Key evidence from clinical trials for ixekizumab

Introduction

Ixekizumab (Taltz^®) is a humanized monoclonal immunoglobulin Sun antibody Developed by Eli Lilly and Company which has been approved in the USA. USA (March 2016) and Europe (April 2016) as treatment for license plate psoriasis.

Ixekizumab is a specific inhibitor of interleukin-17A (IL-17A), a pro-inflammatory cytokine That has a role in the development of various inflammatory conditions, including psoriasis.

the effectiveness of ixekizumab as treatment for moderate to severe plaque psoriasis has been evaluated in three randomized placebocontrolled trials, UNCOVER-1, UNCOVER-2 and UNCOVER-3. UNCOVER-2 and UNCOVER-3 also compared ixekizumab with etanercept.

Experience in clinical trials.

UNCOVER-1: efficacy and Adverse reactions

Uncover-1 was a prospect, double-blind, a multicenter trial that consisted of 1296 patients randomized 1: 1: 1 to receive ixekizumab 80 mg every two weeks (Q2W), ixekizumab 80 mg every four weeks (Q4W) or placebo, respectively.

• Patients in the ixekizumab groups received a single initial dose of 160 mg at week 0 followed by 80 mg Q2W or Q4W.
• All patients received two subcutaneous injections (ixekizumab or placebo) at week 0 and a subcutaneous injection (ixekizumab or placebo) at week 2, 4, 6, 8, and 10.
• In this study, theprimary The efficacy end point at 12 weeks was an improvement of 75% in the composite severity index of the psoriasis area (PASI) score and at least a 2 point increase base in the Static Physician Global Assessment (sPGA) 0 or 1.
• PASI measures the extent and severity of psoriasis by evaluating the redness, thickness, and average desquamation of skin lesions (each rated zero to four. scale), weighted by the body surface area of the affected skin.
• The sPGA is the physician's assessment of the severity of a patient's psoriasis lesions in general at a specific time and is a necessary measure that the FDA uses to assess effectiveness.
• The 89.1% and 82.6% of the patients treated with ixekizumab once every 2 (n = 433) or 4 (n = 432) weeks, respectively for 12 weeks, achieved an improvement in the PASI of ≥75% (PASI 75) in Comparison with 3.5% for placebo recipients (n = 431; p <0.001 for both ixekizumab regimens versus placebo).
• The percentage of achievement of sPGA 0 or 1 was 81.8% and 76.4% for ixekizumab Q2W and Q4W, respectively, compared to 3.2% in those taking a placebo (P <0.001 vs placebo).
• After 12 weeks, patients who responded to ixekizumab were randomized to 48 weeks of treatment with ixekizumab 80 mg every 4 (n = 229) or 12 (n = 227) weeks or placebo (n = 226).
• At week 60, the sPGA of 0 or 1, PASI 75, and PASI 100 were maintained at 72.9, 77.7, and 52% for ixekizumab receptors, respectively.
• The most common (> 1%) adverse events were nasopharyngitis, erythema and pain at the injection site.
• The proportions of patients with candida infection at 12 weeks they were 0.9% and 0.6% for ixekizumab Q2W and ixekizumab Q4W, respectively, compared to 0.5% for placebo.
• Adverse event Comparisons are not statistically significant, as the study was designed to detect differences in efficacy rather than rates of adverse events.

UNCOVER-2: efficacy and adverse events

In UNCOVER-2, 1,224 patients were randomly assigned to receive subcutaneous placebo (n = 168), etanercept (n = 358), or ixekizumab every 2 weeks (Q2W; n = 351) or every 4 weeks (Q4W; n = 347).

• Participants received subcutaneous placebo, etanercept (50 mg twice weekly), or an 80 mg injection of ixekizumab every other week, or every four weeks after a starting dose of 160 mg.
• Blinding was maintained with a double simulation design.
• The co-primary efficacy end points were proportions of patients achieving a sPGA score of 0 or 1 and an improvement of 75% or more in PASI at week 12. Analysis was by intention to treat.
• PASI 90, PASI 100, numerical rating scale for itching and Dermatology Quality of life index (DLQI) were included as secondary endpoints in the study.
• At 12 weeks, the study demonstrated statistically significant superiority of ixekizumab 80 mg Q2W and ixekizumab 80 mg Q4W over placebo.
• The proportion of patients achieving PASI 75 was 89.7% and 77.5% for ixekizumab Q2W and Q4W, respectively, compared to 2.4% in placebo (P <0.0001 vs. placebo).
• The percentage of achievement of sPGA 0 or 1 was 83.2% and 72.9% for ixekizumab Q2W and Q4W, respectively, compared to 2.4% in placebo (P <0.0001 vs. placebo).
• Both ixekizumab dosing regimens were statistically higher to placebo in terms of PASI 90, PASI 100 and DLQI (P <0.0001 vs. placebo).
• Compared to etanercept 50 mg twice weekly, ixekizumab 80 mg Q2W and Q4W were shown to be statistically superior in terms of the proportion of patients achieving PASI 75 and sPGA 0 or 1 at week 12 (P <0.0001 vs etanercept).
• At 12 weeks, a higher proportion of patients receiving ixekizumab 80 mg Q2W and 80 mg Q4W experienced treatment-related adverse events (61.7% and 58.8%, respectively) compared to placebo.
• The most common adverse events were nasopharyngitis, injection site reaction, and headache.
• Infections were reported in (29.7% and 28.8%, patients respectively) receiving ixekizumab 80 mg Q2W and 80 mg Q4W compared to placebo (27.5%).
• The proportions of patients with candida infection at 12 weeks were 1.5% and 0.3% for ixekizumab Q2W and ixekizumab Q4W, respectively, compared to 0.6% for placebo.
• All Candida Infections were mild to moderate in intensity and resolved without interruption of treatment.
• The 12-week serious adverse event rates were 1.4%, 2.3%, and 1.2% for patients receiving ixekizumab Q2W, ixekizumab Q4W, or placebo, respectively.
• At 12 weeks, neutropenia it was reported in 8.6% of patients taking ixekizumab Q2W and 7.6% of patients taking ixekizumab Q4W, compared to 4.8% of patients taking placebo.
• Neutropenia cases were mild and transitory, without associated infections.
• It is important to note that comparisons of adverse events were not statistically significant as the studies had the power to detect differences in efficacy rather than rates of adverse events.

UNCOVER-3: efficacy and adverse events

UNCOVER-3 patients were randomized to receive placebo (n = 193), etanercept (n = 382), ixekizumab every 2 weeks (Q2W; n = 385), or ixekizumab every 4 weeks (Q2W; n = 386).

• The primary and secondary efficacy end points were the same as for UNCOVER-2.
• Like the previous trials, UNCOVER-3 also showed statistically significant superiority of ixekizumab 80 mg Q2W and ixekizumab 80 mg Q4W over placebo.
• The proportion of patients achieving PASI 75 was 87.3% and 84.2% for ixekizumab Q2W and Q4W, respectively, compared to 7.3% in those taking a placebo (P <0.0001 compared to placebo).
• The percentage of achievement of sPGA 0 or 1 was 80.5% and 75.4% for ixekizumab Q2W and Q2W, respectively, compared to 6.7% in placebo (P <0.0001 vs. placebo).
• Both ixekizumab regimens were similar statistically superior to placebo in terms of PASI 90, PASI 100 and DLQI (P <0.0001 vs. placebo).
• As in UNCOVER-2, ixekizumab 80 mg Q2W and Q4W were shown to be statistically superior to etanercept 50 mg twice weekly, in terms of the proportion of patients achieving PASI 75 and sPGA 0 or 1 at week 12 (P <0.0001 vs etanercept).
• The most common adverse events were nasopharyngitis, injection site reaction, upper respiratory tract infection, and headache.
• At 12 weeks, a higher proportion of patients receiving ixekizumab 80 mg Q2W and 80 mg Q4W experienced emerging adverse events from treatment (53.4% and 56.3%, respectively) or infections (21.4% and 23.0%, respectively), in Comparison with placebo (adverse events: 36.3%, infections: 14.0%).
• The proportions of patients with Candida infection at 12 weeks was 1.8% and 0.8% for ixekizumab Q2W and ixekizumab Q4W, respectively, compared to 0.5% for placebo.
• The 12-week serious adverse event rates were 2.3, 1.6, and 2.6% for patients receiving ixekizumab Q2W, ixekizumab Q4W, or placebo, respectively.
• At 12 weeks, neutropenia was reported in 8.9% of patients taking ixekizumab Q2W and 9.5% of patients taking ixekizumab Q4W, compared to 1.0% of patients taking placebo.
• Neutropenia cases were mild and transitory, without associated infections.
• Comparisons of adverse events are not statistically significant, as the study was designed to detect differences in efficacy rather than adverse events between treatment and placebo.
• Table 1 summarizes the efficacy results for UNCOVER 1, 2, and three at week 12.

Table 1: Efficacy results at week 12 in evaluable adults with plaque psoriasis in Trials 1, 2, and 3

N = number of patients in the population by intention to treat

Adverse event outcomes grouped into UNCOVER 1, 2, and 3

Adverse events

Table 2 summarizes the adverse reactions that occurred at a rate of ≥ 1% in the combined proportion of patients in the Ixekizumab group compared to etanercept and placebo during a 12-week treatment period.

Table 2: Adverse reactions in ≥1% of the TALTZ group versus placebo in adults with plaque psoriasis in trials 1, 2 and 3

* The group of upper respiratory tract infections includes nasopharyngitis and rhinovirus infection.

Future directions for ixekizumab

• A large proportion of psoriasis patients achieve fair or near-clear skin during ixekizumab treatment quickly and sustainably, supporting the idea that IL-17A plays a central role in psoriasis. immunopathogenesis.
• Ixekizumab 80 mg Q2W and ixekizumab 80 mg Q4W have been shown to be more effective in terms of PASI 75, PASI 90, and PASI 100 at week 12 compared to etanercept 50 mg twice weekly or placebo. Results hold until week 60 and beyond.

• Secukinumab is currently the only other IL-17 pathway inhibitor approved by the US FDA. USA For the treatment of plaque psoriasis.

• Until now, there have been no direct comparisons of these medications to directly verify the efficacy and safety of one agent over the other.
• A phase III clinical trial showed that ixekizumab was statistically superior to placebo in the treatment of patients with active psoriasis. arthritis at 24 weeks, measured by the proportion of patients achieving an improvement response of 20% from the American College of Rheumatology (ACR20).
• Therefore, ixekizumab may also serve to alleviate the symptoms of psoriatic arthritis and reduce the risk of cardiovascular events associated with elevated levels of IL-17 in patients with psoriasis.