Anti-tumor Necrosis Factor Monoclonal Antibody Research Articles

Targeting the TNF and TNFR superfamilies in autoimmune disease and cancer.

The first anti-tumour necrosis factor (TNF) monoclonal antibody, infliximab (Remicade), celebrated its 25th anniversary of FDA approval in 2023. Inhibitors of TNF have since proved clinically efficacious at reducing inflammation associated with several autoimmune diseases, including rheumatoid arthritis, psoriasis and Crohn's disease. The success of TNF inhibitors raised unrealistic expectations for targeting other members of the TNF superfamily (TNFSF) of ligands and their receptors, with difficulties in part related to their more limited, variable expression and potential redundancy. However, there has been a resurgence of interest and investment, with many of these cytokines or their cognate receptors now under clinical investigation as targets for modulation of autoimmune and inflammatory diseases, as well as cancer. This Review assesses TNFSF-targeted biologics currently in clinical development for immune system-related diseases, highlighting ongoing challenges and future directions.

Psoriasis: Sind Geschlechtsunterschiede bedeutsam?

Background: Psoriasis is a common chronic inflammatory skin disease with an exceptionally high burden for women. Objective: Sex-dependent differences in disease manifestation, severity, treatment choices, subjective disease perception, and the impact on quality of life and risk factors are described and comprehensively discussed. Methods: A literature search was conducted using MEDLINE (PubMed) and the Cochrane Library for systematic reviews to investigate the challenges in treating women with psoriasis. Results and conclusions: : The incidence, prevalence, and manifestation of psoriasis of the skin are similar between different sexes. Genetic and environmental factors such as obesity and metabolic syndrome are risk factors and are not equally relevant or pronounced in women and men. Overall, women have a lower disease severity measured by the Psoriasis Area Severity Index, which is associated with a higher impairment of their life quality measured by the Dermatology Life Quality Index compared with men. In addition, women with psoriasis are more likely to have depression than men. Hormonal factors affect psoriasis, with a correlation of high estrogen levels and improvement of psoriasis. Data regarding differences in prescribing patterns of systemic treatments and the severity of psoriasis are not entirely consistent. Registry studies show that men tend to have more severe psoriasis and, in some cases, are prescribed systemic therapies more frequently. Women tend to respond better to systemic treatments and to experience more adverse events. Treatment options are the same for both sexes, except during pregnancy and lactation. Various treatment options are contraindicated due to fear of fetal or neonate harm and lack of data. Topical steroids can be prescribed with a high degree of safety during pregnancy. For other topical therapies (calcineurin inhibitors and vitamin D analogs), no studies of adverse effects in pregnancy are available, and safety data mainly stem from studies examining effects after systemic administration. Antitumor necrosis factor monoclonal antibodies (except for certolizumab pegol) have been associated with a possible increased risk of preterm birth, low gestational age, and cesarean deliveries. Prospective data on the safety of biologics other than antitumor necrosis factor-alpha antibodies to accurately assess whether novel biologics (eg, anti-interleukin 17, 12/23, 23) can be used for systemic therapy in pregnancy are lacking or currently being conducted. © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Women’s Dermatologic Society.

Best Practice for Therapeutic Drug Monitoring of Infliximab: Position Statement from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.

Infliximab, an anti-tumor necrosis factor monoclonal antibody, has revolutionized the pharmacological management of immune-mediated inflammatory diseases (IMIDs). This position statement critically reviews and examines existing data on therapeutic drug monitoring (TDM) of infliximab in patients with IMIDs. It provides a practical guide on implementing TDM in current clinical practices and outlines priority areas for future research. The endorsing TDM of Biologics and Pharmacometrics Committees of the International Association of TDM and Clinical Toxicology collaborated to create this position statement. Accumulating data support the evidence for TDM of infliximab in the treatment of inflammatory bowel diseases, with limited investigation in other IMIDs. A universal approach to TDM may not fully realize the benefits of improving therapeutic outcomes. Patients at risk for increased infliximab clearance, particularly with a proactive strategy, stand to gain the most from TDM. Personalized exposure targets based on therapeutic goals, patient phenotype, and infliximab administration route are recommended. Rapid assays and home sampling strategies offer flexibility for point-of-care TDM. Ongoing studies on model-informed precision dosing in inflammatory bowel disease will help assess the additional value of precision dosing software tools. Patient education and empowerment, and electronic health record-integrated TDM solutions will facilitate routine TDM implementation. Although optimization of therapeutic effectiveness is a primary focus, the cost-reducing potential of TDM also merits consideration. Successful implementation of TDM for infliximab necessitates interdisciplinary collaboration among clinicians, hospital pharmacists, and (quantitative) clinical pharmacologists to ensure an efficient research trajectory.

Incidence of Uveitis in Patients With Axial Spondylarthritis Treated With Biologics or Targeted Synthetics: A Systematic Review and Network Meta-Analysis.

Anterior uveitis is a common extra-articular manifestation of axial spondyloarthritis (AxSpA). We set to evaluate the risk of anterior uveitis (AU) with biologics and synthetic disease-modifying drugs in AxSpA. We conducted a systematic review and meta-analysis to identify phase II/III double-blinded randomized controlled trials of anti-tumor necrosis factor (TNF) monoclonal antibodies (mAb), anti-interleukin-17 (anti-IL-17), and Janus kinase inhibitors (JAKi) in AxSpA. Patient-exposure years (PEY) were calculated using the per-protocol approach. Incidence rate (IR) of AU/100 person-years were calculated by treatment group using the random effects approach. Network meta-analysis (NMA) was used to estimate risk of AU in treatment groups, expressed as IR ratios (IRRs). Bias was assessed using the Cochrane Risk of Bias-2 tool. Forty-four trials were included: 17 anti-TNF mAb (1,004 PEY), 9 etanercept (180 PEY), 13 anti-IL-17 (1,834 PEY), and 6 JAKi (331 PEY). The IR of AU were as follows for anti-TNF mAb: 4.1, 95% confidence interval (CI) 0-8.5; etanercept: 5.4, 95% CI 0-16.0; anti-IL-17: 2.8, 95% CI 1.6-4.1; JAKi: 1.5, 95% CI 0.0-3.0; and placebo: 10.8, 95% CI 7.4-14.1. In NMA, IRRs of treatments compared with placebo were as follows for anti-TNF mAb: 0.32, 95% CI 0.10-1.04; etanercept 0.42, 95% CI 0.08-2.38; anti-IL-17: 0.43, 95% CI 0.19-0.98; and JAKi: 0.32, 95% CI 0.06-1.67. Comparisons between anti-TNF mAb, anti-IL-17, and JAKi did not demonstrate any significant difference in AU risk. Using the surface under the cumulative ranking curve approach to rank AU risk, anti-TNF mAbs were associated with the lowest risk followed by JAKi, anti-IL-17, and etanercept. All treatments were ranked superior to placebo. Anti-TNF mAbs, JAKi, and anti-IL-17 appear protective against AU events in individuals with AxSpA, with no significant differences in risk of AU between treatments.

Development and validation of a novel therapeutic drug monitoring-based nomogram for prediction of primary endoscopic response to anti-TNF therapy in active Crohn's disease.

Anti-tumor necrosis factor (TNF) monoclonal antibodies, especially infliximab (IFX) and adalimumab (ADA), are considered the first-line treatment for active Crohn's disease (CD). However, the predictive role of therapeutic drug monitoring (TDM) of serum anti-TNF in monitoring the treatment of inflammatory bowel disease (IBD) remains controversial. To explore the correlation between serum anti-TNF levels and early endoscopic response in active CD using a TDM-based nomogram. Cross-sectional study. The simplified endoscopic activity score for CD (SES-CD), Crohn's disease activity index (CDAI), laboratory parameters, and the serum trough levels of IFX and ADA were assessed. The trough levels of IFX or ADA were significantly higher in patients with endoscopic response compared to non-responders in the development cohort (p < 0.001). The IFX and ADA levels showed a weak but significantly negative correlation with SES-CD (p < 0.001), CDAI (p < 0.001), and C-reactive protein (CRP) (p < 0.001) at week 14 post-IFX therapy in the development cohort. Furthermore, the receiver operating characteristic curve revealed that an optimal level of IFX (4.80 μg/mL) and ADA (8.80 μg/mL) exhibited the best performance in predicting endoscopic response. Concomitantly, we developed a novel nomogram prediction model based on the results of multivariate logistic regression analysis, which consisted of CRP, albumin (Alb), and anti-TNF trough levels at week 14. The nomogram showed significant discrimination and calibration for both IFX and ADA in the development cohort and performed well in the external validation cohort. This study demonstrates a robust association between serum concentrations of IFX, ADA, Alb, and CRP and primary endoscopic response in active CD patients. Importantly, the TDM- and laboratory marker-based nomogram may be used to evaluate the primary endoscopic response to anti-TNF therapy, especially for optimizing treatment strategies and switching therapy in CD patients.

Review of Adalimumab Biosimilar SB5 in Immune-Mediated Inflammatory Diseases.

SB5 is an approved biosimilar of adalimumab, a recombinant monoclonal anti-tumor necrosis factor (TNF) antibody. The approval of SB5 was based on the comparison with reference adalimumab in analytical studies, pharmacokinetic (PK) and immunogenicity assessments, and randomized controlled trials. Efficacy data was primarily obtained in patients with rheumatoid arthritis, and extended to include additional indications such as psoriasis, Crohn's disease, or ulcerative colitis by extrapolation. Following its approval, additional post-marketing data have been collected comparing SB5 with reference adalimumab. This review summarizes the clinical data on SB5 from randomized controlled trials and provides a comprehensive overview of the available post-approval data. In "real-world" settings, SB5 was as effective as its reference product across different indications and countries, treatment persistence was well maintained throughout studies, and no new safety concerns were identified. In both controlled and "real-world" settings, switching from reference adalimumab to SB5 was not associated with altered efficacy or clinical complications. In post-approval studies, the quality of SB5 was consistent over time, independent of the batch and process changes, and the SB5 autoinjector was preferred over other autoinjectors by both healthcare professionals and patients. Taken together, these data support the use of SB5 whenever reference adalimumab is appropriate and demonstrate that switching from reference adalimumab to SB5 is feasible.

Seronegative spondyloarthropathy-associated inflammatory bowel disease.

Seronegative spondyloarthropathy (SpA) usually starts in the third decade of life with negative rheumatoid factor, human leukocyte antigen-B27 genetic marker and clinical features of spinal and peripheral arthritis, dactylitis, enthesitis and extra-articular manifestations (EAMs). Cases can be classified as ankylosing spondylitis, psoriatic arthritis, reactive arthritis, enteropathic arthritis, or juvenile-onset spondyloarthritis. Joint and gut inflammation is intricately linked in SpA and inflammatory bowel disease (IBD), with shared genetic and immunopathogenic mechanisms. IBD is a common EAM in SpA patients, while extraintestinal manifestations in IBD patients mostly affect the joints. Although individual protocols are available for the management of each disease, the standard therapeutic guidelines of SpA-associated IBD patients remain to be established. Nonsteroidal anti-inflammatory drugs are recommended as initial therapy of peripheral and axial SpA, whereas their use is controversial in IBD due to associated disease flares. Conventional disease-modifying anti-rheumatic drugs are beneficial for peripheral arthritis but ineffective for axial SpA or IBD therapy. Anti-tumor necrosis factor monoclonal antibodies are effective medications with indicated use in SpA and IBD, and a drug of choice for treating SpA-associated IBD. Janus kinase inhibitors, approved for treating SpA and ulcerative colitis, are promising therapeutics in SpA coexistent with ulcerative colitis. A tight collaboration between gastroenterologists and rheumatologists with mutual referral from early accurate diagnosis to appropriately prompt therapy is required in this complex clinical scenario.

IMMUNOLOGICAL CHANGES IN NEWBORN EXPOSED TO ANTI-TNF-A, A PERSPECTIVE.

<h3>Introduction</h3> Anti-TNF drugs have been used extensively for different autoimmune conditions. There is still an existing debate about the use of anti-tumor necrosis factor monoclonal antibodies during pregnancy vis-à-vis their safety and effects on the fetus developing immune system. <h3>Case Description</h3> A 2 month-old boy was born in the setting of a pregnancy during which the mother was being treated with infliximab for Crohn's disease. Weeks after delivery, mom noted a swollen lymph node appeared on the left side of his neck. As well as lymphadenopathy in both groins which subsequently became infected. He underwent incision and drainage of the cervical and groin lymphadenitis. Patient was placed on Keflex. However, during the course of the treatment, he presented recurrent episodes of lymphadenitis requiring a prolonged therapy with Keflex. Upon his evaluation he was alert and afebrile. A large lymph node of about 3 cm over left side of neck and both groins were noted. The left inguinal lymph node was inflamed, infected and oozing pus. An extensive immunological work up was ordered confirming an elevated Infliximab drug level in the patient's serum. Also, the majority of the cytokines evaluated were within normal range even during the course of an active infection. <h3>Discussion</h3> The decision to use anti-TNF-α during pregnancy with the resulting in-utero exposure to the fetus should be discussed with pregnant patients suffering from autoimmunity. Infliximab does interfere with the IL-12/INF-γ making exposed newborns susceptible to repeated infections by causing a temporary condition analogous to a form of primary immunodeficiency.

Efficacy and safety of biosimilar versus originator infliximab in patients with inflammatory bowel disease: A real-world cohort analysis.

Anti-tumor necrosis factor (anti-TNF) monoclonal antibody, infliximab, is the primary therapeutic modality for patients with Crohn's disease (CD) and ulcerative colitis (UC), refractory to conventional therapy. Biosimilars of infliximab have been shown to have equivalent efficacy to originator infliximab. We compared the safety and efficacy of infliximab biosimilar with the originator in Indian patients with inflammatory bowel disease (IBD). Patients with IBD treated with either originator or biosimilar infliximab from January 2005 to October 2020 were included in this retrospective analysis. The safety and efficacy of originator or biosimilar infliximab in inducing and maintaining clinical remission at weeks 14 and 52 for CD and UC were evaluated. Disease activity was estimated at baseline, after induction therapy, after 1 year of treatment, and during 12 months of follow-up. In all, 137 patients (82 CD; 55 UC) were included, of whom 102 were on originator, and 35 patients received biosimilar. In biosimilar group, clinical response and remission rates at weeks 14 and 52 were 84.2%, 58% and 68.4%, 52.6% in CD and 81.2%, 56.2% and 68.7%, 62.5% in UC patients, respectively. Among patients who were on originator, clinical response and remission rates at weeks 14 and 52 were 79.4%, 46% and 57.1%, 43% in CD and 72%, 64.1% and 66.7%, 56.4% in UC patients, respectively. Thirty-three (24.1%) patients experienced adverse events; eighteen developed tuberculosis (TB), of whom 17 received originator and one patient received biosimilar. Infliximab biosimilar is comparable to originator infliximab in terms of safety profile and its efficacy in inducing and maintaining remission in patients with IBD.

A Randomized Pharmacokinetic Study in Healthy Male Subjects Comparing a High-concentration, Citrate-free SB5 Formulation (40mg/0.4ml) and Prior SB5 (Adalimumab Biosimilar).

IntroductionSB5 is an approved biosimilar of adalimumab, a monoclonal anti-tumor necrosis factor (anti-TNF) antibody. This study compared pharmacokinetics (PK), safety, tolerability, and immunogenicity between a new high-concentration, low-volume, and citrate-free formulation (40 mg/0.4 ml, SB5-HC) and the current low-concentration formulation with higher volume (40 mg/0.8 ml, SB5-LC) to evaluate the bioequivalence of the two formulations.MethodsThis study was a randomized, single-blind, two-arm, parallel-group, single-dose study in healthy male subjects. Subjects were randomized to receive either SB5-HC or SB5-LC via subcutaneous injection using a pre-filled syringe. Primary endpoints were the area under the curve of the concentration–time curve from zero to infinity (AUCinf) and maximum serum concentration (Cmax). Bioequivalence was achieved if the 90% confidence intervals (CIs) for the ratios of the geometric least squares mean (LSMean) of primary endpoints were within the pre-defined bioequivalence margins of 0.80–1.25. Secondary endpoints included safety, tolerability, and immunogenicity.ResultsSubjects (n = 188) were randomized to SB5-HC (n = 94) or SB5-LC (n = 94). Baseline characteristics were comparable between the two treatment groups. The mean values for AUCinf and Cmax were similar between the SB5-HC and SB5-LC groups. For the primary endpoints, the geometric LSMean ratios (90% CI) for AUCinf and Cmax were 0.920 (0.8262–1.0239) and 0.984 (0.9126–1.0604), respectively, placing the corresponding 90% CIs well within the pre-defined bioequivalence margin of 0.80–1.25. All treatment-emergent adverse events (TEAEs) were considered mild to moderate and were reported for 44.7% and 51.1% of subjects in the SB5-HC and SB5-LC groups, respectively. Immunogenicity assessed by frequency of occurrence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) was comparable between groups.ConclusionsThis bridging study demonstrated PK equivalence and comparable safety and tolerability of subcutaneous injection of SB5 via SB5-HC or SB5-LC.Clinicaltrials.gov identifierhttps://clinicaltrials.gov/ct2/show/NCT04514796.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00471-8.

Development of a Machine Learning Model to Predict Non-Durable Response to Anti-TNF Therapy in Crohn's Disease Using Transcriptome Imputed from Genotypes.

Almost half of patients show no primary or secondary response to monoclonal anti-tumor necrosis factor α (anti-TNF) antibody treatment for inflammatory bowel disease (IBD). Thus, the exact mechanisms of a non-durable response (NDR) remain inadequately defined. We used our genome-wide genotype data to impute expression values as features in training machine learning models to predict a NDR. Blood samples from various IBD cohorts were used for genotyping with the Korea Biobank Array. A total of 234 patients with Crohn’s disease (CD) who received their first anti-TNF therapy were enrolled. The expression profiles of 6294 genes in whole-blood tissue imputed from the genotype data were combined with clinical parameters to train a logistic model to predict the NDR. The top two and three most significant features were genetic features (DPY19L3, GSTT1, and NUCB1), not clinical features. The logistic regression of the NDR vs. DR status in our cohort by the imputed expression levels showed that the β coefficients were positive for DPY19L3 and GSTT1, and negative for NUCB1, concordant with the known eQTL information. Machine learning models using imputed gene expression features effectively predicted NDR to anti-TNF agents in patients with CD.

The impact of gender and sex in psoriasis: What to be aware of when treating women with psoriasis.

Background:Psoriasis is a common chronic inflammatory skin disease with an exceptionally high burden for women.Objective:Sex-dependent differences in disease manifestation, severity, treatment choices, subjective disease perception, and the impact on quality of life and risk factors are described and comprehensively discussed.Methods:A literature search was conducted using MEDLINE (PubMed) and the Cochrane Library for systematic reviews to investigate the challenges in treating women with psoriasis.Results and conclusions:The incidence, prevalence, and manifestation of psoriasis of the skin are similar between different sexes. Genetic and environmental factors such as obesity and metabolic syndrome are risk factors and are not equally relevant or pronounced in women and men. Overall, women have a lower disease severity measured by the Psoriasis Area Severity Index, which is associated with a higher impairment of their life quality measured by the Dermatology Life Quality Index compared with men. In addition, women with psoriasis are more likely to have depression than men. Hormonal factors affect psoriasis, with a correlation of high estrogen levels and improvement of psoriasis. Data regarding differences in prescribing patterns of systemic treatments and the severity of psoriasis are not entirely consistent. Registry studies show that men tend to have more severe psoriasis and, in some cases, are prescribed systemic therapies more frequently. Women tend to respond better to systemic treatments and to experience more adverse events. Treatment options are the same for both sexes, except during pregnancy and lactation. Various treatment options are contraindicated due to fear of fetal or neonate harm and lack of data. Topical steroids can be prescribed with a high degree of safety during pregnancy. For other topical therapies (calcineurin inhibitors and vitamin D analogs), no studies of adverse effects in pregnancy are available, and safety data mainly stem from studies examining effects after systemic administration. Antitumor necrosis factor monoclonal antibodies (except for certolizumab pegol) have been associated with a possible increased risk of preterm birth, low gestational age, and cesarean deliveries. Prospective data on the safety of biologics other than antitumor necrosis factor-alpha antibodies to accurately assess whether novel biologics (eg, anti-interleukin 17, 12/23, 23) can be used for systemic therapy in pregnancy are lacking or currently being conducted.

Biologic therapy for Crohn's disease over the last 3 decades.

BACKGROUNDDespite the overload of publications on Crohn’s disease (CD), no comprehensive analysis of biologic therapy for CD has been reported.AIMTo determine knowledge gaps and identify areas of interest of biologic therapy for CD.METHODSThe top 100 highest-cited original articles were identified from January 1991 to December 2020 in the Clarivate Analytics Web of Science Core Collection database. We conducted a bibliometric analysis of biologic therapy for CD based on total citations, summarized the bibliographic information of the articles related to CD biologic therapy, and explored the research hotspots.RESULTSThe top 100 highest-cited original articles were identified with total citations ranging from 307 to 2978. The 2000s (Period II, n = 66) yielded the most influential original articles and saw the most dramatic growth. Among the top 10 countries, including 8 European countries and 2 North American countries, the United States (n = 37) and Belgium (n = 20) contributed the most publications. Among the top 10 institutions, the University Hospital Gasthuisberg in Belgium (n = 23), the University of Chicago in the United States (n = 20), and the Mayo Clinic in the United States (n = 17) published the most papers. Regarding authors, Rutgeerts P in Belgium (n = 32), Sandborn WJ in the United States (n = 23), and Feagan BG in Canada (n = 18) published the highest number of studies. The cooperation relationships between the United States and Europe were most frequent. Gastroenterology (impact factor = 22.682) published the most articles on biologic therapy for CD (n = 32) with 17654 total citations. Anti-tumor necrosis factor biologics and monoclonal antibodies were the most studied topics.CONCLUSIONThe bibliometric analysis emphasized the key contributions to the development of the specialized field. These data would provide useful research insights into biologic therapy for CD for clinicians and researchers.

Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register

ObjectiveTo compare event and incidence rates of herpes zoster (HZ), also known as shingles, in patients with rheumatoid arthritis under treatment with conventional synthetic (cs), targeted synthetic (ts) or biologic...

Vitamin D-Related Genetics as Predictive Biomarker of Clinical Remission in Adalimumab-Treated Patients Affected by Crohn's Disease: A Pilot Study.

Adalimumab (ADA) is a human anti-tumor necrosis factor (TNF-α) monoclonal antibody used in inflammatory bowel diseases, such as Crohn’s disease (CD). Vitamin-D (VD) is important for biological functions, such as the modulation of expression of genes encoding enzymes and transporters involved in drug metabolism and transport. ADA trough levels were associated with VD concentrations in patients with IBD, but no data are present in the literature concerning VD pathway-related gene single-nucleotide polymorphisms (SNPs) in affecting clinical outcomes. For this reason, the aim of this study was to evaluate the ability of VD-related genetics to predict clinical remission at 3 and 12 months in patients affected by CD treated with ADA. Patients affected by CD were included in this study. SNPs in CYP27B1, CYP24A1, GC, and VDR genes were analyzed through real-time PCR. A total of 63 patients were enrolled. Calprotectin, hemoglobin, and C-reactive protein levels were influenced by SNPs in VDR, CYP27B1, and GC genes. After 3 months of therapy, clinical remission was predicted by smoke, systemic steroids, and VDR BsmI, whereas at 12 months by GC 1296AA/AC and VD supplementation. This study reports the association between VD pathway-related genetics and ADA treatment. Further studies are needed to confirm these promising data.

TNF-α: The shape of small molecules to come?

In 2020, the anti-tumor necrosis factor (TNF) monoclonal antibody Humira® generated US$165.8 billion in cumulative sales and snatched the crown for the industry’s most successful drug from Lipitor (atorvastatin). TNF-α is a major component in beneficial and disease-related inflammation and TNF-α-inhibitor biologics have gained widespread use in autoimmune diseases, such as rheumatoid arthritis (RA). Many more diseases could benefit from TNF-α inhibitors, such as Alzheimer’s disease (AD) or major depression. However, the nature of TNF-α-inhibitor biologics prohibits central nervous system (CNS) applications. Moreover, high drug production costs and pricing, together with antidrug immune reactions and insufficient patient coverage, argue for the development of small-molecule drugs. Recently, drug-like orally available small molecules were described with high activity in animal disease models with activities comparable to those of antibodies.

A randomized, double-blind, single-dose, two-way, parallel phase I clinical study comparing the pharmacokinetics and safety of adalimumab injecta and Humira® in healthy Chinese male volunteers

ABSTRACT Background Humira® is a fully humanized anti-tumor necrosis factor (TNF-α) monoclonal antibody that has been marketed and approved in the United States for the clinical treatment of rheumatoid arthritis (RA), ankylosing spondylitis, psoriasis and other immune-mediated diseases. This study compared the bioequivalence, immunogenicity and safety of adalimumab injecta (a biosimilar of Humira® produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Humira® in healthy Chinese male subjects in a phase I clinical study. Methods Healthy Chinese male subjects (N = 164) were randomly given a subcutaneous injection of 40 mg adalimumab or Humira® at a 1:1 ratio. Plasma drug concentrations were detected by enzyme-linked immunosorbent assay (ELISA), and primary pharmacokinetic (PK) parameters were statistically analyzed. To evaluate drug immunogenicity, anti-drug antibody (ADA) and neutralizing antibody (nAb) levels were detected. To evaluate the safety of the drugs, the subjects’ physical indicators, such as multiple vital signs and routine blood tests, were continuously monitored. Results The similarity ratios of adalimumab and Humira® PK parameters were all within 80%-125%, meeting the bioequivalence standards. Drug-induced ADA and nAb levels were similar, and the drug safety in subjects was also similar. Conclusions All study drugs showed similar bioequivalence, immunogenicity and safety. Clinical trial registration CTR20182070 (Chinese Clinical Trial Registry)

Post-approval Safety Surveillance Study of Golimumab in the Treatment of Rheumatic Disease Using a United States Healthcare Claims Database.

Background and ObjectiveGolimumab is a fully human anti-tumor necrosis factor monoclonal antibody approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). This study estimated rates of prespecified outcomes in patients with RA, PsA or AS initiating golimumab versus matched patients initiating non-biologic systemic (NBS) medications.MethodsPatients enrolled in a US health plan with rheumatic disease who initiated a study medication were accrued between April 2009 and November 2014. Golimumab initiators were matched by propensity score to NBS initiators in a 1:4 ratio. Outcomes were identified through September 2015. As-treated, as-matched, and nested case–control (NCC) analyses were conducted in the matched cohorts. Sensitivity analyses evaluated the impact of residual confounding and nondifferential misclassification of exposure and outcomes.ResultsRisks of outcomes were similar between golimumab and NBS initiators. In the as-treated analysis, the rate ratio (RR) for depression was elevated during current golimumab use versus golimumab non-use in the NBS cohort [RR 1.45, 95% confidence interval (CI) 1.31–1.61]. This finding was not replicated in as-matched (RR 1.08, 95% CI 0.97–1.19) or NCC (odds ratio 1.01, 95% CI 0.78–1.31) analyses, which focused on incident cases. Sensitivity analyses suggest that depression was sensitive to misclassification, and the RR changed from greater than to less than one across a plausible range of specificity.ConclusionsThis study suggests that there is no association between exposure to golimumab and an increased risk of prespecified outcomes. Increased depression risk in the as-treated analysis was not replicated in other analyses and may be associated with residual imbalance in baseline history or severity of depression.Electronic supplementary materialThe online version of this article (10.1007/s40261-020-00959-7) contains supplementary material, which is available to authorized users.

Fibrostenotic strictures in Crohn's disease.

The use of biologic agents including anti-tumor necrosis factor monoclonal antibodies followed by anti-integrins and anti-interleukins has drastically changed the treatment paradigm of Crohn’s disease (CD) by improving clinical symptoms and mucosal healing. However, up to 70% of CD patients still eventually undergo surgery mainly due to fibrostenotic strictures. There are no specific anti-fibrotic drugs yet. This review comprehensively addresses the mechanism, prediction, diagnosis and treatment of the fibrostenotic strictures in CD. We also introduce promising anti-fibrotic agents which may be available in the near future and summarize challenges in developing novel therapies to treat fibrostenotic strictures in CD.

Adalimumab in children and adolescents with severe plaque psoriasis: a safety evaluation

ABSTRACTIntroduction: Psoriasis is a chronic inflammatory systemic disease that affects 2% of the population and is associated with an important physical and physiological burden. About 0.5–2% of psoriatic cases onset during the pediatric age range, and often it’s not diagnosed until adulthood. Adalimumab is an antitumor necrosis factor monoclonal antibody approved for use in children in 2008 and now it was used in several diseases in rheumatology, gastroenterology, and in dermatology.Areas covered: The purpose of this article was to summarize what has been described in the literature so far, about safety in the use of adalimumab in pediatric psoriasis. The presented data was extrapolated from a literature review from PubMed searches (using words ‘pediatric psoriasis,’ ‘adalimumab children,’ ‘adalimumab safety,’ ‘pediatric psoriasis treatment,’ ‘adalimumab clinical trial’), treatment guidelines, and reports from European and United States regulatory agencies.Expert opinion: Actually there are some biologic agents for the treatment of pediatric psoriasis, but the lack of safety data from controlled trials is evident. The safety data on the use of adalimumab in pediatric psoriasis was taken from long-term studies in the adult population. These studies confirm the data on the safety of the drug as it is also supported by several works on real-life.