Psoriasis affects 2% of the population and 20% of those affected have moderate to severe disease. Therefore, the demand for systemic treatment options in psoriasis persists and is likely to grow as patient expectations for disease clearance increase.1
In 2016, the FDA approved the first anti-IL-17 monoclonal antibody secukinumab (Cosentyx) for the treatment of psoriatic arthritis, the anti-IL-17 monoclonal antibody ixekizumab (Taltz) to treat moderate to severe plaque psoriasis, and expanded the indication for psoriasis treatment using the fusion-protein tumor necrosis factor (TNF) blocker etanercept (Enbrel) to include children aged 4 to 17 years.
The FDA approved brodalumab (Siliq), an anti-IL-17 receptor A (anti-IL-17RA) monoclonal antibody, to treat adults with moderate to severe plaque psoriasis in February 2017.2 By targeting IL-17RA, brodalumab antagonizes the IL-17 pathway and disrupts the biological activity of IL-17A, IL-17F, IL-17A/F heterodimers, and IL-25 (IL-17E).3 Approval was based on results from 3 multinational phase 3 trials involving 4373 participants enrolled in AMAGINE-1, AMAGINE-2, and AMAGINE-3.
The brodalumab phase 3 trials included a placebo-controlled 12-week induction phase, a 52-week open-label maintenance phase, and an open-label long-term extension. In each trial, the coprimary endpoints were the percentage of patients achieving a Psoriasis Area and Severity Index (PASI 75) response and a static Physician Global Assessment (PGA) of 0 or 1. However, AMAGINE-2 and AMAGINE-3 also included ustekinumab (Stelara) as an active comparator, and PASI 100 was used as the primary endpoint to distinguish brodalumab from ustekinumab responders at week 12.4 In AMAGINE-1, 83% of the participants achieved a PASI 75 response with brodalumab 210 mg every 2 weeks compared with 3% in the placebo group. In AMAGINE-2 and AMAGINE-3, 86% and 85% of participants achieved a PASI 75 response with brodalumab 210 mg every 2 weeks, respectively, compared with 8% and 6% in the placebo treatment arm.4
When compared with ustekinumab, patients treated with brodalumab were more likely to achieve a PASI 100 response at 12 weeks. In AMAGINE-2, 44% of participants treated with brodalumab 210 mg every 2 weeks obtained a PASI 100 response, while only 22% treated with ustekinumab and 1% in the placebo group obtained this same benchmark. Similarly, in AMAGINE-3, 37% of participants treated with brodalumab 210 mg every 2 weeks saw a PASI 100 improvement, while 19% of those treated with ustekinumab and 1% in the placebo group achieved this response.4 Based on results from these trials, subcutaneous brodalumab 210 mg on weeks 0, 1, and 2 followed by 210 mg every 2 weeks is the current FDA-approved dosage.2
The phase 3 brodalumab trials were terminated before completion due to an “unbalanced safety signal” regarding “suicide ideation and behavior.”5 Thus, long-term extension data for brodalumab is unavailable. Furthermore, although the package insert only lists Crohn disease as a contraindication, it is important to note that based on the observed risk of suicidal ideation and behavior, the package insert for brodalumab includes a boxed warning and availability will be restricted through a Risk Evaluation and Mitigation Strategy program.2
In May 2017, the FDA accepted the Biologics License Application (BLA) for tildrakizumab. The investigational drug targets the p19 subunit of IL-23. Tildrakizumab is an anti-IL-23p19 humanized IgG1 monoclonal antibody being evaluated for the treatment of moderate to severe plaque psoriasis. The BLA filing for tildrakizumab was submitted by Merck & Co. Inc.
Two phase 3 trials—reSURFACE 1 and reSURFACE 2—support the BLA filing. Both trials included a 12-week placebo-controlled phase and compared subcutaneous tildrakizumab 100 mg, tildrakizumab 200 mg, and placebo. However, while reSURFACE 1 was strictly placebo-controlled, reSURFACE2 included etanercept 50 mg twice weekly for 12 weeks as an active comparator. Dosing intervals for tildrakizumab in the trials involved 1 injection at baseline, 1 injection a month later, and then every 12 weeks thereafter. The coprimary endpoints were the proportion of patients achieving PASI 75 and PGA score of 0 or 1 at week 12. Secondary endpoints included PASI 90 and PASI 100 response rates.6
The reSURFACE 1 study showed that 64% of patients treated with tildrakizumab 100 mg and 62% of patients treated with tildrakizumab 200 mg achieved a PASI 75 response at week 12 compared with 3% in the placebo group. Findings from reSURFACE 2 demonstrated that 61% of patients treated with tildrakizumab 100 mg and 66% of patients treated with tildrakizumab 200 mg achieved a PASI 75 response at week 12 compared with 48% and 6% of patients treated with etanercept and placebo, respectively.6
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PASI 90 responses during the placebo-controlled phase of reSURFACE 1 totaled 35% in both tildrakizumab 100- and 200-mg groups and 3% in the placebo group. Similarly, PASI 100 responses during the placebo-controlled phase of reSURFACE 1 totaled 14% in both tildrakizumab 100- and 200-mg groups and 1% in the placebo group. PASI 90 responses observed in reSURFACE 2 were 39%, 37%, 21%, and 1% at week 12 for the tildrakizumab 100 mg, tildrakizumab 200 mg, etanercept 50 mg, and placebo groups, respectively.6
Guselkumab (Tremfya) is another anti-IL-23p19 antibody under evaluation. Based on the results of phase 2 and 3 studies, a BLA for guselkumab, a human IgG1 monoclonal antibody, was submitted to the FDA in November 2016. Three phase 3 trials were completed for this drug: VOYAGE-1, VOYAGE-2, and NAVIGATE.7-9 Each was a randomized, double-blinded, placebo-controlled trial. While VOYAGE 1 and VOYAGE 2 involved the use of adalimumab (Humira) as a comparator,7,8 NAVIGATE was designed to assess the efficacy and safety of switching to guselkumab in patients with moderate to severe plaque psoriasis with an inadequate response to ustekinumab.9
For both VOYAGE 1 and VOYAGE 2, PASI 90 and an Investigator Global Assessment (IGA) of 0 or 1, were the coprimary endpoints. Of the patients included in the studies, 73% and 70% vs 3% and 2% of patients treated with guselkumab vs placebo achieved PASI 90 response rates in VOYAGE 1 and VOYAGE 2 at week 16, respectively. By comparison, 50% of patients in VOYAGE 1 and 47% in VOYAGE 2 treated with adalimumab achieved this same response. IGA scores were similar; in VOYAGE 1 7% of placebo, 48% of guselkumab, and 26% of adalimumab patients achieved an IGA 0/1, while in VOYAGE 2 an IGA 0/1 was observed in 9% of placebo, 84% of guselkumab, and 68% of adalimumab treated patients at week 16.7,8 In comparison with ustekinumab and tildrakizumab, which are both dosed with 1 subcutaneous injection at baseline, another injection 1 month later, and then every 12 weeks thereafter, guselkumab was dosed with 1 subcutaneous injection at baseline, another injection 1 month later, and then every 8 weeks thereafter in these trials.
Risankizumab is another anti-IL-23p19 human IgG1 monoclonal antibody that may be available as early as 2019. Risankizumab is in phase 3 trials, but phase 2 results have been reported. At 12 weeks, 77% of patients treated with risankizumab vs 40% treated with ustekinumab achieved a PASI 90 response, and 45% of risankizumab vs 18% of ustekinumab patients obtained a PASI 100. Efficacy was reported to last up to 20 weeks after the final dose of risankizumab.10 However, whether this effect can be replicated and what conclusions may be drawn about the safety of that drug will have to wait until results from larger phase 3 trials have been reported.
TNF inhibitors are still the most widely prescribed class of biologic agents to treat psoriasis. In March 2017, adalimumab became the first biologic treatment to include fingernail psoriasis data in its FDA-approved package insert.11 This was achieved after completion of a phase 3 trial demonstrating the safety and efficacy of adalimumab to treat nail psoriasis in patients with chronic plaque psoriasis. The study’s primary endpoints were to establish the percentage of participants achieving a total fingernail modified Nail Psoriasis Severity Index (mNAPSI) 75 response at week 26 and the percentage of participants with a PGA of fingernails (PGA-F) of “clear” or “minimal” at week 26. Forty-seven percent of patients achieved a mNAPSI 75 response at 25 weeks compared with 3% in the placebo group, while 49% achieved a PGA-F of 0 or 1 vs 7% in the placebo arm of the trial.12 Adalimumab dosing in the trial was similar to previously FDA-approved psoriasis dosing, (ie, 80 mg subcutaneous at week 1 followed by 40 mg of adalimumab every other week).
Certolizumab pegol (Cimzia) is another TNF agent that may be added to the list of FDA-approved psoriasis treatments. Results from 2 phase 3 trials, CIMPASI-1 and CIMPASI-2, on the use of certolizumab pegol in psoriasis were presented at the American Academy of Dermatology Annual Meeting in March 2017.13 The double-blind placebo-controlled trials enrolled patients with moderate to severe plaque psoriasis who were were given either certolizumab pegol 400 mg every 2 weeks, certolizumab pegol 400 mg at weeks 0, 2, and 4 followed by certolizumab pegol 200 mg every 2 weeks or placebo every 2 weeks.
In CIMPASI-1, 76% of patients receiving 400 mg of certolizumab pegol every 2 weeks achieved a PASI 75 at week 16, while 66% in the 200-mg dose group and 7% in the placebo group achieved this response. PGA responses of 0 or 1 were seen in 58% in the 400-mg dose group, 47% in the 200-mg dose group, and 4% in the placebo arm. PASI 90 responses at week 16 were 44% for the 400-mg group, 36% for the 200-mg group, and 0.4% in the placebo group.13
Dr Shuler is an assistant professor of dermatology at the University of South Carolina School of Medicine-Greenville in Greenville, SC.
Disclosure: The author is a speaker for Janssen Biotech, Abbvie, Eli Lilly, and Novartis. He is a consultant/advisory board member for Janssen Biotech and Abbvie.
1. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58(5):826-850.
2. Siliq [package insert]. Bridgewater, NJ: Valeant Pharmaceuticals North America LLC; 2017.
3. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181-1189.
4. Farahnik B, Beroukhim K, Abrouk M, et al. Brodalumab for the treatment of psoriasis: a review of phase III trials. Dermatol Ther (Heidelb). 2016;6(2):111-1124.
5. Center for Drug Evaluation and Research Office of New Drugs. FDA briefing document dermatologic and ophthalmic drugs advisory committee meeting background package for BLA 761032 Siliq (brodalumab) injection, 210 gg/1.5 mL. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisorycommittee/ucm511357.pdf. Published July 19, 2016. Accessed June 26, 2017.
6. Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials [published online June 5, 2017]. Lancet. doi:10.1016/S0140-6736(17)31279-5
7. Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: Results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2017;76(3):405-417.
8. Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76(3):418-431.
9. Langley RG, Tsai TF, Flavin S, et al. Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: Results of the randomized, double-blind, Phase 3 NAVIGATE trial [published online June 21, 2017]. Br J Dermatol. doi:10.1111/bjd.15750
10. Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus ustekinumab for moderate-to-severe plaque psoriasis. N Engl J Med. 2017;376(16):1551-1560.
11. Humira [package insert]. North Chicago, IL: AbbVie Inc; 2017.
12. Clinicaltrials.gov. A study to evaluate the safety and efficacy of adalimumab in subjects with chronic plaque psoriasis and nail psoriasis. https://clinicaltrials.gov/ct2/show/study/NCT02016482. Updated April 25, 2017. Accessed June 26, 2017.
13. Gottlieb A, et al. Certolizumab pegol treatment for chronic plaque psoriasis: 16-week primary results from two phase-3, multicenter, randomized, placebo-controlled studies. Presented at: The American Academy of Dermatology Annual Meeting; March 4, 2017; Orlando, FL.