BioDrugs最新文献

Background: Pegunigalsidase 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.

Methods: Pharmacokinetics 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.

Results: No 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.

Conclusion: The 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.

Functional cure of chronic hepatitis B (CHB)-defined as sustained seroclearance of hepatitis B surface antigen (HBsAg) with unquantifiable hepatitis B virus (HBV) DNA at 24 weeks off treatment, is an optimal treatment endpoint. Nonetheless, it cannot be consistently attained by current treatment modalities. RNA interference (RNAi) is a novel treatment strategy using small-interfering RNA (siRNA) or antisense oligonucleotide (ASO) to target HBV post-transcriptional RNA, in turn suppressing viral protein production and replication. Hence, RNAi has indirect effects in promoting host immune reconstitution against HBV. Multiple RNAi therapeutics have entered phase II/III clinical trials, demonstrating potent, dose-dependent, and sustainable effects in suppressing HBsAg. Incidences of HBsAg seroclearance, particularly with the use of ASO, have also been documented. The combination of RNAi with other antivirals/immunomodulators (e.g. pegylated interferon), have shown promising results in potentiating RNAi effects and enhancing treatment durability. Further research will be required to establish predictors of response, optimal treatment protocols, and long-term outcomes in patients on RNAi. RNAi therapeutics have shown promising results and will likely be the keystone of future HBV treatment.

Background: Advanced therapy medicinal products (ATMPs) are an innovative output of biomedical research, characterized by a high level of uncertainty on long-term efficacy and safety, elevated price tags and often complex administration. All these elements compounded make their European authorization, national price negotiation for reimbursement and subsequent dispensation and administration to the patient less straightforward and often less successful than for less innovative drugs. To assess if these hurdles have affected patient access and how are ATMPs used in Italy, we have analysed availability, access and expenditure of ATMPs in the period spanning from 2016 to 2023.

Methods: We have analysed real world data on the duration of ATMP regulatory evaluations for authorisation and reimbursement, time to first patient access and expenditure for ATMPs through the Italian National Health System (INHS) expenditure data flow, as well as information on patient mobility and availability of health facilities specialized in administering ATMPs.

Findings: Of the 18 ATMPs currently authorized in Europe, 9 are reimbursed by the INHS, but only 6 were actually used, generating a cumulative expenditure of roughly 300 Mln€ from 2016 to 2023, largely owing to CAR-T therapies. Time to patient access reaches an average of 340.6 days from the day publication in the official Gazette of the reimbursement decision to first patient treatment in one of the 107 health facilities authorized for ATMP administration, after an even longer evaluation time by regulatory agencies.

Conclusion: Since the first reimbursement decision for an ATMP in Italy, back in 2016, these innovative drugs became progressively more and more available, both in terms of numbers and in terms of coverage across the country. Almost all Italian regions have at least one centre for ATMP administration and has performed a treatment in 2023. Notwithstanding their high per-treatment prices, ATMPs currently have a rather contained expenditure, however it is bound to keep growing in the next few years.

Background: Nivolumab (Opdivo^®) is the first anti-PD-1 antibody approved in the world. LY01015 is a potential biosimilar of nivolumab.

Objectives: This phase I study aimed to establish the pharmacokinetic equivalence between LY01015 and the original investigational nivolumab (Opdivo^®) in healthy Chinese male subjects. Additionally, safety and immunogenicity were assessed.

Patients and methods: A randomized, double-blind, parallel-controlled, phase I trial was conducted with 176 healthy male adults receiving a single intravenous infusion of LY01015 or nivolumab at 0.3 mg/kg. Pharmacokinetics, safety, and immunogenicity were evaluated over a 99-day period. The primary pharmacokinetics endpoint was AUC_0-∞, and the secondary pharmacokinetic endpoints included AUC_0-t and C_max. Pharmacokinetic bioequivalence was confirmed using standard equivalence margins of 80.00-125.00%.

Results: This study is the first to report on the pharmacokinetics, safety, and immunogenicity of Opdivo^® in healthy individuals. The pharmacokinetics profiles of LY01015 and Opdivo^® were found to be comparable. The geometric mean ratios (90% confidence intervals) for the AUC_0-∞, AUC_0-t, and C_max of LY01015 to Opdivo^® were 94.49% (90.29-98.88%), 94.92% (88.73-101.54%), and 96.55% (93.32-99.90%), respectively, falling within the conventional bioequivalence criteria of 80.00-125.00%. The safety and immunogenicity were also comparable between the two groups.

Conclusions: LY01015 demonstrated highly similar pharmacokinetics to nivolumab in healthy Chinese male subjects. Both drugs exhibited comparable safety and immunogenicity profiles.

Trial registration: This trial is registered at the Chinese Clinical Trial Registry website ( https://www.chictr.org.cn/ #ChiCTR2200064771).

Complex integral membrane proteins, which are embedded in the cell surface lipid bilayer by multiple transmembrane spanning polypeptides, encompass families of proteins that are important target classes for drug discovery. These protein families include G protein-coupled receptors, ion channels, transporters, enzymes, and adhesion molecules. The high specificity of monoclonal antibodies and the ability to engineer their properties offers a significant opportunity to selectively bind these target proteins, allowing direct modulation of pharmacology or enabling other mechanisms of action such as cell killing. Isolation of antibodies that bind these types of membrane proteins and exhibit the desired pharmacological function has, however, remained challenging due to technical issues in preparing membrane protein antigens suitable for enabling and driving antibody drug discovery strategies. In this article, we review progress and emerging themes in defining discovery strategies for a generation of antibodies that target these complex membrane protein antigens. We also comment on how this field may develop with the emerging implementation of computational techniques, artificial intelligence, and machine learning.

A biosimilar medicine is a successor to a reference ('originator'/'original-brand') biologic medicine brought to market once the patent and exclusive marketing rights for the reference have expired. Biosimilar natalizumab (PB006 [biosim-NTZ]; developed by Polpharma Biologics S.A. and marketed globally as Tyruko^®; Sandoz) has been developed as a successor to reference natalizumab (Tysabri^® [ref-NTZ]; Biogen) and is the first US Food and Drug Administration (FDA)-approved and European Medicines Agency (EMA)-approved biosimilar in neurology. As per the FDA and EMA indications for ref-NTZ, biosim-NTZ is approved to treat relapsing forms of multiple sclerosis (USA, EU) and Crohn's disease (USA only). Approval of biosim-NTZ was based on the 'totality of evidence', a comprehensive body of data collected during the development process, demonstrating similarity to its reference medicine. The foundational step of demonstrating structural and functional similarity between biosim-NTZ and ref-NTZ confirmed identical primary and indistinguishable higher order structures, as well as matching binding affinity to α4β1/α4β7 integrins. Following the confirmation of matching structure and function, pharmacokinetic/pharmacodynamic similarity of biosim-NTZ to ref-NTZ in healthy subjects was demonstrated, with no clinically meaningful differences identified in safety and immunogenicity. A comparative, double-blind, randomized study (Antelope) was also conducted in patients with relapsing-remitting multiple sclerosis and demonstrated matching efficacy, safety, and immunogenicity with no clinically meaningful differences between biosim-NTZ and ref-NTZ. This review presents the totality of evidence that confirmed the biosimilarity of biosimilar natalizumab to its reference medicine, which supported its approval by the FDA and the EMA. [Graphical plain language summary available].

Aim: Current recommendations for Fabry disease include α-galactosidase A (AGAL) activity measurements to assess the biochemical response in migalastat-treated patients. Owing to contradictory data from laboratories, we aimed to analyze why AGAL activity measures from dried blood spots (DBS) often fail to detect migalastat-mediated enzymatic activity increases in treated patients.

Methods: 43 patients with 58 visits under migalastat were consecutively recruited. Enzymatic AGAL activities were measured from DBS and peripheral blood mononuclear cells (PBMCs). Migalastat concentrations in sera were determined using modified serum-mediated inhibition assays to assess C_max and serum half-life. Results were set in relation to the time of last migalastat intake and blood sampling to assess an optimal timepoint for AGAL activity measures.

Results: DBS-based AGAL activity measurements of 21 (42.0%) amenable patients were below the limit of detection. Serum samples from migalastat-treated patients showed significant AGAL inhibition, depending on the time between migalastat intake and blood sampling (r² = 0.8140, p < 0.0001). Migalastat concentrations were determined in serum samples confirming a C_max at 3 h and a serum half-life of 4 h. At 24 h after intake, migalastat clearance was significantly associated with renal function (r² = 0.3135, p = 0.0102). Enzymatic AGAL activities were higher in samples from DBS and PBMCs 24 h after migalastat intake (both p < 0.05).

Conclusion: The optimal time for enzymatic AGAL activity measurement in migalastat-treated patients appears to be 24 h after the last migalastat intake. Since migalastat is a competitive inhibitor of AGAL, enzymatic AGAL activity measurements should be better performed from PBMCs to reduce migalastat-mediated interferences.

Introduction: Eblasakimab, a first-in-class monoclonal antibody with a unique mechanism to target the interleukin (IL)-13 receptor alpha 1 (IL-13Rα1), inhibits IL-4/IL-13 signaling in the pathophysiology of atopic dermatitis (AD). This study investigates the impact of eblasakimab on type 2 inflammatory biomarkers in patients with moderate-to-severe AD.

Methods: A double‑blind, multiple ascending dose, phase Ib study evaluated the effect of eblasakimab (200, 400, 600 mg) or placebo administered subcutaneously once weekly for 8 weeks in patients with moderate‑to‑severe AD. Serum levels of thymus and activation-regulated chemokine (TARC), total immunoglobulin E (IgE), and lactate dehydrogenase (LDH) were assessed.

Results: Eblasakimab suppressed TARC, IgE, and LDH in the 400-mg and 600-mg groups over 8 weeks of treatment. Patients in the 400-mg and 600-mg groups experienced a reduction of 72.8% (p = 0.004) and 62.9% (p = 0.003), respectively, for TARC, 35.1% (p = 0.006) and 20.9% (not significant; NS), respectively, for IgE, and 24.6% (NS) and 23.1% (NS), respectively, for LDH between baseline and Week 8. Reduction in serum TARC in the 400-mg group was significantly greater than placebo as early as Week 1, whereas reductions in total IgE were more gradual. Serum TARC and total IgE remained suppressed in the 400-mg and 600-mg eblasakimab groups for 4-6 weeks following the last administered dose.

Conclusion: The effect of eblasakimab on circulating AD‑associated biomarker levels was accompanied by improvements in signs and symptoms of AD, consistent with the inhibition of IL-13 and IL-4 signaling via the type 2 receptor.

Trial registration number: NCT04090229.