Clinical Review

Novel Psoriasis Therapies and Patient Outcomes, Part 3: Systemic Medications

Cutis. 2015 July;96(1):47-53

The therapeutic armamentarium for patients with psoriasis and psoriatic arthritis (PsA) has been strengthened by research affording more individualized treatment regimens with new therapeutic targets. In this article, new systemic therapies for psoriasis are discussed, including a review of the relevant clinical trials for novel therapeutics and their respective mechanisms of action, patient outcomes, and safety profiles. This article is the final installment in a 3-part series on agents in the pipeline for the management of psoriasis and PsA including topical agents, biologic treatments, and systemic therapies in phase 2 through phase 4 clinical trials. These systemic agents offer patients more targeted treatment regimens with the prospect of enhanced therapeutic efficacy and more favorable side-effect profiles with better tolerability.

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Practice Points

A wide spectrum of promising nonbiologic systemic medications presently are in development or were recently approved for the management of moderate to severe psoriasis and psoriatic arthritis (PsA).
Systemic medications broaden the therapeutic armamentarium for patients with psoriasis and PsA, offering targeted therapeutic regimens that afford enhanced clinical outcomes with favorable side-effect profiles.

References

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Evolving knowledge of the underlying pathogenesis of psoriasis has afforded the development of a broad spectrum of nonbiologic systemic medications with therapeutic potential in moderate to severe psoriasis and psoriatic arthritis (PsA). The targets for these medications are antagonists of proinflammatory mediators such as tyrosine kinase, protein kinase, Janus kinase (JAK), p38α mitogen-activated protein (MAP) kinase, phosphodiesterase 4 (PDE-4), calcineurin, Rho-associated kinase (ROCK) 2, cytochrome P450 26 (CYP26), and purine nucleoside phosphorylase (PNP); agonists of anti-inflammatory mediators such as sphingosine-1-phosphate receptor 1 (S1P₁) and adeno-sine A₃ receptor; and myriad other mechanisms. A brief introduction to some of these therapies presently in phase 2 and phase 3 clinical trials are presented (Table).¹

Masitinib (Tyrosine Kinase Inhibitor)

Masitinib (formerly known as AB1010)(AB Sciences) is a tyrosine kinase inhibitor that is purported to decrease inflammation by inhibiting stem cell factor receptor (c-kit) and consequently limiting mast cell degranulation.² A randomized, placebo-controlled, double-blind phase 3 study evaluating its efficacy as an oral formulation was completed, but the results were not available at the time of publication (registered at www.clinicaltrials.gov with the identifier NCT01045577).

Ponesimod (S1P₁ Receptor Agonist)

Ponesimod (formerly known as ACT-128800)(Actelion Pharmaceuticals US, Inc) is an orally formulated S1P₁ receptor agonist. Sphingosine-1-phosphate receptor 1 is necessary for lymphoid chemotaxis.³ A randomized, placebo-controlled, double-blind phase 2 trial of 326 patients demonstrated 75% improvement in psoriasis area and severity index (PASI) score at week 16 in 13.4%, 46.0%, and 48.1% of participants receiving placebo, ponesimod 20 mg, and ponesimod 40 mg, respectively.⁴ At week 28, PASI 75 scores for participants transitioned from ponesimod 40 mg to placebo or ponesimod 20 mg to placebo and those maintained on ponesimod 20 mg and 40 mg were 40.4%, 42.2%, 77.4%, and 71.4%, respectively. This study demonstrated benefit of treatment with ponesimod versus placebo with increased efficacy using maintenance therapy.⁴

Sotrastaurin (Protein Kinase C Inhibitor)

Sotrastaurin (formerly known as AEB071)(Novartis AG) is an oral medication that inhibitsprotein kinase C, thereby limiting CD28-induced activation of T cells. Furthermore, it increases forkhead box P3 expression, which is important, as proinflammatory IL-17 production is stimulated in regulatory T cells with lost forkhead box P3 expression.⁵ In a study of 32 patients who received placebo or sotrastaurin 25, 100, 200, or 300 mg twice daily for 2 weeks, the mean PASI score was reduced by 69% for the 300-mg group versus 5.3% for placebo.⁶ A randomized, placebo-controlled, double-blind phase 2 study was completed for patients with moderate to severe psoriasis, but the results were not available at the time of publication (NCT00885196).

Alitretinoin (Retinoid)

Alitretinoin (9-cis-retinoic acid; Stiefel, a GSK company) is an oral retinoid with purported promise for patients with palmoplantar pustular psoriasis recalcitrant to conventional therapies. In one study, 7 participants with palmoplantar psoriasis received alitretinoin 30 mg daily for 12 weeks with 60% to 90% clinical improvement noted using the visual analog scale and palmoplantar pustular PASI to assess response.⁷ A randomized, placebo-controlled, double-blind phase 2 trial of alitretinoin assessing the success of alitretinoin in patients with palmoplantar psoriasis recalcitrant to topical treatments was completed, but the results were not available at the time of publication (NCT01245140).

Apo805K1 (Unknown Mechanism of Action)

Apo805K1 (ApoPharma Inc) is an oral agent whose mechanism of action has not been disclosed. A randomized, placebo-controlled, double-blind phase 2 trial in patients with moderate to severe psoriasis with a treatment duration of 14 days has been completed. For 12 weeks there was a daily dosing regimen of Apo805K1 10, 30, 60, or 100 mg or placebo, with 12 patients in each treatment group. The proportion of patients achieving PASI 75 was 16.7%, 0%, 0%, 8.3%, and 16.7%, respectively (P=.1975). The number of participants with adverse events reported ranged between 4 to 7, with the greatest number of adverse events reported in the 30-mg subset.⁸ It may be of interest to repeat the study with a larger sample size.

ASP015K (JAK 1 and JAK 3 Inhibitor)

ASP015K (Astellas Pharma US, Inc) is the first of the JAK inhibitors that will be discussed in this section. Janus kinase inhibitors represent a group of tyrosine kinases that regulate cytokine-mediated signaling pathways through the activation of signal transducer and activator of transcription proteins via phosphorylation in the cytoplasm, which in turn control the transcription of genes that generate inflammation. ASP015K and tofacitinib (formerly known as CP-690550)(Pfizer, Inc) inhibit JAK 1 and JAK 3, whereas GSK2586184 (GlaxoSmithKline) inhibits JAK 1 and baricitinib (formerly known as LY3009104 or INCB28050)(Eli Lilly and Company) inhibits JAK 1 and JAK 2.⁹ In a 6-week, dose-escalation phase 2 trial in patients with moderate to severe psoriasis, ASP015K showed a dose-dependent decline in PASI, psoriasis static global assessment, and body surface area.¹⁰

BMS-582949 (p38α MAP Kinase Inhibitor)

BMS-582949 (Bristol-Myers Squibb Company) is an oral p38α MAP kinase inhibitor.¹¹ Along with c-Jun N-terminal kinase and extracellular signal-regulated protein kinases 1 and 2, MAP kinase plays a role in the pathogenesis of psoriasis.¹² A randomized, placebo-controlled, double-blind, 12-week phase 2a study of placebo versus BMS-582949 dosed at 10, 30, and 100 mg has been completed, but the results were not available at the time of publication (NCT00399906).

Apremilast (PDE-4 Inhibitor)

Apremilast (formerly known as CC-10004)(Celgene Corporation) is an oral PDE-4 inhibitor that acts to inhibit the degradation of cyclic adenosine monophosphate. It is approved by the US Food and Drug Administration for moderate to severe plaque psoriasis¹³ and is a particularly good treatment for patients with recalcitrant disease.¹⁴ Several studies on apremilast have been published, including a phase 2 trial of 204 participants receiving placebo or apremilast 20 mg or 40 mg twice daily with American College of Rheumatology (ACR) 20% improvement response of 11.8%, 35.8%, and 43.5%, respectively.¹⁵The phase 3 PALACE 1, 2, 3, and 4 trials also demonstrated therapeutic efficacy.¹⁶ In PALACE 1, 504 patients receiving placebo or apremilast 20 mg and 30 mg twice daily had an ACR20 of 19%, 31%, and 40%, respectively. In the PALACE 4 study, ACR20 was achieved by 58% of participants at week 52, but the ACR50 and ACR70 rates were less impressive.¹⁶

Lestaurtinib (Multikinase Inhibitor)

Lestaurtinib (formerly known as CEP-701)(Teva Pharmaceutical Industries) is an oral multikinase inhibitor for which a 12-week, nonrandomized, dose-escalation phase 2 study was completed, but the results were not available at the time of publication (NCT00236119).

CF101 (Adenosine A₃ Receptor Agonist)

CF101 (IB-MECA; Can-Fite BioPharma Ltd) is an oral adenosine A₃ receptor agonist. Adenosine A₃ is a G protein–coupled receptor that has an anti-inflammatory role, which lends itself to the treatment of inflammatory conditions such as rheumatoid arthritis.¹⁷ In a randomized, placebo-controlled, double-blind phase 2 trial of 75 patients who received placebo or CF101 1, 2, or 4 mg twice daily for 12 weeks, PASI 50 or greater was reported in 35.3% of participants in the 2-mg group, which was statistically significant at weeks 8 (P=.047) and 12 (P=.031).¹⁸ A randomized, placebo-controlled, double-blind, 16-week phase 2/phase 3 trial in patients with moderate to severe psoriasis treated with CF101 2 mg twice daily versus placebo is ongoing but not recruiting participants (NCT01265667).