New Systemic Therapies for Psoriasis
Over the last decade, expanded understanding of psoriasis pathogenesis has led to the development of new systemic agents such as biological drugs that have revolutionized the treatment of psoriasis. Small molecule inhibitors also have been studied and offer patients options for oral administration. This article reviews recently approved and in-the-pipeline biologics (IL-17 inhibitors and IL-23 blockers) as well as small molecule inhibitors (phosphodiesterase 4 [PDE4] and Janus kinase [Jak] inhibitors).
Practice Points
- Secukinumab is an anti–IL-17 antibody approved for the treatment of psoriasis. It is indicated for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.
- The new biological agents have shown promising results with some patients achieving psoriasis area and severity index scores of 90 and 100.
- A number of small molecule inhibitors also are in the pipeline, with apremilast the first one to have reached approval for psoriasis.
Guselkumab
Guselkumab is a human IgG1 monoclonal antibody in clinical development that specifically blocks the p19 subunit of IL-23. In a double-blind, placebo-controlled, phase 1 study, 24 participants with moderate to severe plaque psoriasis were randomized to receive a single 10-mg (n=5), 30-mg (n=5), 100-mg (n=5), or 300-mg (n=5) dose of guselkumab or placebo (n=4).20 At week 12, 50% in the 10-mg group, 60% in both the 30- and 100-mg groups, and 100% in the 300-mg group showed 75% improvement in PASI score versus 0% in the placebo group. Improvements in PASI scores were generally maintained through week 24. The rates of AEs were 65% (13/20) in the combined guselkumab group and 50% (2/4) in the placebo group.20
Small Molecule Inhibitors
In contrast to biologics, which mainly target soluble cytokine or cellular receptors, small molecule inhibitors target enzymes within signaling pathways. Small molecule inhibitors have some advantages over biologics in that they are relatively inexpensive to produce and can be administered orally; thus, they may be preferred by some patients over injectable drugs. There are several agents that are undergoing clinical trials in psoriasis, including PDE4 inhibitors and Jak inhibitors.
Apremilast
Apremilast is an oral small molecule PDE4 inhibitor that was approved by the US Food and Drug Administration in March 2014 for the treatment of adult patients with active psoriatic arthritis; an indication for moderate to severe plaque psoriasis was approved in September 2014.21 Phosphodiesterase 4 is a cyclic adenosine monophosphate–specific phosphodiesterase inhibitor, which is dominant in inflammatory cells. Inhibition of PDE4 increases intracellular cyclic adenosine monophosphate levels, thus downregulating proinflammatory cytokines such as TNF-α, IFN-γ, IL-2, IL-12, and IL-23, and increasing the production of anti-inflammatory cytokines such as IL-10.22
Phase 2 and phase 3 studies have demonstrated the clinical efficacy of apremilast in the treatment of patients with moderate to severe plaque psoriasis. In a 16-week randomized, placebo-controlled, phase 3 trial (ESTEEM 2), 408 participants were randomized to receive oral apremilast 30 mg twice daily (n=275) or placebo (n=138).23 Improvement of 75% in PASI score was achieved by 29% of participants in the apremilast group at week 16. The most common AEs were diarrhea (16%) and nausea (18%), which were predominantly mild, occurring most commonly in the first week and resolving within 1 month. No cases of severe diarrhea or severe nausea were reported. Apremilast had no apparent effect on the results of hematological or serum chemistry tests.23 Although the US Food and Drug Administration warns of a possible link between apremilast and depression,24 data are mostly related to roflumilast, another PDE4 inhibitor. Studies in patients with chronic obstructive pulmonary disease have noted increased cases of depression (1.21% vs 0.82%) and suicidal ideation/attempt (0.03% vs 0.02%) in patients treated with roflumilast versus placebo.25
Jak Inhibitors
Janus kinases are a family of intracellular tyrosine kinases that connect several cytokine receptors to the signal transducer and activator of transcription pathways.26 There are 4 Jak family members: Jak1, Jak2, Jak3, and tyrosine kinase 2. Janus kinases 1 and 2 have roles in interferon signaling, while Jak3 transduces signals from IL-2, IL-7, IL-15, and IL-21, which are T-cell growth and survival factors.
Tofacitinib is a novel oral signal transduction molecule that blocks the Jak3 pathway. A phase 2b, 12-week, dose-ranging study was conducted to assess the efficacy and safety of 3 twice-daily regimens of tofacitinib versus placebo in patients with moderate to severe chronic plaque psoriasis.27 One hundred and ninety-seven participants were randomized to receive oral tofacitinib (2 mg, 5 mg, or 15 mg; n=49 each) or placebo (n=50) twice daily for 12 weeks with a 4-week follow-up period. The primary end point was the proportion of participants achieving at least a 75% reduction in PASI score at week 12 (25.0% with 2 mg, 40.8% with 5 mg, 66.7% with 15 mg, 2.0% with placebo). Similarly, a higher proportion of participants achieving 90% reduction in PASI score was seen at weeks 8 and 12 in all tofacitinib-treated participants versus placebo. The most common AEs were upper respiratory tract infection, sinusitis, nasopharyngitis, and headache. A number of changes in laboratory parameters occurred in the tofacitinib groups. Mild dose-related decreases in hemoglobin were noted at week 12 for all tofacitinib groups, and a small increase (mean, 0.04 mg/dL) in serum creatinine levels was observed in the 15-mg group. Decreases in neutrophil counts were observed with higher doses of tofacitinib, with the maximum mean decrease of 0.9×103/mm3 from baseline observed in the 15-mg group at week 4. After weeks 4 through 8, mean neutrophil counts began to return to baseline levels. Dose-related increases in total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were observed by week 2 and remained at this level through week 12; mean lipid levels decreased to baseline levels after cessation of active treatment. One participant in the 15-mg group developed an elevated alanine aminotransferase level that was more than 2.5 times the highest normal limit. Three participants experienced 5 serious AEs.27 These early results show that tofacitinib can be a safe and effective treatment in patients with psoriasis, but further data from phase 3 studies will need to be awaited.
