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Taltz ® (ixekizumab)
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Taltz® (ixekizumab): Neutropenia
The majority of cases of neutropenia reported with ixekizumab were either grade 1 or grade 2.
UK_cFAQ_IXE344_NEUTROPENIA_PsO_PsA_axSpA
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Table of Contents
Summary
Low grade neutropenia has been commonly observed in patients receiving ixekizumab. However, neutropenia ≥ grade 3 (<1,000 cells/mm3) has been observed infrequently in patients receiving ixekizumab.1
In general, neutropenia
- was transient
- did not require discontinuation of ixekizumab, and
- was not associated with an increased frequency of infections.1
Label Information Related to Neutropenia
Neutropenia was an uncommonly (≥ 1/1,000 to < 1/100) reported adverse reaction in the ixekizumab clinical trials.2
In plaque psoriasis studies,
- 9% of patients receiving ixekizumab developed neutropenia.
In most cases, the blood neutrophil count was ≥1,000 cells/mm3. Such levels of neutropenia may persist, fluctuate or be transient. - 0.1% of patients receiving ixekizumab developed a neutrophil count <1,000 cells/mm3.2
In general, neutropenia did not require discontinuation of ixekizumab.2
The frequency of neutropenia in psoriatic arthritis and axial spondyloarthritis clinical studies is similar to that observed in the plaque psoriasis studies.2
Clinical Trial Laboratory Assessment of Neutropenia Results
Note that multiple, different dosing regimens, including unapproved doses, are included in this response. Please refer to Taltz summary of product characteristics for full prescribing information.
Psoriasis
UNCOVER-1, -2, and -3 Pivotal Trials
Neutropenia Laboratory Assessments Across the 3 UNCOVER Psoriasis Clinical Trials Combined shows the number of patients with reductions in neutrophil counts from normal levels in the 3 UNCOVER psoriasis clinical studies.
The results reflect all patients with at least 1 postbaseline value for neutrophil level across all 3 pivotal UNCOVER clinical trials combined. Results are included for weeks 0 to 12 and weeks 0 to 60.3,4
|
Weeks 0-12 |
Weeks 0-60 |
||
IXE Q2W |
IXE Q4W |
PBO |
All Ixekizumab Exposuresb |
|
Grades 1-4 combined, n (%) |
108 (9.3) |
99 (8.6) |
26 (3.3) |
428 (11.5) |
Grade 1c neutropenia, n (%) |
81 (7.0) |
76 (6.6) |
23 (2.9) |
321 (8.6) |
Grade 2d neutropenia, n (%) |
25 (2.1) |
22 (1.9) |
2 (0.3) |
97 (2.6) |
Grade 3e neutropenia, n (%) |
2 (0.2) |
0 |
1 (0.1) |
8 (0.2) |
Grade 4f neutropenia, n (%) |
0 |
1 (0.1)g |
0 |
2 (0.1) |
Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks following 160 mg starting dose; IXE Q4W = ixekizumab 80 mg every 4 weeks following 160 mg starting dose; n = number of patients who experienced respective neutropenia events; N = total number of patients in each analysis group; Nx = number of evaluable patients in each analysis group (ie, patients with at least 1 postbaseline neutropenia value); PBO = placebo.
Note: % reflects n/Nx (number of patients who experienced respective neutropenia events/number of evaluable patients in each analysis group).
aNeutropenia data include patients with postbaseline neutrophil counts that worsened from a normal level or from the grade at baseline.
bConsists of all patients who received ixekizumab at any point through week 60 including those patients initially randomized to IXE Q2W, IXE Q4W, and PBO across all 3 studies and patients initially randomized to etanercept (N=740) in UNCOVER-2 and UNCOVER-3. Trial design details are available upon request.
cGrade 1 neutropenia defined as ≥1500 to <2000 cells/mm3.
dGrade 2 neutropenia defined as ≥1000 to <1500 cells/mm3.
eGrade 3 neutropenia defined as ≥500 to <1000 cells/mm3.
fGrade 4 neutropenia defined as <500 cells/mm3.
gIn patient with grade 4 neutropenia, neutrophil count was within normal range in a 2-day retest.
All Psoriasis Ixekizumab Exposures Integrated Analysis
An integrated safety analysis was conducted from all ixekizumab adult psoriasis exposures (N=6892; 18,025.7 patient-years [PYs] of exposure) across 17 clinical trials with data up to March 19, 2021. Neutropenia grade ≥3 (<1000 cells/mm3) was reported in 29 (0.4%) patients (IR=0.2 per 100 PYs of exposure).5
Psoriatic Arthritis
SPIRIT-P1 and -P2 Double-Blind Treatment Periods
Neutropenia Laboratory Assessments Through Week 24 of SPIRIT-P1 and SPIRIT-P2 Psoriatic Arthritis Clinical Trials shows the number of patients with reductions in neutrophil counts from normal levels in the SPIRIT-P1 and -P2 clinical studies.
From the 24-week double-blind treatment periods of both SPIRIT-P1 and -P2 studies
- all cases of treatment-emergent neutropenia were either grade 1 or grade 2
- no patients experienced neutropenia grade 3 or higher in either clinical trial
- no infection onset occurred within 14 days of any report of grade 2 neutropenia in either clinical trial, and
- the frequency of neutropenia was similar to that previously observed in the plaque psoriasis trials (Neutropenia Laboratory Assessments Through Week 24 of SPIRIT-P1 and SPIRIT-P2 Psoriatic Arthritis Clinical Trials).6,7
SPIRIT-P1 |
SPIRIT-P2 |
|
Total Ixekizumab |
Total Ixekizumab |
|
Grades combined, n (%) |
23 (11.0) |
22 (9.0) |
Grade 1a neutropenia, n (%) |
13 (6.2) |
19 (7.8) |
10d (4.8) |
3 (1.2) |
Abbreviations: n = number of patients who experienced respective neutropenia events; N = total number of patients in each analysis group; Nx = number of evaluable patients in each analysis group (ie, patients with at least 1 postbaseline neutropenia value).
Note: % reflects n/Nx (number of patients who experienced respective neutropenia events/number of evaluable patients in each analysis group).
Note: There were no instances of grade 3 (≥500 to <1000 cells/mm3) or grade 4 (<500 cells/mm3) neutropenia in either SPIRIT-P1 or SPIRIT-P2.
aGrade 1 neutropenia defined as ≥1500 to <2000 cells/mm3.
bGrade 2 neutropenia defined as ≥1000 to <1500 cells/mm3.
cNo infection onset occurred within 14 days of any report of grade 2 neutropenia in either SPIRIT-P1 or SPIRIT-P2.
dOne patient had grade 2 neutropenia on more than 1 assessment in SPIRIT-P1.
SPIRIT-P1 and -P2 Extension Periods
All Psoriatic Arthritis Ixekizumab Exposures Integrated Analysis
An integrated safety analysis was conducted from all ixekizumab psoriatic arthritis exposures (N=1401; 2247.7 PYs of exposure) across 4 clinical trials with data up to March 19, 2021. Neutropenia grade ≥3 (<1000 cells/mm3) was reported in 8 (0.6%) patients (IR=0.4 per 100 PYs of exposure).10
Axial Spondyloarthritis
Ankylosing Spondylitis/Radiographic Axial Spondyloarthritis Trials
COAST-V and COAST-W Double-Blinded Treatment Periods
Treatment-Emergent Neutropenia During the Double-Blind Treatment Period of COAST-V and Treatment-Emergent Neutropenia During the Double-Blind Treatment Period of COAST-W show the incidence of treatment-emergent neutropenia during the double-blind periods of COAST-V and COAST-W.
In COAST-V and COAST-W, mild neutropenia (grade 1) was reported more often in the ixekizumab groups than in the placebo group.11,12 The cases of grade 1 neutropenia were transient in nature and resolved without discontinuation of ixekizumab.1,11
Event |
COAST-V |
|||
PBO |
ADA Q2W |
IXE Q2W |
IXE Q4W |
|
Grade 1a neutropenia |
2 (2) |
18 (20) |
8 (10) |
6 (8) |
Grade 2b neutropenia |
1 (1) |
3 (3) |
3 (4) |
2 (3) |
Grade 3c neutropenia |
0 |
1 (1) |
0 |
0 |
Grade 4d neutropenia |
0 |
0 |
0 |
0 |
Abbreviations: ADA Q2W = adalimumab 40 mg every 2 weeks; IXE Q2W = ixekizumab 80 mg every 2 weeks after a 160 mg or 80 mg starting dose; IXE Q4W = ixekizumab 80 mg every 4 weeks after a 160 mg or 80 mg starting dose; PBO = placebo.
aGrade 1 neutropenia defined as ≥1.5 to <2.0 × 109 cells/L.
bGrade 2 neutropenia defined as ≥1.0 to <1.5 × 109 cells/L.
cGrade 3 neutropenia defined as ≥0.5 to <1.0 × 109 cells/L.
dGrade 4 neutropenia defined as <0.5 × 109 cells/L.
Event |
COAST-W |
||
PBO |
IXE Q2W |
IXE Q4W |
|
Grade 1a neutropenia |
1 (1) |
8 (8) |
10 (9) |
Grade 2b neutropenia |
0 |
1 (1) |
1 (1) |
Grade 3c neutropenia |
0 |
0 |
0 |
Grade 4d neutropenia |
0 |
0 |
1 (1)e |
Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks after a 160 mg or 80 mg starting dose; IXE Q4W = ixekizumab 80 mg every 4 weeks after a 160 mg or 80 mg starting dose; PBO = placebo.
aGrade 1 neutropenia defined as ≥1.5 to <2.0 × 109 cells/L.
bGrade 2 neutropenia defined as ≥1.0 to <1.5 × 109 cells/L.
cGrade 3 neutropenia defined as ≥0.5 to <1.0 × 109 cells/L.
dGrade 4 neutropenia defined as <0.5 × 109 cells/L.
eThe patient was diagnosed with acute promyelocytic leukemia 4 weeks postbaseline. A post-hoc analysis of a serum sample collected prior to study entry identified a genetic risk factor for acute promyelocytic leukemia. The patient discontinued from the study.
COAST-V and COAST-W Dose Double-Blind Extension Period
During the dose double-blinded extended treatment period of COAST-V and COAST-W (weeks 16-52), no patients reported a treatment-emergent adverse event (TEAE) of grade 3 or 4 neutropenia. The pooled incidence rate of grade 3 or 4 neutropenia was 0.2 per 100 PYs for weeks 0-52.13
Nonradiographic Axial Spondyloarthritis Trials
COAST-X 52-Week Double-Blinded Treatment Period
During the double-blinded treatment period of COAST-X, a TEAE of grade 3 or 4 neutropenia was not reported in patients treated with ixekizumab. Grade 4 neutropenia was reported in one patient in the placebo group (Treatment-Emergent Neutropenia Through the 52-week Double-Blinded Treatment Period of COAST-X).14
Event |
PBO |
IXE Q4W |
IXE Q2W |
Grade 1a neutropenia |
8 (8) |
11 (11) |
13 (13) |
Grade 2b neutropenia |
0 |
1 (1) |
2 (2) |
Grade 3c neutropenia |
0 |
0 |
0 |
Grade 4d neutropenia |
1 (1) |
0 |
0 |
Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; PBO = placebo.
aGrade 1 neutropenia defined as ≥1.5 to <2.0 x 109 cells/L.
bGrade 2 neutropenia defined as ≥1.0 to <1.5 x 109 cells/L.
cGrade 3 neutropenia defined as ≥0.5 to <1.0 x 109 cells/L.
dGrade 4 neutropenia defined as <0.5 x 109 cells/L.
All Axial Spondyloarthritis Ixekizumab Exposures Integrated Analysis
An integrated safety analysis was conducted from all ixekizumab axial spondyloarthritis exposures (N=932; 2096.2 PYs of exposure) across 4 trials (including ankylosing spondylitis/radiographic axial spondyloarthritis and nonradiographic axial spondyloarthritis) with data up to March 19, 2021. Neutropenia grade ≥3 (<1000 cells/mm3) was reported in 4 (0.4%) patients (IR=0.2 per 100 PYs of exposure).10
References
1Data on file, Eli Lilly and Company and/or one of its subsidiaries.
2Taltz [summary of product characteristics]. Eli Lilly and Company (Ireland) Limited, Ireland
3Strober B, Pangallo B, Veenhizen M, et al. Safety and tolerability of ixekizumab: analysis of neutropenia 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.
4Gordon 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
5Griffiths 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. Poster presented at: Annual Meeting of the American Academy of Dermatology (AAD); March 25-29, 2022; Boston, MA.
6Mease 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
7Nash 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
8Mease PJ, Okada M, Kishimoto M, et al. Efficacy and safety of ixekizumab in patients with active psoriatic arthritis: 52-week results from a phase 3 study (SPIRIT P1). Abstract presented at: European League Against Rheumatism (EULAR) Congress; June 8-11, 2016; London, England.
9Genovese MC, Combe B, Kremer JM, et al. Safety and efficacy of ixekizumab in patients with PsA and previous inadequate response to TNF inhibitors: week 52 results from SPIRIT-P2. Rheumatology. 2018;57(11):2001-2011. http://dx.doi.org/10.1093/rheumatology/key182
10Schwartzman 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.
11Deodhar 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
12van 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
13Dougados M, Cheng-Chung Wei J, Landewé R, et al; COAST-V and COAST-W Study Groups. Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spondyloarthritis (COAST-V and COAST-W). Ann Rheum Dis. 2020;79(2):176-185. http://dx.doi.org/10.1136/annrheumdis-2019-216118
14Deodhar 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
Date of Last Review: 16 March 2022
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