The United States Food and Drug Administration's Platform Technology Designation to Expedite the Development of Drugs.

Drug development costs can be significantly reduced if proven "platform" technologies are allowed to be used without having to validate their use. The most recent US Food and Drug Administration (FDA) guideline brings more clarity, as well as a greater focus on the most complex technologies that can now be used for faster drug development. The FDA has highlights the use of lipid nanoparticles (LNPs) to package and deliver mRNA vaccines, gene therapy, and short (2-20 length) synthetic nucleotides (siRNA). Additionally, monoclonal antibody cell development is targeted. The FDA provides a systematic process of requesting platform status to benefit from its advantages. It brings advanced science and rationality into regulatory steps for the FDA's approval of drugs and biologicals.

Innovative Therapeutic Strategies in Alzheimer's Disease: A Synergistic Approach to Neurodegenerative Disorders.

Alzheimer's disease (AD) remains a significant challenge in the field of neurodegenerative disorders, even nearly a century after its discovery, due to the elusive nature of its causes. The development of drugs that target multiple aspects of the disease has emerged as a promising strategy to address the complexities of AD and related conditions. The immune system's role, particularly in AD, has gained considerable interest, with nanobodies representing a new frontier in biomedical research. Advances in targeting antibodies against amyloid-ß (Aß) and using messenger RNA for genetic translation have revolutionized the production of antibodies and drug development, opening new possibilities for treatment. Despite these advancements, conventional therapies for AD, such as Cognex, Exelon, Razadyne, and Aricept, often have limited long-term effectiveness, underscoring the need for innovative solutions. This necessity has led to the incorporation advanced technologies like artificial intelligence and machine learning into the drug discovery process for neurodegenerative diseases. These technologies help identify therapeutic targets and optimize lead compounds, offering a more effective approach to addressing the challenges of AD and similar conditions.

Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders.

Antibodies that can selectively remove rogue proteins in the brain are an obvious choice to treat neurodegenerative disorders (NDs), but after decades of efforts, only two antibodies to treat Alzheimer's disease are approved, dozens are in the testing phase, and one was withdrawn, and the other halted, likely due to efficacy issues. However, these outcomes should have been evident since these antibodies cannot enter the brain sufficiently due to the blood-brain barrier (BBB) protectant. However, all products can be rejuvenated by binding them with transferrin, preferably as smaller fragments. This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. This paper demonstrates that conjugating with transferrin does not alter the binding to brain proteins such as amyloid-ß (Aß) and α-synuclein. We also present a selection of conjugate designs that will allow cleavage upon entering the brain to prevent their exocytosis while keeping the fragments connected to enable optimal binding to proteins. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively.

Transcytosis-Driven Treatment of Neurodegenerative Disorders by mRNA-Expressed Antibody-Transferrin Conjugates.

The recent setbacks in the withdrawal and approval delays of antibody treatments of neurodegenerative disorders (NDs), attributed to their poor entry across the blood-brain barrier (BBB), emphasize the need to bring novel approaches to enhance the entry across the BBB. One such approach is conjugating the antibodies that bind brain proteins responsible for NDs with the transferrin molecule. This glycoprotein transports iron into cells, connecting with the transferrin receptors (TfRs), piggybacking an antibody-transferrin complex that can subsequently release the antibody in the brain or stay connected while letting the antibody bind. This process increases the concentration of antibodies in the brain, enhancing therapeutic efficacy with targeted delivery and minimum systemic side effects. Currently, this approach is experimented with using drug-transferring conjugates assembled in vitro. Still, a more efficient and safer alternative is to express the conjugate using mRNA technology, as detailed in this paper. This approach will expedite safer discoveries that can be made available at a much lower cost than the recombinant process with in vitro conjugation. Most importantly, the recommendations made in this paper may save the antibodies against the NDs that seem to be failing despite their regulatory approvals.

Glucagon-like peptide agonists: A prospective review.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising therapeutic options for addressing Type-2 diabetes, obesity, and related conditions. Among these, semaglutide, tirzepatide, liraglutide etc., all notable GLP-1RA, have gained attention owing to their favourable pharmacological properties and clinical efficacy. AIMS: This comprehensive review aims to provide a detailed analysis of both the currently available GLP-1RAs in the market and those undergoing clinical trials. The focus is on examining their mechanism of action, pharmacokinetics, efficacy in glycemic control and weight management, safety profile, and potential applications. MATERIALS & METHODS: The review employs a systematic approach to gather information on GLP-1RAs. Relevant literature from the currently literature and ongoing clinical trials is thoroughly examined. Detailed scrutiny is applied to understand the mechanism of action, pharmacokinetic properties, and clinical outcomes of these agents. RESULTS: The review presents a comprehensive overview of the GLP-1RAs, highlighting their distinct mechanisms of action, pharmacokinetic profiles, and clinical effectiveness in glycemic control and weight management. Safety profiles are also discussed, providing a holistic understanding of these therapeutic agents. DISCUSSION: The findings are discussed in the context of advancements in the field of GLP-1RAs. Potential applications beyond diabetes and obesity are explored, shedding light on the broader implications of these agents in managing related conditions. CONCLUSION: In conclusion, this review underscores the significance of GLP-1RAs, with a specific focus on semaglutide, in the management of type 2 diabetes, obesity, and beyond. By synthesizing information on their mechanisms, pharmacokinetics, efficacy, and safety, this review provides valuable insights into the potential benefits these agents offer, contributing to the ongoing discourse in the field.

The FDA's New Guideline "Generally Accepted Scientific Knowledge" (GASK): An Opportunity to Expedite the Approval of Biosimilars.

The US FDA's new guideline suggests using "Generally Accepted Science Knowledge" (GASK) to develop nonclinical testing protocols for developing drugs and biologicals to remove unnecessary testing. Interpreting acceptable scientific knowledge as a rational approach has motivated the author to suggest substantial changes to the development of biosimilars, as demonstrated in this paper. The FDA can accept these suggestions without requiring any legislative change to the Act that defines such requirements. Suggested here is the waiving of clinical efficacy testing due to its lower sensitivity compared to analytical and functional testing and pharmacokinetic profiling. Also questioned is the need to test pharmacodynamic markers that do not correlate with clinical response and find new biomarkers requiring extensive testing to validate their use. Should the FDA accept these scientifically rational suggestions, it will significantly reduce the time and cost of approving biosimilars without safety or efficacy risk, as justified based on acceptable scientific knowledge and rationality.

A Critical Analysis of the FDA's Omics-Driven Pharmacodynamic Biomarkers to Establish Biosimilarity.

Demonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.

Non-Invasive Drug Delivery across the Blood-Brain Barrier: A Prospective Analysis.

Non-invasive drug delivery across the blood-brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is a tightly packed layer of endothelial cells that shields the brain from harmful substances in the blood, allowing necessary nutrients to pass through. It is a highly selective barrier, which poses a challenge to delivering therapeutic agents into the brain. Several non-invasive procedures and devices have been developed or are currently being investigated to enhance drug delivery across the BBB. This paper presents a review and a prospective analysis of the art and science that address pharmacology, technology, delivery systems, regulatory approval, ethical concerns, and future possibilities.

The Coming of Age of AI/ML in Drug Discovery, Development, Clinical Testing, and Manufacturing: The FDA Perspectives.

Artificial intelligence (AI) and machine learning (ML) represent significant advancements in computing, building on technologies that humanity has developed over millions of years-from the abacus to quantum computers. These tools have reached a pivotal moment in their development. In 2021 alone, the U.S. Food and Drug Administration (FDA) received over 100 product registration submissions that heavily relied on AI/ML for applications such as monitoring and improving human performance in compiling dossiers. To ensure the safe and effective use of AI/ML in drug discovery and manufacturing, the FDA and numerous other U.S. federal agencies have issued continuously updated, stringent guidelines. Intriguingly, these guidelines are often generated or updated with the aid of AI/ML tools themselves. The overarching goal is to expedite drug discovery, enhance the safety profiles of existing drugs, introduce novel treatment modalities, and improve manufacturing compliance and robustness. Recent FDA publications offer an encouraging outlook on the potential of these tools, emphasizing the need for their careful deployment. This has expanded market opportunities for retraining personnel handling these technologies and enabled innovative applications in emerging therapies such as gene editing, CRISPR-Cas9, CAR-T cells, mRNA-based treatments, and personalized medicine. In summary, the maturation of AI/ML technologies is a testament to human ingenuity. Far from being autonomous entities, these are tools created by and for humans designed to solve complex problems now and in the future. This paper aims to present the status of these technologies, along with examples of their present and future applications.

A Proposed Global Medicines Agency (GMA) to Make Biological Drugs Accessible: Starting with the League of Arab States.

Medical anthropology teaches us of historical disparity in the accessibility of medicines in the developing world due to their lack of availability and affordability, more particularly of biological drugs, including therapeutic proteins, gene therapy, CRISPR-Cas9, mRNA therapeutics, CART therapy, and many more. This challenge can be resolved by establishing an independent regulatory agency, proposed as the Global Medicines Agency (GMA), with a charter to allow originators from the Stringent Regulatory Agency (SRA) countries to receive immediate registrations applicable to all member states, expanding the market potential as an incentive. For non-SRA countries, it will be limited to biological drugs that are allowed their copies to be made, only biosimilars. A transparent approval process will involve using a rapporteur, a third-party product-related current Good Manufacturing Practice (cGMP), and assurance of the integrity of samples tested for analytical similarity and clinical pharmacology testing. GMA membership will be open to all countries. Still, it is suggested that the League of Arab States, representing 22 states with a population of 400 million, takes the lead due to their cultural and language homogeneity, which is likely to provide a concurrence among the member states. However, some states, like the Gulf Cooperative Council, are already accustomed to this approach, albeit with a different perspective. The target drugs are biotechnology and gene therapy pharmaceuticals, and their scope can be expanded to any drug.

Recent Advances in Machine-Learning-Based Chemoinformatics: A Comprehensive Review.

In modern drug discovery, the combination of chemoinformatics and quantitative structure-activity relationship (QSAR) modeling has emerged as a formidable alliance, enabling researchers to harness the vast potential of machine learning (ML) techniques for predictive molecular design and analysis. This review delves into the fundamental aspects of chemoinformatics, elucidating the intricate nature of chemical data and the crucial role of molecular descriptors in unveiling the underlying molecular properties. Molecular descriptors, including 2D fingerprints and topological indices, in conjunction with the structure-activity relationships (SARs), are pivotal in unlocking the pathway to small-molecule drug discovery. Technical intricacies of developing robust ML-QSAR models, including feature selection, model validation, and performance evaluation, are discussed herewith. Various ML algorithms, such as regression analysis and support vector machines, are showcased in the text for their ability to predict and comprehend the relationships between molecular structures and biological activities. This review serves as a comprehensive guide for researchers, providing an understanding of the synergy between chemoinformatics, QSAR, and ML. Due to embracing these cutting-edge technologies, predictive molecular analysis holds promise for expediting the discovery of novel therapeutic agents in the pharmaceutical sciences.

RNA Therapeutics: A Healthcare Paradigm Shift.

COVID-19 brought about the mRNA vaccine and a paradigm shift to a new mode of treating and preventing diseases. Synthetic RNA products are a low-cost solution based on a novel method of using nucleosides to act as an innate medicine factory with unlimited therapeutic possibilities. In addition to the common perception of vaccines preventing infections, the newer applications of RNA therapies include preventing autoimmune disorders, such as diabetes, Parkinson's disease, Alzheimer's disease, and Down syndrome; now, we can deliver monoclonal antibodies, hormones, cytokines, and other complex proteins, reducing the manufacturing hurdles associated with these products. Newer PCR technology removes the need for the bacterial expression of DNA, making mRNA a truly synthetic product. AI-driven product design expands the applications of mRNA technology to repurpose therapeutic proteins and test their safety and efficacy quickly. As the industry focuses on mRNA, many novel opportunities will arise, as hundreds of products under development will bring new perspectives based on this significant paradigm shift-finding newer solutions to existing challenges in healthcare.

Biosimilars Adoption: Recognizing and Removing the RoadBlocks.

Almost two decades since biosimilars arrived, we still await their broader adoption, as anticipated. The roadblocks to this adoption include the high amortized cost of goods due to regulatory burden, hurdles created by the distribution system, perception of safety and efficacy, and lack of focus by stakeholders on removing these roadblocks. In this paper, I analyze the source of these roadblocks and offer practical solutions to remove them. These efforts are needed to maximize the adoption of biosimilars to encourage the entry of 100+ biological molecules that can bring affordable healthcare direly missing today across the globe.

Proposal of International Council for Harmonization (ICH) Guideline for the Approval of Biosimilars.

Objectives: Since the initial release of biosimilars 18 years ago, regulations for their licensing have changed considerably; however, there is no global consensus on these regulations. Establishing harmonized regulatory guidelines for the approval of biosimilars with support from the ICH, an independent, non-profit association under Swiss law, will significantly enhance the affordability of biological drugs. Methods: Regulatory guidelines from the Food and Drug Administration (FDA), European Medicines Agency (EMA), Medicines and Healthcare products Regulatory Agency (MHRA), and World Health Organization (WHO) were analyzed for historical changes and elements critical to the safety and efficacy of biosimilars. Results: Analysis of all EMA and FDA filings show that none of the animal testing and clinical efficacy testing failed because animals do not have the required receptors to initiate pharmacologic responses, and efficacy studies cannot be statistically powered to conclude any results. New analytical technologies will enable good biosimilarity determination, avoiding both tests. Conclusion: Scientifically based ICH guidelines that remove redundant studies will reduce development costs, improve safety, and allow global drug distribution based on single compliance. These guidelines are particularly necessary for emerging countries lacking the expertise and resources to evaluate biosimilar filings.

Computer-Aided Drug Design and Drug Discovery: A Prospective Analysis.

In the dynamic landscape of drug discovery, Computer-Aided Drug Design (CADD) emerges as a transformative force, bridging the realms of biology and technology. This paper overviews CADDs historical evolution, categorization into structure-based and ligand-based approaches, and its crucial role in rationalizing and expediting drug discovery. As CADD advances, incorporating diverse biological data and ensuring data privacy become paramount. Challenges persist, demanding the optimization of algorithms and robust ethical frameworks. Integrating Machine Learning and Artificial Intelligence amplifies CADDs predictive capabilities, yet ethical considerations and scalability challenges linger. Collaborative efforts and global initiatives, exemplified by platforms like Open-Source Malaria, underscore the democratization of drug discovery. The convergence of CADD with personalized medicine offers tailored therapeutic solutions, though ethical dilemmas and accessibility concerns must be navigated. Emerging technologies like quantum computing, immersive technologies, and green chemistry promise to redefine the future of CADD. The trajectory of CADD, marked by rapid advancements, anticipates challenges in ensuring accuracy, addressing biases in AI, and incorporating sustainability metrics. This paper concludes by highlighting the need for proactive measures in navigating the ethical, technological, and educational frontiers of CADD to shape a healthier, brighter future in drug discovery.

Anti-Idiotypic mRNA Vaccine to Treat Autoimmune Disorders.

The 80+ existing autoimmune disorders (ADs) affect billions with little prevention or treatment options, except for temporary symptomatic management, leading to enormous human suffering and a monumental financial burden. The autoantibodies formed in most ADs have been identified, allowing the development of novel anti-idiotypic antibodies to mute the autoantibodies using vaccines. Nucleoside vaccines have been successfully tested as antigen-specific immunotherapies (ASI), with mRNA technology offering multi-epitope targeting to mute multiple autoantibodies. This paper proposes using mRNA technology to produce anti-idiotypic antibodies with broad effectiveness in preventing and treating them. This paper delves into the state-of-the-art mRNA design strategies used to develop novel ASIs by selecting appropriate T cell and B cell epitopes to generate anti-idiotypic antibodies. The low cost and fast development of mRNA vaccines make this technology the most affordable for the global control of ADs.

The Inflation Reduction Act: A boon for the generic and biosimilar industry.

WHAT IS KNOWN AND OBJECTIVE: After more than a year of negotiation, a $740 billion climate and health care bill known as The Inflation Reduction Act (IRA) became law on 16 August 2022. In addition to its impact on the environment, job creation and reducing inflation, a key focus is to reduce the burden of Medicare by over $100B per year and other benefits to 65 million Medicare patients. A fixed number of top expenditures drugs that have stayed as single-source chemical products for 8 years and the biologicals for 12 years; 2 years more are allowed if the approval of a generic or biosimilar is imminent. Once a second source appears, as a generic or biosimilar, the price reduction is removed. The number of products negotiated for price reduction goes from 10 to 20 over the years and stays fixed at this number. Reaching any significant number out of the 14,000 reimbursed will take forever if biosimilars and generics keep entering. The IRA does not apply to private markets. METHODS: The IRA legislation and related statutes were analysed in consultation with legal teams; the spending data were derived from the CMS portals and the FDA databases to rank the most likely products selected when the selection process is initiated. RESULTS AND DISCUSSION: The savings to Medicare will come from reducing the price of only a few products, primarily with $1B and upward spending; when Plan B product scheduling enters, these will be at the bottom of the selection because of their lower expenditure. The total number of products subject to price reduction may be negligible if generics and biosimilars are introduced after the exclusivity period of the listed drug or reference product. The private market with an 80% share may benefit due to price spillover but mainly by the expedited entry of generics and biosimilars. WHAT IS NEW AND THE CONCLUSION: The entry of generics and biosimilars will now be encouraged by brand-name product companies, reducing the intellectual property hurdles like the "patent dance" for biosimilars. The IRA includes restrictions to prevent the brand name companies from exploiting the entry of generics and biosimilars to assure their independence.

Molecular Biosimilarity-An AI-Driven Paradigm Shift.

Scientific, technical, and bioinformatics advances have made it possible to establish analytics-based molecular biosimilarity for the approval of biosimilars. If the molecular structure is identical and other product- and process-related attributes are comparable within the testing limits, then a biosimilar candidate will have the same safety and efficacy as its reference product. Classical testing in animals and patients is much less sensitive in terms of identifying clinically meaningful differences, as is reported in the literature. The recent artificial intelligence (AI)-based protein structure prediction model, AlphaFold-2, has confirmed that the primary structure of proteins always determines their 3D structure; thus, we can deduce that a biosimilar with an identical primary structure will have the same efficacy and safety. Further confirmation of the thesis has been established using technologies that are now much more sensitive. For example, mass spectrometry (MS) is thousands of times more sensitive and accurate when compared to any form of biological testing. While regulatory agencies have begun waiving animal testing and, in some cases, clinical efficacy testing, the removal of clinical pharmacology profiling brings with it a dramatic paradigm shift, reducing development costs without compromising safety or efficacy. A list of 160+ products that are ready to enter as biosimilars has been shared. Major actions from regulatory agencies and developers are required to facilitate this paradigm shift.

No two classes of biosimilars: Urgent advice to the US Congress and the FDA.

WHAT IS KNOWN AND OBJECTIVE: The United States is the only country with legislation to approve two classes of biosimilars. One has "no clinically meaningful difference" from the reference product, and when it is tested for switching and alternating, it can receive an interchangeable status. The objective of this review is to establish whether it is possible from the switching and alternating studies to evaluate additional safety or efficacy. METHODS: Analysed published data to ascertain if the testing with switching and alternating provide additional proof of safety or efficacy. Political and scientific rationale of creating a new class of biosimilars and how this affects the confidence in biosimilars. RESULTS AND DISCUSSION: There is no safety or efficacy concern when switching or alternating biosimilars with the reference product. Unfortunately, the rationale for interchangeability is more political than scientific, and it has brought more confusion and mistrust in using biosimilars in the United States. WHAT IS NEW AND CONCLUSION: The US Congress is requested to remove the interchangeability clause from the Biological Price and Competition Act to enable faster acceptance of biosimilars and remove the threat of lack of confidence in the safety of biosimilars.