Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects

Hillson, Jan; Mant, Tim; Rosano, Molly; Huntenburg, Carolyn; Alai-Safar, Mehrshid; Darne, Siddhesh; Palmer, D. Jason; Pavlova, Borislava G.; Doralt, Jennifer; Reeve, Russell; Goel, Niti; Weilert, Doris; Rhyne, Paul; Chance, Kamali; Caminis, John; Roach, James; Ganguly, Tanmoy

doi:10.1002/prp2.380

Cited by 15 publications

(11 citation statements)

References 22 publications

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“…HOT-3010 and adalimumab exhibited similar safety and immunogenicity profiles; all treatment-related TEAEs were observed to be mild to moderate in severity, with the absence of local reactions, evidencing that the healthy subjects well tolerated the two drugs. The outcomes of this investigation supported the utilization of the biosimilars in the subsequent clinical studies ( Hyland et al, 2016 ; Puri et al, 2017 ; Hillson et al, 2018 ; von Richter et al, 2019 ).…”

Section: Discussionsupporting

confidence: 61%

“…Thus the combination of these drugs was considered less likely to influence the outcomes of PK analysis of adalimumab ( AbbVieInc, 2020 ). The inter-CV of adalimumab was found to be approximately 30–39% (medium), with a realistic sample size in this study, while about 53 subjects were proposed to be included in future bioequivalence studies ( Hyland et al, 2016 ; Wynne et al, 2016 ; Kaur et al, 2017 ; Park et al, 2017 ; Puri et al, 2017 ; Shin et al, 2017 ; Hillson et al, 2018 ; von Richter et al, 2019 ; Cao et al, 2020 ).…”

Section: Discussionmentioning

confidence: 81%

“…The PK parameters such as absorption, distribution, and adalimumab metabolism among the healthy study population were comparable with those in the literature data (Table 2). PK analyzes in RA patients displayed an evident trend toward higher clearance of adalimumab in the presence of antiadalimumab antibodies and poorer clearance with an increase in age among patients in the age range ≥40 years (Hyland et al, 2016;Puri et al, 2017;Hillson et al, 2018;von Richter et al, 2019). ADA certainly influenced drug concentration, and the ADA-positive group exhibited lower concentration within a certain time frame and lower exposure of adalimumab and its biosimilar, such as AUC, although it did not affect the bioequivalence results of this study (Table 2 and Supplement Table S1).…”

Section: Discussionmentioning

confidence: 99%

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A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of HOT-3010 to Adalimumab Among Healthy Chinese Male Subjects

Zhang

Chen

et al. 2021

Front. Pharmacol.

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Objective: This study explored the bioequivalence of a proposed biosimilar HOT-3010 vs. its reference product (adalimumab) among healthy Chinese male subjects. The study also investigated the tolerance, immunogenicity, and pharmacokinetics (PK).Methods: A randomized, double-blind, two-arm, parallel study was performed to examine the bioequivalence of HOT-3010 (40 mg) with that of adalimumab (Humira®, AbbVie) as a reference drug. The study subjects were followed up for 71 days.Results: PK properties exhibited by HOT-3010 (N = 66) and adalimumab (N = 68) groups were similar. The 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0∞ were observed to be in the range 80–125% on comparing the two groups. For anti-drug antibodies (ADA), the number of subjects found to be positive in the HOT-3010 group and adalimumab group were 29 (43.94%) and 32 (47.06%), whereas 27 (40.91%) and 27 (39.71%) subjects were found to be positive for NAb, respectively. Treatment-related treatment-emergent adverse events (TEAEs) were recorded in 32 subjects each in both the groups, respectively.Conclusion: The PK characteristics and immunogenicity exhibited by HOT-3010 were similar to that of the reference product, adalimumab. The safety profiles were similar in both the treatment groups with mild-moderate adverse effects.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of HOT-3010 to Adalimumab Among Healthy Chinese Male Subjects

Zhang

Chen

et al. 2021

Front. Pharmacol.

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“…Despite being the first fully human monoclonal antibody approved by the FDA, adalimumab is highly immunogenic (9). Greater than 70% of healthy volunteers develop ADAs after a single injection (63)(64)(65). The formation of ADAs in rheumatoid arthritis patients was associated with accelerated drug clearance and poor outcomes.…”

Section: Adalimumabmentioning

confidence: 99%

Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies

Kishimoto

2020

Front. Immunol.

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The development of anti-drug antibodies (ADAs) is a common cause for treatment failure and hypersensitivity reactions for many biologics. The focus of this review is the development of ImmTOR, a platform technology designed to prevent the formation of ADAs that can be applied broadly across a wide variety of biologics by inducing immunological tolerance with ImmTOR nanoparticles encapsulating rapamycin. The induction of tolerance is antigen-specific and dependent on the incorporation of rapamycin in nanoparticles and the presence of the antigen at the time of administration of ImmTOR. Evidence for the induction of specific immune tolerance vs. general immune suppression is supported by the findings that: (1) ImmTOR induces regulatory T cells specific to the co-administered antigen; (2) tolerance can be transferred by adoptive transfer of splenocytes from treated animals to naïve recipients; (3) the tolerance is durable to subsequent challenge with antigen alone; and (4) animals tolerized to a specific antigen are capable of responding to an unrelated antigen. ImmTOR nanoparticles can be added to new or existing biologics without the need to modify or reformulate the biologic drug. The ability of ImmTOR to mitigate the formation of ADAs has been demonstrated for coagulation factor VIII in a mouse model of hemophilia A, an anti-TNFα monoclonal antibody in a mouse model of inflammatory arthritis, pegylated uricase in hyperuricemic mice and in non-human primates, acid alpha-glucosidase in a mouse model of Pompe disease, recombinant immunotoxin in a mouse model of mesothelioma, and adeno-associated vectors in a model of repeat dosing of gene therapy vectors in mice and in non-human primates. Human proof-of concept for the mitigation of ADAs has been demonstrated with SEL-212, a combination product consisting of ImmTOR + pegadricase, a highly immunogenic enzyme therapy for the treatment of gout. ImmTOR represents a promising approach to preventing the formation of ADAs to a broad range of biologic drugs.

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“…This study describes the development, validation, and application of a multiplexed multi-tiered immunogenicity assay that combines a screening assay and isotyping analysis together. We selected the human monoclonal therapeutic Humira® as our experimental drug given its well described immunogenicity profile (26)(27)(28)(29)(30). Humira® (adalimumab) is a recombinant human IgG 1 antibody that binds to TNFα and is approved for treatment of rheumatoid arthritis, psoriatic arthritis, Crohn's disease, and other inflammatory diseases.…”

Section: Introductionmentioning

confidence: 99%

Design and Evaluation of a Multiplexed Assay to Assess Human Immunogenicity Against Humira®

Alleyn¹,

Closson²,

Gentile³

et al. 2020

AAPS J

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The use of biologic-based therapeutics has revolutionized our ability to treat complex diseases such as cancer- and autoimmune-related disorders. Biologic-based therapeutics are known to generate anti-drug immune responses or immunogenicity in clinical patients which can lead to altered pharmacokinetics, decreased drug efficacy, and unwanted adverse clinical events. Assays designed to detect and assess anti-drug immune responses are used to help monitor patients and improve drug safety. Utilizing a tiered approach, screening assays are developed first to identify patients that are potentially positive for anti-drug-specific antibodies. Patients that screen positive are subjected to additional tiers of testing that include a confirmation assay to confirm the presence of expected anti-drug-specific antibodies, a titer assay to assess relative levels of anti-drug-specific antibodies, and, depending on the drug’s mechanism of action or concerns of adverse clinical reactions, further characterization such as drug neutralization and anti-drug antibody isotyping. This tiered approach can prove to be detrimental to clinical samples from exposure to multiple cycles of testing, freeze thaws, and repeated handling by lab personnel. Multiplexing some of these assays together may streamline the characterization of anti-drug immune responses and help reduce the repeated usage of clinical samples. In this study, we combined a screening assay and anti-drug isotyping assays into one multiplexed assay using the Luminex® xMAP® Technology. The multiplexed assay was developed and validated to meet the FDA recommended guidelines for immunogenicity assessments. These results show that multiplexed assays perform comparably to industry standards. This study should encourage labs to explore the use of multiplexing immunogenicity assays to characterize anti-drug antibody responses quickly, with less repeat testing and reduced sample handling.

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Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects

Cited by 15 publications

References 22 publications

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of HOT-3010 to Adalimumab Among Healthy Chinese Male Subjects

A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of HOT-3010 to Adalimumab Among Healthy Chinese Male Subjects

Development of ImmTOR Tolerogenic Nanoparticles for the Mitigation of Anti-drug Antibodies

Design and Evaluation of a Multiplexed Assay to Assess Human Immunogenicity Against Humira®

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