New Therapies for Psoriasis and Psoriatic Arthritis

Christopher T. Ritchlin; James G. Krueger

Disclosures

Curr Opin Rheumatol. 2016;28(3):204-210. 

In This Article

Recently Approved and Emerging Therapies

Interleukin-17 Antagonists

Three biologic interleukin-17 antagonists – secukinumab, ixekizumab, and brodalumab – have been studied in large (phase III) trials in psoriasis vulgaris. Results for psoriasis and PsA trials discussed in the following sections can be found in Table 1. Secukinumab is an interleukin-17A monoclonal antibody that has recent FDA approval for the treatment of psoriasis. Treatment with secukinumab has induced a PASI75 response in 87% of patients in the JUNCTURE study[15] and it was shown to be superior to ustekinumab (anti-interleukin-12/23 p40 subunit) in the CLEAR study on the basis of PASI90 and PASI100 outcomes.[16] In general, this agent is well tolerated with only a small risk of increasing infections that include a few cases of mucocutaneous candidiasis, a recognized disease of interleukin-17 deficiency states in humans. Ixekizumab is another interleukin-17A monoclonal antibody. Ixekizumab induced a PASI75 response in 90% of patients in the best-performing cohort in the UNCOVER studies and it too shows a good tolerability profile.[17] Within 2 weeks of starting ixekizumab, there is a strong reduction in interleukin-17-induced genes in keratinocytes that includes reduced expression of S100A7, CCL20, interleukin-19, interleukin-36, cathelicidin/LL-37, and CXCL1, 2, 3, and 8 chemokines[18] and also reduced expression of interleukin-17-regulated genes in circulating monocytes that are associated with cardiovascular disease risk.[19] Brodalumab is a monoclonal antibody to the interleukin-17 receptor A subunit. It blocks binding of interleukin-17 to cognate receptors that are prominently expressed on keratinocytes and other cell types, including some types of leukocytes. It also blocks signaling by other cytokines that use the interleukin-17 receptor A subunit, e.g., interleukin-25. In the AMAGINE-2 study, brodalumab induced an 86% PASI75 response in the best performing cohort and it was shown to be superior to ustekinumab treatment in the AMAGINE-3 study.[20] Side-effects have included mild-to-moderate candida infections, infrequent neutropenia, and some cases of serious infections. An increase in suicidal ideation and completed suicides, observed in a small subset (<1%) of brodalumab treated patients, has delayed its FDA approval and led to sale of the product to another pharmaceutical company that is continuing to pursue FDA approval. From the standpoint of treating psoriasis, treatment with brodalumab had led to very rapid and nearly complete reversal of psoriasis-related genes that are modulated by interleukin-17 and other inflammatory cytokines.[21]

The efficacy and safety of secukinumab were examined in two phase III trials, FUTURE 1 and FUTURE 2.[22,23] In FUTURE 1, 606 PsA patients were randomized to receive and intravenous dose of secukinumab at weeks 0, 2, and 4 followed by monthly administration at 75, 150 mg or secukinumab or placebo. Approximately 30% of patients had prior exposure to anti-TNF therapy. At week 24, those patients on secukinumab 75 or 150 mg had a significantly higher ACR20 response vs. placebo (50.0%, 50.5 vs. 17.3%). Improvements in enthesitis and dactylitis were also noted. In FUTURE 2, 397 PsA patients (65% no prior anti-TNF exposure) were randomized to receive 75, 150, or 300 mg of secukinumab or placebo weekly subcutaneously for 4 weeks and then every 4 weeks. The ACR20 was the primary outcome at 24 weeks and revealed 54% of patients on 300 mg achieved this outcome compared with 51% of patients on 150 mg, 29% on 75 mg, and 15% on placebo. The treatment response was lower with 75 and 150 mg compared with 300 mg per day in patients with prior TNF exposure. Adverse events in both studies were rare and included a numerically but not statistically higher rate of candida infections with no deaths in either trial but longer-term data are required to adequately assess risk. The efficacy and safety of ixekizumab in PsA were examined in the RHAP phase III clinical trial presented at the ACR meeting in November 2016.[24] In a phase III trial, 417 PsA patients were randomized to adalimumab, placebo, or ixekizumab 80 mg every 2 weeks or 160 mg every 4 weeks and the ACR20 endpoint was assessed at 24 weeks. A significantly greater percentage of patients treated with ixekizumab 80 mg Q2W or Q4W achieved ACR20, ACR50, ACR70, and PASI 75/90/100 responses than with placebo at 12 and 24 weeks (P < 0.01). Both ixekizumab groups experienced significantly greater reductions than placebo for measures of dactylitis (LDI-B) at 12 and 24 weeks but not for enthesitis (LEI). Efficacy results with adalimumab vs. placebo were also significant on most measures and both agents inhibited radiographic progression. The incidence of serious adverse events was numerically greater in the ixekizumab and adalimumab groups than placebo (P > 0.27). Lastly, a phase II trial of brodalumab in PsA randomized 168 patients receive 140 or 280 mg of brodalumab weekly vs. placebo.[25] At week 12, 37 and 39% of patients achieved the ACR endpoint vs. 18% of patients on placebo. Results were similar between patients who received prior biologic therapy and those who were biologic naïve. All brodalumab studies were halted as outlined above owing to concerns about suicidal ideation and completed suicides, and the future of this medication is not known.

Interleukin-23 Antagonists

Interleukin-23 is a cytokine composed of p19 and p40 protein subunits, but the same p40 subunit is combined with another protein, p35, to form interleukin-12. Ustekinumab is a monoclonal antibody to the p40 subunit and thus a dual antagonist of interleukin-12 and interleukin-23. Ustekinumab was approved by the FDA in 2009 in accordance with the ability of this agent to induce PASI75 responses in ~70% of treated patients vs. <5% placebo-treated patients. Since approval, ustekinumab has established a record of being well tolerated and of having the ability to maintain PASI75 responses for many years of treatment in most patients. Ustekinumab is also effective in PsA for arthritis, dactylitis, and enthesitis and this agent inhibits radiographic progression.[26,27] More recent work with specific interleukin-23 antagonists (monoclonal antibodies to the p19 subunit) has led to the conclusion that ustekinumab likely improves psoriasis and PsA by interleukin-23 blockade, but with the possibility that co-blockade of interleukin-12 might decrease effectiveness of this agent to a small degree. Three p19 monoclonal antibodies – guselkumab, BI655066, and tildrakizumab – are now in phase III studies in psoriasis vulgaris, after showing very impressive effects in phase II studies. Guselkumab induced a PASI75 response in >90% of treated patients and with superiority to the TNF antagonist adalimumab in a randomized study.[28] Molecular profiling showed a striking ability to reverse the psoriasis tissue phenotype and most disease-defining mRNA products, including the 'driver' cytokine interleukin-17.[29] BI655066 also induced a PASI75 response in >90% treated patients and it was superior to ustekinumab in this randomized trial (personal communication). In a smaller prior study, BI655066 was shown to down regulate interleukin-17 production in skin lesions and thus modulate downstream interleukin-17 regulated genes in keratinocytes and other cell types. Interestingly, a single dose of this antibody induced clearing of psoriasis for 1 year in some treated patients, suggesting that disease remission might be possible by targeting interleukin-23 in psoriasis.[30] Tildrakizumab was shown to induce a PASI75 response in 74% of patients in the highest dose cohort, but it was not tested against an active comparator in phase II.[31] Phase II trials designed to study the efficacy and safety of interleukin-23 inhibition in PsA are underway or in the planning stages but no data are available at this time.

New Oral Therapies

Two small molecule drugs, apremilast and tofacitinib, have now completed phase III trials in psoriasis and the former is now FDA approved for the treatment of psoriasis vulgaris. Apremilast is an inhibitor of PDE4, which is an enzyme that metabolizes cAMP, so this inhibitor raises cAMP levels within cells. Within T-cells, high levels of cAMP act as a brake, but not a complete inhibitor, of T-cell activation through the TCR complex and associated signal transduction, so levels of cytokines produced by activated T-cells will be reduced. Thus treatment of psoriasis is associated with reduced production of interleukin-17, interleukin-22, and TNF in patients that respond well to it, as well as an increase in the anti-inflammatory cytokine interleukin-10.[32] Other immune cell types are also affected by higher cAMP levels – the general response is lower levels of cellular activation/inflammation with treatment. Thus, apremilast should be viewed as a relatively broad-acting immune modulator, but producing less blockade of T-cell activation than some well characterized immune suppressants such as cyclosporine at clinically relevant doses. The effects of apremilast are thus more variable on immune pathways in individual patients than cyclosporine (or biologic antagonists of interleukin-17 or interleukin-23), with responding patients tending to have more reductions in cellular immune infiltrates and associated cytokines[32] and with a PASI75 response induced in 33.1% of apremilast-treated patients vs. 5.3% of placebo-treated patients in the ESTEEM1 study.[33] While fewer patients respond to this agent compared with biologics targeting interleukin-17 or interleukin-23, few adverse events [other than Gastrointestinal (GI) intolerance] have been associated with apremilast use and routine monitoring of hematologic or metabolic parameters is not required, unlike methotrexate which has more defined toxicity in psoriasis patients. As a consequence, apremilast is now used as a first-line targeted therapy by many dermatologists.

The impact of apremilast on musculoskeletal inflammation parallels the magnitude of the response observed in psoriasis with no major safety signals. In the phase III Psoriatic Arthritis Long-Term Assessment of Clinical Efficacy (PALACE) 1 trial, 504 patients were randomized to placebo, apremilast 20 mg or 40 mg per day in a 1:1:1 ratio.[34] At week 16, significantly more apremilast – 20 mg BID (30%) and 30 mg BID (30%) compared with placebo (19%), achieved the ACR20 measure at 16 weeks. The most common GI events were nausea and diarrhea and generally occurred early in the treatment course. Similar ACR responses were reported in the PALACE 3 study and responses were maintained at 52 weeks. A numerical but not statistical improvement was observed for dactylitis and enthesitis.[35] Radiographic endpoints have not been examined in apremilast trials to date. The approved dose of apremilast is 20 mg BID and it is prescribed as monotherapy.

Tofacitinib is an inhibitor of select JAKs with JAK1 and JAK3 being strongly inhibited at therapeutically relevant doses and with JAK2 being weakly inhibited. JAKs 1 and 3 are key signal-transducing kinases for cellular responses to a broad range of immune cytokines, so like apremilast, tofacitinib should be viewed as broad-acting immune modulator, but with stronger and more consistent immune suppression and thus clinical efficacy. In a phase III trial, 63.6% of patients treated with 10 mg of tofacitinib bid had a PASI75 response vs. 5.6% of placebo-treated patients and the response was roughly of the same magnitude (statistically not inferior) to etanercept.[36] Both clinical efficacy and immune suppression are highly dose-dependent and clear signals of immune-suppression, e.g., herpes zoster activation and bacterial infections, were seen in RA patients treated with tofacitinib 10 mg bid, whereas lower rates were observed with use of 5 mg bid (the FDA approved dose in RA). However, used as monotherapy in psoriasis patients 10 mg bid of tofacitinib is much better tolerated and rates of serious Adverse Events (AEs), infections, malignancies, and discontinuations due to AEs have been low across phase III studies.[37] Still, in response to a new drug application for use in psoriasis, the FDA has asked for additional safety information and approval is pending evaluation of those data.

Scientific rationale for the potential efficacy of tofacitinib in PsA was reported in a study[36] that examined the effect of this agent on protein expression in synovial fibroblast cultures and explant tissues. They demonstrated that tofacitinib significantly decreased Signal Transducer and Activator of Transcription (STAT)3, pSTAT1, Nuclear Factor (NF)[kappa]Bp65 and induced Suppressor of Cytokine Signaling (SOCS)53 and Protein Inhibitor Of Activated STAT (PIAS)3 expression in the cells and explant cultures. In addition, interleukin-6, interleukin-8, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase (MMP)9/MMP2, and MMP3 levels also decreased in explant tissues. Unfortunately, data on treatment response in PsA are not available at this time but clinical trials are in progress.

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