Taltz® (ixekizumab): Behandlingsrelaterad herpes zoster i kliniska prövningar

Exclusion Criteria Related to Herpes Zoster in the Ixekizumab Clinical Trials

In 3 phase 3 trials for psoriasis (UNCOVER-1, -2, and -3), 3 phase 3 trials for PsA (SPIRIT-P1, -P2, and –P3), and 3 phase 3 clinical trials for axSpA, including AS/r-axSpA and nr-axSpA (COAST-V, COAST-W, and COAST-X), patients were excluded if they

• currently have or had a herpes zoster or any other clinically apparent varicella-zoster virus infection within 12 weeks of baseline, or

• had any other active or recent infection within 4 weeks of baseline that, in the opinion of the investigator, would pose an unacceptable risk to the patient if participating in the study.^1-6

Herpes Zoster in the Ixekizumab Clinical Development Program

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.⁷

Treatment-Emergent Adverse Events of Herpes Zoster in Ixekizumab Clinical Trials

Psoriasis

12-Week Induction Period

Primary Placebo-Controlled Dataset

The primary PsO placebo-controlled dataset includes patients with PsO from 3 phase 3 studies (UNCOVER-1, -2, and -3) who were randomized to

• ixekizumab 80 mg Q4W (n=1161)

• ixekizumab 80 mg Q2W (n=1167), or

• placebo (n=791).^6,8

During the induction period, herpes zoster was reported as a TEAE by

• 0 patients treated with ixekizumab, and

• 2 patients (0.3%) treated with placebo.^6,8

Placebo and Active-Controlled Dataset

The primary PsO placebo- and active-controlled dataset evaluated safety data through the induction period and includes patients from UNCOVER-2 and -3 who were randomized to

• ixekizumab 80 mg Q4W (n=729)

• ixekizumab 80 mg Q2W (n=734)

• etanercept (n=739), or

• placebo (n=360).^6,8

Herpes zoster was reported as a TEAE in

• 1 patient (0.1%) treated with etancercept, and

• 0 patients who received either ixekizumab or placebo.⁶

Maintenance Period

The PsO maintenance dataset evaluated safety after the induction period from weeks 12 through 60 and includes patients from UNCOVER-1 and -2 who were randomized to

• ixekizumab 80 mg Q4W (n=416)

• ixekizumab 80 mg Q12W (n=408), or

• placebo (n=402).^6,8

Herpes zoster was reported as a TEAE in

• 1 patient (0.2%) treated with ixekizumab 80 mg Q4W

• 1 patient (0.2%) treated with ixekizumab 80 mg Q12W, and

• 1 patient (0.2%) treated with placebo.⁶

Integrated Data

Among all ixekizumab exposures in PsO clinical trials (N=6091; 17,499 PYs) through March 2019, herpes zoster was reported as a TEAE in 110 patients (1.8%; 0.6 EAIR). One case (0%) of herpes zoster infection was categorized as a SAE, and no events led to discontinuation of study drug.⁶

Psoriatic Arthritis

24-Week Double-Blind Period

In the 24-week double-blind period of SPIRIT-P1, one patient who received ixekizumab Q2W had a TEAE of herpes zoster that involved the eyelid, and it was classified as a SAE.⁹ No patients reported a TEAE of herpes zoster during the 24-week double-blind period of SPIRIT-P2.²

Integrated Data

Among all ixekizumab exposures across 4 PsA clinical trials (N=1401; 2229 PYs) as of March 2019, herpes zoster was reported as a TEAE in 16 patients (1.1%; 0.7 EAIR).¹⁰ One case (0.1%) of herpes zoster infection was categorized as a SAE, and no events led to discontinuation of study drug.⁶

Ankylosing Spondylitis

16-Week Double-Blind Period

No patients reported a TEAE of herpes zoster during the 16-week double-blind period of COAST-V.³ In the COAST-W trial, 1 patient (0.9%) who received ixekziumab Q4W had a TEAE of herpes zoster during the double-blind period.⁴

Integrated Data

Among all ixekizumab exposures axSpA trials (including AS/r-axSpA and nr-axSpA) (N=929; 1336.2 PYs), as of April 2019, the MedDRA preferred term, herpes zoster, was reported as a TEAE in 11 patients (1.2%; 0.8 EAIR).¹⁰

Ixekizumab Label Information Related to Infections

Ixekizumab is contraindicated in patients with clinically important active infections (e.g. active tuberculosis).⁷

Treatment with ixekizumab is associated with an increased rate of infections such as upper respiratory tract infection, oral candidiasis, conjunctivitis, and tinea infections.⁷

Ixekizumab should be used with caution in patients with clinically important chronic infection or a history of recurrent infection. Patients should be instructed to seek medical advice if signs or symptoms suggestive of an infection occur. If an infection develops, monitor carefully and discontinue ixekizumab if the patient is not responding to standard therapy or the infection becomes serious. Ixekizumab should not be resumed until the infection resolves.⁷

References

1. Gordon KB, Blauvelt A, Papp KA, et al. 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

2. Nash P, Kirkham B, Okada M, et al. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomized, 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

3. van der Heijde D, Cheng-Chung Wei J, Dougados M, et al. 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

4. Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. 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

5. Deodhar A, van der Heijde D, Gensler LS, et al. 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. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

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

8. Strober 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://dx.doi.org/10.1016/j.jaad.2016.09.026

9. Mease PJ, van der Heijde D, Ritchlin CT, et al. 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

10. Genovese MC, Mysler E, Tomita T, et al. Safety of ixekizumab in adult patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis: data from 21 clinical trials. Rheumatology (Oxford). Published online May 25, 2020. https://doi.org/10.1093/rheumatology/keaa189

Glossary

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

axSpA = axial spondyloarthritis

EAIR = exposure adjusted incidence rate

MedDRA = Medical Dictionary for Regulatory Activities

nr-axSpA = nonradiographic axial spondyloarthritis

PsA = psoriatic arthritis

PsO = psoriasis

PY = patient-years

Q2W = every 2 weeks

Q4W = every 4 weeks

Q12W = every 12 weeks

SAE = serious adverse event

TEAE = treatment-emergent adverse event