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Taltz ® (ixekizumab)
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Candida infections with Taltz® (ixekizumab)
The Candida incidence rate is 1.9/ 100 patient-years (PY) for psoriasis, 2.0/ 100 PY for psoriatic arthritis, and 1.2/ 100 PY for axial spondyloarthritis, as of March 2022.
Table of Contents
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
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
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.2,3
Overall, Candida infections were localized and did not lead to discontinuation from study drug.4 In most cases, the infections were mild-to-moderate in severity, and resolved with standard oral or topical antifungal treatments.5,6 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.5
The exposure-adjusted incidence rate of Candida infections during weeks 0 through 60 was similar to the rate during weeks 0 to 12.2
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).2
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 the infection.2
All Ixekizumab Psoriasis Exposures
In a larger integrated analysis of data across 17 adult plaque psoriasis clinical trials as of March 2022 (N=6892; 18,025.7 patient-years of exposure), the incidence rate of Candida infections was 1.9 per 100 patient-years.7 Fourteen cases of esophageal candidiasis were reported, 2 of which were categorized as a serious adverse event (SAE).8,9 All cases of Candida infections were localized; no systemic cases were observed.7
A post hoc analysis of the integrated safety population from 16 psoriasis 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).8,10
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 24.11
Candida infection occurred more frequently in patients who received ixekizumab than in patients who received placebo.11 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 because of Candida infections.9
All Ixekizumab Psoriatic Arthritis Exposures
In a larger integrated analysis of data across 4 PsA trials as of March 2022 (N=1401; 2247.7 patient-years of exposure), the incidence rate of Candida infections was 2.0 per 100 patient-years.13 Two cases of esophageal candidiasis were reported, both of which were categorized as an SAE.9,13 All cases of Candida infection were localized. No cases of systemic candidiasis were reported.14,15
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.16
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.17
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.18
All Ixekizumab Axial Spondyloarthritis Exposures
In an integrated safety analysis across 4 axial spondyloarthritis trials (including ankylosing spondylitis/radiographic axial spondyloarthritis and nonradiographic axial spondyloarthritis) (N=932; 2097.7 patient-years of exposure to ixekizumab) with data as of March 2022, the incidence rate of Candida infection was 1.2 per 100 patient-years. Four cases of esophageal candidiasis were reported, none of which were reported as an SAE.9,13 No cases of systemic candidiasis were reported.13
Esophageal candidiasis has been rarely reported (frequency of at least 0.01% to less than 0.1%) in spontaneous postmarketing reports.9
Spontaneous reporting of adverse events can be highly variable and is not controlled clinical information on which to assess causality of a drug to an adverse event. Spontaneous reporting has limitations due to bias in reporting including incomplete information concerning the patient. In addition, the Global Patient Safety (GPS) spontaneous database may include reports of adverse events for products that are available from a variety of manufacturers. When verification of product manufactured by Eli Lilly and Company is not obtainable, these cases are included in the spontaneous database.
Candida auris (C. auris) was first reported in the United States in 2016. On March 20th of, 2023, the Centers for Disease Control and Prevention (CDC) issued a press release on C. auris. C. auris has been deemed as an urgent antimicrobial resistance threat because it is often resistant to multiple antifungal drugs, spreads quickly in healthcare facilities, and can cause severe infections.19
In an integrated safety analysis across 25 ixekizumab clinical trials with data as of March 2022 (including plaque psoriasis, psoriatic arthritis, ankylosing spondylitis/radiographic axial spondyloarthritis and nonradiographic axial spondyloarthritis) and spontaneous reporting database of adverse events with data as of March 2023, C. auris has not been reported.9
Some of the potential limitations for diagnosing C. auris are
- lack of microbial culture results in some patients to confirm clinical diagnoses, or
- disparity of experience between dermatologists and rheumatologists in diagnosing cutaneous fungal infections.20
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
- In controlled studies, for up to 24 weeks, oral candidiasis was uncommonly reported (≥ 1/1.000 to < 1/100), and
- Oesophageal candidiasis is a rare adverse reaction (≥1/10,000 to <1/1,000) associated with ixekizumab treatment.1
Ixekizumab should be used with caution in patients with clinically important chronic infection or a history of recurrent infection. 1
1Taltz [summary of product characteristics]. Eli Lilly and Company (Ireland) Limited, Ireland
2Gordon 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
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.
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
5Griffiths 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
6Papp 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.
7Griffiths 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
8Blauvelt 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.
9Data on file, Eli Lilly and Company and/or one of its subsidiaries.
10Blauvelt 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. 2021;35(11):e828-e831. https://doi.org/10.1111/jdv.17554
11Combe 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
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
13Deodhar A, Blauvelt A, Schwartzman S, et al. Long-term safety of ixekizumab in adult patients with psoriasis, psoriatic arthritis, and axial spondyloarthritis. Poster presented at: American College of Rheumatology/ARP - 2022 Annual Scientific Meeting; November 10-14, 2022; Philadelphia, Pennsylvania.
14Schwartzman S, Deodhar A, Combe B, et al. Safety profile of ixekizumab for the treatment of psoriatic arthritis and axial spondyloarthritis up to 3 years: an updated integrated safety analysis. Poster presented at: Annual Meeting of the America College of Rheumatology (ACR Convergence Virtual); November 1-10, 2021.
15Deodhar 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
16van 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
17Deodhar 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
18Deodhar 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
19Increasing Threat of Spread of Antimicrobial-resistant Fungus in Healthcare Facilities. Press release. Centers for Disease Control and Prevention (CDC); March 20, 2023. Accessed June 16, 2023. https://www.cdc.gov/media/releases/2023/p0320-cauris.html#:~:text=CDC%20has%20deemed%20C.,infections%20with%20high%20death%20rates
20Schwartzman S, Puig L, Cohen AD, et al. An Integrated Safety Analysis of Treatment-Emergent Fungal Infections in Patients With Psoriasis, Psoriatic Arthritis, and Axial Spondyloarthritis Treated With Ixekizumab From 26 Clinical Studies. Poster Presented at: Congress of Clinical Rheumatology-East (CCR-E); May 4-7, 2023; Destin, Florida.
Date of Last Review: 16 June 2023