Search Results (241)

Introduction: Oncological diseases are one of the leading causes of mortality worldwide, with the high cost of therapies representing a critical barrier for health systems. Generic drugs have emerged as an alternative to reduce costs and improve access; however, their quality, safety, and efficacy remain a subject of regulatory and clinical debate. This issue is particularly sensitive in oncology, where generics often involve cytotoxic agents, narrow therapeutic indices, and complex formulations, all of which amplify the risks of therapeutic interchangeability. Materials and Methods: A multidisciplinary team composed of 19 experts in oncology, hepatology, gastroenterology, toxicology, endocrinology, and pharmacology was convened based on established academic contributions, clinical expertise, and participation in regulatory or guideline development. Evidence was synthesized through a non-systematic narrative review of PubMed, Embase, and regional databases. Consensus recommendations were developed using a two-round Delphi process, with agreement defined as ≥75%. Results: The Delphi panel produced six key recommendations: (1) stricter requirements for bioequivalence and bioavailability, tailored to oncology; (2) strengthened pharmacovigilance and real-world monitoring; (3) standardized protocols for therapeutic interchangeability, particularly for narrow therapeutic index agents; (4) active physician involvement in formulary decision-making; (5) harmonized regional regulatory frameworks, informed by FDA and EMA standards; and (6) expanded research on oncology-specific pharmacokinetic markers. While safety concerns dominated discussions, experts also acknowledged the potential of generics to reduce costs, improve equity, and enhance the sustainability of oncology care. Conclusions: The findings underscore the need for oncology-specific regulatory frameworks that extend beyond conventional bioequivalence standards. A balance is required: cost savings and equity gains offered by generics must be matched with robust safety mechanisms, regulatory harmonization, and physician-led oversight. Future research should expand expert representation, integrate real-world data, and address biosimilars in dedicated analyses to ensure safe and equitable integration of non-innovator therapies in cancer care. Full article

Peptide mapping is a well-established method for confirming the identity of therapeutic proteins as part of batch release testing and product characterization for regulatory filings. Traditionally based on enzymatic digestion followed by reversed-phase liquid chromatography and UV detection, the method has evolved with technological advancements to incorporate mass spectrometry (MS), enabling more detailed structural insights. Residue-level confirmation of amino acid sequences requires MS/MS fragmentation, which produces large amounts of data that must be processed using specialized software. In regulated environments, the use of academic algorithms is often limited by validation requirements, making it necessary to rely on commercially approved tools, although their built-in scoring systems have limitations that can affect sequence assignment accuracy. Here, we present representative examples of incorrect peptide assignments generated by commercial software. In antibody sequence analysis, misidentifications resulted from isobaric and near-isobaric dipeptides (e.g., SA vs. GT). Additional examples from the analysis of SARS-CoV-2 spike protein variants revealed software-induced artifacts, including artificial succinylation of aspartic acid residues to compensate for sequence mismatches, and incorrect deamidation site assignments due to misinterpretation of isotopic peaks. These findings underscore the necessity for expert manual review of MS/MS data, even when using validated commercial platforms, and highlight the molecular challenges in distinguishing true sequence variants from software-driven artifacts. Full article

Background/Objectives: Advanced hepatocellular carcinoma (HCC) presents limited treatment options; however, immunotherapy demonstrates encouraging outcomes and acceptable adverse reactions in advanced HCC. This study evaluates the efficacy and safety of combining serplulimab, the bevacizumab biosimilar HLX04, and hepatic arterial infusion chemotherapy (HAIC) as a first-line therapy. Methods: This prospective, observational, single-center phase II trial enrolled untreated HCC patients with Barcelona Clinic Liver Cancer (BCLC) stage C. All patients received serplulimab (4.5 mg/kg) and HLX04 (15.0 mg/kg) every 3 weeks, followed by the HAIC-FOLFOX regimen. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival (PFS), and safety. Results: A total of 32 patients were enrolled. The best outcomes showed an ORR of 53.1%, including 17 partial responses (PR, 53.1%) and 12 stable diseases (SD, 37.5%), resulting in a DCR of 90.6%. Subgroup analysis showed a higher ORR in patients with a single lesion and those receiving ≥3 treatment cycles, with an ORR of 60.7% in the latter group. Additionally, five patients underwent successful hepatectomy after ≥3 treatment cycles, with postoperative pathology confirming extensive tumor necrosis. Kaplan–Meier analysis estimated PFS rates of 89.9% (95% CI: 79.5–100.0%) at 6 months and 70.8% (95% CI: 54.2–92.4%) at 12 months. No deaths related to adverse events (AEs) occurred; four (12.5%) patients experienced grade IV AEs and twelve (37.5%) patients experienced grade III AEs. Conclusions: Serplulimab, HLX04, and HAIC combined as a first-line treatment for advanced HCC have demonstrated promising efficacy, particularly in patients completing ≥3 cycles, with an acceptable safety profile. Further investigation in larger trials is required. Full article

Background/Objectives: The use of artificial intelligence (AI) in oncology has the potential to improve decision making, particularly in managing the risk associated with targeted therapies. This study aimed to develop and validate a machine learning-based clinical decision support system (CDSS) capable of predicting complications associated with Bevacizumab or its biosimilars and to translate the resulting predictive model into a clinically applicable tool. Methods: A prospective observational study was conducted on 395 records from patients treated with Bevacizumab or biosimilars for solid tumors. Pretherapeutic variables, such as demographic data, medical history, tumor characteristics and laboratory findings, were retrieved from medical records. Several machine learning models (logistic regression, Random Forest, XGBoost) were trained using 70/30 and 80/20 data splits. Their predictive performances were compared using accuracy, AUC-ROC, sensitivity, specificity, F1-scores and error rate. The best-performing model was used to derive a logistic-based risk score, which was further implemented as an interactive HTML form. Results: The optimized Random Forest model trained on the 80/20 split demonstrated the best balance between accuracy (70.63%), sensitivity (66.67%), specificity (73.85%), and AUC-ROC (0.75). The derived logistic risk score showed good performance (AUC-ROC = 0.720) and calibration. It identified variables, such as age ≥ 65, anemia, elevated urea, leukocytosis, tumor differentiation, and stage, as significant predictors of complications. The final tool provides clinicians with an easy-to-use, offline form that estimates individual risk levels and stratifies patients into low-, intermediate-, or high-risk categories. Conclusions: This study offers a proof of concept for developing AI-supported predictive tools in oncology using real-world data. The resulting logistic risk score and interactive form can assist clinicians in tailoring therapeutic decisions for patients receiving targeted therapies, enhancing the personalization of care without replacing clinical judgment. Full article

Background/Objectives: Formulating recombinant therapeutic proteins is essential to ensure their safety, efficacy, and stability. A growing trend in biopharmaceutical development is the move toward buffer-free formulations, which aim to reduce immunogenicity, improve tolerability, and simplify production. This review explores technological advances, regulatory perspectives, and safety considerations related to this shift. Methods: A systematic documentary review was conducted using the PSALSAR framework. Scientific publications, patents, and regulatory documents (2020–2025) were retrieved from PubMed, Scopus, Web of Science, and regulatory databases (FDA, EMA). Inclusion criteria focused on recombinant proteins, buffer-free formulations, and regulatory alignment. Results: The findings reveal an increasing adoption of self-buffering strategies in high-concentration subcutaneous biologics. Technologies such as Fc-fusion, PASylation, and XTENylation enhance stability without conventional buffers. Regulatory bodies are progressively accepting minimalist formulations, provided safety and biosimilarity are demonstrated. However, intellectual property barriers limit formulation transparency. A synthesis of recent FDA and EMA approvals illustrates this formulation evolution. Conclusions: Buffer-free formulations offer a promising alternative for therapeutic protein development by improving patient experience and reducing formulation complexity. They align with biosimilar goals and regulatory trends, although long-term transparency and safety assessments remain critical for widespread adoption. Full article

Background/Objectives: MB09 is a denosumab biosimilar to the reference products (RPs) Xgeva and Prolia. A population pharmacokinetic (popPK) meta-analysis was conducted to characterize the denosumab PK profile and to support MB09 biosimilarity. Methods: Pooled denosumab PK data from one phase I study [255 healthy adult men receiving a single 35 mg subcutaneous (SC) dose] and one phase III study (555 postmenopausal women with osteoporosis receiving two 60 mg SC doses, one every six months) were used. A one-compartment model with first-order absorption and elimination and parallel non-linear saturable clearance was used. Body weight was included on clearance as a structural covariate and treatment was tested as a covariate on all PK parameters. PK biosimilarity was assessed at 35 mg dose. Results: For a 70 kg subject, the apparent clearance and central volume of distribution for denosumab were 0.123 L/day [95% confidence interval (CI): 0.114, 0.132] and 9.33 L (95% CI: 9.11, 9.55), respectively. The Michaelis constant was 0.124 ng/mL and the maximum rate for the non-linear clearance was 0.139 ng/day. Model-based bioequivalence criteria were met for RP Xgeva, European and US-sourced, versus MB09 for a dose of 60 mg SC. The mean area under the plasma concentration curve (AUC) resultant from the simulation of MB09 120 mg SC was similar to the published mean AUC observed for Xgeva 120 mg SC every four weeks. Conclusions: This analysis provides a valuable assessment of denosumab PK characteristics and elucidates in more detail how the MB09 PK profile compares to the denosumab RPs, supporting the totality of evidence on MB09 biosimilarity. Full article

Background/Objectives: Forced degradation studies are critical for identifying potential degradation pathways of monoclonal antibodies (mAbs), particularly under thermal stress. Due to their structural complexity and sensitivity to elevated temperatures, mAbs are prone to fragmentation, aggregation, and post-translational modifications. This study aimed to evaluate and compare the degradation profiles of biosimilar anti-VEGF mAb and its originator counterparts sourced from both the United States (U.S.) and the European Union (EU) under thermal stress conditions. To our knowledge, this represents one of the few studies conducting a direct head-to-head comparability assessment across biosimilar and two geographically sourced originators, integrating orthogonal analytical approaches. Methods: Biosimilar candidate and originator products (U.S. and EU) were incubated at 37 °C and 50 °C for 3, 7, and 14 days. Fragmentation profiles were assessed using validated non-reduced and reduced capillary electrophoresis–sodium dodecyl sulfate (CE-SDS) methods. Additionally, size-exclusion ultra-performance liquid chromatography (SE-UPLC) and liquid chromatography–tandem mass spectrometry (LC-MS/MS) assays were performed on samples stressed for 14 days to provide deeper insights into degradation pathways. Results: Non-reduced CE-SDS analysis indicated a time- and temperature-dependent increase in low-molecular-weight fragments and a corresponding decrease in the intact form, with more pronounced effects observed at 50 °C. Reduced CE-SDS revealed a more rapid increase in total impurity levels at 50 °C, accompanied by a decrease in total light and heavy chain content. SE-UPLC showed enhanced aggregation under thermal stress, more pronounced at 50 °C. LC-MS/MS analysis identified increased asparagine deamidation in the PENNY peptide and pyroglutamic acid formation (pE) at the N-terminus of the heavy chain. Conclusions: The degradation profiles of the biosimilar and originator mAbs were highly comparable under thermal stress, with no significant qualitative differences detected. By applying a multi-tiered analytical characterization technique, this study provides a comprehensive comparability assessment that underscores the robustness of biosimilarity even under forced degradation conditions. Full article

Introduction. The Italian Committee for Tailored BIOlogic Therapy (ITABIO), in a first report, has reviewed the literature to identify the best strategy for the choice of second-line biologic therapy in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA). To verify the application of ITABIO recommendations in real life and how the recommendations perform in maintaining the health status of patients affected by inflammatory arthritis (RA, SpA, PsA), a database has been developed by Pharmaceutical Governance to evaluate the appropriateness of prescriptions. Methods. We have analyzed retrospectively 616 patients, 288 (46.7%) affected by RA, 117 (19%) affected by SpA, and 211 (34.3%) affected by PsA. Age, sex, diagnosis, current treatment, previous treatments with csDMARDs, b-DMARDs, ts-DMARDs, presence of risk factors for cardiovascular (CV) events, liver disease, infections, extra-articular manifestations such as interstitial lung disease (ILD) for RA, enthesitis, dactylitis, uveitis, inflammatory bowel disease for SpA and PsA, neoplasms, diabetes, presence or absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) for RA were evaluated. Results. The percentage of treatments with anti-TNF biosimilars was 65.1, 52.4, and 24.3% in SpA (76 patients(pt)), PsA (110 pt), and RA (69 pt), respectively. The percentage of monotherapy was 68% (418 pt) in the three diseases. For RA, 34.2% of patients were difficult to treat (D2T) (98 pt), 54.8% (157 pt) were in monotherapy (tocilizumab-sarilumab-upadacitinib-filgotinib). Abatacept was the most prescribed treatment in RF and ACPA-positive patients and in those with ILD. The anti-IL-17A secukinumab was prescribed in 12% of SpA, of which 71% had enthesitis and dactylitis (14 pt). Ixekizumab was prescribed in 10.4% of PsA patients over 65 years with previous CV events, enthesitis, and dactylitis (21 pt). Apremilast was present in 71% of PsA with previous cancer. Conclusions. The cross-sectional analysis of prescriptions in patients with RA, SpA, and PsA demonstrates how the ITABIO recommendations can guide towards the correct appropriateness of prescription. RA and especially D2T-RA remains the disease with the greatest therapeutic failures, with the highest percentage of monotherapy (anti-IL-6 and Jak-i) and of discontinuation of MTX. Full article

The biopharmaceutical industry is undergoing a fundamental transformation from traditional batch manufacturing to continuous manufacturing (CM) for recombinant drugs and biosimilars, driven by regulatory support through the International Council for Harmonization (ICH) Q13 guidance and compelling economic advantages. This comprehensive review examines the technical, economic, and regulatory aspects of implementing continuous manufacturing specifically for recombinant protein production and biosimilar development, synthesizing validated data from peer-reviewed research, regulatory sources, and global implementation case studies. The analysis demonstrates that continuous manufacturing offers substantial benefits, including a reduced equipment footprint of up to 70%, a 3- to 5-fold increase in volumetric productivity, enhanced product quality consistency, and facility cost reductions of 30–50% compared to traditional batch processes. Leading biomanufacturers across North America, Europe, and the Asia–Pacific region are successfully integrating perfusion upstream processes with connected downstream bioprocesses, enabling the fully end-to-end continuous manufacture of biopharmaceuticals with demonstrated commercial viability. The regulatory framework has been comprehensively established through ICH Q13 guidance and region-specific implementations across the FDA, EMA, PMDA, and emerging market authorities. This review provides a critical analysis of advanced technologies, including single-use perfusion bioreactors, continuous chromatography systems, real-time process analytical technology, and Industry 4.0 integration strategies. The economic modeling presents favorable return-on-investment profiles, accompanied by a detailed analysis of global market dynamics, regional implementation patterns, and supply chain integration opportunities. Full article

Quantum mechanics (QM) revolutionizes drug discovery by providing precise molecular insights unattainable with classical methods. This review explores QM’s role in computational drug design, detailing key methods like density functional theory (DFT), Hartree–Fock (HF), quantum mechanics/molecular mechanics (QM/MM), and fragment molecular orbital (FMO). These methods model electronic structures, binding affinities, and reaction mechanisms, enhancing structure-based and fragment-based drug design. This article highlights the applicability of QM to various drug classes, including small-molecule kinase inhibitors, metalloenzyme inhibitors, covalent inhibitors, and fragment-based leads. Quantum computing’s potential to accelerate quantum mechanical (QM) calculations is discussed alongside novel applications in biological drugs (e.g., gene therapies, monoclonal antibodies, biosimilars), protein–receptor dynamics, and new therapeutic indications. A molecular dynamics (MD) simulation exercise is included to teach QM/MM applications. Future projections for 2030–2035 emphasize QM’s transformative impact on personalized medicine and undruggable targets. The qualifications and tools required for researchers, including advanced degrees, programming skills, and software such as Gaussian and Qiskit, are outlined, along with sources for training and resources. Specific publications on quantum mechanics (QM) in drug discovery relevant to QM and molecular dynamics (MD) studies are incorporated. Challenges, such as computational cost and expertise requirements, are addressed, offering a roadmap for educators and researchers to leverage quantum mechanics (QM) and molecular dynamics (MD) in drug discovery. Full article

The formulation of biosimilar products critically determines their stability, safety, immunogenicity, and market accessibility. This article presents a novel integrative framework for biosimilar formulation that balances scientific, regulatory, and intellectual property dimensions, offering a holistic perspective rarely unified in the literature. It highlights the growing trend toward buffer-free, high-concentration systems that leverage protein self-buffering to improve patient comfort and formulation stability. The article also addresses regulatory flexibility from the FDA and EMA, which allows scientifically justified deviations from reference formulations to ensure pharmaceutical equivalence and minimize immunogenicity. A novelty of this article is its comprehensive analysis of how digital innovations, such as Quality-by-Design, Process-Analytical-Technology, and AI-based in silico simulations, are transforming formulation design and bioprocess optimization to reduce immunogenic risks and enhance bioequivalence. Two important key takeaways emerge: (1) strategic innovation in formulation, especially using buffer-free and high concentration systems, improve product stability and patient tolerability while complying with regulatory standards; and (2) intellectual property challenges, including patent thickets, strongly influence formulation decisions, making early legal-strategic alignment essential for market entry. The article confirms that practical recommendations for the selection of recombinant therapeutic protein formulations can effectively guide developers and regulators toward safer, more efficient, and commercially viable biosimilar products. Full article

Background/Objectives: Long-acting insulin glargine (iGlar) has been available as a biosimilar since 2014 in the UK. We reviewed previous prescribing to evaluate if the anticipated cost savings with biosimilars were realized with iGlar. Methods: This study investigated prescribing patterns of long-acting iGlar (100 units/mL) in cartridges and pre-filled pens from 2020 to 2024 across primary care organizations in England, Northern Ireland, Scotland, and Wales. Results: iGlar prescribing declined in all of the four nations. From 2020 to 2024, the total prescribed quantity of biosimilars persistently increased in all countries, reaching 24% in England, 5% in Northern Ireland, 24% in Scotland, and 11% in Wales, all in 2024. Consequently, the proportion of Lantus prescriptions (as quantity) decreased but continued to exceed that of all available iGlar products combined in all countries in all years analyzed. By 2024, Lantus was also priced lower than the most common biosimilar, Abasaglar, across all nations. Conclusions: The introduction of biosimilars does not automatically result in altered prescribing practices, though we show that the most commonly prescribed iGlar was also the least expensive product at the end of the analysis period. At launch and for several years after, biosimilars failed to gain strong utilization, despite cost advantages, highlighting the need for active switching policies and prescriber engagement. Full article

Background: Recombinant monoclonal antibodies represent a vital category of biologics, constituting the largest class of molecules used to treat autoimmune disorders, cancers, rheumatoid arthritis, and other chronic conditions. The IgG1 subclass is the most potent among all the immunoglobulin gamma (IgG) antibodies, inducing Fc-related effector functions. N-linked glycan distribution of therapeutic IgG1s affects Fc-related effector functions such as CDC (complement-dependent cytotoxicity) and ADCC (antibody dependent cell-mediated cytotoxicity) biological activities and efficacy in vivo. Hence, as a critical quality attribute (CQA), the glycosylation profile of therapeutic IgG1s must be consistently preserved, which is primarily influenced by manufacturing process factors. In the era of biosimilars, it is challenging for biopharmaceutical manufacturers to not only obtain the desired glycan distribution consistently but also to meet the innovator molecule specifications as per the regulatory agencies. Methods: This study investigates the CHO fed-batch process parameters that affect the titer and terminal galactosylation of the TNF-α blocker-IgG1. It was hypothesized that galactose supplementation would enhance the galactosylation of TNF-α blocker-IgG1. Results: It was observed that such in-cultivation process shift does not affect cell culture parameters yet significantly enhances the galactosylation of TNF-α blocker-IgG1. Interestingly, the results indicate that supplementing D-galactose from the exponential phase of the CHO fed-batch process had the greatest effect on Fc galactosylation, increasing the amount of total galactosylated TNF-α blocker-IgG1 from 7.7% to 15.8%. Conclusions: Our results demonstrate a relatively easy and viable technique for cell culture engineering that is more appropriate for industrial production than costly in vitro glycoengineering. Full article

The discovery of new drugs offers valuable alternatives, particularly for treating diseases that are resistant to existing therapies or involving complex, multi-organ conditions such as metabolic syndrome. Although treatment algorithms are generally well established and primarily based on synthetic pharmaceuticals, they are increasingly being supplemented by biological and biosimilar agents. This trend is particularly evident in the development and advancement of anti-diabetic and hypolipemic therapies. This review explores advances in the treatment of hypercholesterolemia and hypertriglyceridemia, elevated lipoprotein(a) [Lp(a)], diabetes, and obesity associated with metabolic syndrome. It focuses mainly on biopharmaceuticals such as proteins and nucleotide-based drugs (antisense oligonucleotides, small interfering RNA), but also on dipeptidyl peptidase-4 (DPP-4) inhibitors classified as incretin drugs along with glucagon-like peptide-1 (GLP-1) analogues. Due to the substantial role of SGLT-2 (sodium/glucose cotransporter 2) inhibitors in novel diabetes therapies, especially for managing cardiovascular risk, this group of compounds was also included in this review. Many clinical data in the field of effectiveness of biopharmaceuticals in metabolic disorders are provided. Therefore, in this review, we mainly include a brief history of drug development and approval, first synthesis and structure modifications, which relevantly influence pharmacokinetics, and safety. We provide only brief comparison of biological drugs with metformin and sulphonylureas derivatives. Databases such as PubMed, Scopus, and Google Scholar are searched for the period between 2000 and 2024. Full article

Background: Biosimilar versions of rituximab have similar safety and efficacy as the reference product across all indications based on the extrapolation principle. Our organization replaced intravenous (IV) rituximab (Mabthera) with IV rituximab (Truxima-Biosimilar) in 2021. Hence, our practice changed to providing first cycles of IV rituximab (Truxima-Biosimilar) instead of rituximab (Mabthera), and if the first cycle was completed without severe infusion-related reactions (IRRs), then subsequent cycles were given with subcutaneous (SC) rituximab as per institutional guidelines. However, the safety of this approach has not been evaluated. Methods: A retrospective study was conducted at the Princess Nourah Oncology Center in Saudi Arabia. The primary objective was to assess IRRs after using IV rituximab (Truxima-Biosimilar) in the first cycle followed by SC rituximab in subsequent cycles. Results: Of the 71 patients reviewed, 35 patients met the eligibility criteria. Only one (3%) patient developed an IRR. However, it was a Grade 1 IRR, as per CTCAE.V5, and the patient was able to complete the remaining IV infusion successfully. Hence, all patients transitioned from IV rituximab biosimilar to SC rituximab Mabthera. Conclusions: This real-world study demonstrates that transitioning from IV rituximab biosimilar to SC Mabthera is a well-tolerated and safe practice, confirming the extrapolation principle of biosimilars. Full article