Taltz® (ixekizumab): How many patients developed uveitis with and without a prior history?

Background Information

This response includes reports of anterior uveitis (MedDRA-preferred term "iridocyclitis") in psoriasis, psoriatic arthritis, and axSpA (including AS/r-axSpA and nr-axSpA) clinical trials. 

The most common extra-muscular-skeletal feature of spondyloarthritis is uveitis. Up to 50% of patients with AS/r-axSpA will experience uveitis, and the most common type is anterior uveitis. The occurrence of uveitis has been associated with HLA-B27 status and duration of the spondyloarthropathy.¹

Uveitis as Adverse Drug Reaction

Uveitis is not listed as adverse drug reaction in the Taltz summary of product characteristics. ²

Exclusion Criteria in Ixekizumab Clinical Trials Related to Uveitis

Ankylosing Spondylitis/Radiographic Axial Spondyloarthritis Trials

Patients were excluded from COAST-V and COAST-W if they had evidence of active anterior uveitis (an acute episode) within the last 4 weeks prior to baseline randomization. These patients were allowed to be rescreened only 1 time ≥4 weeks after resolution of acute symptoms. Other patients with a previous history of uveitis were allowed to be enrolled in the study.^3,4

Non-radiographic Axial Spondyloarthritis

Patients were excluded from COAST-X if they had evidence of active anterior uveitis (an acute episode) within the last 42 days prior to baseline randomization. These patients were allowed to be rescreened only 1 time ≥4 weeks after resolution of acute symptoms. Other patients with a previous history of uveitis were allowed to be enrolled in the study.⁵

Psoriatic Arthritis Trials

Patients with active vasculitis or uveitis were excluded from participation in the phase 3 psoriatic arthritis clinical trials.^6,7

Plaque Psoriasis Trials

No specific exclusion criteria for uveitis were included in the pivotal phase 3 plaque psoriasis clinical trials.⁸

History of Anterior Uveitis and Treatment-Emergent Adverse Events of Anterior Uveitis in Ixekizumab Clinical Trials

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.²

New Onset and Flares of Anterior Uveitis in Ankylosing Spondylitis/Radiographic Axial Spondyloarthritis Trials

See  for information on new onset and flares of anterior uveitis during the 16-week blinded dosing period of COAST-V and COAST-W. A brief description of clinical trials referenced in this response is available in Appendix: Brief Clinical Trial Descriptions.

Table 1. Treatment-Emergent Anterior Uveitis^a in COAST-V and COAST-W Trials During 16-Week Double-Blind Treatment Period (Integrated)^3,4,7,9

Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; MedDRA = Medical Dictionary for Regulatory Activities; PBO = placebo; TE = treatment-emergent.

^a Acute anterior uveitis was identified using the preferred term “iridocyclitis” (MedDRA Version 21.0).

Of the 38 patients in the ixekizumab 80 mg Q4W treatment arm with a history of anterior uveitis, 2 patients experienced TE-anterior uveitis.⁷

Similarly, of the 47 patients in the ixekizumab 80 mg Q2W treatment arm with a history of anterior uveitis, 2 patients experienced TE-anterior uveitis.⁷

In each of the ixekizumab 80 mg treatment arms, there was 1 patient with no prior history of anterior uveitis that experienced TE-anterior uveitis.⁷

Reports of Anterior Uveitis Through 52 Weeks in Ankylosing Spondylitis/Radiographic Axial Spondyloarthritis Trials

Across both studies, 22.1% of patients had a history of acute anterior uveitis, and 20 patients reported events of acute anterior uveitis. Of those patients who reported events of anterior uveitis during the trials, 15 had a history of the condition (Table 2).¹⁰

One case resulted in ixekizumab treatment interruption, and 1 case resulted in permanent discontinuation of ixekizumab treatment. The EAIR for acute anterior uveitis through 52 weeks was 3.9 per 100 PY.¹⁰

Table 2. Treatment-Emergent Anterior Uveitis^a in COAST-V and COAST-W Trials Through 52 Weeks of Treatment (Integrated)¹⁰

Abbreviations: EAIR = exposure-adjusted incidence rate; MedDRA = Medical Dictionary for Regulatory Activities; PY = patient-year; TE = treatment-emergent.

^a Acute anterior uveitis was identified using the preferred term “iridocyclitis” (MedDRA Version 21.0). Active anterior uveitis cases were evaluated by ophthalmologists.

New Onset and Flares of Anterior Uveitis in Non-radiographic Axial Spondyloarthritis Trials

 shows information on new onset and flares of anterior uveitis during the double-blind treatment period of COAST-X. A brief description of the clinical trial referenced in this response is available in Appendix: Brief Clinical Trial Descriptions.

Table 3.  Treatment-Emergent Anterior Uveitis^a in COAST-X Trial During 52-Week Double-Blind Treatment Period^b5,7

Abbreviations: IXE Q2W = ixekizumab 80 mg every 2 weeks; IXE Q4W = ixekizumab 80 mg every 4 weeks; MedDRA = Medical Dictionary for Regulatory Activities; PBO = placebo; TE = treatment-emergent.

^a Acute anterior uveitis was identified using the preferred term “iridocyclitis” (MedDRA Version 21.0).

^b Prior to biologic rescue with ixekizumab 80 mg Q2W.

Of the 14 patients in the ixekizumab 80 mg Q4W treatment arm with a history of anterior uveitis, 1 patient experienced TE-anterior uveitis.⁷

Of the 8 patients in the ixekizumab 80 mg Q2W treatment arm with a history of anterior uveitis, 2 patients experienced TE-anterior uveitis.⁷

In each of the ixekizumab 80 mg treatment arms, all patients with TE-anterior uveitis had a history of anterior uveitis.⁷

Incidence of Anterior Uveitis in All Axial Spondyloarthritis Trials

Among all ixekizumab exposures in 4 axSpA trials (including AS/r-axSpA and nr-axSpA) (N=932; 1849 PY), as of March 19, 2020, anterior uveitis (MedDRA-preferred term "iridocyclitis") was reported as a TEAE in 52 patients (IR 2.8 per 100 PY). Among the 52 patients with iridocyclitis, 37 (71%) had a history of iridocyclitis and 2 (3.8%) patients discontinued due to iridocyclitis.¹¹

Preexisting and Treatment-Emergent Adverse Events of Anterior Uveitis in Psoriatic Arthritis Trials

Anterior uveitis (MedDRA-preferred term "iridocyclitis") was reported as a historical illness in 1 patient and as a preexisting condition in no patients randomized to ixekizumab 80 mg Q4W (N=454) in SPIRIT-P1 and SPIRIT-P2. Anterior uveitis was not reported as a preexisting condition and was reported as a historical illness in 1 patient in the phase 3 long-term efficacy trial SPIRIT-P3.⁷

No TEAEs of anterior uveitis (MedDRA-preferred term "iridocyclitis") were reported of 1401 patients (accounting for 2247.7 PYs of exposure) exposed to ixekizumab across PsA clinical trials as of March 19, 2020.⁷

Preexisting and Treatment-Emergent Adverse Events of Anterior Uveitis in Plaque Psoriasis Trials

Anterior uveitis was reported as a historical illness in 1 patient and as a preexisting condition in no patients randomized to ixekizumab through week 12 (N=2328) in UNCOVER -1, -2, and -3.⁷

Two (0.0%) TEAEs of anterior uveitis (MedDRA-preferred term "iridocyclitis") were reported of 6645 patients (accounting for 17,902.0 PY of exposure) exposed to ixekizumab across adult and pediatric plaque psoriasis clinical trials (including phase 1, phase 2, and phase 3) as of March 19, 2020.⁷

References

1. Khan MA, Haroon M, Rosenbaum JT. Acute anterior uveitis and spondyloarthritis: more than meets the eye. Curr Rheumatol Rep. 2015;17(9):59. https://dx.doi.org/10.1007/s11926-015-0536-x

2. Taltz [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

3. Deodhar 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

4. van 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

5. Deodhar 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

6. Nash 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

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

8. Gordon 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

9. Marzo-Ortega H, Mysler E, Tomita T, et al. Long-term safety of ixekizumab in patients with radiographic axial spondyloarthritis/ankylosing spondylitis: An integrated analysis of COAST-V and COAST-W. Poster presented at: European League Against Rheumatism; June 12-15, 2019; Madrid, Spain.

10. Schwartzman S, Deodhar A, Kronbergs A, et al. Inflammatory bowel disease and anterior uveitis in patients treated with ixekizumab for radiographic axial spondyloarthritis: Results from two phase 3 studies through 52 weeks. Poster presented at: American College of Rheumatology/ARHP Annual Scientific Meeting; November 8-13, 2019; Atlanta, GA.

11. Schwartzman S, Sandoval D, Kronbergs A, et al. Long-term safety profile of ixekizumab treatment on patients with axial spondyloarthritis. Abstract presented at: American College of Rheumatology/ARP 2020 Annual Scientific Meeting (Virtual); November 5-9, 2020.

12. Mease 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

13. A long-term efficacy and safety study of ixekizumab (LY2439821) in participants with active psoriatic arthritis (SPIRIT P3). ClinicalTrials.gov identifier: NCT02584855. Updated November 15, 2019. Accessed September 25, 2020. https://www.clinicaltrials.gov/ct2/show/NCT02584855

14. A long term extension study of ixekizumab (LY2439821) in participants with axial spondyloarthritis. ClinicalTrials.gov identifier: NCT03129100. Updated November 4, 2020. Accessed January 20, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03129100

Glossary

AS/r-axSpA = ankylosing spondylitis/radiographic axial spondyloarthritis

axSpA = axial spondyloarthritis

bDMARD = biologic disease-modifying antirheumatic drug

EAIR = exposure adjusted incidence rate

IR = incidence rate

MedDRA = Medical Dictionary for Regulatory Activities

nr-axSpA = nonradiographic axial spondyloarthritis

PsA = psoriatic arthritis

PY = patient-years

Q2W = every 2 weeks

Q4W = every 4 weeks

TEAE = treatment-emergent adverse event

TE = treatment-emergent

TNF = tumor necrosis factor

Appendix: Brief Clinical Trial Descriptions

Plaque Psoriasis Trials

• UNCOVER-1, -2, and -3 (N=3866) phase 3 trials in moderate-to-severe plaque psoriasis were integrated to evaluate the safety of ixekizumab in comparison to placebo up to 12 weeks after treatment initiation.

• The phase 3 trials examined the efficacy and safety of ixekizumab compared with placebo and etanercept (UNCOVER-2 and -3) during induction treatment and vs placebo in maintenance (UNCOVER-1 and -2).⁸

Figure 1. Induction (UNCOVER-1, -2, -3) and Maintenance (UNCOVER-1, -2) Dosing Period Study Designs⁸

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.

Notes:
ETN arm was not included in UNCOVER-1.

Responders (sPGA 0 or 1) to ixekizumab at week 12 were re-randomized to receive IXE Q4W, IXE Q12W, or PBO.

Nonresponders to ETN at week 12 in UNCOVER-2 were switched to IXE Q4W (without a 160 mg starting dose) after a 4-week washout period.

Nonresponders to PBO at week 12 received a 160 mg starting dose of ixekizumab followed by IXE Q4W.

⁞ (dotted line) = relapse (sPGA≥3).

UNCOVER-3 is not represented in maintenance period design as the extension period consisted of open-label treatment with IXE Q4W.

 Some dosing schedules shown in Figure 1 are not consistent with the approved dosing schedule for plaque psoriasis in the Taltz summary of product characteristics. Please refer to the Taltz summary of product characteristics for approved dosing.²

Psoriatic Arthritis Trials

• SPIRIT-P1 (N=417) is a phase 3, 24-week double-blind, placebo-controlled trial with an active reference arm in patients with active PsA who are naïve to bDMARDs with an extension period of up to 3 years.¹²

• SPIRIT-P2 (N=363) is a phase 3, 24-week double-blind, placebo-controlled trial in patients with active PsA and an inadequate response or intolerance to TNF inhibitor, with an extension period of up to 3 years.⁶

• SPIRIT-P3 (N=570) consists of a 36-week open-label period followed by a randomized double-blind withdrawal period from week 36 to week 104. This trial is being conducted in patients naïve to bDMARDs.¹³

Axial Spondyloarthritis Trials

• COAST-V (N=341) is a phase 3, 16-week double-blind, placebo-controlled trial with an active reference arm and a dose double-blind extension period to 52 weeks in patients with active AS/r-axSpA who are naive to bDMARDs.⁴

• COAST-W (N=316) is a phase 3, 16-week double-blind, placebo-controlled trial with a dose double-blind extension period to 52 weeks in patients with active AS/r-axSpA and an inadequate response or intolerance to 1 or 2 TNF inhibitors.³

• COAST-X (N=303) is a phase 3, 52-week double-blind, placebo-controlled trial in patients with nr-axSpA who are naive to bDMARDs.⁵

• COAST-Y (N=750) is a phase 3, 104-week, long-term extension trial including a double-blind, placebo-controlled 40-week randomized withdrawal-retreatment period in patients with axial spondyloarthritis who have completed the final study visit in COAST-V, COAST-W, or COAST-X.¹⁴