Taltz® (ixekizumab): Effekt vid psoriasis i hårbotten

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. ¹

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

Three multicenter, randomized, double-blind, placebo-controlled studies (UNCOVER-1, -2, and -3) enrolled a total of 3866 plaque psoriasis patients 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

 provides a brief description of the UNCOVER clinical trials.

Efficacy in scalp psoriasis, measured using PSSI, was a secondary endpoint in all 3 UNCOVER trials.⁴

Complete resolution of scalp psoriasis was assessed as either PSSI 100 or PSSI score=0.⁴

Baseline Scalp Involvement in the Pivotal Phase 3 Psoriasis Clinical Trials

Across all 3 UNCOVER trials, 91% to 92% of patients in all treatment groups had scalp psoriasis at baseline, defined as PSSI >0.⁴ Only patients with baseline scalp psoriasis were included in the analyses described in this response.

Scalp Psoriasis Efficacy Results

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

Table 1 depicts PSSI response rates for patients with any baseline scalp psoriasis involvement from the 3 pivotal UNCOVER clinical trials. Ixekizumab treatment resulted in significant improvement in scalp psoriasis compared with

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

• etanercept at week 12 for the UNCOVER-2 and -3 subpopulation (p<.001 for all PSSI endpoints for ixekizumab Q4W and Q2W).⁴

The dosing schedule IXEQ4W during the first 12 weeks of treatment (induction phase) is 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

Table 1. Integrated UNCOVER-1, -2, and -3: Scalp Psoriasis Efficacy Outcomes in Patients With any Scalp Involvement at Baseline, NRI⁴

	Placebo N=719 n (%)	ETNa N=670 n (%)	IXE Q4W N=1073 n (%)	IXE Q2W N=1062 n (%)
PSSI 75	91 (12.7)	453 (67.6)b	897 (83.6)b,c	955 (89.9)b,c
PSSI 90	55 (7.6)	372 (55.5)b	811 (75.6)b,c	868 (81.7)b,c
PSSI 100	48 (6.7)	322 (48.1)b	739 (68.9)b,c	792 (74.6)b,c

Abbreviations: ETN = etanercept; IXE = ixekizumab; NRI = nonresponder imputation; PSSI 75 = 75% improvement from baseline in Psoriasis Scalp Severity Index; PSSI 90 = 90% improvement from baseline in Psoriasis Scalp Severity Index; PSSI 100 = 100% improvement from baseline in Psoriasis Scalp 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 done based on the subpopulation of patients in UNCOVER-2 and -3 only.

^b p<.001 vs placebo.

^c p<.001 vs ETN.

UNCOVER-3: Week 60 Results

Figure 1 shows response rates for PSSI 100 through week 60 in patients with baseline scalp psoriasis (PSSI >0) in UNCOVER-3.

In the long-term extension period of UNCOVER-3 through week 60, the improvement in scalp psoriasis from week 12 was maintained. 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 percentage of patients with scalp response rates at week 60 were

• 83.1% for PSSI 75

• 79.1% for PSSI 90, and

• 75.9% for PSSI 100.⁴

Figure 1. UNCOVER-3: PSSI 100 Responses Through Week 60, NRI⁴

Abbreviations: ETN = etanercept; IXE = ixekizumab; NRI = nonresponder imputation; PBO = placebo; PSSI 100 = 100% improvement from baseline in Psoriasis Scalp Severity Index; Q2W = every 2 weeks; Q4W = every 4 weeks.

* p<.001 vs PBO.

† p<.001 vs ETN.

UNCOVER-1 and -3: Long-Term Results

Figure 2 and Figure 3 show long-term scalp psoriasis efficacy responses in patients with baseline scalp psoriasis receiving the approved ixekizumab dosing regimen. In both studies, the authors concluded that the high scalp psoriasis efficacy results were sustained through 5 years of ixekizumab treatment.^5,6

Figure 2. UNCOVER-1: Scalp Psoriasis Response Rates From Week 60 Through Week 264, Observed Cases⁵

Abbreviation: PSSI 75 = 75% improvement from baseline in Psoriasis Scalp Severity Index; PSSI 90 = 90% improvement from baseline in Psoriasis Scalp Severity Index; PSSI 100 = 100% improvement from baseline in Psoriasis Scalp Severity Index.

Figure 3. UNCOVER-3: Complete Resolution of Scalp Psoriasis (PSSI=0) Response Rates Through Week 264 in Patients With Baseline Scalp Involvement^6,7

Abbreviations: IXE = ixekizumab; Q2W = every 2 weeks; Q4W = every 4 weeks; MI = multiple imputation; mNRI = modified nonresponder imputation; PSSI = Psoriasis Scalp Severity Index.

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. Reich K, Leonardi C, Lebwohl M, et al. Sustained response with ixekizumab treatment of moderate-to-severe psoriasis with scalp involvement: results from three phase 3 trials (UNCOVER-1, UNCOVER-2, UNCOVER-3). J Derm Treat. 2017;28(4):282-287. https://doi.org/10.1080/09546634.2016.1249820

5. 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.

6. 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

7. 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

PSSI = Psoriasis Scalp Severity Index

PSSI 75 = 75% improvement from baseline in Psoriasis Scalp Severity Index

PSSI 90 = 90% improvement from baseline in Psoriasis Scalp Severity Index

PSSI 100 = 100% improvement from baseline in Psoriasis Scalp 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.