Taltz ® (ixekizumab) injektion

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Taltz® (ixekizumab): Effekt hos palmoplantar Psoriasis

Palmoplantar psoriasis visade signifikant större förbättring vid vecka 12 med ixekizumab jämfört med placebo och etanercept.

Background Information

Ixekizumab is an IgG4 monoclonal antibody that binds with high affinity (<3 pM) and specificity to interleukin 17A (both IL‑17A and IL‑17A/F). Elevated concentrations of IL‑17A have been implicated in

  • the pathogenesis of psoriasis
    by promoting keratinocyte proliferation and activation, as well as in

  • the pathogenesis of psoriatic arthritis and axial spondyloarthritis
    by driving inflammation leading to erosive bone damage and pathological new bone formation. 

Neutralisation of IL‑17A by ixekizumab inhibits these actions.1

Ixekizumab does not bind to ligands

  • IL‑17B,

  • IL‑17C,

  • IL‑17D,

  • IL‑17E or

  • IL‑17F.1 

Three multicenter, randomized, double-blind, placebo-controlled studies (UNCOVER-1, UNCOVER-2, and UNCOVER-3) enrolled a total of 3866 patients with plaque psoriasis 18 years of age and older who were candidates for phototherapy and/or systemic therapy with

  • BSA ≥10% involvement

  • sPGA ≥3 on a severity scale of 0 to 5, and

  • PASI ≥12 on a severity scale of 0 to 72.2

All 3 pivotal studies used the same efficacy outcome measures and co-primary endpoints at week 12. The co-primary endpoints were the proportion of patients

  • with an sPGA (0,1) with at least a 2-point improvement from baseline, and

  • achieving PASI 75 from baseline.2,3

Significantly greater improvements at Week 12 from baseline compared to placebo and etanercept were demonstrated in palmoplantar psoriasis (as measured by Psoriasis Palmoplantar Severity Index [PPASI]). These improvements in palmoplantar psoriasis were maintained at Week 60 in patients treated with ixekizumab who were sPGA (0,1) responders at Week 12.1

Efficacy in palmoplantar psoriasis, measured using PPASI, was a secondary endpoint in all 3 UNCOVER trials.2

Baseline Palmoplantar Involvement in the Pivotal Phase 3 Psoriasis Clinical Trials

In the UNCOVER-1, -2, and -3 trials, 1092 patients (28.3%) had any palmoplantar psoriasis at baseline (PPASI >0). Moreover, 350 patients (9.1% of total study population) had moderate-to-severe palmoplantar psoriasis (defined as PPASI ≥8) at baseline.4 Patients were excluded if they had pustular, erythrodermic, and/or guttate forms of psoriasis.2

Palmoplantar Psoriasis Efficacy Results

UNCOVER-1, -2, and -3: Integrated Week 12 Results

Table 1 depicts PPASI response rates for patients with moderate-to-severe palmoplantar psoriasis (PPASI >8 at baseline) from the 3 pivotal UNCOVER clinical trials. Ixekizumab treatment resulted in significant improvement in palmoplantar psoriasis compared with 

  • placebo at week 12 (p<.001 for all PPASI endpoints for both ixekizumab Q4W and Q2W), and

  • etanercept at week 12 for the UNCOVER-2 and -3 subpopulation (p<.05 for all PPASI endpoints for ixekizumab Q2W and PPASI 50 and 75 for ixekizumab Q4W).4

Table 1. Integrated UNCOVER-1, -2, and -3: Palmoplantar Efficacy at Week 12 in Patients With Moderate-to-Severe Nonpustular Palmoplantar Involvement at Baseline, NRI4

 

Placebo
N=85
n (%)

ETNa
N=59
n (%)

IXE Q4W
N=92
n (%)

IXE Q2W
N=114
n (%)

PPASI 50 

28 (32.9)

40 (67.8)b

79 (85.9)c,d

91 (79.8)c,d

PPASI 75 

16 (18.8)

26 (44.1)b

68 (73.9)c,d

79 (69.3)c,d

PPASI 100 

7 (8.2)

19 (32.2)b

45 (48.9)c

59 (51.8)c,d

Abbreviations: ETN = etanercept; IXE = ixekizumab; NRI = nonresponder imputation; PPASI = Palmoplantar Psoriasis Area and Severity Index; Q2W = every 2 weeks; Q4W = every 4 weeks.

a Etanercept arm included in UNCOVER-2 and -3 only. All comparisons to ETN were based on the subpopulation of patients in UNCOVER-2 and -3 only.

b p<.05 vs placebo.

c p<.001 vs placebo.

d p<.05 vs ETN.

UNCOVER-3: Week 60 Results

Figure 1 shows response rates for PPASI 75 through week 60 in patients with baseline moderate-to-severe palmoplantar psoriasis (PPASI ≥8) in UNCOVER-3.

In the long-term extension period of UNCOVER-3 through week 60, the improvement in palmoplantar psoriasis from week 12 was maintained or showed improvement. For the approved moderate-to-severe psoriasis ixekizumab dosing regimen (ixekizumab 80 mg Q2W through week 12 following a 160-mg starting dose at week 0 then 80 mg Q4W after week 12), the percentages of patients with palmoplantar response rates at week 60 were

  • 73.7% for PPASI 50

  • 71.1% for PPASI 75, and

  • 57.9% for PPASI 100.4,5

Figure 1. UNCOVER-3: PPASI 75 Responses Through Week 60 in Patients With Moderate-to-Severe Palmoplantar Psoriasis, NRI5

Abbreviations: ETN = etanercept; IXE = ixekizumab; LTE = long-term extension; NRI = nonresponder imputation; PBO = placebo; PPASI = Palmoplantar Psoriasis Area and Severity Index; Q2W = every 2 weeks; Q4W = every 4 weeks.

*p<.01 vs PBO.

p<.05 vs ETN.

Patients treated with ETN had a washout period between week 12 and week 16 (dotted magenta line).

UNCOVER-1 and -3: Long-term Results

Figure 2 and Figure 1 show long-term palmoplantar efficacy responses in patients with any baseline palmoplantar psoriasis receiving the approved ixekizumab dosing regimen. In both studies, the authors concluded that the high palmoplantar efficacy results were sustained through 5 years of ixekizumab treatment.6,7

Figure 2. UNCOVER-1: Palmoplantar Response Rates From Week 60 Through Week 264 in Patients With Baseline Palmoplantar Psoriasis, Observed Cases6

Abbreviations: PPASI 75 = 75% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index; PPASI 90 = 90% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index; PPASI 100 = 100% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index.

Figure 3. UNCOVER-3: PPASI 100 Response Rates Through Week 264 in Patients With Baseline Palmoplantar Psoriasis7,8

Abbreviations: IXE = ixekizumab; Q2W = every 2 weeks; Q4W = every 4 weeks; MI = multiple imputation; mNRI = modified nonresponder imputation; PPASI 100 = 100% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index

Please note that dosing schedules are mentioned in this response that 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. 1

References

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

2. 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

3. Griffiths CEM, Reich K, Lebwohl M, et al. 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. http://dx.doi.org/10.1016/S0140-6736(15)60125-8

4. Menter A, Warren RB, Langley RG, et al. Efficacy of ixekizumab compared to etanercept and placebo in patients with moderate-to-severe plaque psoriasis and non-pustular palmoplantar involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2 and UNCOVER-3). J Eur Acad Dermatol Venereol. 2017;31(10):1686-1692. http://dx.doi.org/10.1111/jdv.14237

5. Warren RB, Morita A, Menter A, et al. Efficacy and safety of ixekizumab compared to etanercept or placebo treatment of patients with moderate-to-severe plaque psoriasis and palmoplantar involvement over a 60-week dosing period: results from UNCOVER-3, a phase 3 trial. Poster presented at: 5th Congress of the Psoriasis International Network; July 7-9, 2016; Paris, France.

6. Papp K, Gerdes S, Elmaraghy H, et al. Sustained high efficacy and a favorable safety profile in hard-to-treat areas in patients with moderate-to-severe psoriasis: five year results from a phase 3 trial. Poster presented at: 28th Annual Meeting of the European Academy of Dermatology and Venereology (EADV); October 9-13, 2019; Madrid, Spain.

7. Blauvelt A, Lebwohl MG, Mabuchi T, et al. Long-term efficacy and safety of ixekizumab: 5-year analysis of the UNCOVER-3 randomized controlled trial. J Am Acad Dermatol. Published online November 28, 2020. http://dx.doi.org/10.1016/j.jaad.2020.11.022

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

Glossary

BSA = body surface area

IgG4 = immunoglobulin G subclass 4

IL-17 = interleukin-17

mAb(s) = monoclonal antibody

PASI = Psoriasis Area and Severity Index

PASI 75 = 75% improvement from baseline in Psoriasis Area and Severity Index

PPASI = Palmoplantar Psoriasis Area and Severity Index

PPASI 50 = 50% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index

PPASI 75 = 75% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index

PPASI 100 = 100% improvement from baseline in Palmoplantar Psoriasis Area and Severity Index

Q2W = every 2 weeks

Q4W = every 4 weeks

sPGA = static Physician Global Assessment

Appendix A: Brief Clinical Trial Designs

Figure 4. Study Design of Induction (UNCOVER-1, -2, and -3) and Maintenance (UNCOVER-1 and -2) Dosing Periods2

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:
Etanercept arm was not included in UNCOVER-1.

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

In UNCOVER-2 study, nonresponders to ETN at week 12 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) indicates relapse (sPGA ≥3).

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

Datum fӧr senaste ӧversyn 2020 M12 07


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