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Taltz ® (ixekizumab)
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What is the long-term safety of Taltz® (ixekizumab)?
Exposure-adjusted IR for TEAEs and SAEs remained stable or decreased over time in ixekizumab clinical trials.
Table of contents
Note
- Please find the full list of adverse drug reactions of ixekizumab in the Taltz summary of product characteristics.1
- Note that data from multiple, different dosing regimens, including unapproved doses, are included in this response.
- Brief descriptions of the pivotal clinical trials for plaque psoriasis and psoriatic arthritis are provided at the end of this response (Appendix: Clinical trial brief descriptions ).
Plaque Psoriasis
- The long-term safety of ixekizumab has been evaluated in 6892 patients with psoriasis who received ixekizumab up to 5 years (a total of 18,025.7 patient years (PY) of ixekizumab exposure). The safety profile is consistent with previous reports in patients who received ixekizumab for the treatment of psoriasis (PsO) and the rates of reported adverse events (AEs) did not increase with long-term exposure to ixekizumab.2
- Comparisons between treatment periods described for the phase 3 UNCOVER trials summarized in this response are descriptive in nature, and not statistical comparisons.
Adverse events in first 60 weeks of ixekizumab treatment
In an integrated analysis of safety data from 3 pivotal phase 3 clinical trials which had an induction period of 12 weeks, 2 of which were followed by a randomized withdrawal maintenance period of 48 additional weeks, the exposure adjusted incidence rate (EAIR) per 100 PYs for treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) remained stable or decreased over time through week 60 (Incidence Rates of Treatment-Emergent Adverse Events and Serious Adverse Events Through Week 60 in Phase 3 UNCOVER Clinical Trials).2,3
Across the 12-week induction periods of UNCOVER-1, -2, and -3, the 48-week maintenance periods of UNCOVER-1 and -2, and the long-term extension period to week 60 of UNCOVER-3, most TEAEs were mild or moderate in severity and generally did not lead to treatment discontinuation.4-6 In all 3 trials, long-term safety was evaluated for up to a total of 5 years in patients who participate through the entire studies.5
Event |
12-Week Induction Period From UNCOVER-1, UNCOVER-2, and UNCOVER-3 |
48-Week Maintenance Period From UNCOVER-1 and UNCOVER-2 |
||||
Placebo |
IXE every 2 wks |
IXE every 4 wks |
Placebo |
IXE every 4 wks |
IXE every 12 wks |
|
Any TEAE, IRa |
205.5 |
253.6b |
256.8b |
123.8 |
95.6b |
106.2 |
Any SAE, IRa |
6.7 |
7.4 |
9.8 |
8.0 |
7.5 |
8.1 |
Abbreviations: IR = incidence rate; IXE = ixekizumab; PY = patient-years; SAE = serious adverse event; TEAE =-treatment-emergent adverse event.
aIncidence rates were calculated by dividing the total number of patients experiencing the TEAE by the sum of all patients’ time (in 100 years) of exposure during the treatment period.
bp<.05 vs placebo.
Adverse events in 264 weeks of ixekizumab treatment (long term)
Treatment-Emergent Adverse Events, Serious Adverse Events, Deaths, and Discontinuations in the Open-Label Long-Term Extension Period of UNCOVER-3 summarizes safety data on TEAEs, SAEs, deaths, and discontinuations due to AEs from the open-label long-term extension period of the 264-week UNCOVER-3 trial for the patients who received the approved ixekizumab dosing regimen and all patients who received ixekizumab.8
Event |
All IXE Exposure Population |
|
Patients with ≥1 TEAE |
323 (21.6) |
1134 (21.9) |
Patients with ≥1 SAE |
55 (3.7) |
253 (4.9) |
Deaths |
3 (0.2) |
11 (0.2) |
Discontinuation due to AE |
33 (2.2) |
131 (2.5) |
Abbreviations: AE = adverse event; IR = incidence rate; IXE = ixekizumab; LTE = long-term extension; PY = patient-years; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
Notes: Patients may be counted in more than one category. Patients with multiple occurrences of the same event are categorized by the highest severity.
aThe approved ixekizumab dosing regimen for moderate-to-severe plaque psoriasis is ixekizumab 160 mg at week 0, followed by 80 mg every 2 weeks through week 12, and 80 mg every 4 weeks thereafter. In UNCOVER-3, patients were allowed to escalate to every 2 weeks dosing after week 60 and remained on every 2 weeks dosing until study completion or discontinuation. The patients that dose-escalated are included in this approved dosing regimen population.
bIR per 100 PY.
Adverse events in all ixekizumab exposures
In 17 ixekizumab clinical trials for psoriasis, 6892 patients received at least 1 dose of ixekizumab, representing 18,025.7 PY of exposure as of the data cutoff of March 2021.2
Treatment-Emergent Adverse Events and Serious Adverse Events in All Treatment Periods in All Psoriasis Ixekizumab Exposures Integrated Analysis Set provides the numbers of TEAEs, SAEs, deaths, and discontinuations due to an AE as of March 2021 in the all psoriasis integrated exposures dataset.
Adverse Events of Special Interest in All Treatment Periods in All Psoriasis Ixekizumab Exposures Integrated Analysis Set summarizes the AEs of special interest as of the March 2021 dataset.
Event, n [IR]a |
Pooled IXE |
Patients with ≥1 TEAE |
5857 [32.5]c |
Patients with ≥1 SAE |
969 [5.4] |
Deaths |
36 [0.2] |
Discontinuation due to AE |
519 [2.9] |
Abbreviations: AE = adverse event; IR = incidence rate; IXE = ixekizumab; PY = patient-years; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
Notes: Patients may be counted in more than one category. Patients with multiple occurrences of the same event are categorized by the highest severity. Deaths are included among SAEs and among discontinuations due to AEs.
aIR per 100 PY.
bData through March 2021.
cThe most commonly reported TEAEs (IR per 100 PYs) were nasopharyngitis (8.8) and upper respiratory tract infection (6.2).
Event, n [IR]a |
Pooled IXE |
Infections |
4307 [23.9] |
Serious infections |
231 [1.3] |
Candida infections |
337 [1.9] |
Opportunistic infections |
318 [1.8] |
Injection site reactionsc |
1056 [5.9] |
Allergic/hypersensitivity reactions |
1002 [5.6] |
Cytopeniasd |
171 [0.9] |
Malignancies |
141 [0.8] |
MACEe |
91 [0.5] |
Depressionf |
215 [1.2] |
Inflammatory bowel diseaseg |
26 [0.1] |
Ulcerative colitis |
16 [0.1] |
Crohn's disease |
10 [0.1] |
Abbreviations: EPIMAD = Registre Epidemiologique des Maladies de l'Appareil Digestif; IR = incidence rate; IXE = ixekizumab; MACE = major adverse cerebro-cardiovascular events; MEdDRA = Medical Dictionary for Regulatory Activities; PY = patient-years; SMQ = standardized MedDRA query; TEAE = treatment-emergent adverse event.
aIR per 100 PY.
bData through March 2021.
cHigh level term.
dBroad, according to SMQ classification.
eConfirmed events.
fBroad, according to SMQ or sub-SMQ classification.
gThe data represent cases classified as ‘‘definite’’ and ‘‘probable’’ per external adjudication. IR was calculated as the total of ‘‘definite’’ and ‘‘probable’’ cases/total patient-years, then multiplied by 100. There were five cases of adjudicated IBD that were not considered TEAEs. Total adjudicated IBD n = 31 (IR of 0.2 per 100 PY, 0.4%).
The rates of reported AEs did not increase with longer ixekizumab exposure, up to 5 years (Incidence Rates of Select Categories of Adverse Events at 1-Year Intervals, All Psoriasis Program Patients Exposed to Ixekizumab With Up To 5 Years of Treatment).2,9
Figure 1 description: Incidence rates did not increase over 5 years for all treatment-emergent adverse events, serious adverse events, serious infections, injection-site reactions, infections, depression, major adverse cerebro-cardiovascular events, malignancies, and inflammatory bowel disease.
Abbreviations: IBD = inflammatory bowel disease; IR = incidence rate; IXE = ixekizumab; MACE = major adverse cerebro-cardiovascular events; PY = patient-years; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
Notes: Inflammatory bowel disease IR summarized here represent confirmed cases per external adjudication. MACE were adjudicated events.
Psoriatic Arthritis
The long-term safety of ixekizumab was evaluated in 1401 patients with PsA who received ixekizumab up to 3 years (accounting for 2247.7 patient-years [PYs]). The safety profile is consistent with previous reports in patients who received ixekizumab for the treatment of psoriasis (PsO) or PsA and the rates of reported treatment-emergent adverse event (TEAEs) remained stable or decreased over time with continued ixekizumab exposure.10
Adverse events in all ixekizumab exposures
Across 4 ixekizumab PsA clinical trials, 1401 patients with active PsA received at least one dose of ixekizumab, representing 2247.7 PYs of exposure as of the data cutoff of March 19, 2020.10
Treatment-Emergent Adverse Events and Serious Adverse Events in All Treatment Periods in All Psoriatic Arthritis Ixekizumab Exposures Integrated Analysis Set Through March 2020 shows the number of TEAEs, serious adverse event (SAEs), deaths, and discontinuations due to an adverse event (AE) as of March 19, 2020. The most commonly reported TEAEs (exposure-adjusted incidence rate [IR] per 100 PYs) were
- nasopharyngitis (9.0)
- upper respiratory tract infection (8.3), and
- injection site reactions (6.9).10
Event, n (%) [IR]a |
Pooled IXE |
Patients with ≥1 TEAEb |
1131 (80.7) [50.3]c |
Mild |
461 (32.9) [20.5] |
Moderate |
556 (39.7) [24.7] |
Severe |
114 (8.1) [5.1] |
Patients with ≥1 SAE |
134 (9.6) [6.0] |
Deaths |
6 (0.4) [0.3] |
Discontinuation due to AE |
115 (8.2) [5.1] |
Abbreviations: AE = adverse event; IR = exposure-adjusted incidence rate; IXE = ixekizumab; PY = patient-years; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
Note: Patients with multiple occurrences of the same event are categorized by the highest severity. Deaths are included among SAEs and among discontinuations due to AEs.
aIncidence rate per 100 PYs.
bPatients with multiple occurrences of the same event were counted under the highest severity.
cThe most commonly reported TEAEs (IR per 100 PYs) were nasopharyngitis (9.0), upper respiratory tract infection (8.3), and injection site reactions (6.9).
Adverse Events of Special Interest in All Treatment Periods in All Psoriatic Arthritis Ixekizumab Exposures Integrated Analysis Set Through March 2020 shows the number of AEs of special interest as of March 19, 2020.10
Event, n (%) [IR]a |
Pooled IXE |
Infections |
759 (54.2) [33.8] |
Serious infections |
28 (2.0) [1.2] |
Candida infections |
45 (3.2) [2.0] |
Opportunistic infections |
40 (2.9) [1.8] |
Injection site reactionsb |
260 (18.6) [11.6] |
Hepatic reactionsc |
112 (8.0) [5.0] |
Allergic/hypersensitivity reactions |
102 (7.3) [4.5] |
Cytopeniasd |
56 (4.0) [2.5] |
Inflammatory bowel disease (adjudicated) |
3 (0.2) [0.1]e |
MACE (adjudicated) |
12 (0.9) [0.5] |
Malignancies |
15 (1.1) [0.7] |
Depression |
37 (2.6) [1.6] |
Asthma |
10 (0.7) [0.4] |
Suicidal behaviour/self-injury |
1 (0.1) [0] |
Abbreviations: IR = exposure-adjusted incidence rate; IXE = ixekizumab; MACE = major adverse cerebrocardiovascular events; MedDRA = Medical Dictionary for Regulatory Activities; PY = patient-years; SMQ = standardized Medical Dictionary for Regulatory Activities query.
aIR per 100 PYs.
bMedDRA high-level term.
cThe most common hepatic reactions were alanine aminotransferase increased (n=37), aspartate aminotransferase increased (n=28), gamma-glutamyltransferase increased (n=21), and hepatic steatosis (n=21).
dBroad according to SMQ classification. The most common cytopenias were neutropenia (n=29), leukopenia (n=18), and neutrophil count decreased (n=9).
eThree patients had events of IBD confirmed by adjudication. One patient had more than 1 event. Crohn's disease, n=2; ulcerative colitis, n=1.
The rates of TEAEs decreased over time and the rates of SAEs and discontinuations due to AEs were low and remained stable over time with continued exposure to ixekizumab up to 3 years (Incidence Rates of Select Categories of Adverse Events at 1-Year Intervals Up to 3 Years of Treatment in Patients Exposed to Ixekizumab Across 4 Psoriatic Arthritis Trials).10,11
Figure 2 description: Across 4 psoriatic arthritis trials, the incidence rates for the treatment emergent adverse events decreased over time. The incidence rates for serious adverse events and discontinuations due to adverse events remained low and stable throughout the treatment period. Similarly, the incidence rates for serious infections were also low and stable over time. Incidence rates for injection-site reactions and allergic reactions/hypersensitivities decreased over the three-year treatment period with ixekizumab.
Abbreviations: AE = adverse event; IR = incidence rate; PY = patient-years; SAE = serious adverse event; TEAE = treatment-emergent adverse event.
a Adjudicated cases. For IBD, 3 patients had IBD confirmed by adjudication. One patient had more than 1 event.
References
1Taltz [summary of product characteristics]. Eli Lilly and Company (Ireland) Limited, Ireland
2Griffiths CEM, Gooderham M, Colombel JF, et al. Safety of ixekizumab in adult patients with moderate-to-severe psoriasis: data from 17 clinical trials with over 18,000 patient-years of exposure. Dermatol Ther (Heidelb). 2022;12(6):1431-1446. https://doi.org/10.1007/s13555-022-00743-9
3Strober B, Papp KA, Leonardi C, et al. Integrated safety of ixekizumab in patients with moderate-to-severe psoriasis: results from a pooled analysis of 7 clinical trials. Poster presented at: 74th Annual Meeting of the American Academy of Dermatology; March 4-8, 2016; Washington, DC.
4Blauvelt A, Papp KA, Langley R, et al. Efficacy and safety of continuous ixekizumab treatment for 60 weeks in moderate-to-severe plaque psoriasis: Results from the UNCOVER-3 trial. Poster presented at: 74th Annual Meeting of the American Academy of Dermatology, March 4-8, 2016; Washington, DC
5Gordon KB, Blauvelt A, Papp KA, et al; UNCOVER-1, UNCOVER-2, and UNCOVER-3 Study Groups. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375(4):345-356. http://dx.doi.org/10.1056/NEJMoa1512711
6Griffiths CEM, Reich K, Lebwohl M, et al; UNCOVER-2, UNCOVER-3 Investigators. 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. https://doi.org/10.1016/S0140-6736(15)60125-8
7Strober B, Leonardi C, Papp KA, et al. Short- and long-term safety outcomes with ixekizumab from 7 clinical trials in psoriasis: etanercept comparisons and integrated data. J Am Acad Dermatol. 2017;76(3):432-440.e17. http://www.sciencedirect.com/science/article/pii/S0190962216308684
8Blauvelt A, Lebwohl MG, Mabuchi T, et al. Long-term efficacy and safety of ixekizumab: a 5-year analysis of the UNCOVER-3 randomized controlled trial. J Am Acad Dermatol. 2020;85(2):360-368. https://doi.org/10.1016/j.jaad.2020.11.022
9Griffiths CEM, Reich K, Gooderham M, et al. Long-term safety of ixekizumab in patients with moderate-to-severe psoriasis up to 5 years: pooled data from 16 clinical trials. Poster presented at: 29th Annual Meeting of the European Academy of Dermatology and Venereology (EADVirtual); October 29-31, 2020.
10Deodhar AA, Combe B, Accioly AP, et al. Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure. Ann Rheum Dis. 2022;81(7):944-950. https://doi.org/10.1136/annrheumdis-2021-222027
11Sesin C, Gallo G, Gellett AM, et al. Safety of ixekizumab in patients with psoriatic arthritis: an integrated analysis of 4 clinical trials. Ann Rheum Dis. 2021;80(suppl 1):789. European League Against Rheumatism Virtual Congress abstract POS1033. https://doi.org/10.1136/annrheumdis-2021-eular.567
12Mease PJ, van der Heijde D, Ritchlin CT, et al; SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87. http://dx.doi.org/10.1136/annrheumdis-2016-209709
13Nash P, Kirkham B, Okada M, et al; SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389(10086):2317-2327. http://dx.doi.org/10.1016/S0140-6736(17)31429-0
14Coates LC, Pillai SG, Tahir H, et al; SPIRIT-P3 Study Group. Withdrawing ixekizumab in patients with psoriatic arthritis who achieved minimal disease activity: results from a randomized, double-blind withdrawal study. Arthritis Rheumatol. 2021;73(9):1663-1672. https://doi.org/10.1002/art.41716
15Mease PJ, Smolen JS, Behrens F, et al; SPIRIT H2H Study Group. A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naïve patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial. Ann Rheum Dis. 2020;79(1):123-131. https://doi.org/10.1136/annrheumdis-2019-215386
Appendix: Clinical trial brief descriptions
Plaque Psoriasis
Figure 3 description: The study design for UNCOVER-1, -2, and -3 12-week induction period and maintenance dosing periods for UNCOVER 1 and 2 are presented. Etanercept arm was not included in UNCOVER-1. Responders (static Physician Global Assessment 0 or 1) to ixekizumab at week 12 were rerandomized to receive ixekizumab every 4 weeks, ixekizumab every 12 weeks, or placebo. In UNCOVER-2 study, nonresponders to etanercept at week 12 were switched to ixekizumab every 4 weeks (without a 160-mg starting dose) after a 4‑week washout period. Nonresponders to placebo at week 12 received a 160-mg starting dose of ixekizumab followed by ixekizumab every 4 weeks. UNCOVER-3 study is not represented in maintenance period design as the extension period consisted of open-label treatment with ixekizumab every 4 weeks.
Abbreviations: ETN = etanercept; IXE Q2W = ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; IXE Q12W = ixekizumab 80 mg every 12 weeks; PBO = placebo; R = randomization; sPGA = static Physician Global Assessment.
Note: ⁞ (dotted line) indicates relapse (sPGA ≥3).
Psoriatic Arthritis
- SPIRIT-P1 (N=417) was a phase 3, 24-week double-blind, placebo-controlled trial with an active reference arm, conducted in patients with active PsA who were naïve to disease-modifying antirheumatic drugs (bDMARDs) with an extension period of up to 3 years.12
- SPIRIT-P2 (N=363) was a phase 3, 24-week double-blind, placebo-controlled trial, conducted in patients with active PsA and an inadequate response or intolerance to TNF inhibitors, with an extension period of up to 3 years.13
- SPIRIT-P3 (N=394) consisted of a 36-week open-label period followed by a randomized double-blind withdrawal period from week 36 to week 104. This trial was conducted in patients who were naïve to bDMARDs.14
- SPIRIT-H2H (N=566) was a phase 3, 52-week open-label, blinded-assessor trial that compared the efficacy and safety of ixekizumab and adalimumab, conducted in patients with active PsA who were naïve to bDMARDs.15
Date of Last Review: 14 June 2022