIDD (Emory Institute for Drug Development), which were created to circumvent unintended impediments for carrying out academic drug discovery and development. Although DRIVE/EIDD is a wholly-owned, not-for-profit subsidiary of Emory University, it contains many attributes that enables it to operate much more nimbly than a typical academic laboratory. With an experienced drug development team and no shareholders to distract them, DRIVE/EIDD was able to focus its attention of the development of drugs to address viral diseases of global concern. In particular, their strategy to identify and develop an antiviral agent active against multiple single-stranded RNA viruses led to molnupiravir, a broadly active, oral drug that received Emergency Use Authorization for the treatment of SARS-CoV-2 infections (i.e., COVID-19).

[Phenotypic drug discovery promotes research and development of innovative drugs based on traditional Chinese medicine].

Traditional Chinese medicine with rich resources in China and definite therapeutic effects on complex diseases demonstrates great development potential. However, the complex composition, the unclear pharmacodynamic substances and mechanisms of action, and the lack of reasonable methods for evaluating clinical safety and efficacy have limited the research and development of innovative drugs based on traditional Chinese medicine. The progress in cutting-edge disciplines such as artificial intelligence and biomimetics, especially the emergence of cell painting and organ-on-a-chip, helps to identify and characterize the active ingredients in traditional Chinese medicine based on the changes in model characteristics, thus providing more accurate guidance for the development and application of traditional Chinese medicine. The application of phenotypic drug discovery in the research and development of innovative drugs based on traditional Chinese medicine is gaining increasing attention. In recent years, the technology for phenotypic drug discovery keeps advancing, which improves the early discovery rate of new drugs and the success rate of drug research and development. Accordingly, phenotypic drug discovery gradually becomes a key tool for the research on new drugs. This paper discusses the enormous potential of traditional Chinese medicine in the discovery and development of innovative drugs and illustrates how the application of phenotypic drug discovery, supported by cutting-edge technologies such as cell painting, deep learning, and organ-on-a-chip, propels traditional Chinese medicine into a new stage of development.

FAK inhibitors in cancer, a patent review - an update on progress.

INTRODUCTION: Focal adhesion kinase (FAK) is a cytoplasmic non-receptor tyrosine kinase over-expressed in various malignancies which is related to various cellular functions such as adhesion, metastasis and proliferation. AREAS COVERED: There is growing evidence that FAK is a promising therapeutic target for designing inhibitors by regulating the downstream pathways of FAK. Some potential FAK inhibitors have entered clinical phase research. EXPERT OPINION: FAK could be an effective target in medicinal chemistry research and there were a variety of FAKIs have been patented recently. Here, we updated an overview of design, synthesis and structure-activity relationship of chemotherapeutic FAK inhibitors (FAKIs) from 2017 until now based on our previous work. We hope our efforts can broaden the understanding of FAKIs and provide new ideas and insights for future cancer treatment from medicinal chemistry point of view.

Recent progress in the development of hypoxia-inducible factor 2α (HIF-2α) modulators: Inhibitors, agonists, and degraders (2009-2024).

Hypoxia-inducible factor 2α (HIF-2α) is a critical transcription factor that regulates cellular responses under hypoxic conditions. In situations of insufficient oxygen supply or patients with Von Hippel-Lindau (VHL) mutations, HIF-2α accumulates and forms a heterodimeric complex with aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-ß). This complex further binds to coactivator p300 and interacts with hypoxia response elements (HREs) on the DNA of downstream target genes, regulating the transcription of a variety of genes (e.g. VEGFA, CCND1, CXCR4, SLC2A1, etc) involved in various processes like angiogenesis, mitochondrial metabolism, cell proliferation, and metastasis. Targeting HIF-2α holds great promise for effectively addressing solid tumors associated with aberrant oxygen-sensing pathways and hypoxia mechanisms, offering broad application prospects. In this review, we provide an overview of recent advancements (2009-2024) in HIF-2α modulators such as inhibitors, agonists, and degraders for cancer therapy. Additionally, we discuss in detail the challenges and future directions regarding HIF-2α modulators.

Therapeutic potential of boswellic acids: an update patent review (2016-2023).

INTRODUCTION: Boswellic acids (BAs) are a group of pentacyclic triterpenoids of the ursane and oleanane type. They have shown very interesting biological properties that have led to the development of a number of synthesis protocols. Both natural BAs and their synthetic derivatives may be useful in the treatment of a variety of cancers, viral infections and inflammatory diseases. AREAS COVERED: This review covers patents relating to the therapeutic activities of natural BAs and their synthetic derivatives. The latest patented studies of boswellic acids (are summarized by using the keywords 'boswellic acid,' in SciFinder, PubMed, and Google Patents and databases in the year from 2016 to 2023. EXPERT OPINION: Boswellic acids have shown potent antiviral, anticancer and anti-inflammatory potential. Few BAs analogues have been prepared by modification at the C24-CO2H functional groups. In particular, the C-24 amide and amino analogues have shown enhanced anticancer effects compared to the parent AKBA. In addition, BAs have the ability to form conjugates with other antiviral, anti-inflammatory and anticancer drugs that synergistically enhance their biological efficacy. In addition, this conjugation strategy will increase the solubility and bioavailability of BAs, which is one of the most important issues in the development of BAs.

The antibiotic resistance crisis and the development of new antibiotics.

The Global Burden of Disease report of 2019 estimated 14 million infection-related deaths, making it the second leading cause of death after ischaemic heart disease. Bacterial pathogens accounted for 7.7 million deaths and deaths attributable to bacterial antibiotic resistance amounted to 1.3 million, describing a clear demand for novel antibiotics. Antibiotic development had its golden age in 1930-1960. Following failures in the screening of chemical libraries for novel antibiotics at the beginning of this century, the high cost of launching new antibiotics (estimated at US$ 1.4 billion per registered drug) and difficulties in achieving a return of investment for novel antibiotics, pharmaceutical industry has mostly left the field. The current Lilliput review analyses the question whether scientific or economic hurdles prevented the registration of new antibiotics. Scientifically, substantial progress has been achieved over recent years to define the chemical properties needed to overcome the permeation barrier in Gram-negative pathogens; in extending the chemical space of antibiotic candidates by full modular synthesis of suitable molecules; by extending bioprospecting to previously 'unculturable' bacteria or unusual bacteria; by attacking bacterial targets on the outer bacterial membrane; and by looking for support from structural biology, genomics, molecular genetics, phylogenetic analyses and deep machine learning approaches. However, these research activities were mostly conducted by academic researchers and biotech companies with limited financial resources. It thus seems that the development of new antibiotics, frequently described as the drying of the pipeline, is less limited by lack of scientific insight than by lack of the mobilization of the monetary resources needed to bring these discoveries to the market despite recent financial push and pull efforts of the public sector.

Understanding the Regulatory Pathways Used to Develop, Evaluate, Authorize, and Approve New Drugs and Vaccines in the United States.

The United States (U.S.) Food and Drug Administration (FDA) oversees the safety and quality of drugs and vaccines that are used in the U.S. Administration of the FDA falls under the jurisdiction of the U.S. Department of Health and Human Services (HHS). The regulatory oversight of the FDA is complex and comprehensive, requiring the various roles and responsibilities to be divided across six main centers. The activities of two of these centers, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) are the primary focus of this review.

Journey from lab to clinic: Design, preclinical, and clinical development of systemic, targeted dendrimer-N-acetylcysteine (D-NAC) nanomedicines.

Drug discovery is challenging task with numerous obstacles in translating drug candidates into clinical products. Dendrimers are highly adaptable nanostructured polymers with significant potential to improve the chances of clinical success for drugs. Yet, dendrimer-based drug products are still in their infancy. However, Hydroxyl polyamidoamine (PAMAM) dendrimers showed significant promise in drug discovery efforts, owning their remarkable potential to selectively target and deliver drugs specifically to activated microglia and astrocytes at the site of brain injury in several preclinical models. After a decade's worth of academic research and pre-clinical efforts, the hydroxyl PAMAM dendrimer-N-acetyl cysteine conjugate (OP-101) nanomedicine has made a significant advancement in the field of nanomedicine and targeted delivery. The OP-101 conjugate, primarily developed and validated in academic labs, has now entered clinical trials as a potential treatment for hyperinflammation in hospitalized adults with severe COVID-19 through Ashvattha Therapeutics. This chapter, we delve into the journey of the hydroxyl PAMAM dendrimer-N-acetylcysteine (NAC) OP-101 formulation from the laboratory to the clinic. It will specifically focus on the design, synthesis, preclinical, and clinical development of OP-101, highlighting the potential it holds for the future of medicine and the positive Phase 2a results for treating severe COVID-19.

Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases.

The extracellular signal-regulated kinases-1 and 2 (ERK1/2) are ubiquitous regulators of many cellular functions, including proliferation, differentiation, migration, and cell death. ERK1/2 regulate cell functions by phosphorylating a diverse collection of protein substrates consisting of other kinases, transcription factors, structural proteins, and other regulatory proteins. ERK1/2 regulation of cell functions is tightly regulated through the balance between activating phosphorylation by upstream kinases and inactivating dephosphorylation by phosphatases. Disruption of homeostatic ERK1/2 regulation caused by elevated extracellular signals or mutations in upstream regulatory proteins leads to the constitutive activation of ERK1/2 signaling and uncontrolled cell proliferation observed in many types of cancer. Many inhibitors of upstream kinase regulators of ERK1/2 have been developed and are part of targeted therapeutic options to treat a variety of cancers. However, the efficacy of these drugs in providing sustained patient responses is limited by the development of acquired resistance often involving re-activation of ERK1/2. As such, recent drug discovery efforts have focused on the direct targeting of ERK1/2. Several ATP competitive ERK1/2 inhibitors have been identified and are being tested in cancer clinical trials. One drug, Ulixertinib (BVD-523), has received FDA approval for use in the Expanded Access Program for patients with no other therapeutic options. This review provides an update on ERK1/2 inhibitors in clinical trials, their successes and limitations, and new academic drug discovery efforts to modulate ERK1/2 signaling for treating cancer and other diseases.

How debunking biases in research and development decisions could lead to more equitable healthcare?

Decades of research have demonstrated that a variety of cognitive biases can affect our judgment and ability to make rational decisions in personal and professional environments. The lengthy, risky, and costly nature of pharmaceutical research and development (R&D) makes it vulnerable to biased decision-making. Moreover, cognitive biases can play a role in regulatory and clinical decision-making, the latter impacting diagnostic and treatment decisions in the therapeutic use of medicines. These inherent and/or institutionalized biases (e.g., in assumptions, data, or decision-making practices) could conceivably contribute to health inequities. In this mini-review, we provide a broad perspective on how cognitive biases can affect pharmaceutical R&D, regulatory evaluation, and therapeutic decision-making. Example approaches to mitigate the effect of common biases in the development, approval, and use of new therapeutics, such as quantitative decision criteria, multidisciplinary reviews, regulatory and treatment guidelines, and evidence-based clinical decision support systems are illustrated. Mitigating the impact of cognitive biases could increase pharma R&D efficiency, change the perspective and prioritization of unmet medical needs, increase representativeness and quality of evidence generated through clinical trials and real-world research, leading to higher quality insights and more effective medication use, and as such could eventually contribute to more equitable healthcare.

Pharmacotherapeutic options for metabolic dysfunction-associated steatotic liver disease: where are we today?

INTRODUCTION: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by hepatic steatosis and cardiometabolic risk factors like obesity, type 2 diabetes, and dyslipidemia. Persistent metabolic injury may promote inflammatory processes resulting in metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. Mechanistic insights helped to identify potential drug targets, thereby supporting the development of novel compounds modulating disease drivers. AREAS COVERED: The U.S. Food and Drug Administration has recently approved the thyroid hormone receptor ß-selective thyromimetic resmetirom as the first compound to treat MASH and liver fibrosis. This review provides a comprehensive overview of current and potential future pharmacotherapeutic options and their modes of action. Lessons learned from terminated clinical trials are discussed together with the first results of trials investigating novel combinational therapeutic approaches. EXPERT OPINION: Approval of resmetirom as the first anti-MASH agent may revolutionize the therapeutic landscape. However, long-term efficacy and safety data for resmetirom are currently lacking. In addition, heterogeneity of MASLD reflects a major challenge to define effective agents. Several lead compounds demonstrated efficacy in reducing obesity and hepatic steatosis, while anti-inflammatory and antifibrotic effects of monotherapy appear less robust. Better mechanistic understanding, exploration of combination therapies, and patient stratification hold great promise for MASLD therapy.

A Modern Curriculum for Training Scientists in Model-Informed Drug Development: Progress Report on FDA Grant to Train Regulatory Scientists.

Under US Food and Drug Administration (FDA) grant (2U18FD005320-06), the Critical Path Institute (C-Path) and experienced private sector partners collaborated with global health organizations to create didactic video materials in an e-learning format on model-informed drug development (MIDD) topics relevant to a non-modeling audience. Several multinational pharmaceutical companies contributed case studies illustrating the application of the MIDD approach in practice. Training videos were created and divided into several modules: introducing the MIDD landscape for drug development and regulatory science, a review of various model types used for MIDD, discussions of how models inform drug development and regulatory decisions, future goals of MIDD, and discussions on the interconnectedness of models used for MIDD. Examples and vignettes from stakeholders and thought leaders were included. These educational materials fill a gap between academic and "on the job training" for regulators, academic, and industry scientists, delivering insights and value for those performing modeling and non-modelers reviewing the output of modeling and simulation work. A total of 13 hours of video content is currently available. A small panel of FDA reviewers is currently beta-testing the learning management system (LMS). Future efforts for this MIDD training initiative will include expansion of the content via an expanded and diverse faculty, 1:1 online mentorship sessions, and eventually broader access to this resource consistent with an open science approach and curriculum. The MIDD training LMS can accommodate a diverse learning ecosystem; further development may also accommodate different audiences in the future.