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 (Xeljanz) 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
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.
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
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
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.
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31. Reich K, Rich P, Maari C, et al; AMAF Investigators. Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study. Br J Dermatol. 2019;181(1):88-95. doi:10.1111/bjd.17628
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33. Janssen Pharmaceutical Companies of Johnson & Johnson. TREMFYA® (guselkumab), a first-in-class IL-23 p19 subunit inhibitor, meets primary endpoints of superior ACR20 responses versus placebo at week 24 in phase 3 psoriatic arthritis studies. Press Release. November 11, 2019. Accessed March 2, 2020. https://www.biospace.com/article/releases/tremfya-guselkumab-a-first-in-class-il-23-p19-subunit-inhibitor-meets-primary-endpoints-of-superior-acr20-responses-versus-placebo-at-week-24-in-phase-3-psoriatic-arthritis-studies/
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36. Gottlieb A, Orbai A, Ballerini R, et al. Tildrakizumab efficacy on psoriasis in patients with psoriatic arthritis—an analysis from a phase 2 study. Arthritis Rheumatol. 2019;71 (suppl 10). Accessed March 3, 2020. https://acrabstracts.org/abstract/tildrakizumab-efficacy-on-psoriasis-in-patients-with-psoriatic-arthritis-an-analysis-from-a-phase-2-study/
37. Armstrong AW, Puig L, Joshi A, et al. Comparison of biologics and oral treatments for plaque psoriasis: a meta-analysis [published online February 5, 2020]. JAMA Dermatol. doi:10.1001/jamadermatol.2019.4029
38. Strobre B, Gordon KB. Comparative effectiveness studies for psoriasis—the methods matter [published online February 5, 2020]. JAMA Dermatol. doi:10.1001/jamadermatol.2019.4025