Taltz ® (ixekizumab)

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Are Major Cardiovascular Events with Taltz® (ixekizumab) Common?

In clinical trials, major adverse cerebrocardiovascular events were uncommon with ixekizumab treatment.

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MACE - Major Adverse Cerebrocardiovascular Events

Ixekizumab exposure has not been found to be associated with an increased risk of major adverse cerebrocardiovascular events (MACE).1-4

In ixekizumab clinical trials, all reported MACE were independently adjudicated by a sponsor-independent external adjudication committee.1,2,4-8

Clinical Trials in Moderate-to-Severe Psoriasis

Patients with moderate-to-severe psoriasis are reported to be at an increased risk of cardiovascular mortality compared with the general population and patients with mild psoriasis.9-12

In an integrated analysis of the UNCOVER clinical trial data, MACE were uncommon, balanced across treatment groups, and exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) remained stable over time.1,13

The most common MACE were

  • nonfatal myocardial infarction (MI)
  • nonfatal stroke (including ischemic, hemorrhagic, and undetermined stroke type), and
  • vascular death (including cardiovascular and cerebrovascular causes excluding hemorrhagic deaths outside of the central nervous system).8,14

As of March 2021 in the psoriasis clinical trials, 91 patients experienced MACE (70 were severe, and 19 were moderate). MACE outcomes were (N)

  • fatal (20)
  • recovered (55)
  • recovered with sequelae (17)
  • recovering (4), and
  • not recovered (3).8

 Most of the patients (59%) had pre-existing risk factors including

  • hypertension
  • dyslipidemia
  • type 2 diabetes mellitus
  • hypercholesterolemia
  • obesity, and
  • cardiac disorders.8

Incidence of Major Adverse Cerebrocardiovascular Events in Ixekizumab-Treated Psoriasis Patients shows total MACE incidence and EAIRs integrated across all ixekizumab psoriasis exposures in adult patients as of March 2021.

Incidence of Major Adverse Cerebrocardiovascular Events in Ixekizumab-Treated Psoriasis Patients8,13,14
 
All IXE-Treated Patients
(N=6892)
PY=18,025.7a

Total adjudicated MACE, n (%) [IR]

91b (1.3) [0.5]

Vascular deathc

20 (0.3) [0.1]

Nonfatal MI

49 (0.7) [0.3]

Nonfatal stroked

23 (0.3) [0.1]

Abbreviations: IR = incidence rate (per 100 patient-years); IXE = ixekizumab; MACE = major adverse cerebrocardiovascular events; MI = myocardial infarction; PY = patient-years.

aData as of March 2021.

bOne patient experienced both a nonfatal stroke and vascular death.

cIncluding cardiovascular and cerebrovascular causes excluding hemorrhagic deaths outside of the central nervous system.

dNonfatal stroke includes ischemic, hemorrhagic, and undetermined stroke type.

The incidence rate of MACE were consistent over time, did not increase with longer ixekizumab exposure, up to 5 years.8,13

Clinical Trials in Psoriatic Arthritis

In the psoriatic arthritis (PsA) clinical trials, 12 patients experienced serious MACE (9 were severe, and 3 were moderate). Two of the events were fatal, and 10 were resolved or recovered.7

Nine of the twelve patients who experienced MACE had cardiovascular risk factors including

  • hypertension
  • Raynaud’s phenomenon
  • hypercholesterolemia
  • dyslipidemia, and
  • obesity.7

Incidence of Major Adverse Cerebrocardiovascular Events in Ixekizumab-Treated Psoriatic Arthritis Patients shows total MACE incidence and EAIRs integrated across all ixekizumab PsA exposures as of March 2021.

Incidence of Major Adverse Cerebrocardiovascular Events in Ixekizumab-Treated Psoriatic Arthritis Patients7,14,15

 

All IXE-Treated Patients
(N=1401)
PY=2247.7a

Total adjudicated MACE, n (%) [IR]

12 (0.9) [0.5]

Vascular deathb

2 (0.1) [0.1]

Nonfatal MI

6 (0.4) [0.3]

Nonfatal strokec

4 (0.3) [0.2]

Abbreviations: IR = incidence rate (per 100 patient-years); IXE = ixekizumab; MACE = major adverse cerebrocardiovascular events; MI = myocardial infarction; PY = patient-years.

aData as of March 2021.

bIncluding cardiovascular and cerebrovascular causes excluding hemorrhagic deaths outside of the central nervous system.

cNonfatal stroke includes ischemic, hemorrhagic, and undetermined stroke type.

Rates of MACE were similar in psoriasis and psoriatic arthritis (PsA) clinical trials. There was no pattern of increased risk of MACE with longer exposures to ixekizumab, and rates of MACE were consistent over time and consistent with the overall background rates among patients with PsA.7,14,16

There is no evidence that treatment with ixekizumab in patients with PsA modifies the underlying risk for adverse cerebrocardiovascular events such as MI or stroke.14

Clinical Trials in Axial Spondyloarthritis

Incidence of Major Adverse Cerebrocardiovascular Events in Ixekizumab-Treated Axial Spondyloarthritis Patients shows total MACE incidence and EAIRs integrated across all ixekizumab axial spondyloarthritis (axSpA) exposures (including ankylosing spondylitis/radiographic axial spondyloarthritis and nonradiographic axial spondyloarthritis patients) as of March 2021.

Incidence of Major Adverse Cerebrocardiovascular Events in Ixekizumab-Treated Axial Spondyloarthritis Patients14,15

All IXE-Treated Patients
(N=932)
PY=2096.2a

Total adjudicated MACE, n (%) [IR]

6 (0.6) [0.3]

Vascular deathb

0 [0.0]

Nonfatal MI

6 (0.6) [0.3]

Nonfatal strokec

0 [0.0]

Abbreviations: IR = incidence rate; IXE = ixekizumab; MACE = major adverse cerebrocardiovascular events; MI = myocardial infarction; PY = patient-years.

aData as of March 2021.

bIncluding cardiovascular and cerebrovascular causes excluding hemorrhagic deaths outside of the central nervous system.

cNonfatal stroke includes ischemic, hemorrhagic, and undetermined stroke type.

The incidence rate of MACE did not increase with longer ixekizumab exposure, up to 3 years.15 

References

1Papp K, Bissonette R, Ohtsuki M, et al. Ixekizumab shows no association with major adverse cardiac events (MACE) in patients with moderate-to-severe psoriasis: an integrated safety analysis of clinical trials. Poster presented at: 74th Annual Meeting of the American Academy of Dermatology; March 4-8, 2016; Washington, DC. Accessed February 24, 2022. https://www.aad.org/eposters/Submissions/getFile.aspx?id=3413&type=sub

2Deodhar 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

3Mease 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

4van 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

5Gottlieb A, Papp K, Xu W, et al. Long-term safety of ixekizumab with over 18,000 patient years of exposure: analysis from 13 moderate-to-severe plaque psoriasis studies and 3 psoriatic arthritis studies. Poster presented at: 77th Annual Meeting of the American Academy of Dermatology; March 1-5, 2019; Washington, DC.

6Deodhar 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

7Deodhar A, 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. Published online May 25, 2022. https://doi.org/10.1136/annrheumdis-2021-222027

8Griffiths 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). Published online May 27, 2022. http://dx.doi.org/10.1007/s13555-022-00743-9

9Gelfand JM, Troxel AB, Lewis JD, et al. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007;143(12):1493-1499. http://dx.doi.org/10.1001/archderm.143.12.1493

10Gulliver W. Long-term prognosis in patients with psoriasis. Br J Dermatol. 2008;159(suppl 2):2-9. http://dx.doi.org/10.1111/j.1365-2133.2008.08779.x

11Mehta NN, Yu Y, Pinnelas R, et al. Attributable risk estimate of severe psoriasis on major cardiovascular events. Am J Med. 2011;124(8):775.e1-775.e6. https://doi.org/10.1016/j.amjmed.2011.03.028

12Edson-Heredia E, Zhu B, Lefevre C, et al. Prevalence and incidence rates of cardiovascular, autoimmune, and other diseases in patients with psoriatic or psoriatic arthritis: a retrospective study using Clinical Practice Research Datalink. J Eur Acad Dermatol Venereol. 2015;29(5):955-963. http://dx.doi.org/10.1111/jdv.12742

13Griffiths 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.

14Data on file, Eli Lilly and Company and/or one of its subsidiaries.

15Schwartzman 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.

16Genovese MC, Kameda H, Rahman P, et al. Safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis and psoriatic arthritis: integrated analysis of 18 clinical trials. Poster presented at: American College of Rheumatology/ARP; November 8-13, 2019; Atlanta, GA.

Date of Last Review: 07 June 2022


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