Phase 3 Trials of Ixekizumab 
in Moderate-to-Severe Plaque Psoriasis

Sapna Charania, Mercer University College of Pharmacy

 

Psoriasis is a chronic inflammatory disease that is mediated by aberrant immune responses and driven by self-perpetuating cytokine networks. [1] According to American Academy of Dermatology, the usual standard of care for patients presenting with extensive or moderate-to-severe plaque psoriasis is systemic therapies with or without the use of topical treatments. It is also suggested that newer systemic treatments such as biologic response modifiers (BRMs) may be the treatments of choice, especially for patients with comorbidities such as Psoriatic Arthritis (PsA). BRMs are also recommended if traditional systemic treatments such as methotrexate or cyclosporine are contraindicated. [2]

Taltz™(Ixekizumab) is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. Ixekizumab is administered subcutaneously and the recommended dose is 160 mg (two 80 mg injections) at Week 0, followed by 80 mg at Weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks. [3]

 

Title: Phase 3 Trials of Ixekizumab
in Moderate-to-Severe Plaque Psoriasis [1]
Design Multicenter, randomized, double-blind, placebo-controlled phase 3 trial; N= 1296
Objective Assess whether ixekizumab is superior to placebo
Study Groups Placebo (431), 2-week dosing (433), 4-week dosing (432)
Methods Patients were assigned to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg at week 0 (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg at week 0 (4-wk dosing group).

At week 12, the patients who had a response to ixekizumab were reassigned to receive placebo 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. The primary endpoints were collected at patient visits during weeks 0, 1, 2, 4, 8, and 12. The sPGA was scored by evaluation of overall lesions for induration, erythema, and scaling. For the analysis of responses, the patient’s psoriasis was determined to be clear (0), minimal (1), mild (2), moderate (3), severe (4), or very severe (5). The PASI was a combination of the extent of body-surface involvement in four anatomical regions (head, trunk, arms, and legs) and the severity of scaling, erythema, and induration (thickness) of plaques, resulting in an overall score of 0 for clear and 72 for the worst possible psoriasis.

Duration 60 weeks
Primary Outcome Measure Response rate defined as an sPGA score of 0 [clear] or 1 [minimal psoriasis] or not having had a response defined as an sPGA score > 1
Baseline Characteristics UNCOVER-1

(N= 1296)

Placebo

(N= 431)

Ixekizumab

4-week (N= 432)

Ixekizumab

2-week (N= 433)

Age-year 46 ± 13 46 ± 13 45 ± 12
Male sex- no

(%)

303 (70.3) 289 (66.9) 291 (67.2)
White race- no (%) 401 (93.0) 397 (91.9) 401 (92.6)
Weight-kg 92 ± 25 92 ± 24 92 ± 23
Duration of psoriasis- year 20 ±12 19 ±12 20 ± 12
Percent of body-surface area involved 27 ± 18 27 ± 16 28 ± 18
sPGA score ≥ 4-no(%) 227 (52.7) 235 (54.4) 202 (46.7)
PASI score 20 ± 9 20 ± 7 20 ± 8
Previous therapy-no (%) 418 (97.0) 419 (97.0) 424 (97.9)
Results UNCOVER-1 (Induction) 2-week 4-week Placebo p-value
sPGA score (0/1) 81.8% 76.4% 3.2% <0.001
PASI 75 response 89.1% 82.6% 3.9% <0.001
UNCOVER-1 (Maintenance) 4-week 12-week Placebo p-value
sPGA score (0/1) 73.8% 39% 7% <0.001
Adverse Events

(UNCOVER-1, UNCOVER-2 and UNCOVER-3)

*Common Adverse Events: Nasopharyngitis (19%), upper respiratory tract infection (10%), injection-site reaction (10%), headache (6%)
Serious Adverse Events: Infection (1.4%), major adverse cardiovascular and cerebrovascular events (0.6%), crohn’s disease (0.1%), ulcerative colitis (<0.1%), nonmelanoma skin cancer (0.1%), cancer excluding nonmelanoma skin cancers (0.3%)
Percentage that Discontinued due to Adverse Events (4%)
Study Author Conclusions Ixekizumab was effective through 60 weeks of treatment in patients with psoriasis.

 

* The adverse event data was presented between all three trials in the induction and maintenance phase.

 

The UNCOVER-2 and UNCOVER-3 trials showed that after a 12-week induction period, ixekizumab was superior to placebo and to twice-weekly etanercept for the treatment of moderate-to-severe psoriasis. These trials also reported that at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. [1]

 

The benefits of ixekizumab need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. Eli Lilly, the manufacturer of ixekizumab, sponsored the trial. Hence, bias cannot be ruled out. Inflammatory bowel disease was reported as an adverse event in all three UNCOVER trials. So, further evaluation is needed to understand the relationship between interleukin 17A (IL-17A) inhibitors and inflammatory bowel disease.

 

References:

 

  1. Gordon KB, Blauvelt A, Papp KA, et al. Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis. N Engl J Med. 2016.

 

  1. Hsu S, Papp KA, Lebwohl MG, et al. Consensus guidelines for the management of plaque psoriasis. Arch Dermatol. 2012; 148(1): 95-102.

 

  1. Taltz (ixekizumab) [prescribing information]. Indianapolis, IN: Eli Lilly and Co; March 2016

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s