Role of IL-23 Inhibition in the Management of Plaque Psoriasis

Specialty Pharmacy Times, September/October, Volume 9, Issue 6

The inhibition of the tumor necrosis factor alpha (TNF-α) pathway and its proinflammatory processes has been central in psoriasis management.

Psoriasis is a complex autoimmune disease that affects approximately 2% of the world- wide population. This disease, if inadequately treated, can lead to significant adverse effects (AEs).1,2 Although often considered a disease of dermatologic origin, psoriasis is linked with numerous other complications. These significant comorbidities include psoriatic arthritis, metabolic syndrome, cardiovascular disease, and psychosocial issues.1,3 Therefore, it is paramount that patients obtain proper treatment in order to reduce the complications and overall burden of the disease.

The inhibition of the tumor necrosis factor alpha (TNF-α) pathway and its proinflammatory processes has been central in psoriasis management.2 However, advances in understanding the disease pathogenesis have illuminated the central role of cytokines. Key mediators identified include interleukin (IL)-17, IL-12, and IL-23. Approved targeted agents for IL-17 have demonstrated the capacity for effective disease management and skin clearance.2

IL-12 and IL-23 are heterodimeric pleiotropic proteins that share a common p40 subunit. Blockade of p40 via nonselective agents, such as ustekinumab (Stelara), decreases the activity of IL-12 and IL-23.4 Evidence from recent studies point to IL-23 inhibition as being the key mediator of efficacy in psoriasis therapy. A unique subunit, IL- 23p19, can affect the activity of IL-23 alone, if selectively blocked, without affecting IL-12.5 Narrowed targeting promises effective disease management coupled with an appealing safety pro- file.4-6 As such, the development of new therapies directed at the IL-23p19 subunit has led to the approval of new treatment options for psoriasis.

Evidence Review of Selective IL-23 Inhibitors

At this time, 2 agents that specifically target IL-23 are approved by the FDA for the management of psoriasis. Guselkumab (Tremfya) gained approval in July 2017, with tildrakizumab (Ilumya) following in March 2018. AbbVie submitted a biologic licensing application in April 2018 to the FDA for its psoriasis treatment, risankizumab, after promising results in phase 3 clinical trials.7

Guselkumab was approved for the treatment of moderate to severe plaque psoriasis. Standard dosing is 100 mg self-administered subcutaneously at weeks 0 and 4, and then every 8 weeks thereafter.8 Its approval was based on the results of 3 phase 3 trials: VOYAGE I, VOYAGE II, and NAVIGATE. The major findings of these trials demonstrate the efficacy of guselkumab for psoriasis management and its superiority to adalimumab (Humira) and ustekinumab.9-11

In VOYAGE I, 85.1% of patients treated with guselkumab had an Investigator’s Global Assessment (IGA) score of less than 1, correlating to minimal disease as early as week 16,12 an effect that was sustained as incidence of IGA ≤1 was 80.5% at week 40. This is in contrast to adalimumab, which had an IGA ≤1 incidence of 65.9% at week 16 that declined to 55.4% at week 48.9 In VOYAGE II, 112 patients treated with adalimumab who had not achieved a psoriasis area and severity index score of 90 (PASI 90) switched over to guselkumab at week 28 due to inadequate response. By week 48, 66.1% of those patients achieved PASI 90, showing the efficacy of IL-23 inhibition in patients who have failed TNF therapy.

Patients in VOYAGE II who had therapy withdrawn experienced a decreased PASI score, thus validating the necessity for maintenance of clinical benefit.10 NAVIGATE transitioned patients who failed to achieve IGA ≤1 during a 16-week run-in phase with ustekinumab to guselkumab. Ustekinumab nonresponders had significantly higher rates of IGA ≤1 achievement when switched to guselkumab compared with those who continued ustekinumab.11

Tildrakizumab was approved for the treatment of moderate to severe plaque psoriasis. Conventional dosing is a 100-mg subcutaneous injection at weeks 0 and 4 and then every 12 weeks thereafter.13 Tildrakizumab requires administration by a health care provider due to the rare occurrence of angioedema and urticaria seen in clinical trials.

The approval of tildrakizumab was based on results from 2 pivotal trials, reSURFACE 1 and reSURFACE 2. The reSURFACE 1 trial established superior efficacy compared with placebo. Incidence of a psoriasis area and severity index score of 75 (PASI 75) at week 12 was 64% with tildrakizumab 100 mg, a difference of 58% (51.1%-64.1%; P <.001) from placebo. The reSURFACE 2 trial findings showed the superior efficacy of tildrakizumab 100 mg compared with etanercept (Enbrel) 50 mg. Incidence of PASI 75 at week 12 was 61% with tildrakizumab 100 mg, while etanercept achieved only 48% incidence, a difference of 13.1 percentage points (5.3%-20.7%; P = .001).

The effect was sustained through week 28, with 73% of patients on tildrakizumab achieving PASI 75 compared with 54% on Enbrel, a difference of 20.1 percentage points (12.4%-27.6%; P <.0001). Tildrakizumab-treated patients achieved PASI 90 or psoriasis area and severity index score of 100 (PASI 100) at respective rates of 55% and 23% at 8 weeks.14 In both trials, tildrakizumab was studied at 100-mg and 200-mg doses, but the analysis revealed no significant difference in efficacy after 28 weeks. Further publications detailing the long-term efficacy and safety are expected, as reSURFACE 1 and reSURFACE 2 addressed results through week 28, despite the trials being 64 weeks and 52 weeks, respectively.

Risankizumab, the newest agent in this class currently under FDA review, is a subcutaneous injection dosed at 150 mg at weeks 0 and 4 and every 12 weeks thereafter. Results from phase 2 and 3 trials have consistently shown higher efficacy compared with IL-12/23 blockade and TNF inhibition.15-17 IMMhance results exhibited risankizumab’s superiority to placebo, with 73% achieving PASI 90 and 47% achieving PASI 100 at week 16 compared with <2% for both outcomes with placebo.16 Long-term efficacy was also exhibited, with a physician global assessment score ≤1, indicating minimal disease activity of 87% after 1 year of therapy.

The capacity for clinically superior results versus adalimumab was shown in IMMvent. PASI 90 and PASI 100 in risankizumab-treatment groups were 72% and 40%, respectively. This was a significant improvement compared with 47% and 23%, respectively, in adalimumab at week 16.17 Most recently, ultIMMa-1 and ultIMMa-2 reinforced superiority to placebo, and, more importantly, their findings demonstrated greater efficacy compared with ustekinumab. Similar rates of PASI 90 and PASI 100 were achieved at week 16, but the rates after 1 year of therapy were more impressive. PASI 90 with the intervention was 82% in ultIMMa-1 and 81% in ultIMMa-2 compared with 44% and 51% with ustekinumab, respectively.18 The rates of PASI 100 with risankizumab were 56% and 60%, respectively, versus 21% with ustekinumab in both trials.

The safety of IL-23—inhibiting therapies, as demonstrated in clinical trials and post marketing surveillance, has not revealed any major signals for concern. Similar to other biologics, the most frequently reported AE is infection. At this time, none of the approved agents have black box warnings, and given the safety profile exhibited during clinical trials, risankizumab will likely not carry one. Standard pretreatment laboratory work-up to rule out tuberculosis and other serious infection should be completed, with regular surveillance to ensure safety. Tildrakizumab is the only agent in this drug class with unique safety concerns, as angioedema and urticaria were observed during clinical trials.13 The overall incidence was <1%, and this risk is mitigated by having tildrakizumab as a health care-administered therapy. Given the consistent clinical benefit and mild AE profile, targeted IL-23 agents are an appealing therapy option for patients with plaque psoriasis.

Targeted IL-23 Inhibitors’ Place in Therapy

The advent of biologic therapies, especially targeted agents, has ushered in a new era for psoriasis management. Strides in research have allowed for the development of novel therapy options that extend beyond the traditional TNF-α antagonism to a more expansive selec- tion of agents. The American Academy of Dermatology’s guidelines of care for the management of psoriasis and psoriatic arthritis were last updated in 2011, prior to the FDA approval of newer targeted therapies. Thus, the exact place of these novel agents in the treatment armamentarium remains poorly defined.

The National Psoriasis Foundation published guidance criteria regarding treatment goals. To help guide therapy, the foundation suggests that the accept- able response to therapy is body surface area (BSA) involvement of <3% after 3 months or an improvement of >75% from baseline, with the ultimate target of <1% BSA to be reassessed every 6 months.19 Using this concept as a framework, the need for agents that can achieve a high degree of skin clearing is vital. Research indicates that targeted IL-23 inhibition may be an important step in achieving that goal.

Given the years of clinical experience with TNF antagonists, PDE4 antagonists, and, more recently, IL-17 agents, it is not likely that targeted IL-23 inhibitors will be recommended as first-line thera- py for several reasons. First, although no safety signals emerged in clinical trials, the safety profile with prolonged use remains to be seen. Second, although prior studies’ results indicated sustained efficacy, the clinical benefit from use over years or decades remains to be seen. Third, the existing studies evalu- ated targeted IL-23 inhibition in direct comparison with TNF antagonists and ustekinumab, which demonstrated supe- rior efficacy. No studies have compared targeted IL-23 agents with IL-17 agents, a therapy class that also achieves a high degree of disease control. The true value and place in therapy is difficult to establish with these gaps.

Targeted IL-23 inhibition demonstrates profound clinical results. This represents a valuable treatment option for patients who may be challenging to manage. At this time, providers can increase the dosages of biologic therapies to illicit greater clinical benefit. However, this move can lead to dose-related increases in AEs, namely an infection risk caused by greater immunosuppression.

Trial results show that patients who fail to derive sufficient benefit from TNF or IL-12/23 blockade may respond to targeted IL-23 inhibitors. Those who may have only achieved psoriasis area and severity index score of 50 (PASI 50) with alternate biologic therapy could achieve up to PASI 100, equating to a significant improvement in disease burden with safety similar to conventionally dosed biologics. Another benefit with current targeted IL-23 inhibitors is the infrequent administration schedule, favoring patients who are hesitant to initiate an injectable therapy. Patients who have contraindications to TNF antagonists or IL-17 agents, such as those with multiple sclerosis or concurrent inflammatory bowel disease (IBD), may be ideal candidates for this new treatment option.

Currently, targeted IL-23 inhibition is being studied for other autoimmune diseases, including psoriatic arthritis and IBD.20 As the standard of care in psoriasis continues to move toward total skin clearance, the need for highly efficacious agents is paramount. Direct targeting of IL-23 appears capable of producing positive disease state outcomes in psoriasis and offering new treatment options for patients who may have failed with, or are ineligible for, other modalities. Moving forward, IL-23 therapies offer a potentially important treatment option for patients with psoriasis.


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17. Risankizumab meets all co-primary and ranked secondary endpoints, achieving significantly greater efficacy versus standard biologic therapies in three pivotal phase 3 psoriasis studies. North Chicago, IL: AbbVie; October 26, 2017. Accessed June 25, 2018.

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