BioDrugs最新文献

Drug-resistant bacteria have become one of the greatest threats to human health in recent decades. With the large-scale abuse of antibiotics, bacteria resistant to traditional antibiotics are becoming increasingly common while clinical options for treating refractory infections are rapidly diminishing. Antimicrobial peptides (AMPs) as a promising alternative to traditional antibiotics, exhibit unique antibacterial mechanisms and potent antimicrobial activity. In recent years, numerous AMPs have been identified and validated in laboratory settings for their efficacy against the 'ESKAPE' pathogens, including Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. Although the clinical translation of AMPs is currently hindered by challenges such as stability, toxicity, and production costs, advances in biotechnology and continued research are paving the way for their development as promising alternatives for treating drug-resistant ESKAPE pathogens. This review focuses on summarizing AMPs with demonstrated efficacy against ESKAPE pathogens and explores their clinical application potential, aiming to provide insights for future AMP research and therapeutic development.

Objectives: This study aims to assess perspectives of stakeholders on scientific and regulatory challenges associated with biosimilarity demonstration and to formulate consensus-based recommendations to foster regulatory convergence and streamline biosimilar development globally.

Methods: A modified Nominal Group Technique with an international panel of regulators, academics, and industry representatives involved three phases: (i) first individual grading, (ii) focus group discussions, and (iii) second individual grading. High consensus was defined as ≥80% agreement with a weighted mean score of ≥ 4.0.

Results: Overall, four focus groups were held in September 2023 with 21 participants (2 academics, 7 regulators, and 12 industry representatives). In total, 22 recommendations were proposed, with 16 obtaining high consensus. Highest-rated recommendations included enhancing stakeholder education on science-based biosimilarity principles (mean score: 4.65/5), promoting regulatory convergence through reliance (mean score: 4.65/5), aligning regulatory requirements based on current scientific knowledge (mean score: 4.60/5), reconsidering the requirement for comparative clinical efficacy studies (mean score: 4.65/5), harmonizing reference product selection criteria (mean score: 4.55/5), facilitating proactive knowledge sharing among regulators (mean score: 4.50/5), eliminating in vivo animal studies (mean score: 4.50/5), and accepting clinical studies conducted for global submissions (mean score: 4.50/5). Two recommendations received the lowest consensus: providing incentives for the development of new pharmacodynamic biomarkers (mean score: 2.80/5) and developing distinct International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines for biosimilar assessment (mean score: 3.20/5).

Conclusions: The consensus-based recommendations identified in this study outline priority areas and measures for streamlining biosimilar development and fostering regulatory convergence.

Anti-CD20 monoclonal antibodies are gaining clinical relevance in the nephrology community due to their demonstrated efficacy and favorable safety profiles across short-, medium-, and long-term use. Initially developed for hematologic malignancies and multiple sclerosis, B-cell depletion therapies are now being investigated across a broader spectrum of autoimmune diseases, including glomerulopathies, both with and without associated podocytopathy. Recent advances have led to the development of novel anti-CD20 agents that are being used not only as potential alternatives to corticosteroids but also as adjunctive therapies in complex clinical settings. However, their efficacy is not uniform across all conditions, whether used for induction therapy, relapse management, or as rescue treatment following first-line therapy failure. A thorough understanding of their mechanisms of action, along with the potential for resistance and therapeutic failure, is essential for advancing precision medicine in this field. This review provides a molecular and clinical overview, incorporating pharmacokinetic and pharmacodynamic insights into the most widely used and emerging anti-CD20 monoclonal antibodies in nephrology. It serves as a practical guide to understand how these agents' function, why they may fail, and what alternative strategies should be considered in cases of adverse reactions or inadequate response. Finally, it highlights their evolving role in precision therapy, both as monotherapy in podocytopathies and as part of a multi-targeted treatment approach for glomerular diseases with systemic involvement.

Background: Advanced therapy medicinal products (ATMPs) often require long-term monitoring to assess both safety and efficacy post-authorisation due to uncertainties identified during the approval process. This study aims to characterise the use of real-world data (RWD) in post-authorisation measures (PAMs) for ATMPs approved in the European Union.

Methods: A systematic extraction of all PAMs from publicly available European Medicines Agency (EMA) regulatory documents for ATMPs approved between January 2013 and December 2024 was performed, followed by the identification of the presence and sources of RWD. Additional databases including the HMA-EMA Catalogue of RWD studies and sources and ClinicalTrials.gov were consulted.

Results: Amongst 25 ATMPs approved by the European Commission over the study period, a total of 118 PAMs were identified, of which 49 (41.5%) involved RWD. Most RWD-PAMs were imposed by the EMA (n = 34; 69.4%), secondary data use was the most referenced data use type (n = 28; 57.1%) and registries were the main source of RWD being mentioned (n = 26; 53.1%). Further, 5 (10.2%) included a comparator group and 13 (32.5%) incorporated patient-reported outcomes.

Conclusions: This study emphasises the instrumental role of RWD in the post-authorisation monitoring of ATMPs in the European Union. PAMs reflect the regulatory flexibility for these products, shifting some efforts to the post-authorisation phase to address benefit-risk gaps. Enhancing the use of RWD in this context could improve evidence generation, minimise uncertainties and support more informed regulatory decisions.

The interplay between inflammatory bowel disease pharmacotherapies and the gut microbiota is increasingly recognized as a pivotal factor influencing treatment efficacy and patient outcomes. This review provides a comprehensive and up-to-date synthesis of the bidirectional interactions between inflammatory bowel disease drugs and gut microbiota, emphasizing the emerging field of pharmacomicrobiomics and associated therapeutic implications. Emerging evidence reveals that microbial composition and function not only shape drug metabolism, bioavailability, and efficacy, but are themselves profoundly altered by pharmacologic interventions. In addition to traditional oral drugs and biological therapy used in inflammatory bowel disease, recent approvals of Janus kinase inhibitors, sphingosine-1-phosphate receptor modulators as well as late-stage developmental drugs indicate that drug-microbiota interactions may increase in prominence. Understanding these intricate interactions offers significant potential: microbial signatures may help guide therapeutic decisions as companion diagnostic tools, helping clinicians predict the therapeutic outcome. Moreover, targeted manipulation of the microbiota may open entirely new avenues to complement and enhance the effectiveness of established inflammatory bowel disease therapies. By illuminating current knowledge, knowledge gaps, and future research directions, this review underscores the potential of integrating pharmacomicrobiomic insights into the next generation of personalized inflammatory bowel disease care.

Since blinatumomab's approval as the first bispecific antibody (BsAb) in cancer therapy, these immunomodulatory agents have achieved substantial success in lymphoid malignancies. A decade after provisional approval in relapsed settings, blinatumomab became part of first-line induction therapy for patients with B-cell acute lymphoblastic leukemia (B-ALL). Now, six additional BsAbs have FDA approvals for the treatment of B-cell non-Hodgkin's lymphomas and multiple myeloma (MM), achieving high response rates in otherwise refractory scenarios. In lymphoma, epcoritamab, glofitamab, and mosunetuzumab show proof-of-principle for complete remission (CR) without chemotherapy or cell-based treatment. Single-agent remissions do not appear durable, but fortunately, these immunotherapies are readily combined with other treatment modalities. Therefore, their true potential to contribute to cures may be close on the horizon owing to ongoing and future trials. In MM, teclistamab, talquetamab, and elranatamab achieve impressive CR rates in the relapsed setting and similarly, are being investigated in earlier line combinations and in precursor entities such as smoldering myeloma and monoclonal gammopathy of undetermined significance (MGUS). With a unique mechanism of action and continued testing in earlier lines, BsAbs are poised to be among the winners in the race to the frontline treatment of hematologic malignancies.

Background: Increasing therapeutic options for inflammatory bowel disease calls for tools to aid choice of sequencing. We investigated if pharmacokinetic (PK) and pharmacodynamic (PD) failure mechanisms prompting therapy change influenced subsequent outcomes when switching to a different biologic drug class.

Methods: Retrospective single-center cohort study including patients treated first with tumor necrosis factor (TNF) inhibitors, followed by vedolizumab, and then ustekinumab. Clinical and objective disease remission were conventionally classified by validated indices. PK-PD failure was defined according to maintenance drug concentrations (PK below thresholds and PD above thresholds): infliximab 8.0 µg/mL, adalimumab 12.0 µg/mL, golimumab 1.4 µg/mL, vedolizumab 15 µg/mL. Primary treatment failure despite dose intensification was ascribed to PD. Primary endpoints were steroid-free treatment persistence and 1-year remission.

Results: The study included 112 patients switching from TNF inhibitors to vedolizumab (infliximab n = 61, adalimumab n = 32, golimumab n = 16, certolizumab pegol n = 3) and 31 subsequently to ustekinumab. Treatment persistence on vedolizumab did not differ between patients discontinuing TNF inhibitors due to PK (n = 28, 31%) or PD (n = 63, 69%) (mean 989 days [95% confidence interval: 554-1424] vs. 951 [659-1242], p = 0.93). One-year steroid-free clinical and objective remission rates on VDZ were also comparable between PK-PD groups (29% vs. 35%, p = 0.63 and 35% vs. 43%, p = 0.48, respectively). Findings for UST were similar. Sensitivity analyses with exclusion of primary non-responders and multivariate analyses correcting for potential confounders supported findings.

Conclusion: PK-PD failure mechanisms do not appear to influence subsequent treatment outcomes when switching to biologics with different modes of action. Sequencing may rather rely on aspects such as efficacy, safety, and costs.

Despite the modern era of effective and safe high-intensity statins and non-statin agents, a significant portion of patients are still unable to achieve guideline-recommended lipid goals for the prevention of atherosclerotic cardiovascular disease (ASCVD) events. Accordingly, novel strategies are needed to further mitigate residual risk for patients on the background of maximally tolerated lipid-lowering therapies. The past decade has seen an explosion of new agents leveraging ribonucleic acid (RNA)-based technology which reduce plasma lipoprotein levels. In this state-of-the-art review, we examine the ongoing clinical development of lipid-lowering RNA therapeutics. We discuss the efficacy and safety profiles of antisense oligonucleotides and small interfering RNA agents targeting low-density lipoprotein, lipoprotein(a), and triglyceride-rich lipoproteins. We also present challenges future clinical trials must answer to prove RNA therapeutics as a viable strategy for ASCVD prevention among patients with refractory hyperlipidemia.

Comparative immunogenicity is a key regulatory requirement for biosimilars. In a streamlined biosimilar development process, absent a comparative clinical efficacy study, the analytical data and clinical pharmacokinetics (PK) study need to provide sufficient evidence for a conclusion of comparable immunogenicity. In this case study, we have reviewed the role of analytical and clinical data in the immunogenicity assessment of all currently available ustekinumab biosimilars and their reference product. Public information for European Medicines Agency-and US Food and Drug Administration-approved biosimilars reveal that the single-dose clinical PK studies were sensitive in detecting differences in terms of immunogenicity between the biosimilar and the reference product, a finding that was replicated in the comparative clinical efficacy studies. The rates for anti-drug antibodies and neutralizing antibodies were comparable albeit numerically lower for all biosimilars compared to their reference product, which correlates with lower levels of non-human glycans such as α-1,3 galactose known to be potentially relevant for immunogenicity. Our study demonstrates that the single-dose clinical PK studies were sensitive in confirming comparable immunogenicity of ustekinumab biosimilars with their reference product. The comparative clinical efficacy studies revealed no additional information. This finding adds on to the evidence that clinical PK and the comparative analytical assessment, specifically the comparison of quality attributes with potential immunogenic relevance, suffice for the evaluation of immunogenicity of biosimilars in general.

Background and objective: Denosumab is a fully human monoclonal antibody (IgG2) k subclass that targets and binds with high affinity and specificity to receptor activator of nuclear factor-κB ligand (RANKL). Gedeon Richter's denosumab RGB-14-P and RGB-14-X are proposed biosimilar drug products to the reference medicinal products Prolia^® and Xgeva^® (marketing authorisation holder: Amgen Europe B.V. in the European Union [EU] and Amgen Inc. in USA, respectively). The present study demonstrates the structural, physico-chemical and functional similarity between RGB-14 and reference drug products marketed in the EU and US.

Methods: Using an extensive, state-of-the-art analytical and functional panel of 38 methods ensured the comprehensive characterisation of the biosimilar and reference drug products. To assess biosimilarity, physico-chemical and biological functional tests were performed using multiple orthogonal techniques, in addition to the in-depth comparison of the primary and higher-order structures of the therapeutic proteins.

Results: It has been demonstrated that the primary and higher order structures of RGB-14-P and RGB-14-X drug products are identical or highly similar to those of EU/US Prolia^® and Xgeva^®. The purity profiles of the biosimilar and reference products were similar. Only minor differences were observed in glycosylation patterns and charge variant profiles. A wide range of bioassays was used demonstrating similarity in terms of potency, ligand and receptor binding. Additionally, during comprehensive analysis of the reference product data as the function of expiry dates, shifts were revealed in certain quality parameters, although these did not impact the biological activity of the products.

Conclusion: The extensive analytical and functional similarity assessment study provides robust evidence that the structure and function of RGB-14-P and RGB-14-X are highly similar to those of EU/US Prolia^® and Xgeva^®.