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Emerging Treatments for Psoriasis
Recently approved therapies, drugs in development, and expanded labels for existing psoriasis drugs continue to offer clinicians and patients an expanding range of options for treatments.
The psoriasis treatment landscape continues to expand. In 2017, 3 new drugs gained FDA approval for the treatment of psoriatic arthritis (PsA) and in March 2018 a new monoclonal antibody, tildrakizumab (Ilumya) was FDA approved for plaque psoriasis. Furthermore, 2018 has already seen the expansion of indications for established therapies, such as ixekizumab (Taltz) with the possibility of new medicines gaining approval before the end of the year.
New Therapy Approvals
For PsA, abatacept (Orencia), tofacitinib (Xeljanz), intravenous (IV) golimumab (Simponi Aria), and ixekizumab were all FDA approved in 2017. Importantly, each of these medications represents a unique mechanism of action. Abatacept is a fusion protein administered subcutaneously for the treatment of PsA, which binds to antigen presenting cells and thereby disrupts T-cell activation. It gained FDA approval based on a 20% improvement in the American College of Rheumatology (ACR20) metric in 39.4% of abatacept-treated patients vs 22.3% of placebo controls in a 24-week phase 3 study. Unfortunately, “the psoriatic skin response was more modest compared with the musculoskeletal response.”1 Dermatologists should be aware of this new indication, however, as the concomitant use of abatacept and tumor necrosis factor (TNF) inhibitors has been shown to be associated with increased risks of infection and is contraindicated.
Tofacitinib, an oral Janus kinase 1 and 3 (JAK1 & JAK3) inhibitor that modulates inflammatory cytokine production by disrupting the JAK-STAT signaling pathway, was approved for the treatment of PsA in August 2017 based on results from 2 phase 3 trials—OPAL Beyond and OPAL Broaden. In OPAL Beyond, 50% of patients receiving tofacitinib 5 mg orally twice daily reached ACR20 vs 24% in the placebo group at 3 months.2 In OPAL Broaden, 50% of patients receiving tofacitinib achieved ACR20 vs 33% in the placebo group at 3 months.3 A Psoriasis Area and Severity Index (PASI 75) response was recorded in 21.3% of patients receiving tofacitinib 5 mg twice daily in OPAL Beyond and 42.7% in OPAL Broaden.4,5 Radiographic evidence of disease progression was also examined, however, rates of nonprogression were similar across all groups and thus “treatment effect on inhibition of radiographic progression in PsA could not be established.”6 To improve patient convenience and compliance, tofacitinib is also available as an 11-mg extended release tablet (Xeljanz XR) to be taken once daily.
In October 2017, golimumab became the only fully human, anti-TNF antibody approved for IV infusion. Previously approved for rheumatoid arthritis the label was expanded to include PsA based on phase 3 testing that showed 75.1% of patients treated with 2 mg/kg of IV golimumab achieving an ACR20 vs 21.8% in the placebo group at week 14. Inhibition of structural joint damage as compared to those in the placebo arms was noted at week 24.7
Expansions of Treatment
The ixekizumab label also recently expanded with the FDA approval for the treatment of PsA, and a label update to include genital psoriasis. Approval for the treatment of PsA was granted in December 2017 based on the results of two 24-week phase 3 trials, SPIRIT-P18 and SPIRIT P-2.9 In SPIRIT-P1, 58% of patients treated with ixekizumab 80 mg subcutaneous (SC) every 4 weeks achieved an ACR20 response compared with 30% in the placebo group, while 53% similarly treated with ixekizumab in SPIRIT-P2 achieved an ACR20 compared with 34% in the placebo arm. In addition, as a result of data gathered in SPIRIT-P1, ixekizumab became the first anti-IL-17A antibody to include efficacy data detailing the inhibition of structural joint damage progression in the package insert.10
In May 2018, ixekizumab also became the first biologic to receive a label update from the FDA for use in genital psoriasis. Approval was based on a phase 3 trial in which patients who had “failed to respond to or were intolerant of at least one topical therapy” were treated with 160 mg SC of ixekizumab followed by 80 mg every 2 weeks for 12 weeks. The trial’s primary endpoint was the proportion of individuals achieving a static Physician’s Global Assessment (PGA) rating of 0 or 1, indicating clear or minimal genital psoriasis. A total of 73% of treated patients reached this primary endpoint.11
Ixekizumab and secukinumab (Cosentyx) exclusively block and bind to the cytokine IL-17A. In contrast, brodalumab (Siliq), binds and blocks the IL-17RA receptor. Brodalumab blocks the activity of 5 IL-17 subtypes: IL-17A, IL-17C, IL-17E (IL-25), and IL-17F, but recent research suggests future antibodies may target both IL-17A and IL-17F simultaneously. Results from a phase 2b dose-ranging study for bimekizumab, a humanized IgG1 monoclonal antibody which selectively binds and inhibits IL-17A and IL-17F, were recently published. Increasing efficacy was noted with increasing dosage, and 79.1% of patients achieved a PASI 90 and 60% achieved a PASI 100 vs 0% in the placebo at 12 weeks.12 A similarly designed trial was conducted for PsA; however, results have not yet been published for peer review. 13
Other Emerging Treatments
Phase 2b testing for another IL-17A/F drug, M1095, may soon begin.14 M1095 is a nanobody and represents a new class and form of biologics. Based on unique heavy-chain only antibodies naturally occurring in members of the Camelidae family (eg, camels, llamas, and alpacas), these single-domain antibodies are smaller than conventional antibodies and thus may offer greater tissue permeability and a shorter half-life. However, whether these smaller antibodies cross the blood-brain barrier, and what effect that may have clinically remains uncertain.
Tildrakizumab, an anti-IL-23p19 humanized IgG1 monoclonal antibody, is now FDA approved for plaque psoriasis based on the results of 2 phase 3 trials—reSURFACE 1 and reSURFACE 2. Both of these trials had a 12-week placebo-controlled portion, however, while reSURFACE1 was strictly placebo-controlled, reSURFACE2 included etanercept (Enbrel) 50 mg twice weekly for 12 weeks as an active comparator. Primary endpoints for these trials involved an analysis of the number of patients achieving PASI 75 or a PGA score of 0 or 1 at Week 12. PASI 90 and PASI 100 response rates were both included as secondary endpoints.
In reSURFACE1, 64% of patients treated with tildrakizumab 100 mg achieved a PASI 75 response at week 12 compared with 3% treated with placebo. In reSURFACE2, 61% of patients treated with tildrakizumab 100 mg achieved a PASI 75 response at week 12 compared with 58% treated with etanercept and 6% treated with placebo. PASI 90 response was reported in 35% and PASI 100 in 14% of patients in the treatment arm of reSURFACE1 vs 3% and 1%, respectively, in the placebo arm. Similarly, in reSURFACE2, PASI 90 responses of 39%, 21%, and 1% were recorded at week 12 for the tildrakizumab 100 mg, etanercept, and placebo groups, respectively. Although both trials included doses of 100 mg and 200 mg of tildrakizumab, 100 mg at weeks 0, 4, and every 12 weeks thereafter is now the approved dose.15
Certolizumab pegol (Cimzia), a humanized monoclonal antibody conjugated to polyethylene glycol and targeting TNF-α also recently received a label update and now includes FDA approval for psoriasis and PsA. Certolizumab pegol uniquely lacks an Fc region and consequently does not bind placental Fc receptors. Thus, it shows minimal to no maternal-fetal transfer.16 Approval was based on results from 3 phase 3 trials, CIMPASI-1, CIMPASI-2, and CIMPACT. In CIMPASI-1 and CIMPASI-2 patients 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. CIMPACT included etanercept as an active comparator.
In CIMPASI-1, 76% of patients receiving 400 mg of certolizumab pegol every 2 weeks achieved PASI 75 at week 16, while 67% in the 200-mg dose group and 7% in the placebo group achieved this endpoint. For CIMPASI-2, 83% of patients receiving 400 mg of certolizumab pegol every 2 weeks achieved a PASI 75 at week 16 compared with 81% in the 200-mg dose group and 12% in the placebo group. PASI 90 responses at week 16 were: 44% for the 400-mg group, 36% for the 200-mg group, and 0% in the placebo group in CIMPASI-1, and 55% for the 400-mg group, 53% for the 200-mg group, and 5% for the placebo group for CIMPASI-2.17
In CIMPACT, 67% of patients receiving 400 mg of certolizumab pegol every 2 weeks achieved PASI 75 at week 12 compared with 61% in the 200-mg dose group, 53% in the etanercept group, and 5% in the placebo group. PASI 90 responses at week 12 were 34% for the 400-mg group, 31% for the 200-mg group, and 0% for the placebo group.18 Based on these results, the recommended dose is 400 mg SC every other week, but includes the caveat that patients weighing ≤90 kg may be treated with 400 mg initially and at weeks 2 and 4, followed by 200 mg every other week thereafter.
Finally, continuing a trend of combining existing medications into a single formulation in efforts to improve efficacy, compliance, and patient safety, results of 2 phase 3 trials involving a combination of halobetasol and tazarotene were published in March 2018. In these studies, patients were instructed to apply a thin layer of halobetasol propionate 0.01%/tazarotene 0.045% lotion (IDP-118) to psoriatic plaques daily for 8 weeks. After 8 weeks, an average of 41% of patients in the trials scored a 2-grade improvement from baseline and an Investigator’s Global Assessment score of 0, “clear” or 1, “almost clear” compared with around 10% in the placebo group.19 Although, not yet FDA approved, a provisional name, Duobrii, has been trademarked by the manufacturer. Ortho Dermatologics, a division of Valeant Pharmaceuticals International, Inc., recently received a Complete Response Letter from the FDA regarding its New Drug Application for halobetasol propionate and tazarotene lotion and its pharmacokinetic data in the treatment of plaque psoriasis. Joseph C. Papa, chairman and chief executive officer of Valeant. said, “We are working to resolve this matter expeditiously and have already requested a meeting with the FDA. We hope to bring forward this important new treatment option for those who suffer from plaque psoriasis as quickly as possible.”20
The additions to the psoriasis armamentarium provide additional options for clinicians treating patients who have psoriasis and PsA. For recommendations on selecting the optimal treatment option for each patient, please see page 17.
Dr Shuler is an assistant professor of dermatology at University of South Carolina School of Medicine-Greenville in Greenville, SC.
Disclosure: Dr Shuler reports no relevant financial relationships.
References
1. Mease PJ,Gotlieb AB, van der Heijde D, et al. Efficacy and safety of abatacept, a t-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis. Ann Rheum Dis. 2017;76(9):1550-1558.
2. Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med. 2017;377(16):1525-1536.
3. Mease P, Hall S, Fitzgerald O, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med. 2017;377(16):1537-1550.
4. Gladman DD, Rigby W, Azevedo VF, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in patients with active psoriatic arthritis and an inadequate response to tumor necrosis factor inhibitors: OPAL Beyond, a randomized, double blind, placebo-controlled, phase 3 trial. J Am Acad Dermatol. 2017;(76)(suppl 1):AB114.
5. Mease P, Fitzgerald O, van der Heijde D, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, or adalimumab in patients with active psoriatic arthritis and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs: OPAL Broaden, a randomized, placebo-controlled, phase 3 trial. J Am Acad Dermatol. 2017;(76)(supp l):AB114.
6. Xeljanz [package insert]. New York, NY: Pfizer Inc; 2018.
7. Simponi Aria [package insert]. Horsham, PA: Janssen Biotech Inc; 2018.
8. Mease PJ, van der Heijde D, Ritchlin, CT, et al; SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79-87.
9. Nash P, Kirkham B, Okada, M, et al; SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389(10086):2317-2327.
10. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2018.
11. A study of ixekizumab (LY2439821) in participants with moderate-to-severe genital psoriasis (IXORA-Q). Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02718898?term=LY2439821&draw=2&rank=19. Accessed June 20, 2018.
12. Papp KA, Merola JF, Gottlieb AB, et al. Dual neutralization of both IL-17A and IL-17F with bimekizumab in patients with psoriasis: results from BE ABLE 1, a 12-week randomized, double-blinded placebo-controlled phase 2b trial [published online March 30, 2018]. J Am Acad Dermatol. doi:10.1016/j.jaad.2018.03.037
13. A multicenter study to evaluate the dose response based on the efficacy, safety and tolerability of bimekizumab in subjects with active psoriatic arthritis which is a type of inflammatory arthritis. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02969525. Accessed June 20, 2018.
14. A phase 2b study of the efficacy, safety, and tolerability of m1095 in subjects with moderate to severe psoriasis. Clnicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03384745?term=M1095&rank=1. Accessed June 20, 2018.
15. Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390(10091):276-288.
16. Mariette X, Förger F, Abraham B, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis. 2018;77(2):228-233.
17. Gottlieb AB, Blauvelt A, Thaçi D, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks from two phase 3, multicenter, randomized, double-blinded, placebo-controlled studies (CIMPASI-1 and CIMPASI-2) [published online Aprril 13, 2018]. J Am Acad Dermatol. doi:10.1016/j.jaad.2018.04.012
18. Lebwohl, Blauvelt A, Paul C, et al. Certolizumab pegol for the treatment of chronic plaque psoriasis: results through 48 weeks of a phase 3, multicenter, randomized, double-blinded, etanercept- and placebo-controlled study (CIMPACT)[published online April 14, 2018]. J Am Acad Dermatol. doi:10.1016/j.jaad.2018.04.013
19. Gold LS, Lebwohl MG, Sugarman JL, et al. Safety and efficacy of a halobetasol/tazarotene fixed combination in the treatment of moderate-to-severe plaque psoriasis: results of two phase 3 randomized controlled trials [published online April 1, 2018]. J Am Acad Dermatol. doi:10.1016/j.jaad.2018.03.040
20. FDA issues complete response letter for DUOBRII™ (halobetasol propionate and tazarotene) lotion. PR Newsire. June 18, 2018. https://www.prnewswire.com/news-releases/fda-issues-complete-response-letter-for-duobrii-halobetasol-propionate-and-tazarotene-lotion-300667565.html. Accessed June 22, 2018.
