Options With IL-23 Inhibitors for the Patient With Psoriasis

New and emerging therapies such as biologics continue to improve quality of life and outcomes for patients with psoriasis. Biologics that block IL-23 functions present a unique opportunity to provide long-term, effective treatment.

Though the exact causes are still unknown, psoriasis has been linked to the immune system and genetics.¹ Traditional oral systemic medications, such as cyclosporine, methotrexate, and acitretin (Soriatane), target the whole immune system or work to decrease keratinocyte hyperproliferation,² but some patients do not respond to these treatments or seek a treatment that requires less frequent administration. Similarly, while generally effective,³ phototherapies are time-consuming, can be ineffective for some patients, and require frequent visits to the dermatology office. In addition, topical treatments can slow down excessive cellular reproduction and reduce inflammation,⁴ but these do not necessarily address an underlying cause for the cutaneous symptoms.

Among the newer therapies available for this immune-mediated disease are biologics, large molecular-weight proteins that target specific components of the immune system. Tumor necrosis factors (TNFs; cell-signaling cytokine involved in inflammation) and interleukins (ILs; leukocyte-produced glycoproteins that regulate immune response) are secretions by dendritic cells and macrophages (eg, IL-12, IL-23) that activate T helper (T_H) cells and have an active role in controlling the immune response.^5,6 Elevated levels of TNF-α and IL-12 have been expressed in psoriatic lesions,^7,8 prompting the introduction of biologic therapies that target those particular components and categorizing psoriasis as a T_H1-mediated disease.⁹ The earliest TNF blocker still available in the market is etanercept (Enbrel), and the earliest IL inhibitor is ustekinumab (Stelara).¹⁰ 

Ustekinumab was identified as a potential therapy for psoriatic disease and focused on IL-12, a driving factor in T_H1 differentiation. IL-12 is a heterodimer composed of a p40 and p35 subunit. Research showed that the p40 subunit of IL-12 also paired with a unique p19 subunit. This new, additional cytokine was classified as IL-23,¹¹ and it was later discovered to play a more central role in psoriasis than IL-12.⁹ Thus, research shifted from the inhibition of IL-12 to IL-23.

Interestingly, IL-23 regulates T_H17 cells, which produce various cytokines including IL-17, the major effector cytokine in psoriatic disease.¹² IL-17 production subsequently leads to the proliferation and differentiation of keratinocytes, which then produce proinflammatory cytokines and chemokines.^12-14 This cascade shapes the inflammatory response, presumably causing the classic presentation of psoriatic disease. In addition, these inflammatory pathways have been demonstrated in common comorbidities of psoriasis, including cardiovascular disease and obesity.^13-17

Several IL-17 inhibitors have been approved by the FDA and are currently available in the market, including brodalumab (Siliq), ixekizumab (Taltz), and secukinumab (Cosentyx).^10,18 These therapies have proven incredibly effective in treating the spectrum of psoriatic disease, particularly with a rapid onset of action.¹⁹ In addition, secukinumab and ixekizumab are approved for the treatment of ankylosing spondylitis, another inflammatory disease.²⁰ Though they are well tolerated overall, IL-17 inhibitors do display some adverse events, such as increased risk of infection (particularly mucocutaneous candidiasis), inflammatory bowel disease, and suicidal ideation and depression.¹⁰

Because of its ability to affect IL-17 production via IL-23 without blocking IL-17 activity, IL-23 inhibitor biologics (Table) may be advantageous in the treatment of psoriasis. These biologics may provide more efficacy, convenience, and safety than other biologics for certain populations of patients with psoriasis.

Guselkumab
Guselkumab is a human p19 monoclonal antibody approved for moderate to severe plaque psoriasis in adults.¹⁰ Essentially, guselkumab requires six injections per year.²¹

When compared with adalimumab (Humira) and placebo in a phase 3 randomized controlled trial, 70.0% of patients with psoriasis who received guselkumab achieved Psoriasis Area and Severity Index (PASI) 90 vs 46.2% of those who received adalimumab and 2.4% of those who received placebo.²² Of patients who did not respond to adalimumab and were subsequently switched to guselkumab, 66.1% achieved PASI 90 at week 48. Notably, guselkumab has been found to be effective in the treatment of scalp, nail, and plaque-type palmoplantar psoriasis.²³

Risankizumab-rzaa
The most recent addition to the approved anti-IL-23p19 biologic family,²⁴ risankizumab-rzaa requires four injections per year of a maintenance dose following the initial two injections.²¹

Risankizumab-rzaa induced and maintained a decrease in proteins and transcriptomic biomarkers associated with IL-23 over an 8-week period in 81 lesional skin biopsy samples.²³ It was also shown to more strongly downregulate the expression of genes associated with keratinocytes, epidermal cells, and monocytes compared with ustekinumab.²⁵ As for clinical effectiveness, risankizumab-rzaa was tested in two phase 3 trials (UltIMMa-1 and UltIMMa-2); at week 16 of UltIMMa-1, 75.3% of patients achieved PASI 90, and for UltIMMa-2, 74.8% of patients achieved PASI 90.²⁶ For comparison, only 42.0% and 47.5% of patients who received ustekinumab in UltIMMa-1 and UltIMMa-2, respectively, achieved PASI 90.

Tildrakizumab
Whereas guselkumab and risankizumab-rzaa can be self-injected by the patient, tildrakizumab is indicated for physician-administered injection.¹⁰ It may also require only four injections per year (every 12 weeks) after the initial two injections at weeks 0 and 4.23 The median length of time for patients to lose PASI 75 after cessation of therapy with tildrakizumab is 7.5 months,²⁷ showing a long-term therapeutic effect.²¹ A 3-year follow up of a pooled analysis of participants in the reSURFACE1 and reSURFACE2 trials found that a minimum of PASI 75 was maintained in 91% and 92% of patients who continued to receive the 100-mg and 200-mg dosings of tildrakizumab, respectively.²⁸

Ustekinumab
As mentioned previously, ustekinumab targets the p40 subunit of IL-12 as well as IL-23, though most of its action comes through IL-23p40.²¹ It is the only biologic in the anti-IL-23 family approved for use in adolescents aged 12 years and older.²⁹ While ustekinumab has been used as a comparator for the newer IL-23p19 biologics, it is still a highly efficacious and generally well-tolerated therapy for moderate to severe plaque psoriasis.³⁰

Mirikizumab
Study on mirikizumab, an IL-23 inhibitor by Eli Lilly and Company, is currently underway. In a phase 2 study, 67% of patients who received 300 mg of mirikizumab at 8-week intervals achieved a PASI 90.³¹ The estimated primary completion date of OASIS-2, a phase 3 study on mirikizumab, is March 3, 2020, and the study’s estimated completion date is December 2020.³² 

IL-23 Inhibitors for Psoriatic Arthritis (PsA)
Out of the four anti-IL-23 biologics, only ustekinumab is approved to treat PsA. The other three options, however, are currently under study.

A recent late-breaking abstract at the American College of Rheumatology and Association of Rheumatology Professionals (ACR/ARP) 2019 Annual Meeting demonstrated the potential of guselkumab to meet ACR 20% improvement criteria (ACR20) in the management of PsA.³³ In the first phase 3 trial, DISCOVER-1, ACR20 was achieved in 59% and 52% of patients who received guselkumab every 4 weeks and at weeks 0, 4, and 8 weeks thereafter, respectively, after 24 weeks of treatment. In DISCOVER-2, 64% of patients who received both therapeutic regimens achieved ACR20 at 24 weeks.

For risankizumab-rzaa, a phase 3 trial is currently underway.³⁴ Results from the phase 2 trial showed 57.1% to 65.0% of patients with PsA across all arms treated with risankizumab-rzaa achieved ACR20.³⁵ PASI 75, PASI 90, and PASI 100 responses were also significantly higher in patients who received risankizumab-rzaa than those who received placebo.

Tildrakizumab is also undergoing phase 3 trials for PsA.²³ In a phase 2 trial for patients with PsA, 61.5%, 43.3%, and 26.0% of the combined arms treated with tildrakizumab achieved PASI 75, PASI 90, and PASI 100 vs only 16.7%, 7.1%, and 4.8% of the placebo, respectively.³⁶

Recent Literature Review
A systematic literature review identified 60 trials assessing the short- and long-term efficacy of biologics, including TNF, IL-17, and IL-23 inhibitors, in adults with moderate to severe psoriasis with reported data on PASI.³⁷ Response rates of PASI 75, 90, and 100 at 10 to 16 weeks or 44 to 60 weeks of treatment were compared with initial baseline data. Among the results, risankizumab-rzaa and guselkumab showed some of the highest PASI 90 rates for short-term efficacy at 71.6% and 67.3%, respectively; IL-17 inhibitors brodalumab and ixekizumab demonstrated 70.8% and 70.6% efficacy, respectively. When long-term (44 to 60 weeks) efficacy was examined, the two IL-23 inhibitors risankizumab-rzaa and guselkumab reported the highest PASI 90 rates of 79.4% and 76.5%, respectively. Following at third and fourth in PASI 90 in the long term were brodalumab (74.0%) and ixekizumab (73.9%). The results of PASI 75 and PASI 100 were similar for both periods. While further studies are certainly needed to confirm these results,³⁷ as it only examines registrational clinical trials,³⁸ it may support the theory of improvements in long-term patient outcomes with the use of IL-23 biologics. 

References
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