Taltz ® (ixekizumab) injektion

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Taltz® ▼ (ixekizumab): Hur verkar ixekizumab jämfört med guselkumab vid psoriasis?

I IXORA-R visade sig ixekizumab vara effektivare än guselkumab för att nå det primära effektmåttet för PASI 100 i vecka 12.

Brief Summary

  • Ixekizumab met the primary endpoint by demonstrating superiority at week 12 in the proportion of patients achieving complete skin clearance compared to guselkumab as measured by PASI 100 and all major secondary endpoints up to week 12.1

  • Secondary efficacy endpoint, PASI 100 at week 24, was type-1 error controlled but did not achieve superiority. Noninferiority analysis of PASI 100 at week 24 was prespecified and achieved but was not type-I error controlled.2-4

  • No new safety signals were observed in IXORA-R.3

IXORA-R: Head-to-Head Trial of Ixekizumab and Guselkumab in Plaque Psoriasis

Study Design

IXORA-R (study I1F-MC-RHCR) was a 24-week multicenter, double-blind, randomized, parallel-group phase 4 study designed to evaluate the efficacy and safety of ixekizumab compared with guselkumab in adult patients with moderate-to-severe plaque psoriasis. The trial was designed to examine speed of response with multiple major secondary endpoints at early time points.1

Patients were randomized 1:1 to ixekizumab (N=520) or guselkumab (N=507). Dosing regimen was the approved label dosing, which is either

  • ixekizumab 160 mg starting dose at week 0 followed by ixekizumab 80 mg Q2W through week 12 then ixekizumab 80 mg Q4W, or

  • guselkumab 100 mg at week 0 and week 4, then guselkumab 100 mg Q8W.1

The primary endpoint of IXORA-R assessed whether ixekizumab was superior to guselkumab as measured by the proportion of patients achieving PASI 100 at week 12.1

The major secondary endpoints of IXORA-R are the proportion of patients achieving

  • PASI 50 at week 1

  • PASI 75 at week 2

  • PASI 90 at weeks 4 and 8

  • PASI 100 at weeks 4, 8, and 24, and

  • sPGA (0) at week 12.1

Efficacy Results

As shown in Figure 1 and Table 1, ixekizumab met the primary endpoint by demonstrating superiority at week 12 in the proportion of patients achieving complete skin clearance compared to guselkumab as measured by PASI 100 and all major secondary endpoints up to week 12. More patients on ixekizumab showed improvement over guselkumab as early as

  • week 1 for PASI 50

  • week 2 for PASI 75, and

  • week 4 for sPGA (0), PASI 90, and PASI 100.1

Secondary efficacy endpoint, PASI 100 at week 24, was type-1 error controlled but did not achieve superiority. Noninferiority analysis of PASI 100 at week 24 was prespecified and achieved but was not type-I error controlled.2-4

Figure 1. IXORA-R: PASI 100, PASI 90, sPGA (0), and PatGA (0) Efficacy Endpoints, ITT Population, NRI3

Abbreviations: GUS = guselkumab; ITT = intent-to-treat; IXE = ixekizumab; NRI = nonresponder imputation; PASI = Psoriasis Area and Severity Index; PatGA = Patient’s Global Assessment; sPGA = static Physician’s Global Assessment.

* p<.05 vs GUS.

p<.01 vs GUS.

p<.001 vs GUS.

Red box indicates the primary endpoint for the study.

PASI 100 at weeks 4, 8, 12, and 24, PASI 90 at weeks 4 and 8, and sPGA (0) at week 12 were type-1 error controlled. All other analyses were not type-1 error controlled.

Table 1. IXORA-R: Response Rates of the Gated Primary and Major Secondary Efficacy Endpoints, ITT Population, NRI1-4

 

Guselkumab
N=507
n (%)

Ixekizumab
N=520
n (%)

P Valuea

Primary Efficacy Endpoint

PASI 100 at week 12

126 (25)

215 (41)

<.001

Major Secondary Endpoints

PASI 50 at week 1

47 (9)

143 (28)

<.001

PASI 75 at week 2

26 (5)

119 (23)

<.001

PASI 90 at week 4

40 (8)

109 (21)

<.001

PASI 90 at week 8

182 (36)

304 (58)

<.001

PASI 100 at week 4

7 (1)

35 (7)

<.001

PASI 100 at week 8

69 (14)

154 (30)

<.001

sPGA (0) at week 12

128 (25)

218 (42)

<.001

PASI 100 at week 24b

265 (52)

260 (50)

.414

Abbreviations: ITT = intent-to-treat; NRI = nonresponder imputation; PASI = Psoriasis Area and Severity Index; sPGA = static Physician’s Global Assessment.

a Comparisons in the ITT population were made using Cochran-Mantel-Haenszel test adjusted by pooled site using nonresponder imputation for missing data.

b Secondary efficacy endpoint, PASI 100 at week 24, was type-1 error controlled but did not achieve superiority. Noninferiority analysis of PASI 100 at week 24 was prespecified and achieved but was not type-I error controlled.

Safety Data

An overview of the safety data for all patients who received ≥1 dose of either drug is presented in Table 2. The authors concluded there were no new safety signals observed in IXORA-R.3

Table 2. IXORA-R: Safety Overview Through Week 243

 

Guselkumab
N=506
n (%)

Ixekizumab
N=519
n (%)

TEAE overall

286 (57)

323 (62)

Severea

21 (4)

18 (3)

Death

0

0

Serious adverse event

16 (3)

18 (3)

Discontinuation due to adverse event

8 (2)

15 (3)

AEs of special interest

Neutropenias

2 (0.4)

2 (0.4)

Infections

143 (28)

162 (31)

Serious infections

2 (0.4)

2 (0.4)

Opportunistic infectionsb

1 (0.2)

5 (1)

Reactivated tuberculosis

0

0

Depression

7 (1)

5 (1)

Malignancies

3 (1)

4 (1)

Allergic reactions

13 (3)

19 (4)

Potential anaphylaxisc

1 (0.2)

0

Injection site reactionsd

19 (4)

67 (13)

MACEe

2 (0.4)

4 (1)

Cerebrocardiovascular events

4 (1)

7 (1)

Inflammatory bowel diseasef

0

1 (0.2)

Crohn's disease

0

1 (0.2)g

Ulcerative colitis

0

0

Hepatic eventsh

8 (2)

7 (1)

Abbreviation: AE = adverse event; MACE = major adverse cardiac event; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment-emergent adverse event.

a Patients with multiple occurrences of the same event are counted under the highest severity.

b The opportunistic infections identified by investigators were mucocutaneous candidiasis and herpes zoster.

c The potential anaphylaxis was related to the use of amoxicillin.

d Numbers reported here are for the high level MedDRA term “injection site reactions” which includes multiple lower level MedDRA terms, including but not limited to, injection site reaction, injection site pain, injection site erythema, injection site swelling, injection site pruritus, injection site discomfort, injection site oedema, and injection site warmth.

e Positively adjudicated by external committee.

f One case of ulcerative colitis was reported during the follow-up period.

g Patient had prior history of ulcerative colitis.

h Patients with at least 1 hepatic-related TEAE.

Ixekizumab and Guselkumab Mechanism of Action

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. Neutralisation of IL‑17A by ixekizumab inhibits these actions. Ixekizumab does not bind to ligands IL‑17B, IL‑17C, IL‑17D, IL‑17E or IL‑17F. 

In vitro binding assays confirmed that ixekizumab does not bind to human Fcγ receptors I, IIa, and IIIa or to complement component C1q.5

Guselkumab is a human IgG1λ mAb that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.6

References

1. Blauvelt A, Papp K, Gottlieb A, et al. A head-to-head comparison of ixekizumab versus guselkumab in patients with moderate-to-severe plaque psoriasis: 12-week efficacy, safety, and speed of response from a randomized, double-blinded trial. Br J Dermatol. 2020;182(6):1348-1358. http://dx.doi.org/10.1111/bjd.18851

2. Blauvelt A, Pinter A, Tada Y, et al. Ixekizumab versus guselkumab: 24-week clinical responses and 4-week gene expression data. In: Proceedings from the 2020 Society for Investigative Dermatology Annual Meeting Virtual Conference; May 13-16, 2020. https://www.sidannualmeeting.org/wp-content/uploads/2020/05/2020-Virtual-Meeting-Abstract-BookletFINAL-1.pdf

3. Blauvelt A, Pinter A, Tada Y, et al. Ixekizumab vs guselkumab: 24-week clinical responses and 4-week gene expression data. Poster presented at: Maui Derm Virtual Congress; June 24-27, 2020.

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

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

6. Tremfya [package insert]. Horsham, PA: Janssen Biotech, Inc; 2020.

Glossary

IgG1 = immunoglobulin G subclass 1

IgG4 = immunoglobulin G subclass 4

IL = interleukin

Lilly = Eli Lilly and Company

mAb(s) = monoclonal antibody

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

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

PASI 90 = 90% improvement from baseline in Psoriasis Area and Severity Index

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

sPGA = static Physician Global Assessment

Q2W = every 2 weeks

Q4W = every 4 weeks

Q8W = every 8 weeks

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2020 M06 22


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