Vertex Biopharm Consulting

The combination of immune checkpoint inhibitors and antibody-drug conjugates in the treatment of urogenital tumors: a review insights from phase 2 and 3 studies With the high incidence of urogenital tumors worldwide, urinary system tumors are among the top 10 most common tumors in men, with prostate cancer ranking first and bladder cancer fourth. Patients with resistant urogenital tumors often have poor prognosis. In recent years, researchers have discovered numerous specific cancer antigens, which has led to the development of several new anti-cancer drugs. Using protein analysis techniques, researchers developed immune checkpoint inhibitors (ICIs) and antibody-conjugated drugs (ADCs) for the treatment of advanced urogenital tumors. However, tumor resistance often leads to the failure of monotherapy. Therefore, clinical trials of the combination of ICIs and ADCs have been carried out in numerous centers around the world. This article reviewed phase 2 and 3 clinical studies of ICIs, ADCs, and their combination in the treatment of urogenital tumors to highlight safe and effective methods for selecting individualized therapeutic strategies for patients. ICIs activate the immune system, whereas ADCs link monoclonal antibodies to toxins, which can achieve a synergistic effect when the two drugs are combined. This synergistic effect provides multiple advantages for the treatment of urogenital tumors. ICIs (PD-1/PD-L1 and CTLA-4) inhibitors play a crucial role in activating the body’s natural anti-tumor-immune response by restoring anti-tumor immunity, reversing immune evasion, and promoting cell death pathways of tumor cells. There are two mechanisms by which ADCs eliminate tumors: (1) The first mechanism is to use the antibody component of ADCs to target tumor-specific antigens and release small-molecule cytotoxic drugs that directly kill tumor cells. (2) The second mechanism involves inducing the bystander effect of ADCs. The two mechanisms synergistically affect the TME, leading to tumor cell death. Created with BioRender.com. https://lnkd.in/edfZJTqt

FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize Vertex Biopharm Consulting [12/19/2024]?FDA re-evaluated its determination from October 2, 2024, on the status of the #tirzepatide shortage. Today, FDA has issued a?new decision?determining the tirzepatide injection shortage is resolved. FDA’s determination is based on its analysis of all the information before the agency.? In addition to the statements FDA made regarding enforcement in connection with litigation (see FDA’s updates on October 22, 2024, below), to avoid unnecessary disruption to patient treatment, the agency does not intend to take action against compounders for violations of the FD&C Act arising from conditions that depend on tirzepatide injection products’ inclusion on FDA’s drug shortage list:? For a state-licensed pharmacy under section 503A of the FD&C Act compounding, distributing or dispensing tirzepatide injections within 60 calendar days from today’s announcement, until February 18, 2025. For outsourcing facilities under section 503B compounding, distributing or dispensing tirzepatide injections within 90 calendar days from today’s announcement, until March 19, 2025. Current shortage status of other GLP-1 products (as of December 19, 2024):? FDA continues to actively monitor drug availability and is currently working to determine whether the demand or projected demand for each drug in shortage exceeds the available supply.? - #Dulaglutide injection:?In shortage. Manufacturer has reported all presentations are available. - #Semaglutide injection:?In shortage. Manufacturer has reported all presentations are available.? - #Liraglutide injection:?In shortage. Manufacturer has reported two presentations are available, and three have limited availability. https://lnkd.in/erxn6Swa

Cleaning Process Design for Peptide Therapeutics There are more than 60 peptide therapeutics approved around the world and hundreds currently in clinical studies (1). A peptide is a polymer consisting of less than 100 amino acids (AA) linked by an amide or peptide bond. These therapeutics are desirable as they exhibit low toxicity and high biological activity. The two major peptide manufacturing pathways consist of recombinant and synthetic. Recombinant manufacturing uses an engineered living microorganism, such as?Escherichia coli?(E. coli), to synthesize the peptide. Synthetic peptide manufacturing originated with solution-phase peptide synthesis to groundbreaking solid-phase peptide synthesis (SPPS) and hybrid methods (2). Further advances in the SPPS technology improved the deprotection and cleavage steps (see?Figure 1), resulting in the ability to safely manufacture synthetic peptides for personalized medicine to commercial manufacturing of greater than 100 kilograms (3). The manufacturing of commercial peptide therapeutics requires current good manufacturing practices (CGMPs) including validation of the manufacturing and cleaning process (4,5). Cleaning validation consists of three phases: the design phase to understand critical cleaning parameters as well as defining cleaning quality attributes; the qualification phase to ensure the cleaning process consistently meets pre-established acceptance criteria; and the continuous monitoring phase to ensure the cleaning process remains in a state of control (6,7). If multiple peptides are manufactured in shared equipment, then a grouping or bracketing approach can be used to identify the worst-case peptide for validation (8–10). The most common factors used for grouping drug actives are solubility, toxicity, and difficulty of cleaning. Other considerations could include structure, molecular weight, availability of analytical methods, bioavailability, permeability, and degradation profiles (11). https://lnkd.in/e3Mjmeya

Peptide-based drug discovery through artificial intelligence: towards an autonomous design of therapeutic peptides With their diverse biological activities, peptides are promising candidates for therapeutic applications, showing antimicrobial, antitumour and hormonal signalling capabilities. Despite their advantages, therapeutic peptides face challenges such as short half-life, limited oral bioavailability and susceptibility to plasma degradation. The rise of computational tools and artificial intelligence (AI) in peptide research has spurred the development of advanced methodologies and databases that are pivotal in the exploration of these complex macromolecules. This perspective delves into integrating AI in peptide development, encompassing classifier methods, predictive systems and the avant-garde design facilitated by deep-generative models like generative adversarial networks and variational autoencoders. There are still challenges, such as the need for processing optimization and careful validation of predictive models. This work outlines traditional strategies for machine learning model construction and training techniques and proposes a comprehensive AI-assisted peptide design and validation pipeline. The evolving landscape of peptide design using AI is emphasized, showcasing the practicality of these methods in expediting the development and discovery of novel peptides within the context of peptide-based drug discovery. https://lnkd.in/ebNbmj5r

Bioprocessing 4.0: a pragmatic review and future perspectives In the dynamic landscape of industrial evolution, Industry 4.0 (I4.0) presents opportunities to revolutionise products, processes, and production. It is now clear that enabling technologies of this paradigm, such as the industrial internet of things (IIoT), artificial intelligence (AI), and Digital Twins (DTs), have reached an adequate level of technical maturity in the decade that followed the inception of I4.0. These technologies enable more agile, modular, and efficient operations, which are desirable business outcomes for particularly biomanufacturing companies seeking to deliver on a heterogeneous pipeline of treatments and drug product portfolios. Despite the widespread interest in the field, the level of adoption of I4.0 technologies in the biomanufacturing industry is scarce, often reserved to the big pharmaceutical manufacturers that can invest the capital in experimenting with new operating models, even though by now AI and IIoT have been democratised. This shift in approach to digitalisation is hampered by the lack of common standards and know-how describing ways I4.0 technologies should come together. As such, for the first time, this work provides a pragmatic review of the field, key patterns, trends, and potential standard operating models for smart biopharmaceutical manufacturing. This analysis aims to describe how the Quality by Design framework can evolve to become more profitable under I4.0, the recent advancements in digital twin development and how the expansion of the Process Analytical Technology (PAT) toolbox could lead to smart manufacturing. Ultimately, we aim to summarise guiding principles for executing a digital transformation strategy and outline operating models to encourage future adoption of I4.0 technologies in the biopharmaceutical industry. https://lnkd.in/dA_R9es4

Future perspectives on engineered T cells for cancer Highlights - The efficacy of chimeric antigen receptor (CAR) T cells targeting solid tumors is constrained by target heterogeneity, treatment-associated toxicities, and immunosuppressive factors in the tumor microenvironment, such as poor T cell infiltration, metabolic stress, and T cell exhaustion. - Toxicities associated with CAR T cell therapies can limit administration of therapeutic doses of CAR T cells. - Locoregional CAR T cell delivery can enhance CAR T cell efficacy and reduce on-target off-tumor toxicities.

The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm of solid tumors. To date, many ongoing studies of ADC combinations with a variety of anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical studies and clinical trial settings. Nevertheless, combination therapy does not always guarantee a synergistic or additive effect and may entail overlapping toxicity risks. Therefore, understanding the current status and underlying mechanisms of ADC combination therapy is urgently required. This comprehensive review analyzes existing evidence concerning the additive or synergistic effect of ADCs with other classes of oncology medicines. Here, we discuss the biological mechanisms of different ADC combination therapy strategies, provide prominent examples, and assess their benefits and challenges. Finally, we discuss future opportunities for ADC combination therapy in clinical practice. https://lnkd.in/ehVE5dhX

Future perspectives on engineered T cells for cancer Highlights - The efficacy of chimeric antigen receptor (CAR) T cells targeting solid tumors is constrained by target heterogeneity, treatment-associated toxicities, and immunosuppressive factors in the tumor microenvironment, such as poor T cell infiltration, metabolic stress, and T cell exhaustion. - Toxicities associated with CAR T cell therapies can limit administration of therapeutic doses of CAR T cells. - Locoregional CAR T cell delivery can enhance CAR T cell efficacy and reduce on-target off-tumor toxicities. Chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary treatment for hematological malignancies, but its adaptation to solid tumors is impeded by multiple challenges, particularly T cell dysfunction and exhaustion. The heterogeneity and inhospitableness of the solid tumor microenvironment (TME) contribute to diminished CAR T cell efficacy exhibited by reduced cytotoxicity, proliferation, cytokine secretion, and the upregulation of inhibitory receptors, similar to the phenotype of tumor-infiltrating lymphocytes (TILs). In this review, we highlight recent advances in T cell therapy for solid tumors, particularly brain cancer. Innovative strategies, including locoregional delivery and ‘armoring’ CAR T cells with cytokines such as interleukin (IL)-18, are under investigation to improve efficacy and safety. We also highlight emerging issues with toxicity management of CAR T cell adverse events. This review discusses the obstacles associated with CAR T cell therapy in the context of solid tumors and outlines current and future strategies to overcome these challenges. https://lnkd.in/eMVth3q8 - Armoring CAR T cells with cytokines such as interleukin (IL)-12 and IL-18 can enhance CAR T cell potency and efficacy. - CAR T cells can be synthetically engineered to bypass normal T cell homeostasis and prolong antitumor cytotoxicity.

CAR T-Cell Therapy Shows Promise in Preclinical Models of HER2-Positive Solid Tumors Researchers create a CAR-T therapy targeting p95HER2, showing complete tumor response in HER2+ breast cancer. One-third of HER2-positive (HER2+) tumors express the P95HER2 protein, which associates with an aggressive form of breast cancer with a poorer prognosis. Investigators of the Vall d'Hebron Institute of Oncology's (VHIO) Growth Factors Group, in collaboration with researchers of the Cancer Research Program of Hospital del Mar Research Institute (HMRIB), Barcelona, have developed novel chimeric antigen receptor (CAR) T-cell therapy that can produce a potent antitumor response against p95HER2-expressing cells. This novel approach consists of T cells engineered to express a CAR against p95HER2 and secrete the TECH2Me bispecific antibody that specifically recognizes tumor cells. In addition, this bispecific antibody activates immune cells within the tumor microenvironment (TME). This new therapeutic strategy has been evaluated in patient-derived models of HER2+ P95HER2-expressing solid tumors. https://lnkd.in/e5RUJRFX

AstraZeneca plans $3.5 billion expansion of research, manufacturing operations across?US Big pharma firm looks for $2 billion in new investment from coast to coast AstraZeneca plans to invest $3.5 billion by the end of 2026 to expand its research and manufacturing operations across the United States. The United Kingdom-based pharmaceutical giant said Tuesday its capital commitment to the expansion includes $2 billion in new investment. “By expanding our R&D and manufacturing footprint, we aim to enhance the development of cutting-edge therapies and support the United States leadership in healthcare innovation,” AstraZeneca’s CEO Pascal Soriot said in a statement. The company's plan to expand comes as demand in the U.S. for life science space, including lab, research and development, and other biotech facilities, shows signs of increasing. The sector had surged early in the pandemic then slowed dramatically as capital markets tightened and venture capitalists looked elsewhere to make investments. https://lnkd.in/eMMJ3zcR