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Taltz ® (ixekizumab)
What was the incidence of Candida infections in Taltz® (ixekizumab) clinical trials?
In clinical trials, oral candidiasis occurred more frequently in the ixekizumab group than in the placebo group.
Ixekizumab Label Information Related to Infections
Treatment with ixekizumab is associated with an increased rate of infections such as upper respiratory tract infection, oral candidiasis, conjunctivitis, and tinea infections.1
Ixekizumab should be used with caution in patients with clinically important chronic infection or a history of recurrent infection. 1
If an infection develops,
- patients should be carefully monitored and
- ixekizumab discontinued if
- the patient is not responding to standard therapy or if
- the infection becomes serious.1
Ixekizumab should not be resumed until the infection resolves.1
In controlled studies, for up to 24 weeks, oral candidiasis was uncommonly reported (≥ 1/1.000 to < 1/100).1
Incidence of Candida Infections from the UNCOVER Phase 3 Clinical Trials
In the UNCOVER clinical trials, Candida infections occurred in 1.4% of patients who received ixekizumab 80 mg every 2 weeks (Q2W) and in 0.6% of patients who received ixekizumab 80 mg every 4 weeks (Q4W) through week 12.2,3
Oral candidiasis occurred more frequently in the ixekizumab group than in the placebo group. In the first 12 weeks of treatment, dose-dependent oral candidiasis was observed with ixekizumab. Across the trials, oral candidiasis was reported in
- 0.8% of patients dosed with ixekizumab Q2W (p<.05 vs Q4W)
- 0.2% of patients dosed with ixekizumab Q4W
- 0.1% of patients dosed with etanercept, and
- 0.0% of patients dosed with placebo.4
Overall, Candida infections were noninvasive and did not lead to discontinuation from study drug.4
One patient who received ixekizumab 80 mg Q2W experienced a moderate skin Candida infection of the axilla and groin, which was treated with topical clotrimazole twice daily for 1 month, followed by a topical combination product containing isoconazole and corticosteroid for approximately 2 weeks. The patient continued treatment with ixekizumab.2
The exposure-adjusted incidence rate of Candida infections during weeks 0 through 60 was similar to the rate during weeks 0 to 12.3
In patients exposed to ixekizumab across the 3 pivotal UNCOVER trials (N=3736), the exposure-adjusted incidence rate for all Candida infections with ixekizumab was
- 3.7 per 100 patient-years for weeks 0 to 60 (n=128), and
- 6.0 per 100 patient-years for weeks 0 to 12 (n=16) (ixekizumab 80 mg Q2W only).3
Through week 60 of these trials, 2 patients had esophageal candidiasis confirmed by gastroscopy (both moderate severity) and neither patient discontinued from the study because of their infection.3
All Ixekizumab Psoriasis Exposures
In a larger integrated analysis of data across 15 adult and 1 pediatric PsO clinical trials as of March 2020 (N=6645; 17,902 patient-years of exposure), the incidence rate of Candida infections was 1.9 per 100 patient-years.6 Fourteen cases of esophageal candidiasis were reported, and 2 of which were categorized as a serious adverse event (SAE). No cases of deep organ or blood stream candidiasis were reported in the safety analysis.7
A post hoc analysis of the integrated safety population from 16 PsO clinical trials as of March 2020 evaluated fungal infection types and subtypes through medical adjudication by 2 unblinded independent dermatologists. The median duration of Candida infections was 4.6 weeks (interquartile range of 1.6-13.5 weeks).8,9
Incidence of Candida Infections Through Week 24 From SPIRIT-P1 and SPIRIT-P2 Phase 3 Clinical Trials
In the SPIRIT-P1 and SPIRIT-P2 PsA trials, Candida infections occurred in 3.6% of patients who received ixekizumab 80 mg Q2W and in 1.7% of patients who received ixekizumab 80 mg Q4W through week 24.10
Candida infection occurred more frequently in patients who received ixekizumab than in patients who received placebo.10 Most Candida infections during the first 24 weeks of SPIRIT-P1 and SPIRIT-P2 were mild or moderate in severity. No patients discontinued from the studies due to Candida infections.7
All Ixekizumab Psoriatic Arthritis Exposures
In a larger integrated analysis of data across 4 PsA trials as of March 2020 (N=1401; 2247.7 PYs of exposure), the IR of Candida infections was 2.0 per 100 PYs.12 Two cases of esophageal candidiasis were reported, both of which were categorized as an SAE. No cases of deep organ or blood stream candidiasis were reported in the safety analysis.7
Incidence of Candida Infections Through week 16 of AS/r-axSpA Trials
In the 16-week, double-blind treatment period of COAST-V, no cases of Candida infections were reported in ixekizumab or placebo groups. One case of skin Candida infection was reported in the adalimumab active reference arm.13
In the 16-week, double-blind treatment period of COAST-W, 2 Candida infections were reported in the ixekizumab Q2W study arm (1 esophageal and 1 genital candidiasis). No infections were reported in the placebo group.14
52-week Double-Blind Treatment Period of Nonradiographic Axial Spondyloarthritis Trial
No cases of oral candidiasis were reported in either ixekizumab treatment group in COAST-X through week 52. One case of oral candidiasis was reported in a patient in the placebo group.15
All Ixekizumab Axial Spondyloarthritis Exposures
In an integrated safety analysis across 4 axSpA trials (including AS/r-axSpA and nr-axSpA) (N=932; 1792.2 PYs of exposure to ixekizumab) with data as of March 2020, the IR of Candida infection was 1.5 per 100 PYs.16 Four cases of esophageal candidiasis were reported and none of which were reported as an SAE. No cases of deep organ or blood stream candidiasis were reported in the safety analysis.7
Note that multiple, different dosing regimens, including unapproved doses, are included in this response. Please refer to the Taltz Summary of Product Characteristics for approved dosing.1
What is the role of interleukin-17 in Candida infections?
T helper 17 cells, which produce IL-17, protect against extracellular pathogens and are involved in the immune response to intracellular bacteria, particularly at mucosal surfaces.17
1Taltz [summary of product characteristics]. Eli Lilly and Company (Ireland) Limited, Ireland
2Griffiths 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
3Gordon 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
4Strober 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
5Papp K, Winthrop KL, Braun D, et al. Safety and tolerability of ixekizumab: analysis of infections in 7 clinical studies of moderate-to-severe plaque psoriasis. Poster presented at: 24th European Academy of Dermatology and Venereology Congress; October 7-11, 2015; Copenhagen, Denmark.
6Griffiths 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.
7Data on file, Eli Lilly and Company and/or one of its subsidiaries.
8Blauvelt A, Ramharter M, Cohen AD, et al. An integrated safety analysis of treatment-emergent fungal infections in patients with psoriasis treated with ixekizumab from 16 clinical studies. J Eur Acad Dermatol Venereol. Published online July 26, 2021. https://dx.doi.org/10.1111/jdv.17554
9Blauvelt A, Ramharter M, Cohen A, et al. An integrated safety analysis of treatment-emergent fungal infections in patients with psoriasis treated with ixekizumab from 16 clinical studies. Poster presented at: American Academy of Dermatology Virtual Meeting Experience; April 23-25, 2021.
10Combe B, Rahman P, Kameda H, et al. Safety results of ixekizumab with 1822.2 patient-years of exposure: an integrated analysis of 3 clinical trials in adult patients with psoriatic arthritis. Arthritis Res Ther. 2020;22(1):14. http://dx.doi.org/10.1186/s13075-020-2099-0
11Mease 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
12Sesin C, Gallo G, Gellett AM, et al. Safety of ixekizumab in patients with psoriatic arthritis: an integrated analysis of 4 clinical trials. Poster presented at: European League Against Rheumatism Virtual Congress; June 2-5, 2021.
13van der Heijde D, Cheng-Chung Wei J, Dougados M, et al; COAST-V Study Group. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392(10163):2441-2451. http://dx.doi.org/10.1016/s0140-6736(18)31946-9
14Deodhar A, Poddubnyy D, Pacheco-Tena C, et al; COAST-W Study Group. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 2019;71(4):599-611. http://dx.doi.org/10.1002/art.40753
15Deodhar A, van der Heijde D, Gensler LS, et al; COAST-X Study Group. Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial. Lancet. 2020;395(10217):53-64. http://dx.doi.org/10.1016/S0140-6736(19)32971-X
16Schwartzman S, Sandoval D, Kronbergs A, et al. Long-term safety profile of ixekizumab treatment on patients with axial spondyloarthritis. Abstract presented at: Florida Society of Rheumatology 2021 Annual Meeting; July 9-11, 2021; Orlando, FL.
17Huppler AR, Bishu S, Gaffen SL. Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy. Arthritis Res Ther. 2012;14(4):217. http://dx.doi.org/10.1186/ar3893
18Mengesha BG, Conti HR. The role of IL-17 in protection against mucosal Candida infections. J Fungi (Basel). 2017;3(4):52. https://doi.org/10.3390/jof3040052
19Conti HR, Gaffen SL. IL-17–mediated immunity to the opportunistic fungal pathogen Candida albicans. J Immunol. 2015;195(3):780-788. http://dx.doi.org/10.4049/jimmunol.1500909
AS/r-axSpA = ankylosing spondylitis/radiographic axial spondyloarthritis
axSpA = axial spondyloarthritis
EAIR = exposure adjusted incidence rate
IL-17 = interleukin-17
IR = incidence rate
nr-axSpA = nonradiographic axial spondyloarthritis
PsA = psoriatic arthritis
PsO = plaque psoriasis
PY = patient-years
Q2W = every 2 weeks
Q4W = every 4 weeks
SAE = serious adverse event
TEAE = treatment-emergent adverse event
Date of Last Review: August 20, 2021