Ixekizumab
(Synonyms: 伊西贝单抗; LY2439821) 目录号 : GC62224
Ixekizumab 是一种人源化 IgG4 单克隆抗体，可选择性结合和中和白细胞介素 IL-17A (KD<3 pM)。Ixekizumab 直接阻断 IL-17A 与 IL-17RA 的结合，但不与其他 IL-17 家族成员结合。Ixekizumab 用于中重度斑块型银屑病的研究。
Cas No.:1143503-69-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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Ixekizumab (LY2439821) is a humanized IgG4 monoclonal antibody that selectively binds and neutralizes interleukin IL-17A (KD<3 pM). Ixekizumab directly blocks IL-17A binding to IL-17RA (IL-17A receptor) but does not bind to other IL-17 family members. Ixekizumab is used for the research of moderate-to-severe plaque psoriasis[1][2].
The equilibrium KD of Ixekizumab for human and cynomolgus monkey IL-17A were 1.8 pM and 0.8 pM, respectively. Ixekizumab also bound to rabbit IL-17A, but the affinity was lower, and the binding was heterogeneous (KD of 1.3 nM and 14 nM). Ixekizumab shows no binding to either mouse or rat IL-17A[1].Ixekizumab (0.1-10000 pM) inhibits human IL-17A- or human IL-17A/F heterodimer-induced growth-regulated oncogene (GRO)α secretion from HT-29 cells in a dose-dependent fashion. Ixekizumab inhibits cynomolgus monkey IL-17A-induced GROα secretion from HT-29 cells in a dose-dependent fashion[1].
Ixekizumab (0.001-1 mg/kg; i.v.) is able to decrease human IL-17A-induced keratinocyte chemoattractant (KC) secretion in the plasma of the C57BL/6 mice in a dose-dependent manner[1].In male cynomolgus monkeys, following IV administration of 1 mg/kg, Ixekizumab is eliminated with a mean half-life of 6.5 days. After SC administration of 1 mg/kg, Ixekizumab reaches an average maximal plasma concentration of 11.1 µg/mL ~72 hours postdose. The mean elimination half-life following the SC injection was 10.3 days[1].
[1]. Liu L, et al. Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A. J Inflamm Res. 2016;9:39-50. Published 2016 Apr 19.
[2]. Griffiths CE, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386(9993):541-551.
| Cas No. | 1143503-69-8 | SDF | |
| 别名 | 伊西贝单抗; LY2439821 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at 4°C, do not freeze | |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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Ixekizumab for the treatment of psoriasis: up-to-date
Expert Opin Biol Ther 2020 Jun;20(6):549-557.PMID:32050819DOI:10.1080/14712598.2020.1729736.
Introduction: Ixekizumab (an IL-17A antagonist) is a biologic therapeutic licensed for use in moderate-to-severe plaque psoriasis and psoriatic arthritis. IL-17 antagonists (also including Secukinumab and Brodalumab) represent a new generation of biologic therapy with rapid and high response rates, quickly becoming a crucial part of the psoriasis treatment armamentarium.Areas covered: In this review, we describe how IL-17A antagonists disrupt inflammatory cascades in psoriasis and summarize results from clinical trials examining the safety and efficacy of Ixekizumab against placebo and comparators.Expert opinion: Ixekizumab induces a 75% reduction in psoriasis area severity index (PASI 75) in 89% of patients after 12 weeks and after 1 year, PASI 75 is maintained in 80% of patients. Ixekizumab is superior to both etanercept and ustekinumab, however, further comparator trials are needed to determine superiority between newer agents. Network meta-analysis suggests that Ixekizumab is one of the most rapid and efficacious agents for treating psoriasis, but ideally more long-term real-world data are needed to determine the persistence of response. Candida may be commonly encountered during treatment and IL-17 agents should be avoided in patients with inflammatory bowel disease. Overall, Ixekizumab represents an efficacious and well-studied therapeutic that can offer biologic-naïve and bio-failure patients durable disease control.
Ixekizumab for Psoriatic Arthritis: Safety, Efficacy, and Patient Selection
J Inflamm Res 2021 Dec 17;14:6975-6991.PMID:34949934DOI:10.2147/JIR.S229752.
Objective: Ixekizumab is a monoclonal antibody targeting IL-17A and licensed for psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis. Review objectives were to summarize: 1) Ixekizumab safety in people with PsA, 2) Ixekizumab efficacy from Phase III randomized controlled trials, and 3) Ixekizumab study participant PsA phenotypes. Methods: We conducted a search in PubMed limited to phase III randomized controlled trials (RCT) and corresponding long-term extension studies where the intervention was treatment with Ixekizumab in a population with PsA. Results: We identified 17 publications and 13 met inclusion criteria. Injection site reactions (ISR) and allergic reactions occurred in up to 25.3% and 6.2% with Ixekizumab and 4.5% and 1.85, respectively, with placebo. ISR occurred in 9.5-10.6% at 24 and 52 weeks with Ixekizumab versus 3.2-3.5% with adalimumab (p < 0.01) in biologic-naïve PsA. Serious adverse events at 24 weeks occurred in 8.5% with adalimumab versus 3.5% with Ixekizumab (p = 0.02), and at 52 weeks in 12.45 with adalimumab and 4.25 with Ixekizumab (p < 0.01). Ixekizumab had similar efficacy to adalimumab across all PsA musculoskeletal, symptom and patient-reported outcome domains and surpassed adalimumab in psoriasis outcomes as well as all combined musculoskeletal and psoriasis outcomes. The study subject population was overwhelmingly white, balanced men-women, BMI at the obese threshold, had on average 7-year PsA duration and 15-year psoriasis duration. Disease activity was high with 7/66 swollen joints, 13/68 tender joints, 55% enthesitis, variable dactylitis (12-51%), and active psoriasis in >92%. Conclusion: Ixekizumab treatment in PsA was associated with a statistically significant higher risk of injection site reactions versus placebo or adalimumab. Ixekizumab had statistically significantly fewer serious adverse events than adalimumab. Ixekizumab demonstrated efficacy for all PsA disease activity domains as well as for slowing radiographic disease progression. The main shortcoming of the Ixekizumab PsA program is lack of representation of African American study participants.
A head-to-head comparison of Ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 24-week efficacy and safety results from a randomized, double-blinded trial
Br J Dermatol 2021 Jun;184(6):1047-1058.PMID:32880909DOI:10.1111/bjd.19509.
Background: Significantly more patients with moderate-to-severe plaque psoriasis treated with the interleukin (IL)-17A inhibitor Ixekizumab vs. the IL-23p19 inhibitor guselkumab in the IXORA-R head-to-head trial achieved 100% improvement in Psoriasis Area and Severity Index (PASI 100) at week 12. Objectives: To compare skin and nail clearance and patient-reported outcomes for Ixekizumab vs. guselkumab, up to week 24. Methods: IXORA-R enrolled adults with moderate-to-severe plaque psoriasis, defined as static Physician's Global Assessment ≥ 3, PASI ≥ 12 and involved body surface area ≥ 10%. Statistical comparisons were performed using the Cochran-Mantel-Haenszel test stratified by pooled site. Time-to-first-event comparisons were performed using Kaplan-Meier analysis, and P-values were generated using adjusted log-rank tests stratified by treatment group. Cumulative days at clinical and patient-reported responses were compared by ancova. The trial was registered with ClinicalTrials.gov (NCT03573323). Results: Of the 1027 patients randomly assigned, 90% completed the trial (465 of 520 Ixekizumab and 459 of 507 guselkumab). As early as week 2 and through week 16, more patients on Ixekizumab achieved PASI 100 (P < 0·01). At week 24, Ixekizumab was noninferior to guselkumab (50% vs. 52%, difference -2·3%), with no statistically significant difference in PASI 100 (P = 0·41). More patients receiving Ixekizumab showed completely clear nails at week 24 (52% vs. 31%, P = 0·007). The median time to first PASI 50/75/90 and PASI 100 were 2 and 7·5 weeks shorter, respectively, for patients on Ixekizumab vs. guselkumab (P < 0·001). Patients on Ixekizumab also had a greater cumulative benefit, with more days at PASI 90 and 100, with Dermatology Life Quality Index of 0 or 1, and itch free (P < 0·05). The frequency of serious adverse events was 3% for each group, with no new safety signals. Conclusions: Ixekizumab was noninferior to guselkumab in complete skin clearance and superior in clearing nails at week 24. Ixekizumab cleared skin more rapidly in patients with moderate-to-severe plaque psoriasis, with a greater cumulative benefit, than guselkumab. Overall, the safety findings were consistent with the known safety profile for Ixekizumab.
Drug Survival Associated With Effectiveness and Safety of Treatment With Guselkumab, Ixekizumab, Secukinumab, Ustekinumab, and Adalimumab in Patients With Psoriasis
JAMA Dermatol 2022 Oct 1;158(10):1131-1141.PMID:PMC9260644DOI:10.1001/jamadermatol.2022.2909.
Importance: Drug survival of biologic therapies for psoriasis is a proxy for longer-term treatment effectiveness and safety. Patient factors that are associated with the survival of each biologic differently (effect modifiers) may inform the decision to choose between biologics. Objective: To assess the drug survival associated with the effectiveness and safety of commonly used biologics for psoriasis in the UK and Ireland and identify effect modifiers for these biologics and their survival. Design, setting, and participants: We conducted a prospective cohort study of patients with psoriasis using data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) between November 2007 and August 2021. Exposures: Adalimumab, ustekinumab, secukinumab, guselkumab, Ixekizumab. Main outcomes and measures: We conducted a survival analysis and fitted separate flexible parametric models for drug survival as a proxy for effectiveness and safety. Results: A total of 16 122 treatment courses were included: 6607 (41.0%) in which treatment with adalimumab was initiated, 5405 (33.5%) with ustekinumab, 2677 (16.6%) with secukinumab, 730 (4.5%) with guselkumab, and 703 (4.4%) with Ixekizumab. The crude survival functions at year 1 for measures of effectiveness for treatment with adalimumab was 0.81 (95% CI, 0.80-0.82), 0.89 for ustekinumab (95% CI, 0.88-0.89), 0.86 for secukinumab (95% CI, 0.85-0.87), 0.94 for guselkumab (95% CI, 0.92-0.96), and 0.86 for Ixekizumab (95% CI, 0.83-0.89). The adjusted survival curves from the multivariable model for effectiveness showed that treatment with guselkumab had the higher survival (adjusted hazard ratio, 0.13; 95% CI, 0.03-0.56) and adalimumab had the lower survival (adjusted hazard ratio, 2.37; 95% CI, 2.03-2.76) compared with ustekinumab. Secukinumab and Ixekizumab had similar survival curves over time. Psoriatic arthritis, previous biologic exposure, nail involvement, and ethnicity were effect modifiers for survival in association with treatment effectiveness. The crude survival functions at year 1 for safety were 0.91 for treatment with adalimumab (95% CI, 0.90-0.91), 0.94 for ustekinumab (95% CI, 0.94-0.95), 0.94 for secukinumab (95% CI, 0.92-0.94), 0.96 for guselkumab (95% CI, 0.94-0.98), and 0.92 for Ixekizumab (95% CI, 0.89-0.94). Guselkumab, ustekinumab, and secukinumab had similar adjusted survival curves for safety, while adalimumab (adjusted hazard ratio, 1.66; 95% CI, 1.46-1.89) and Ixekizumab (adjusted hazard ratio, 1.52; 95% CI, 1.13-2.03) had lower survival compared with ustekinumab. Conclusions and relevance: The results of this cohort study suggest that guselkumab had the highest drug survival in BADBIR of the included biologics for treatment persistence that was associated with effectiveness, and guselkumab had highest drug survival for safety compared with other biologics except ustekinumab. Psoriatic arthritis, nail involvement, previous biologic exposure, and ethnicity were effect modifiers for biologics and their survival in association with treatment effectiveness. This information on longer-term treatment persistence, safety, and tolerability may help patients and their clinicians make an informed decision to initiate treatment with a biologic therapy.
Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial
Lancet 2020 Jan 4;395(10217):53-64.PMID:31813637DOI:10.1016/S0140-6736(19)32971-X.
Background: Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of Ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. Methods: COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg Ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label Ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0-10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label Ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352. Findings: Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to Ixekizumab Q4W, and 102 to Ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (Ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; Ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (Ixekizumab Q4W: 29 [30%] of 96, p=0·0045; Ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the Ixekizumab Q4W group, and 79 (77%) of 102 in the Ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the Ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the Ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. Interpretation: Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous Ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. Funding: Eli Lilly and Company.