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Ixekizumab (Taltz) for the Treatment of Plaque Psoriasis

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Psoriasis is a common skin disease with a global prevalence of 2-3%, and affects over 40,000 people in Singapore. The chronic inflammatory condition with predominant skin, nail and joint involvement is an immune-mediated disease characterised by red, thickened plaques with a silvery scale. It has far-reaching systemic complications, with up to 40% of individuals at risk of developing psoriatic arthritis within 5-10 years of cutaneous disease onset, alongside other cardiovascular co-morbidities.

Current therapies

Patients with moderate to severe chronic plaque psoriasis refractory to conventional therapies (topical treatment, phototherapy and oral therapy) are likely to require biologic treatment escalation. Local expert consensus confirms that any biologic may be harnessed as first-line biologic therapy. However, interleukin inhibitors (IL) are usually preferred over anti-TNFα biologics for patients with psoriasis alone, while anti-TNFα biologics are considered for patients who have concomitant psoriatic arthritis.

Introduction to Ixekizumab (Taltz)

Anti-IL therapies have emerged as a major treatment modality for moderate-to-severe psoriasis, with IL-17/IL-23 pathways identified as key in the immunopathogenesis of psoriasis. Ixekizumab, an IL-17 antagonist, is a recombinant humanised monoclonal antibody produced in hamster cells. It is available in Singapore as 80mg/mL pre-filled pen for subcutaneous injection.

The drug was first approved for use by the Health Sciences Authority (HSA, Singapore) in June 2018 for the adult treatment of moderate to severe plaque psoriasis at a recommended dosage of 160mg at Week 0, then 80mg every 2 weeks until Week 12, followed by 80mg every 4 weeks.

In October 2021, approval was granted for an expansion of its labelled use to include the paediatric treatment of moderate to severe plaque psoriasis in children from the age of 6 years and adolescents who are candidates for systemic therapy. Its other labelled indications include:

  • Psoriatic arthritis (active)
  • Ankylosing spondylitis (active)
  • Active non-radiographic axial spondylarthritis with objective signs of inflammation 

Efficacy

Several Phase III studies have corroborated the efficacy of ixekizumab in the treatment of psoriasis, with data suggesting its superiority to placebo and standard of care active-comparators both within and without its drug class. 

UNCOVER trials

The UNCOVER trials were conducted to evaluate the efficacy and safety of different dosing frequencies of ixekizumab compared to placebo and an anti-TNFα, etanercept.

  • The studies recruited patients with chronic plaque psoriasis aged 18 years or older. The patients had:
    • 10% or greater body-surface area (BSA) involvement
    • At least a moderate clinical severity measured by a static physician global assessment (sPGA) score of ≥3
    • A psoriasis area and severity index (PASI) score of 12.
  • The co-primary endpoints were proportions of patients achieving sPGA score 0 or 1 and ≥75% improvement in PASI from baseline at Week 12 (PASI 75).
  • UNCOVER-1 (n=1,296) randomised patients to receive either ixekizumab or placebo at 2-weekly (Q2W) and 4-weekly (Q4W) intervals
  • UNCOVER-2 (n=1,224) and UNCOVER-3 (n=1,346) trials evaluated Q2W and Q4W ixekizumab against placebo or etanercept. 
    • By Week 12, each of the three studies demonstrated statistically significant superiority of ixekizumab 80mg Q2W and Q4W over placebo (p<0.001 for all groups compared to placebo)
    • Within the studies, the pooled proportion of patients reaching PASI 75 was 88.7% and 81.6% for ixekizumab Q2W and Q4W respectively, compared to 4.4% in those on placebo
    • The pooled percentages of patients achieving sPGA 0 or 1 were 81.1% and 75.0% for ixekizumab Q2W and Q4W respectively, compared to 3.9% in those who took placebo.
    • In UNCOVER-2 and UNCOVER-3, ixekizumab 80 mg Q2W and 80 mg Q4W were also found to perform significantly better than etanercept 50 mg twice weekly in achieving PASI 75 and sPGA 0 or 1.
    • An extension phase confirmed that positive findings from the UNCOVER trials were maintained through to 60-weeks of treatment.
      • UNCOVER-1 and UNCOVER-2 patients who achieved sPGA 0 or 1 scores at Week 12 were reallocated to three arms: 73.8% of patients on ixekizumab 80mg Q4W, 39.0% of patients on ixekizumab 80mg Q12W and 7.0% of patients on placebo maintained their sPGA score of 0 or 1 at Week 60
      • In UNCOVER-3, ixekizumab 80 mg Q4W was administered through to Week 60, and at least 73% of patients maintained a sPGA score of 0 or 1 and 80% kept PASI 75 improvement at Week 60. 

IXORA trials

The IXORA-S (n=302) and IXORA-R (n=1,027) Phase III trials evaluated ixekizumab against an IL-12/23 inhibitors, ustekinumab and guselkumab respectively in patients with moderate-to-severe plaque psoriasis. 

  • In IXORA-S:
    • The primary outcome of PASI 90 was met at Week 12 in 72.8% of the ixekizumab group and 42.2% of the ustekinumab group (response difference: 32.1%, p<0.001)
    • Response rates for PASI 75, PASI 100 and sPGA 0 or 1 were also significantly higher for ixekizumab treated patients (adjusted p<0.05)
    • After 12 weeks, the ixekizumab dosing interval was extended per the manufacturer’s recommendation and the superiority of ixekizumab to ustekinumab was maintained through week 24 (PASI 90 = 83.1% and 59.0% respectively). 
  • In IXORA-R, the primary endpoint of PASI 100 at Week 12 was met in 41% of the ixekizumab group and 25% of the guselkumab (p<0.001).

Safety

UNCOVER trials

Pooled data from the three UNCOVER studies revealed adverse event (AE) rates of:

  • 54.8% among patients taking ixekizumab 80mg Q2W
  • 58.8% among patients taking ixekizumab 80mg Q4W
  • 46.8% among patients on placebo

In a separate analysis of UNCOVER-2 and UNCOVER-3, the safety profile of ixekizumab was comparable with etanercept, although overall treatment-emergent AEs (TEAEs) were more frequently recorded with ixekizumab. Most AEs were mild or moderate in severity and most commonly involved nasopharyngitis, upper respiratory tract infection (URTI), injection-site reaction and headache. A small portion of patients (<9%) experienced low-grade neutropenia. The cases were transient and not associated with infections.

Mild and moderate Candida infections were observed more frequently among patients on ixekizumab than placebo, corroborating the theoretical risk seen in patients with genetic IL-17 immunity deficiencies. All Candida infections were mild to moderate in intensity and resolved with treatment discontinuation.  

IXORA trials

Safety findings were similar in IXORA-S and IXORA-S8,9. In the latter, serious AEs were experienced by 3% of patients in the ustekinumab group and 2.2% patients in the ixekizumab group (p=0.735). There were also no statistically significant TEAEs between treatment groups (p=0.299). The most common TEAE was nasopharyngitis which occurred in 24.4% of the ixekizumab group and 27.1% of the ustekinumab group. In IXORA-S, serious AEs occurred in 3% of each group and no new safety signals were identified.

Local Clinical Practice

Evidence to date has been convincing and consistent in validating the comparative efficacy of IL-17 inhibitor, ixekizumab, against existing biologics. In Singapore, ixekizumab is the singular IL inhibitor approved for reimbursement under the Medication Assistance Fund (MAF) for the treatment of chronic plaque psoriasis. The MOH Drug Advisory Committee (DAC) issued a guidance in early 2021 acknowledging that IL inhibitors were superior in efficacy to anti- TNFα biologics for treating chronic plaque psoriasis.

However, in the absence of consistent results, the DAC considered all IL inhibitors to be comparable in efficacy. Based on a cost-minimisation approach, ixekizumab was approved over other IL inhibitors as it ranked the most cost-effective option, with an annual cost impact estimated at less than SG$1 million within the first year of its reimbursement listing. 

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