Search Results (234)

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

Background: Dose tapering in patients with psoriatic arthritis (PsA) who achieve sustained treatment targets is a common but underexplored strategy, particularly in those receiving TNFα inhibitor biosimilars (TNFibs). This study aimed to assess the prevalence of dose optimization and identify factors associated with its implementation in clinical practice. Methods: We systematically selected 130 PsA patients with sustained treatment response from a database of individuals treated with advanced therapies. We evaluated the prevalence of dose optimization (defined as sustained dose reduction) and explored associated factors using multivariate logistic regression models. Results: Of the 130 patients, 95 were receiving TNF inhibitors and 35 other advanced therapies. Among those on TNFis, 88 (93%) were treated with TNFibs. A total of 32 patients (24.6%) were undergoing dose optimization, including 30 from the TNFi group (p = 0.002). We found that 7 of the 88 patients on TNFibs (8%) experienced loss of therapeutic response during follow-up. One in three patients on TNFis underwent dose tapering. Factors independently associated with dose reduction included no history of tobacco exposure [OR 3.98, 95%CI: 1.3–14.2; p = 0.021], male sex [OR 3.26, 95%CI: 1.26–9.04; p = 0.018] and use of TNFis as first-line advanced therapy [OR 4.8, 95%CI: 1.7–16.7; p = 0.003]. Conclusions: Approximately one in four PsA patients who achieve sustained treatment targets undergo dose optimization, most commonly with TNFibs. This strategy appears to be more feasible in male patients, non-smokers and those treated with TNFis as a first-line option. Full article

This detailed review looks at how the rules for proving biosimilarity are changing, mainly focusing on the requirements for comparative efficacy studies (CESs). As analytical technologies progress, mounting evidence suggests that when we establish robust analytical similarity and pharmacokinetic equivalence, CESs become less valuable. This review combines findings from over 600 studies on biosimilars found in PubMed (showing that no biosimilar with proven analytical similarity has ever failed a CES), looks at the differences in global regulations on this topic, and explains how the Food and Drug Administration’s pharmacokinetic testing rules for biosimilars are similar to the bioequivalence testing for generics. Finally, specific changes to the Biologics Price Competition and Innovation Act (BPCIA) are suggested to make US rules match the growing global scientific agreement, which could lower development costs and speed up patient access to biosimilars while still keeping safety and effectiveness intact. Full article

Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that leads to significant deterioration in patients’ quality of life. Biologic therapy, including the use of ustekinumab (UST), is a modern approach to treating the moderate to severe form of CD, especially in patients refractory to traditional treatments. UST, which acts as an interleukin IL-12 and IL-23 antagonist, has shown high efficacy in reducing inflammation, improving quality of life, and promoting mucosal regeneration and fistula healing. However, the use of biologic therapies, such as UST, has challenges related to the timing of treatment and patient response, including the problem of immunogenicity. To determine the clinical efficacy and safety profile of UST in the treatment of CD, a review of the literature published in the PubMed database over the last 5 years was conducted. After excluding articles that did not meet the inclusion criteria, we analyzed 42 clinical studies. The review discusses the available data on the efficacy and safety of UST, as well as its comparison with other biologic therapies, such as infliximab and adalimumab. UST, although not significantly greater to adalimumab, has lower immunogenicity and higher treatment retention. The therapeutic value of UST is also confirmed by biosimilars such as ABP 65 and FYB202, which show comparable efficacy and safety profile. The analysis of predictive biomarkers, such as serum drug levels and baseline eosinophil levels, could be an important element in the future personalization of CD treatment. The review’s findings point to the importance of further research to improve the tailoring of therapies to individual patients and improve long-term treatment outcomes. Full article

Background/Objectives: Infliximab biosimilars entered the United States (US) market in November 2016. Uptake of infliximab biosimilars has been slow in adult studies. We aimed to assess variation in the initiation of infliximab biosimilars in a large pediatric cohort. Methods: We performed a retrospective cohort study using data from 2016 to 2023 prospectively collected by the ImproveCareNow (ICN) Network, a multicenter pediatric inflammatory bowel disease (IBD) quality improvement collaborative. Pediatric patients with IBD who started any infliximab therapy were included. Descriptive statistics were used to summarize patient characteristics and changes in the use of infliximab agents. Chi-square or Fisher’s exact tests were used to evaluate differences in infliximab biosimilar initiation over time by race, age, ethnicity, and region. Results: In total, 4602 patients from 73 ICN centers started an infliximab agent. Infliximab biosimilar initiation rose steadily from 1% in 2018 to nearly 42% in 2023, with 88% of centers using biosimilars in 2023. Overall, from 2016 to 2023, the total percentage of patients who were started on an infliximab biosimilar was 17.3%. There were no differences in infliximab biosimilar initiation by age, race, or ethnicity, except in 2020 for age and race. The Midwest, West, and Southwest regions had higher initiation rates of infliximab biosimilars than the rest of the US. Conclusions: The percentage of patients with IBD initiating an infliximab biosimilar rose slowly to nearly 42% by 2023, and eight (12%) centers never recorded prescribing an infliximab biosimilar in the ICN Network. There were no differences in biosimilar initiation based on race or ethnicity. Full article

O-glycosylation is a common post-translational modification on extracellular and secreted proteins driving biochemical and biophysical interactions at the cell surface. Glycosylation affects drug immunogenicity, efficacy, and clearance, making it a critical attribute of biotherapeutics. Unlike N-linked glycans, O-linked glycans are difficult to characterize because there is no consensus sequence for glycosylation sites on the polypeptide and a universal enzyme to release O-glycans from proteins. To overcome these hurdles, O-glycan analysis and localization require an appropriate and well-validated approach, particularly for recombinant human follicle stimulating hormone-C-terminal peptide (rhFSH-CTP). FSH-CTP consists of a native FSH α/β subunit fused with the C-terminal fragment of a human chorionic gonadotropin (hCG) β subunit, which is heavily O-glycosylated. However, few FSH-CTP O-glycosylation identification methods exist. Thus, we developed a characterization method for the O-linked glycan profile and glycosylation sites of rhFSH-CTP. By means of O-glycan profiling, we identified predominantly core 1-based structures with good reproducibility. For site-specific localization, the O-glycopeptidase OpeRATOR, used with sialidase, helped identify O-glycosylated peptides. Electron transfer/higher-energy collision dissociation (EThcD), combined with OpeRATOR, identified all six glycosylation sites. This approach improves quality control for rhFSH-CTP biosimilars and other CTP-fusion proteins, contributing to the development of standardized O-glycan identification methods. Full article

Aims: To describe and analyze trends in the utilization, spending, and average per prescription price of disease-modifying antirheumatic drugs (DMARDs) in the US Medicaid population. Methods: Using the publicly available national outpatient Medicaid State Drug Utilization Data, a retrospective, descriptive trend analysis was conducted on DMARDs from 1991 to 2022. Annual prescription counts and reimbursement amounts were calculated for nonbiologic and biologic DMARDs. Average per prescription price and Market share competition were calculated and analyzed for DMARDs. Results: Medicaid utilization of nonbiologic peaked in 2021 with 884,000 while biologic DMARDs with 688,000 prescriptions. In 2022, biologic utilization took the lead and exceed nonbiologic with 1.5 million prescriptions. Over the last 32 years, biologics captured 94% of Medicaid expenditures toward DMARDs, of which, 56% was toward adalimumab alone. On the other hand, spending on conventional DMARDs accounted for 33% while 67% accounted toward Janus Kinase Inhibitors. Biologic DMARDs average prices increased from around $800 to around $6000. However, the average adalimumab price increased 12-fold from around $1200 in 2003 to over $15,000 in 2021. Medicaid spending toward adalimumab increased by 179%. Conclusions: The substantial increase of DMARDs utilization and expenditure contributed significant burden to Medicaid budget. Introducing biosimilars into the market in the past few years is eroding the market share for several established biologics. Further cost-containment policies may be necessary for costly DMARD pharmacotherapy. Full article

The use of adalimumab biosimilars has become increasingly common in clinical practice, reflecting their growing acceptance and efficacy as therapeutic alternatives to reference biologics. However, studies investigating the molecular interactions between anti-adalimumab antibodies (AAA) elicited in patients and different adalimumab biosimilars remain limited. This study aims to characterize the kinetic interactions between purified AAA from pediatric patients with Juvenile Idiopathic Arthritis and three adalimumab formulations: the originator Humira^®, and the biosimilars GP2017 (Hyrimoz^®) and SB5 (Imraldi^®). For this purpose, adalimumab formulations were immobilized on a gold chip, and purified AAA were flowed to perform further kinetic analysis using the surface plasmon resonance (SPR) technology. Results showed that the K_D values for purified AAA from patients treated with biosimilars GP2017 (Hyrimoz^®) or SB5 (Imraldi^®) were comparable across all formulations tested, including the originator Humira^®. AAA interacted with Humira^®, Hyrimoz^®, and Imraldi^® with similar apparent affinity (10⁻⁹ M > K_D > 10⁻¹⁰ M); slight variations have been observed among patients, less among biosimilars. The similarity in K_D values across biosimilars and the originator supports the notion that, at the level of immunogenicity, biosimilars can be considered clinically comparable to the originator. Full article