An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology
Issue link: http://jcadonline.epubxp.com/i/729153
S 8 S U P P L E M E N T T O T H E J O U R N A L O F C L I N I C A L A N D A E S T H E T I C D E R M AT O L O G Y [ S E P T E M B E R 2 0 1 6 • V O L U M E 9 • N U M B E R 9 ] BI-655066 are thought to have an indirect effect on those cytokines. IL-17a is expressed by memory natural killer (NK) and T-cells and occurs in increased amounts in psoriatic skin. IL-17a is known to increase inflammation and enhance angiogenesis. IL-22 is expressed in high levels by Th17 and occurs abundantly in psoriasis (both skin and plasma) with levels increasing with severity of the disease. IL-22 is known to induce keratinocyte hyperproliferation both in vitro and in vivo. 25 Guselkumab. When compared to adalimumab in a randomized, placebo-controlled, Phase 2 clinical trial of plaque psoriasis patients, at 16 weeks, significantly more guselkumab patients achieved PASI 75 response than placebo patients (43.9% 5mg every 12 weeks; 75.6% 15mg every 8 weeks; 81.0% 50mg every 12 weeks; 78.6% 100mg every 8 weeks; 81.0% 200mg every 12 weeks compared to 4.8% placebo and 69.8% adalimumab patients, p<0.001 all comparisons to placebo). 2 6 Three serious infections, one malignancy, and three major adverse cardiac events (MACEs) were reported, but no anaphylaxis was reported. Tildrakizumab. Tildrakizumab is a novel anti-IL- 23p19 monoclonal antibody, but unlike ustekinumab (which blocks IL-12), tildrakizumab blocks only IL-23. In a phase 2 study of psoriasis patients, at 16 weeks, 76.2 percent of patients achieved PASI 75 and 51.2 percent PASI 90 with all doses (5, 25, 100, and 200mg) statistically significant versus placebo. Tildrakizumab was reported to be generally safe and well-tolerated by investigators. 27 BI-655066. BI-655066 is a novel anti-IL23p19 monoclonal antibody that has been termed an "immunologic disrupter." In a Phase 2 proof-of-concept study, patients with a history of psoriasis achieved PASI 75 and PASI 90 at rates of 87 and 58 percent with a single intravenous or subcutaneous dose. Further, 33 percent of responders were able to maintain results over 66 weeks with that single dose. 28 Secukinumab. Secukinumab is a human IL-17A antagonist indicated for the treatment of moderate-to- severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The recommended dose regimen is 300mg subcutaneous injection at Weeks 0, 1, 2, 3, and 4, followed by 300mg subcutaneous injection every four weeks. Note that in some patients, a dose of 150mg may be acceptable. Efficacy of secukinumab in placebo-controlled studies and extension periods has been demonstrated with response in a Phase 3 trial occurring as early as three or four weeks. 29 The adverse events associated with secukinumab are of special interest. Mild-to-moderate candidiasis occurred in 4.7 percent (300mg) and 2.3 percent (150mg) of secukinumab patients versus less than one percent in etanercept patients and in no placebo patients. Grade 3 neutropenia was reported in one percent of secukinumab patients, 0.3 percent of etanercept patients, and in no placebo patients. 29 According to the package insert, secukinumab may exacerbate Crohn's disease. 30 Ixekizumab. Ixekizumab is a humanized monoclonal antibody that blocks IL-17A. This new agent was evaluated in two large Phase 3 randomized clinical trials (UNCOVER-2 and UNCOVER-3), which found ixekizumab was more effective than placebo and etanercept at 12 weeks in treating moderate-to-severe psoriasis. 3 1 The rate of any infection in these studies was 26 percent (for both doses of ixekizumab), 22 percent for etanercept, and 21 percent for placebo. No deaths were reported for any treatments. The rate of serious non-fatal adverse events was two percent for all groups, including placebo. Brodalumab. The novel agent brodalumab faces an unclear future. Although effective in treatment of psoriasis, its manufacturer, Amgen, halted development on the drug in the middle of 2015 although partners are continuing efforts to advance it. It has been accepted for review by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Of particular concern are certain psychological symptoms associated with the drug, ranging from depression to suicidal ideation and suicide. However, the mechanism that might explain a relationship between IL-17 inhibition and suicidal ideation remains unclear. 32 New choices in highly effective drugs. With multiple potential agents on the market and different treatment strategies available to clinicians, it can be difficult to determine the most effective course of therapy. An important and readily grasped concept in terms of choosing effective drugs is the number needed to treat (NNT). The NNT may be defined as the number of patients who need to be treated in order to achieve one good outcome, that is, how many patients need to be treated for one to benefit compared with a control is a clinical trial. 33 Thus, NNT might be seen as the inverse of the absolute risk reduction. Based on information from package inserts, the NNT values for certain psoriasis drugs appears in Tables 2, 3, and 4. Dermatologists at one time tried to manage patient expectations about psoriasis clearance, advising patients that complete clearance was an unrealistic therapeutic goal. Today, many forces are driving us toward agents that will allow complete or nearly complete clearance, as our increased understanding of IL17 and IL23 antagonism creates ever-improved biologics. The old treatment paradigm for psoriasis involved a stepwise progression of over-the-counter remedies to prescription topical agents, then phototherapy, and finally systemic therapy. It was only when a patient failed to achieve results with one step that he or she moved to the next more aggressive step. Today, psoriasis treatment does not follow that old sequential pattern. If a patient failed topical therapy, the patient should advance to either traditional systemic agents (such as apremilast, methotrexate, and others) or biologics (such as adalimumab, infliximab, and others), or phototherapy.