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Objective. To assess the efficacy of etanercept in the treatment of early active nonsteroidal antiinflammatory drug (NSAID)-refractory nonradiographic axial spondyloarthritis (SpA).Methods. The study population consisted of patients who met the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA but not the modified New York radiographic criteria for ankylosing spondylitis (as assessed by a radiologist at the central trial site), had a symptom duration of >3 months but <5 years, had a score of >4 on the Bath Ankylosing Spondylitis Disease Activity Index, and had been treated unsuccessfully with >2 NSAIDs. Patients were randomized to receive etanercept 50 mg/week or placebo and continued background NSAID treatment for 12 weeks (double-blind study); ClinicalTrials.gov identifier: NCT01258738.

Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with continuously evolving analyses of immunogenicity. Here, we review factors associated with immunogenicity of biopharmaceuticals, potential clinical ramifications, and current regulatory guidance for evaluating immunogenicity, and discuss methods to assess immunogenicity in non-clinical and clinical studies. We also describe special considerations for evaluating the immunogenicity of biosimilar candidates.

BackgroundThis double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10–25 mg/week). We report results for the first 26 weeks of treatment.MethodsPatients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (−12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28–4(CRP)], European League Against Rheumatism (EULAR) response, DAS28–4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26.ResultsPatients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28–4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was −2.98% and corresponding CIs—95% CI (−10.38%, 4.44%) and 90% CI (−9.25%, 3.28%)—were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU).ConclusionsThe study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX.Trial registrationClinicalTrials.gov Identifier: NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29. Start date: October 27, 2014.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1676-y) contains supplementary material, which is available to authorized users.

Anaemia during peginterferon (PEG-IFN) and ribavirin (RBV) therapy is common in human immunodeficiency virus/hepatitis C virus (HIV/HCV)-coinfected patients despite the use of lower doses of RBV than are recommended for HIV-seronegative persons. In addition, concurrent zidovudine (ZDV) may exacerbate the anaemia caused by PEG-IFN and RBV. We retrospectively analysed the incidence of anaemia, RBV dose reduction and epoetin-alpha (EPO) use among coinfected patients treated with PEG-IFN and weight-based RBV (800-1400 mg/day) who enrolled in two clinical trials and had haemoglobin (Hb) levels assessed at baseline and after 4 and/or 12 weeks of HCV treatment. Overall, 217 patients were included; pre-treatment Hb levels (mean 14.7 g/dL) were similar in all patients, including ZDV users (29% of patients). After 4 weeks of therapy, the mean Hb decline was greater among ZDV recipients (3.13 g/dL) compared with those on other anti-retroviral treatment (ART) (2.13 g/dL) or on no ART (1.47 g/dL) (P < 0.0001). RBV dose reduction and EPO use were more common in patients taking ZDV compared with those not taking ZDV (P < 0.0001). RBV dose was not associated with Hb reduction, RBV dose reduction or EPO use. Virologic response after 12 weeks of therapy and the treatment discontinuation rate did not differ by ZDV use. The use of ZDV but not weight-based RBV dosing was associated with an increased risk of anaemia, RBV dose reduction or EPO use in coinfected patients treated with PEG-IFN/RBV. However, ZDV use was not associated with higher rates of treatment discontinuation or lower early virologic response rates. HIV and hepatitis C care providers should be cognizant of these data.