BackgroundXeligekimab is a novel immunoglobulin G4 (IgG4) monoclonal antibody targeting interleukin-17A (IL-17A). In a phase III trial in patients with plaque psoriasis, xeligekimab showed efficacy and safety consistent with other IL-17A inhibitors, supporting its potential application in the treatment of spondyloarthritis.ObjectiveThis phase III trial aimed to investigate the efficacy and safety of xeligekimab in patients with radiographic axial spondyloarthritis (r-axSpA).MethodsThis was a phase III study conducted at multiple centers in China. Eligible patients were randomly assigned (1:1:1) to receive xeligekimab 100 mg, xeligekimab 200 mg, or placebo. Randomization was stratified by medication history (biologic-experienced vs. biologic-naïve) and weight (≥ 70 kg vs. < 70 kg). The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis International Society 20 (ASAS20) response at week 16. A key secondary endpoint was the ASAS40 response rate at the same time point.ResultsA total of 465 patients were recruited. A significantly higher proportion of patients receiving xeligekimab 200 mg (n = 114 (74.0%); p < 0.001, 95% confidence interval (CI) 28.5–48.4) and xeligekimab 100 mg (n = 102 (65.8%); p < 0.001, 95% CI 19.4–41.0) achieved an ASAS20 response compared to the placebo group (n = 56 (35.9%)) at week 16. Similarly, a significantly higher ASAS40 response rate was observed in the xeligekimab 100 mg group (n = 62 (40.0%); p < 0.001) and the xeligekimab 200 mg group (n = 64 (41.6%); p < 0.001) compared to placebo. Adverse events were similar across all groups, with serious adverse events occurring in 1.6% of the treatment group during the core treatment period. No unexpected safety signals were reported through week 48.ConclusionXeligekimab demonstrated significant efficacy in improving the signs and symptoms of active r-axSpA in Chinese patients at week 16, with sustained effects observed through week 48 and no new safety signals identified.Trial RegistrationClinicalTrials.gov identifier: NCT05881785 (Date: 21 May 2023).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-025-00750-0.

BackgroundAdvanced 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.MethodsA 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.ResultsAmongst 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.ConclusionsThis 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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-025-00737-x.

Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thrombosis in paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy in atypical hemolytic uremic syndrome, respectively. Nevertheless, many patients still have difficulty accessing eculizumab treatment because of its high costs. Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs. Clinical use of biosimilars in Europe in the last 15 years has demonstrated that they are as safe and effective as their reference products, and can also drive cost reductions and increase patients’ access to treatment. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general and the concept of extrapolation in particular.

Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs’ benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.

BackgroundPegunigalsidase alfa is a newly approved drug for the treatment of Fabry disease, designed to increase the plasma half-life and reduce immunogenicity of infused α-galactosidase A (AGAL). We provide the first comprehensive pharmacokinetic and immunogenic data apart from industry-initiated studies.MethodsPharmacokinetics of pegunigalsidase alfa, amino acid, and polyethylene glycol (PEG)-specific antibodies and immune complexes were measured in treated patients (11 switched, two naïve). Measurements were performed in serum samples drawn directly before and after infusions over three to ten consecutive infusions. Only three patients started directly with 1.0 mg/kg body weight.ResultsNo infusion-associated reactions were reported under pegunigalsidase alfa during the observation. Patients without pre-existing neutralizing anti-AGAL antibodies showed high enzymatic AGAL peak activities and sustained AGAL serum concentrations until the next infusion, which was not observed in those with neutralizing anti-AGAL antibodies. Nine (69.2%) patients presented with pre-existing anti-PEG antibodies (IgG or IgM), which seemed to have no impact on pharmacokinetics during the observation. No new anti-PEG or anti-AGAL antibody formation was observed after treatment initiation. Three (75.0%) patients with pre-existing neutralizing anti-AGAL antibodies showed a titer increase and one (25.0%) patient a decrease. In patients with anti-AGAL antibodies (n = 4) immune-complex formation was detected.ConclusionThe pharmacokinetics of pegunigalsidase alfa show different profiles depending on the presence of pre-existing neutralizing antibodies, with reduced plasma half-life and peak enzyme activity after infusion in patients with antibodies. The clinical significance of a reduced pegunigalsidase alfa half-life and the formation of immune complexes in antibody-positive patients needs to be analyzed in future studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-024-00690-1.

Antimicrobial resistance (AMR) can potentially harm global public health. Horizontal gene transfer (HGT), which speeds up the emergence of AMR and increases the burden of drug resistance in mobile genetic elements (MGEs), is the primary method by which AMR genes are transferred across bacterial pathogens. New approaches are urgently needed to halt the spread of bacterial diseases and antibiotic resistance. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), an RNA-guided adaptive immune system, protects prokaryotes from foreign DNA like plasmids and phages. This approach may be essential in limiting horizontal gene transfer and halting the spread of antibiotic resistance. The CRISPR-Cas system has been crucial in identifying and understanding resistance mechanisms and developing novel therapeutic approaches. This review article investigates the CRISPR-Cas system's potential as a tool to combat bacterial AMR. Antibiotic-resistant bacteria can be targeted and eliminated by the CRISPR-Cas system. It has been proven to be an efficient method for removing carbapenem-resistant plasmids and regaining antibiotic susceptibility. The CRISPR-Cas system has enormous potential as a weapon against bacterial AMR. It precisely targets and eliminates antibiotic-resistant bacteria, facilitates resistance mechanism identification, and offers new possibilities in diagnostics and therapeutics.

Gene therapy for many diseases is rapidly becoming a reality, as demonstrated by the recent approval of various nucleic acid-based therapeutics. Non-viral systems such as lipid-based carriers, lipid nanoparticles (LNPs), for delivering different payloads including small interfering RNA, plasmid DNA, and messenger RNA have been particularly extensively explored and developed for clinical uses. One of the most important issues in LNP development is delivery to extrahepatic tissues. To achieve this, various lipids and lipid-like materials are being examined and screened. Several LNP formulations that target extrahepatic tissues, such as the spleen and the lungs have been developed by adjusting the lipid compositions of LNPs. However, mechanistic details of how the characteristics of LNPs affect delivery efficiency remains unclear. The purpose of this review is to provide an overview of LNP-based nucleic acid delivery focusing on LNP components and their structures, as well as discussing biological factors, such as biomolecular corona and cellular responses related to the delivery efficiency.

Inflammatory bowel disease remains a difficult disease to effectively treat, especially fistulizing Crohn’s disease. Perianal fistulas in the setting of Crohn’s disease remain an area of unmet need with significant morbidity in this patient population. Up to one third of Crohn’s patients will have perianal fistulizing disease and current medical and surgical interventions are of limited efficacy. Thus, most patients experience significant morbidity, narcotic use, and loss of employment and end up with multiple surgical interventions. Mesenchymal stem cells (MSCs) have shown efficacy in phase 3 clinical trials, but considerable infrastructure challenges make MSCs limited with regard to scalability in clinical practice. Extracellular vesicles, being derived from MSCs and capturing the secretome functionality of MSCs, offer similar physiological utility regarding mechanism, while also providing an off the shelf regenerative medicine product that could be widely used in daily clinical practice.

Background and ObjectiveBiosimilars represent an opportunity to realise savings against the costs of innovative medicines. Despite efforts made by stakeholders, there are numerous barriers to the uptake of biosimilars. To realise the promise of biosimilars reducing costs, barriers must be identified, understood, and overcome, and enablers magnified. The aim of this systematic review is to summarise the enablers and barriers affecting uptake of biosimilars through the application of a classification system to organise them into healthcare professional (HCP), patient, or systemic categories.MethodsA systematic literature search was performed in PubMed, Scopus, CINAHL, eConlit, and Embase. Included were primary research studies published in English between Jan 2017 through June 2023 focused on enablers and barriers affecting uptake of biosimilars. Excluded studies comprised comparisons of biosimilar efficacy and safety versus the reference biologic. One reviewer extracted data that included classification of barriers or enablers, the sub-classification, and the identification of the degree of agency associated with the actor through their role and associations as a mediator within their network, through the application of Actor Network Theory. The data were validated by a second reviewer (PV).ResultsOf the 94 studies included, 59 were cross-sectional, 20 were qualitative research, 12 were cohort studies, and three were economic evaluations. Within the review, 51 of the studies included HCP populations and 35 included patients. Policies and guidelines were the most cited group of enablers, overall. Systemic enablers were addressed in 29 studies. For patients, the most frequently cited enabler was positive framing of a biosimilar, while for HCPs, cost benefit was the most frequently noted enabler. The most frequently discussed systemic barrier to biosimilar acceptance was lack of effective policies or guidelines, followed by lack of financial incentives, while the most significant barriers for HCPs and patients, respectively, were their lack of general knowledge about biosimilars and concerns about safety and efficacy. Systemic actors and HCPs most frequently acted with broad degree of agency as mediators, while patient most frequently acted with a narrow degree of agency as mediators within their networks.ConclusionsBarriers and enablers affecting uptake of biosimilars are interconnected within networks, and can be divided into systemic, HCP, and patient categories. Understanding the agency of actors within networks may allow for more comprehensive and effective approaches. Systemic enablers in the form of policies appear to be the most effective overall levers in affecting uptake of biosimilars, with policy makers advised to give careful consideration to appropriately educating HCPs and positively framing biosimilars for patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-024-00659-0.