How does TALTZ® (ixekizumab) compare with TREMFYA® (guselkumab) for psoriasis and psoriatic arthritis?

Ixekizumab and Guselkumab Mechanism of Action and Structure

Ixekizumab is a humanized IgG4 mAb that selectively binds with the IL-17A cytokine and inhibits its interaction with the IL-17 receptor. Interleukin-17A is a naturally occurring cytokine involved in normal inflammatory and immune responses. Ixekizumab inhibits the release of proinflammatory cytokines and chemokines.¹

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. Interleukin-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.²

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.³

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.³

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 12.³

The major secondary endpoints of IXORA-R were 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 12.³

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 100.³

Secondary efficacy endpoint, PASI 100 at week 24, was type-I 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.^4,5

Figure 1. IXORA-R: PASI 100, PASI 90, and sPGA (0) Efficacy Endpoints, ITT Population, NRI⁴

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

‡ p<.05 vs GUS.

† p<.01 vs GUS.

* p<.001 vs GUS.

Black 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-I error controlled. All other analyses were not type-I error controlled.

Table 1. IXORA-R: Response Rates of the Gated Primary and Major Secondary Efficacy Endpoints, ITT Population, NRI^3,4

	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 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-I 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

Table 2 presents an overview of the safety data for all patients who received ≥1 dose of either drug. The authors concluded that the safety profiles of ixekizumab and guselkumab were consistent with previous studies.⁴

Table 2. IXORA-R: Safety Overview Through Week 24^4,6

	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 AE	8 (2)	15 (3)
Common TEAEsb
Upper respiratory tract infection	41 (8)	40 (8)
Nasopharyngitis	27 (5)	34 (7)
Injection site reactionc	6 (1)	49 (9)
Headache	15 (3)	22 (4)
Diarrhea	17 (3)	16 (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 infectionsd	1 (0.2)	5 (1)
Mucocutaneous candidiasis	0	3 (0.6)
Herpes zoster	1 (0.2)	2 (0.4)
Reactivated tuberculosis	0	0
Depression	7 (1)	5 (1)
Malignancies	3 (0.6)	4 (0.8)
Allergic reactions	13 (3)	19 (4)
Potential anaphylaxise	1 (0.2)	0
Injection site reactionsf	19 (4)	67 (13)
MACEg	2 (0.4)	4 (0.8)
Cerebrocardiovascular eventsg	4 (0.8)	7 (1)
Inflammatory bowel diseaseg	0	1 (0.2)
Crohn's disease	0	1 (0.2)h
Ulcerative colitisi	0	0
Hepatic eventsj	8 (2)	7 (1)

Abbreviations: AE = adverse event; MACE = major adverse cardiac events; MedDRA = Medical Dictionary for Regulatory Activities; TEAEs = treatment-emergent adverse events.

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

^b Common TEAEs are defined as TEAEs that occurred at a frequency of ≥3% overall.

^c Numbers reported here only include TEAEs with the MedDRA low-level term "injection site reaction."

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

^e The potential anaphylaxis was related to the use of amoxicillin.

^f 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 edema, and injection site warmth.

^g Positively adjudicated by external committee.

^h Patient had a prior history of ulcerative colitis.

ⁱ One case of ulcerative colitis was reported during the follow-up period for a patient who had received ixekizumab.

^j Patients with at least 1 hepatic-related TEAE.

Ixekizumab and Guselkumab in Psoriatic Arthritis: Lack of Head-to-Head Data

Lilly has not conducted any studies to compare the safety and efficacy of ixekizumab to that of guselkumab in patients with psoriatic arthritis.

As clinical trials are conducted under widely varying and controlled conditions, efficacy outcomes and adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Enclosed Prescribing Information

TALTZ® (ixekizumab) injection, for subcutaneous administration, Lilly

References

The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).

1. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

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

3. 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

4. Blauvelt A, Leonardi C, Elewski B, et al. A head-to-head comparison of ixekizumab versus guselkumab in patients with moderate-to-severe plaque psoriasis: 24-week efficacy and safety results from a randomised, double-blinded trial. Br J Dermatol. Published online September 02, 2020. http://dx.doi.org/10.1111/bjd.19509

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

6. 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.

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

Q2W = every 2 weeks

Q4W = every 4 weeks

Q8W = every 8 weeks

sPGA = static Physician Global Assessment