BioDrugs最新文献

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by the destruction of insulin-producing beta cells in the pancreas, leading to insulin deficiency and chronic hyperglycemia. The main current therapeutic strategies for clinically overt T1D - primarily exogenous insulin administration combined with blood glucose monitoring - fail to fully mimic physiological insulin regulation, often resulting in suboptimal or insufficient glycemic control. Islet cell transplantation has emerged as a promising avenue for functionally replacing endogenous insulin production and achieving long-term glycemic stability. Here, we provide an overview of current islet replacement strategies, ranging from islet transplantation to stem cell-derived islet cell transplantation, and highlight emerging approaches such as immunoengineering. We examine the advancements in immunosuppressive protocols to enhance graft survival, innovative encapsulation, and immunomodulation techniques to protect transplanted islets, and the ongoing challenges in achieving durable and functional islet integration. Additionally, we discuss the latest clinical outcomes, the potential of gene editing technologies, and the emerging strategies for islet cell regeneration. This review aims to highlight the potential of these approaches to transform the management of T1D and improve the quality of life of individuals affected by this condition.

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), remains challenging to manage, with a substantial proportion of patients not responding to conventional therapies or developing complications. The tumor necrosis factor (TNF) superfamily member TL1A has emerged as an important player in the pathogenesis of IBD, influencing pathways of inflammation and fibrosis. This leading article reviews the role of TL1A in IBD, evaluates the efficacy of anti-TL1A therapies in clinical trials, and discusses future directions for research and treatment. TL1A is implicated in IBD through its interaction with death domain receptor 3 (DR3), promoting T-cell activation and contributing to both inflammatory responses and fibrotic changes. Phase 2 clinical trials of anti-TL1A agents have demonstrated promising results, showing improvements in endoscopic and histologic outcomes for both UC and CD. Phase 2 and 3 clinical trials are ongoing, which are expected to provide further clarity on the efficacy and safety of TL1A-targeting agents in treating IBD.

A biosimilar is a biologic medication that is highly similar to and has no clinically meaningful differences from an existing approved biologic referred to as "reference product." From the introduction of the first biosimilar in 2006 to today, a variety of challenges to biosimilar development and uptake have arisen across global markets, threatening sustainability. Consequences of an unsustainable market can include drug shortages, limited competition, and less innovation. However, there are few frameworks to facilitate systematic evaluation and action to address these threats. This study used a contemporary, targeted review of the global biosimilars literature to establish the key dimensions of biosimilar market sustainability. The most commonly referenced stakeholder groups were healthcare payers, government/legal/regulatory authorities, healthcare providers, biologic manufacturers, patients, and biologic purchasers. The most prevalent sustainability dimensions discussed were pricing and cost-savings, legal and regulatory barriers to market entry and access, manufacturer processes, provider choice in selecting biologic therapy, knowledge and preferences, and procurement processes. We incorporated these findings into a framework of biosimilar market sustainability dimensions that should be considered by stakeholders looking to ensure the long-term viability of the market.

Background: Different biosimilar-promoting policies have been implemented worldwide to improve biosimilar uptake and reduce expenditures on costly biologics.

Objective: The aim was to review biosimilar-promoting policies in 13 countries, and examine biosimilar uptake and expenditure reduction for adalimumab, etanercept, and infliximab, among countries with different biosimilar-promoting policies.

Methods: Quarterly IQVIA MIDAS sales data from 2012 to 2023 for the three originators and their biosimilars in 13 countries were used. Two countries for a given setting (retail or hospital) and originator were paired if they differed only on one specific policy. Biosimilar uptake and relative expenditure reduction were compared between pairs. Biosimilar uptake was calculated by dividing the sales volume of biosimilars by the total sales volume of biosimilars and their corresponding originator. Expenditure reduction was the difference between the actual expenditure in 2023 and the but-for-biosimilar expenditure (based on the price of the originator in the year before biosimilar launch).

Results: Biosimilar uptake and relative expenditure reduction have grown over time across the three originators in all country-settings. We identified ten country-setting-anti-tumor necrosis factor (anti-TNF) pairs for three policies: tendering, price link, and quotas. All three policies appeared to facilitate greater biosimilar uptake, but this did not consistently translate to greater expenditure reductions. Tendering facilitated greater reductions in three out of four paired comparisons in the retail setting and zero of two comparisons in the hospital setting. Price link with low discount rates (- 20 to - 25% of originator price) and prescribing quotas facilitated greater reductions in one of three comparisons and zero of one comparison in the hospital setting, respectively.

Conclusions: Procurement of biosimilars through tendering could potentially reduce spending on anti-TNFs in the retail setting, whereas price links at low discounts did not appear to help. The impact of prescribing quotas needs to be further investigated.

Background: Evidence comparing the impact of various biologics for psoriasis on the progression to psoriatic arthritis (PsA) is limited. We therefore assessed the risk of PsA associated with interleukin (IL)-23 inhibitor, IL-17 inhibitor, or IL-12/23 inhibitor use compared with tumor necrosis factor (TNF) inhibitor use among patients with psoriasis.

Methods: This population-based cohort study used the nationwide claims database from South Korea (2007-2023). New users of IL or TNF inhibitors with psoriasis who did not have PsA or other inflammatory arthritis were categorized into each class of the IL inhibitors for comparison with TNF inhibitor users. The outcome measured was the development of incident PsA. We calculated multinomial overlap weights to balance predefined covariates. Hazard ratio (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models.

Results: We identified 9499 patients with psoriasis (mean age 45.1 years; 33.6% female), of whom 3913 (41.2%), 2126 (22.4%), 2773 (28.8%), and 727 (7.7%) were exposed to IL-23 inhibitor, IL-17 inhibitor, IL-12/23 inhibitor, and TNF inhibitor, respectively. PsA developed in 281 (3.0%) patients during 23,275 person-years. The weighted HR for any IL inhibitors was 0.40 (95% CI 0.25-0.62), with specific HRs of 0.22 (95% CI 0.13-0.37), 0.47 (95% CI 0.28-0.80), and 0.46 (95% CI 0.29-0.74) for IL-23 inhibitor, IL-17 inhibitor, and IL-12/23 inhibitor, respectively. IL-23 inhibitors exhibited the greatest rate difference of - 2.61 (95% CI - 3.67 to - 1.55) cases of PsA per 100 person-years.

Conclusions: The use of IL inhibitors, particularly IL-23 inhibitors, compared with TNF inhibitors, was associated with a lower risk of developing PsA.

Background: Despite the global use of trastuzumab biosimilars, concerns remain regarding their efficacy and safety. In particular, when used concurrently with pertuzumab, trastuzumab biosimilars lack extensive real-world data and safety information. Additionally, as cancer drug expenditures continue to rise worldwide, cost savings from biosimilars have become increasingly important.

Objective: This study aims to assess the safety, efficacy, and cost effectiveness of trastuzumab originators and their biosimilars in real-world clinical settings, focusing on a large patient population.

Methods: The analysis included 31,661 patients with HER2-positive breast cancer from the Medical Data Vision Co., Ltd. database in Japan. Additionally, adverse event reports for the trastuzumab originator and its biosimilars were obtained for 58,799 patients from the World Health Organization's VigiBase, the global adverse event reporting database.

Results: No significant differences were observed in heart failure hospitalizations, liver dysfunction, or infusion reaction rates in both the Medical Data Vision Co., Ltd. database and the World Health Organization's VigiBase. In the Medical Data Vision Co., Ltd. database, the addition of pertuzumab did not significantly influence the incidence of adverse events, and the use of biosimilars significantly reduced medical costs, with no significant difference in breast cancer recurrence rates.

Conclusions: By analyzing two large and diverse datasets from multiple perspectives, we obtained reliable results that the trastuzumab originator and its biosimilars have similar safety profiles. The concurrent use of pertuzumab was also found to be safe. The use of biosimilars can lead to cost savings. These findings provide crucial insights for the evaluation and adoption of biosimilars in clinical practice.

Chimeric antigen receptor T-cell therapies have markedly improved the survival rates of patients with B-cell malignancies. However, their efficacy in other hematological cancers, such as acute myeloid leukemia, and in solid tumors has been limited. Key obstacles include the downregulation or loss of antigen expression on cancer cells, restricted accessibility to target cells, and the poor persistence of these "living drugs" because of the highly immunosuppressive tumor microenvironment. Additionally, manufacturing these immunotherapies presents significant challenges, and patients frequently experience side effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. This review emphasizes the potential of small-molecule inhibitors, many of which are already approved for clinical use, to facilitate chimeric antigen receptor T-cell manufacturing, enhance their anti-tumor efficacy, and mitigate their side effects. Although substantial work remains, the robust pre-clinical data and the growing clinical interest suggest significant promise for using cancer signaling pathway inhibitors to enhance and refine chimeric antigen receptor T-cell therapy for both hematological and solid tumors. Exploring these combination strategies could lead to more effective therapies, offering new hope for patients with resistant forms of cancer.

Hidradenitis suppurativa (HS) is a chronic, debilitating, inflammatory dermatosis that significantly impacts patients' quality of life, primarily manifesting as inflammatory nodules, abscesses, and tunnels. The pathogenesis of HS is not fully understood and appears to be multifactorial, involving genetic, immunological, and endocrinological factors, as well as dysbiosis of skin microbiota. Increasing evidence highlights the role of the interleukin (IL)-17 pathway in the inflammatory process and pathogenesis of HS. Consequently, IL-17 inhibitors have emerged as a promising alternative to current therapies. Recently, secukinumab received approval from both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while bimekizumab received approval from the EMA, for the treatment of moderate-to-severe HS in adults, with ongoing clinical trials aiming to further clarify the efficacy and safety of other drugs within this class. IL-17 inhibitors have shown effectiveness in treating moderate-to-severe HS, with safety profiles of drugs such as secukinumab and bimekizumab being comparable to their use in other dermatological conditions. On the other hand, innovative drugs such as sonelokimab and izokibep show promising results and are currently in phase III clinical trials. This review provides a comprehensive overview of current knowledge and scientific advances in HS, focusing on the IL-17 pathway's role and its inhibition as a treatment strategy, alongside examining the most recent and significant clinical studies on various IL-17 inhibitors in the treatment of HS.

After decades of gradual progress from conceptualization to early clinical trials (1960-2000), the therapeutic potential of bispecific antibodies (bisp Abs) is now being fully realized. Insights gained from both successful and unsuccessful trials are helping to identify which mechanisms of action, antibody formats, and targets prove most effective, and which may benefit from further refinement. While T-cell engagers remain the most commonly used class of bisp Abs, current efforts aim to increase their effectiveness by co-engaging costimulatory molecules, reducing escape mechanisms, and countering immunosuppression. Strategies to minimize cytokine release syndrome (CRS) are also actively under development. In addition, novel antibody formats that are selectively activated within tumors are an exciting area of research, as is the precise targeting of specific T-cell subsets. Beyond T cells, the recruitment of macrophages and dendritic cells is attracting increasing interest, with researchers exploring various macrophage receptors to promote phagocytosis or to carry out specialized functions, such as the immunologically silent clearance of amyloid-beta plaques in the brain. While bisp Abs targeting B cells are relatively limited, they are primarily aimed at inhibiting B-cell activity in autoimmune diseases. Another evolving application involves the forced interaction between proteins. Beyond the successful development of Hemlibra for hemophilia, bispecific antibodies that mimic cytokine activity are being explored. Additionally, the recruitment of cell surface ubiquitin ligases and other enzymes represents a novel and promising therapeutic strategy. In regard to antibody formats, some applications such as the combination of T-cell engagers with costimulatory molecules are driving the development of trispecific antibodies, at least in preclinical settings. However, the increasing structural complexity of multispecific antibodies often leads to more challenging development paths, and the number of multispecific antibodies in clinical trials remains low. The clinical success of certain applications and well-established production methods position this therapeutic class to expand its benefits into other therapeutic areas.