BioDrugs最新文献

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune disease that results in recurring, often severe attacks on the optic nerves and spinal cord that may result in profound visual loss and paralysis. Since the late 1990s, NMOSD was treated with traditional immunosuppressive therapies. Recently, four monoclonal antibodies (mAbs) were granted Food and Drug Administration approval for aquaporin-4 antibody (AQP4-IgG)-seropositive NMOSD treatment: eculizumab, inebilizumab, satralizumab, and ravulizumab. These targeted immunomodulatory therapies have emerged as a transformative approach to effectively reduce NMOSD attack frequency in AQP4-IgG-seropositive patients. We explore the role of these preventative mAbs for NMOSD management by reviewing the efficacy, safety, mechanisms of action, and administration of these agents, and compare them to rituximab and traditional immunosuppressants. We discuss therapy selection and the clinical challenges of therapeutic management, including medication adherence, therapeutic monitoring strategies, economic considerations, and medication accessibility, while managing therapy failure and indications for transitioning to alternative therapies.

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves' disease. It is an autoimmune disorder that may present with signs of inflammation and extracellular matrix modification, leading to the characteristic features of swelling within the orbit, proptosis, diplopia, and vision loss. Recently, a growing body of work has focused on novel therapies for the treatment of TED. We review novel therapeutic agents aimed at treating TED. A review of the literature was performed through search of PubMed, Scopus, and Web of Science databases for terms related to the treatment of TED. There are multiple therapeutic agents available for the treatment of TED, focusing on the different molecular pathways that are dysregulated in the pathogenesis of the condition. Therapeutic targets include: B cells (rituximab), cytokines (interleukin [IL]-6] and IL-11), insulin-like growth factor 1 receptor, and antibodies (neonatal fragment crystallizable receptor). Currently, clinical evidence supports the use of anti-insulin-like growth factor 1 receptor therapy. However, research involving anti-IL-11, anti-IL-6, and the neonatal fragment crystallizable receptor is promising.

The introduction of biosimilars into healthcare systems globally is recognized by many as a healthcare success. Despite this, questions have been raised about whether biosimilars can deliver sufficient value to patients and healthcare professionals, as well as sufficient cost saving, for their use in treatment to be worthwhile. In this review, we discuss how the increasing financial burden of complex therapeutic medicines, such as biologics, can be ameliorated by off-patent biosimilar medicines, particularly with increasing worldwide incidences of cancer and other chronic diseases. We then describe real-world cases that demonstrate the significant direct and indirect benefits of biosimilars to patients and healthcare systems beyond costs. Healthcare sustainability is crucial to ensuring that healthcare systems can continue to deliver high-quality care to patients. The savings realized from the introduction of biosimilars have expanded treatment options and improved access to therapies across a spectrum of diseases. Cost savings from biosimilar use have also led to changes in treatment guidelines, increasing the availability of biologic medicines for earlier lines of therapy. This expansion of access can have a positive impact on the overall patient experience and can reduce the overall disease burden. However, the adoption of biosimilars has not been universally successful, and faces challenges in the current healthcare landscape and in the pharmaceutical development pipeline.

Over the past 25 years, the approval of several nucleic acid-based drugs by the US Food and Drug Administration (FDA) has marked a significant milestone, establishing nucleic acid drugs as a viable therapeutic modality. These groundbreaking discoveries are the result of some crucial points in the timeline of nucleic acid drug development. The inventions used in fomivirsen (Vitravene; Isis Pharmaceuticals) development paved the road for structural backbone modifications as well as nucleobase and sugar modifications. The approval of patisiran (Onpattro; Alnylam) demonstrated an effective and safe delivery system for small interfering RNA (siRNA), extending potential applications to other nucleic acids such as messenger RNA (mRNA). Givosiran (Givlaari; Alnylam) further revolutionized the field with a carrier-free, targeted platform, utilizing N-Acetylgalactosamine (GalNAc)-siRNA conjugates to enable efficient delivery, expanding therapeutic applications beyond rare genetic disorders to more common conditions such as hyperlipidemia and hypertension. In this review paper, we highlight the evolution of nucleic acid-based drug development, focusing on the pioneering agents fomivirsen, patisiran, and givosiran, and discuss the ongoing challenges in advancing these therapeutics and vaccines.

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.

The development of immune checkpoint inhibitors has revolutionized the treatment of patients with cancer. Targeting the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1(PD-L1) interaction using monoclonal antibodies has emerged as a prominent focus in tumor therapy with rapid advancements. However, the efficacy of anti-PD-1/PD-L1 treatment is hindered by primary or acquired resistance, limiting the effectiveness of single-drug approaches. Moreover, combining PD-1/PD-L1 with other immune drugs, targeted therapies, or chemotherapy significantly enhances response rates while exacerbating adverse reactions. Multispecific antibodies, capable of binding to different epitopes, offer improved antitumor efficacy while reducing drug-related side effects, serving as a promising therapeutic approach in cancer treatment. Several bispecific antibodies (bsAbs) targeting PD-1/PD-L1 have received regulatory approval, and many more are currently in clinical development. Additionally, tri-specific antibodies (TsAbs) and tetra-specific antibodies (TetraMabs) are under development. This review comprehensively explores the fundamental structure, preclinical principles, clinical trial progress, and challenges associated with bsAbs targeting PD-1/PD-L1.

Background: Thymic stromal lymphopoietin (TSLP) plays a pivotal role in immune responses. CM326 is a humanized monoclonal antibody targeting TSLP.

Objective: The aim of this study was to evaluate the preclinical characterization, safety, tolerability, pharmacokinetics, and immunogenicity of CM326 in healthy adults.

Methods: In vitro pharmacologic activity of CM326 was compared with that of tezepelumab. In vivo efficacy of CM326 was assessed in allergic cynomolgus monkeys. Subjects in single ascending dose trials were randomized 2:1 (22 mg), 4:1 (55/110/220/440/660/880 mg), and 3:1 (330 mg) to receive CM326 or placebo subcutaneously. Subjects in multiple ascending dose trials were randomized 4:1 (55/110/220 mg every 2 weeks [Q2W], 220 mg Q4W) and 3:1 (440 mg Q2W) to receive CM326 or placebo.

Results: CM326 revealed higher potency over tezepelumab in blocking T_h2-driven inflammation in vitro and ameliorated lung function and normalized the inflammatory microenvironment in vivo. CM326 was well tolerated with no discernible safety signals. CM326 showed linear pharmacokinetics over the dose range 22-880 mg. Mean accumulation ratio of AUC was 4.04, 3.87, and 3.74 for 55 mg, 110 mg, and 220 mg Q2W after six doses and 2.16 for 440 mg Q2W after three doses. The mean accumulation ratio of maximum concentration (C_max) was 3.66 and 1.52 for 220 mg Q2W and Q4W, respectively. Anti-drug antibodies (ADAs) were positive in 2/58 subjects after a single dose of CM326, 2/12 receiving placebo and 3/44 receiving CM326 after multiple doses.

Conclusions: CM326 improved T_h2 inflammation preclinically and demonstrated an acceptable safety profile with linear pharmacokinetics and low immunogenicity in healthy adults.

Clinical trial registration: ClinicalTrials.gov identifiers: NCT04842201 (registered on 8 April 2021), NCT05171348 (registered on 9 December 2021), NCT05715333 (registered on 27 January 2023).

Autoimmune diseases are highly prevalent and affect people at all ages, women more often than men. The most prominent immunological manifestation is the production of antibodies directed against self-antigens. In many cases, these antibodies (Abs) drive the pathogenesis by attacking the body's own healthy cells, causing serious health problems that may be life threatening. Most autoantibodies are of the immunoglobulin G (IgG) isotype, which has a long plasma half-life and potent effector functions. Thus, there is a need for specific treatment options that rapidly eliminate these pathogenic IgG auto-Abs. In this review, we discuss how the neonatal Fc receptor (FcRn) acts as a regulator of the high levels of not only IgG Abs, but also albumin, by rescuing both these soluble proteins from cellular catabolism, and how a molecular and cellular understanding of this complex biology has spurred an intense interest in the development of FcRn-targeting strategies for the treatment of IgG-driven autoimmune diseases. We find that this emerging therapeutic class demonstrates efficacy within several autoimmune diseases with distinct pathophysiology. This offers hope for both new therapeutic avenues for highly prevalent diseases currently treated by other means, and rare diseases with no approved therapies to date. In addition, we elaborate on studies that have led to approval of the first FcRn antagonists, the clinical progress and structural design of molecules in the pipeline, their position in the overall therapeutic landscape of autoimmunity, the design of next-generation antagonists as well as the use of this receptor-targeting principle for other therapeutic applications.

Recent advances in extracellular vesicle (EV) research in organ transplantation have highlighted the crucial role of donor-derived EVs in triggering alloimmune responses, ultimately contributing to transplant rejection. Following transplantation, EVs carrying donor major histocompatibility complex (MHC) molecules activate recipient antigen-presenting cells (APCs), initiating both alloreactive and regulatory T-cell responses. While immunosuppressive drugs are essential for preventing rejection, they may also influence the biogenesis and release of EVs from donor cells. This review examines the impact of maintenance immunosuppressive therapy on EV biogenesis and release post-transplantation. In addition, EV release and uptake may be influenced by specific factors such as the patient's end-stage organ disease and the transplant procedure itself. In-vitro studies using primary human parenchymal and immune cells-integrated with cutting-edge multi-omics techniques, including genomics, proteomics, lipidomics, and single-EV analysis-will offer deeper insights into EV biology and the mechanisms by which immunosuppressive agents regulate EV-initiated immune processes. A detailed understanding of how organ failure, the transplantation procedure and immunosuppressive drugs affect the biology of EVs may uncover new roles for EVs in immune activation and regulation in patients, ultimately leading to improved immunosuppressive strategies and better transplant outcomes.