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Secukinumab Demonstrates Significantly Lower Immunogenicity Potential Compared to Ixekizumab.

ABSTRACT: INTRODUCTION:Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL-17A, has been shown to have significant efficacy in the treatment of moderate to severe plaque psoriasis (PsO) and psoriatic arthritis (PsA), demonstrating a rapid onset of action and sustained responses with a favorable safety profile. All biotherapeutics, including monoclonal antibodies (mAbs), can be immunogenic, leading to formation of anti-drug antibodies (ADAs) that can result in loss of response and adverse events such as hypersensitivity reactions. Thus, the immunogenicity potential of biotherapeutics is of particular interest for physicians. Of the 2842 patients receiving secukinumab across six phase 3 psoriasis clinical trials, only 0.4% developed treatment-emergent ADAs over 3 years of treatment. Direct comparison of clinical immunogenicity incidence rates is hampered by the nature of clinical immunogenicity assays, differences in study designs, patient populations, and treatment regimens. METHODS:We evaluated side-by-side in the same healthy donors two recently approved IL-17A selective antibodies, secukinumab and ixekizumab, along with adalimumab and ustekinumab, for their capacity to induce anti-drug related T cell responses in vitro and estimated their potential for developing ADAs in patients. RESULTS:We found that healthy donors show both significantly less frequent T cell responses and lower numbers of pre-existing T cells to secukinumab than to ixekizumab and adalimumab. Although there was a tendency for a lower response to ustekinumab, this difference was not significant. CONCLUSION:In summary, this in vitro study confirms the significantly lower immunogenicity potential and provides an explanation for the lower clinical immunogenicity incidence found for secukinumab in comparison to other approved therapeutic antibodies used to treat plaque psoriasis. FUNDING:Novartis Pharmaceuticals AG.

SUBMITTER: Spindeldreher S

PROVIDER: S-EPMC5825325 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:To conduct a cost-effectiveness analysis from the perspective of the Spanish National Health System (NHS) comparing ixekizumab versus secukinumab. DESIGN:A Markov model with a lifetime horizon and monthly cycles was developed based on the York model. Four health states were included: a biological disease-modifying antirheumatic drug (bDMARD) induction period of 12 or 16?weeks, maintenance therapy, best supportive care (BSC) and death. Treatment response was assessed based on both Psoriatic Arthritis Response Criteria (PsARC) and ?90% improvement in the Psoriasis Area Severity Index score (PASI90). At the end of the induction period, responders transitioned to maintenance therapy. Non-responders and patients who discontinued maintenance therapy transitioned to BSC. Clinical efficacy data were derived from a network meta-analysis. Health utilities were generated by applying a regression analysis to Psoriasis Area Severity Index and Health Assessment Questionnaire?Disability Index scores collected in the ixekizumab SPIRIT studies. Results were subject to extensive sensitivity and scenario analysis. SETTING:Spanish NHS. PARTICIPANTS:A hypothetical cohort of bDMARD-naïve patients with psoriatic arthritis and concomitant moderate-to-severe psoriasis was modelled. INTERVENTIONS:Ixekizumab and secukinumab. RESULTS:Ixekizumab performed favourably over secukinumab in the base-case analysis, although cost savings and quality-adjusted life-year (QALY) gains were modest. Total costs were €153?901 compared with €156?559 for secukinumab (difference -€2658). Total QALYs were 9.175 vs 9.082 (difference 0.093). Base-case results were most sensitive to the annual bDMARD discontinuation rate and the modification of PsARC and PASI90 response to ixekizumab or secukinumab. CONCLUSION:Ixekizumab provided more QALYs at a lower cost than secukinumab, with differences being on a relatively small scale. Sensitivity analysis showed that base-case results were generally robust to changes in most input parameters. TRIAL REGISTRATION NUMBER:SPIRIT-P1: NCT01695239; Post-results, SPIRIT-P2: NCT02349295; Post-results.

Project description:BACKGROUND:For psoriatic patients receiving biologics, the concern of tuberculosis (TB) infection exists. Although the TB risk of anti-interleukin (IL)-17A agents is generally considered very low, more real-world data are needed to support the safety. OBJECTIVES:This study aims to provide the real-world experience of using serial QuantiFERON-TB Gold In-Tube (QFT-GIT) test among patients treated with secukinumab or ixekizumab in Taiwan, an intermediate TB burden country, for the detection of latent TB infection (LTBI) reactivation or newly acquired TB infection. METHODS:This retrospective review evaluated 100 consecutive patients with psoriasis receiving anti-IL-17A therapies who were checked with at least twice QFT-GIT between 2016 and 2019 in National Taiwan University Hospital, Taipei and Hsin-Chu, Taiwan. RESULTS:Among the 100 patients, the baseline QFT-GIT results were negative in 81.0% (81/100), positive in 18.0% (18/100), and indeterminate in 1.0% (1/100) of patients. The overall outcomes in patients receiving at least 6 months of cumulative exposure to anti-IL-17A agents were persistently seronegative in 80 patients (80.0%), persistently seropositive in 14 patients (14.0%), seroconversion in 1 patient (1.0%), seroreversion in 3 patients (3.0%), and others in 2 patients (2.0%). In patients with at least 11 months of cumulative exposure, the seroconversion rate was 1.3% (1/79). The only case with seroconversion had a positive QFT-GIT result previously. No case of TB reactivation or newly acquired TB infection was identified during the follow-up. CONCLUSIONS:In patients treated with anti-IL-17A monoclonal antibodies for psoriasis, routine serial repeat QFT-GIT testing was associated with lower seroconversion rate compared to real-world data of tumor necrosis factor-? inhibitors and anti-IL-12/23 antibody in Taiwan and in pivotal studies. Because clinical TB symptoms and signs are often preceded by QFT-GIF seroconversion, this result further supports the safety of anti-IL-17A agents in patients with psoriasis for LTBI.

Project description:Rheumatic disease is not a single disorder, but a group of more than 100 diseases that affect joints, connective tissues, and/or internal organs. Although rheumatic diseases like rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis (AS) differ in their pathogenesis and clinical presentation, the treatment of these inflammatory disorders overlaps. Non-steroid anti-inflammatory drugs are used to reduce pain and inflammation. Additional disease-modifying anti-rheumatic drugs are prescribed to slowdown disease progression, and is in RA more frequently and effectively applied than in AS. Biologicals are a relatively new class of treatments that specifically target cytokines or cells of the immune system, like tumor necrosis factor alpha inhibitors or B-cell blockers. A new kid on the block is the interleukin-17 (IL-17) inhibitor secukinumab, which has been recently approved by the US Food and Drug Administration for moderate-to-severe plaque psoriasis, psoriatic arthritis, and AS. IL-17 is a proinflammatory cytokine that has an important role in host defense, but its proinflammatory and destructive effects have also been linked to pathogenic processes in autoimmune diseases like RA and psoriasis. Animal models have greatly contributed to further insights in the potential of IL-17 blockade in autoimmune and autoinflammatory diseases, and have resulted in the development of various potential drugs targeting the IL-17 pathway. Secukinumab (AIN457) is a fully human monoclonal antibody that selectively binds to IL-17A and recently entered the market under the brand name Cosentyx(®). By binding to IL-17A, secukinumab prevents it from binding to its receptor and inhibits its ability to trigger inflammatory responses that play a role in the development of various autoimmune diseases. With secukinumab being the first in class to receive Food and Drug Administration approval, this article will further focus on this new biologic agent and review the milestones in its development and marketing.

Project description:Although B cell depletion is an effective therapy of multiple sclerosis (MS), the pathogenic functions of B cells in MS remain incompletely understood. We asked whether cerebrospinal fluid (CSF) B cells in MS secrete different cytokines than control-subject B cells and whether cytokine secretion affects MS phenotype. We blindly studied CSF B cells after their immortalization by Epstein-Barr Virus (EBV) in prospectively-collected MS patients and control subjects with other inflammatory-(OIND) or non-inflammatory neurological diseases (NIND) and healthy volunteers (HV). The pilot cohort (n = 80) was analyzed using intracellular cytokine staining (n = 101 B cell lines [BCL] derived from 35 out of 80 subjects). We validated differences in cytokine production in newly-generated CSF BCL (n = 207 BCL derived from subsequent 112 prospectively-recruited subjects representing validation cohort), using ELISA enhanced by objective, flow-cytometry-based B cell counting. After unblinding the pilot cohort, the immortalization efficiency was almost 5 times higher in MS patients compared to controls (p < 0.001). MS subjects' BCLs produced significantly more vascular endothelial growth factor (VEGF) compared to control BCLs. Progressive MS patients BCLs produced significantly more tumor necrosis factor (TNF)-? and lymphotoxin (LT)-? than BCL from relapsing-remitting MS (RRMS) patients. In the validation cohort, we observed lower secretion of IL-1? in RRMS patients, compared to all other diagnostic categories. The validation cohort validated enhanced VEGF-C production by BCL from RRMS patients and higher TNF-? and LT-? secretion by BCL from progressive MS. No significant differences among diagnostic categories were observed in secretion of IL-6 or GM-CSF. However, B cell secretion of IL-1?, TNF-?, and GM-CSF correlated significantly with the rate of accumulation of disability measured by MS disease severity scale (MS-DSS). Finally, all three cytokines with increased secretion in different stages of MS (i.e., VEGF-C, TNF-?, and LT-?) enhance lymphangiogenesis, suggesting that intrathecal B cells directly facilitate the formation of tertiary lymphoid follicles, thus compartmentalizing inflammation to the central nervous system.

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Secukinumab Demonstrates Significantly Lower Immunogenicity Potential Compared to Ixekizumab.

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