Clinical Review

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

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

References

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5. He X, Koenen HJ, Smeets RL, et al. Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production. J Invest Dermatol. 2014;134:975-983.

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8. Study to evaluate Apo805K1 in subjects with moderate to severe chronic plaque psoriasis (NCT01483924). https://clinicaltrials.gov/ct2/results?term=NCT01483924&Search=Search. Updated February 9, 2015. Accessed June 23, 2015.

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11. Liu C, Lin J, Wrobleski ST, et al. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38a MAP kinase inhibitor for the treatment of inflammatory diseases. J Med Chem. 2010;53:6629-6639.

12. Mavropoulos A, Rigopoulou EI, Liaskos C, et al. The role of p38 MAPK in the aetiopathogenesis of psoriasis and psoriatic arthritis. Clin Dev Immunol. 2013;2013:569751.

13. Oral OTEZLA^® (apremilast) approved by the U.S. Food and Drug Administration for the treatment of patients with moderate to severe plaque psoriasis [news release]. Summit, NJ: Celegene Corporation; September 23, 2014. http://ir.celgene.com/releasedetail.cfm?releaseid=872240. Accessed June 23, 2015.

14. Gottlieb AB, Matheson RT, Menter A, et al. Efficacy, tolerability, and pharmacodynamics of apremilast in recalcitrant plaque psoriasis: a phase II open-label study. J Drugs Dermatol. 2013;12:888-897.

15. Moustafa F, Feldman SR. A review of phosphodiesterase-inhibition and the potential role for phosphodiesterase 4-inhibitors in clinical dermatology. Dermatol Online J. 2014;20:22608.

16. Huynh D, Kavanaugh A. Psoriatic arthritis: current therapy and future approaches. Rheumatology (Oxford). 2015;54:20-28.

17. Fishman P, Bar-Yehuda S, Liang BT, et al. Pharmacological and therapeutic effects of A3 adenosine receptor agonists. Drug Discov Today. 2012;17:359-366.

18. David M, Akerman L, Ziv M, et al. Treatment of plaque-type psoriasis with oral CF101: data from an exploratory randomized phase 2 clinical trial. J Eur Acad Dermatol Venereol. 2012;26:361-367.

19. Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol. 2012;167:668-677.

20. Menter A, Papp KA, Tan H, et al. Efficacy of tofacitinib, an oral Janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions. J Drugs Dermatol. 2014;13:252-256.

21. A phase 3, multi site, randomized, double blind, placebo controlled study of the efficacy and safety comparing CP-690,550 and etanercept in subjects with moderate to severe chronic plaque psoriasis (NCT01241591). https://clinicaltrials.gov/ct2/show/NCT01241591?term=01241591&rank=1. Updated May 8, 2014. Accessed June 16, 2015.

22. A study to evaluate the effects and safety of treatment, treatment withdrawal, followed by re-treatment with CP-690,550 in subjects with moderate to severe chronic plaque psoriasis (NCT01186744). https://clinicaltrials.gov/ct2/show/NCT01186744?term=01186744&rank=1. Updated May 14, 2014. Accessed June 16, 2015.

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27. A study to evaluate the safety and effectiveness of doxercalciferol capsules in participants with moderate to severe psoriasis (NCT00601107). https://clinicaltrials.gov/ct2/show/NCT00601107?term=00601107&rank=1. Updated April 2, 2014. Accessed June 16, 2015.

28. GSK discloses good efficacy in psoriasis with GSK2856184 [news release]. Mechelen, Belgium: Galapagos NV; November 6, 2014. http://www.globenewswire.com/news-release/2014/11/06/680358/10106744/en/GSK-discloses-good-efficacy-in-psoriasis-with-GSK2856184.html. Accessed June 24, 2015.

29. Bissonnette R, Papp K, Poulin Y, et al. A randomized, multicenter, double-blind, placebo-controlled phase 2 trial of ISA247 in patients with chronic plaque psoriasis. J Am Acad Dermatol. 2006;54:472-478.

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35. Bantia S, Parker C, Upshaw R, et al. Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes—a novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies. Int Immunopharmacol. 2010;10:784-790.

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Tofacitinib (JAK 1 and JAK 3 Inhibitor)

Tofacitinib is a JAK 1 and JAK 3 inhibitor that is available in both topical and oral formulations. Many studies have been published on tofacitinib, including a dose-ranging phase 2b trial of 197 patients randomized to placebo or tofacitinib 2, 5, or 15 mg daily in which 2.0%, 25.0% (P<.001), 40.8% (P<.0001), and 66.7% (P<.0001) of participants in each treatment group, respectively, achieved PASI 75 at week 12.¹⁹ Another 12-week phase 2b trial in patients with moderate to severe psoriasis explored the effectiveness of oral formulations of tofacitinib based on body location, namely the head and neck, arms, trunk, and legs.²⁰ Designed with twice-daily placebo and tofacitinib 2-, 5-, and 15-mg treatment arms, the target plaque severity score demonstrated a statistically significant dose-responsive improvement in each of the 4 anatomic regions (P<.01).

Two randomized, double-blinded, placebo-controlled phase 3 trials of tofacitinib have been completed. One trial compared the safety and effectiveness of tofacitinib and etanercept in patients with moderate to severe psoriasis.²¹ The 329 participants were randomized to treatment with oral tofacitinib 5 mg or 10 mg twice daily with placebo subcutaneous (SQ) injections twice weekly; oral placebo twice daily with etanercept 50-mg SQ injections twice weekly; or oral placebo twice daily with placebo SQ injection twice weekly. At week 12, PASI 75 was achieved in 39.51%, 63.64%, 58.81%, and 5.61% of participants in each treatment group, respectively. Thus, tofacitinib 10 mg and etanercept 50 mg were the first and second best performers in this study design.²¹

In the other phase 3 trial, the efficacy and safety of treatment, treatment withdrawal, and subsequent resumption of treatment with tofacitinib was examined in 290 patients who received either tofacitinib 5 mg or 10 mg or placebo twice daily for 24 weeks.²² In the withdrawal period, the percentage of patients who maintained a PASI 75 response in the tofacitinib 5-mg group was 56.2% versus 23.3% in the placebo group at week 16 (P<.0008). In the 10-mg group, 62.3% of participants maintained PASI 75 at week 16 versus 26.1% in the placebo group (P<.0001). During the re-treatment period for those who showed a greater than 50% reduction in week 24 PASI during treatment withdrawal (N=102), 50.0% of the tofacitinib 5-mg group showed PASI 75 versus 31.58% of the placebo group at week 16. In the tofacitinib 10-mg group, PASI 75 was seen in 0% versus 50.85% in the placebo group. Of note, only 5 participants who demonstrated a greater than 50% reduction in week 24 PASI response following withdrawal of therapy were in the tofacitinib 5- or 10-mg groups, as the rest were in the placebo group.²²

FP187 (Fumaric Acid Ester)

FP187 (Forward Pharma A/S) is an oral fumaric acid ester whose underlying mechanism is thought to be elevation of glutathione levels that decreases the amount of inflammatory cytokines by blocking the translocation of nuclear factor κB. Other fumaric acid esters such as monoethyl fumarate and dimethyl fumarate have been used in Europe for the management of psoriasis.²³ A phase 2 study of the safety and effectiveness of FP187 for moderate to severe psoriasis has been completed, but the results were not available at the time of publication (NCT01230138). A phase 3 trial examining the efficacy of FP187 in managing moderate to severe psoriasis was not yet open for participant recruitment at the time of publication (NCT01815723).

Doxercalciferol (Vitamin D₂ Analogue)

Doxercalciferol (1α-hydroxyvitamin D₂; Genzyme Corporation, a Sanofi company) is an oral prodrug of vitamin D.²⁴ Topical preparations of vitamin D analogues approved by the US Food and Drug Administration such as calcipotriene are mainstays in psoriasis management. Doxercalciferol has been used for other therapeutic applications such as decreasing elevated parathyroid hormone levels.²⁵ Research has demonstrated that CYP24A1 can extrahepatically regulate the activation of vitamin D prodrugs in cutaneous tissues.²⁶ In a phase 2 study examining the efficacy and safety of doxercalciferol in patients with moderate to severe psoriasis, 111 patients were randomized to placebo or doxercalciferol 2.5, 5, or 7.5 mg daily for 24 weeks (NCT00601107). At week 12, PASI 50 was similar regardless of the treatment administered, reported at 20.0%, 20.0%, 17.9%, and 20.0%, respectively (P=1.000).²⁷

GSK2586184 (JAK 1 Inhibitor)

GSK2586184 is an oral JAK 1 inhibitor. A placebo-controlled, double-blind, dose-dependent phase 2 study of GSK2586184 in patients with chronic plaque psoriasis who were randomized to placebo or GSK2586184 100, 200, and 400 mg twice daily for 84 days has been completed, but the results were not available at the time of publication (NCT01782664). Of note, despite clinical promise, due to potential adverse effects of the medication that included a possible interaction with statin medication, the manufacturer decided against pursuing GSK2586184 as a treatment in the management of psoriasis.²⁸

Voclosporin (Calcineurin Inhibitor)

Voclosporin (formerly known as ISA247)(Aurinia Pharmaceuticals Inc) is an oral calcineurin inhibitor that is purported to be as effective as cyclospor-ine A with less associated toxicity. A 12-week randomized, placebo-controlled, double-blind phase 2 trial demonstrated PASI 75 in 0%, 18.2%, and 66.7% of 201 participants receiving placebo, voclospo-rin 0.5 mg/kg, and voclosporin 1.5 mg/kg twice daily, respectively (P<.0001). Elevated serum creatinine levels within the high range of normal were noted in the 1.5-mg/kg group.²⁹ A 12-week phase 3 study of 451 patients randomized to placebo or voclospo-rin 0.2-, 0.3-, or 0.4-mg/kg treatment groups similarly demonstrated a dose-responsive PASI 75 of 4%, 16%, 25%, and 47%, respectively, that was maintained at week 24. Mild to moderate decreases in glomerular filtration rates were noted in 8 patients in the 0.3- and 0.4-mg/kg subsets.³⁰ Another phase 2 study of voclosporin in patients with moderate to severe psoriasis showed improvements according to the psoriasis disability index and dermatology life quality index.³¹

Three randomized, placebo-controlled, double-blind phase 3 trials have been completed for voclosporin, but the results were not available at the time of publication. The phase 3 ESSENCE trial compared voclosporin to placebo and ciclosporin controls (NCT00408187). Two phase 3 trials known as the SPIRIT trials—one a 12-week study (NCT00244842) and the other a 36-week extension trial (NCT00258713)—compared the efficacy of placebo to voclosporin administered at 0.2-, 0.3-, and 0.4-mg/kg doses.

KD025 (ROCK 2 Inhibitor)

KD025 (Kadmon Corporation, LLC) is an oral ROCK 2 inhibitor. The inhibition of ROCK in the ras homolog gene family, member A/ROCK pathway has been targeted therapeutically for pulmonary arterial hypertension,³² glaucoma,³³ and many other uses. A phase 2a study assessing the tolerability and safety profile of KD025 in patients with moderate to severe psoriasis was completed, but the results were not available at the time of publication (NCT02106195).

LAS41008 (Fumaric Acid Ester)

LAS41008 (Almirall, S.A.) is purported to be an oral dimethyl fumarate that inhibits endothelial cell proliferation, migration, and differentiation.³⁴ A phase 3 trial comparing the safety and effectiveness of LAS41008, LASW1835 (an active comparator), and placebo in patients with moderate to severe psoriasis is ongoing but not recruiting participants (NCT01726933).

LEO 22811 (Anti-inflammatory)

LEO 22811 (LEO Pharma) is an oral anti-inflammatory agent for the treatment of psoriasis. Two clinical trials have been completed, the results of which have not yet been published. A phase 1 trial assessing the tolerability and safety profile of LEO 22811 (NCT00833872) and a phase 2 proof-of-concept study assessing dose response of LEO 22811 versus placebo (NCT01116895) were completed, but the results were not available at the time of publication.

Baricitinib (JAK 1 and JAK 2 Inhibitor)

As noted above, baricitinib (LY3009104 or INCB28050) is a JAK 1 and JAK 2 inhibitor. A phase 2b trial examining dose response for LY3009104 or baricitinib administration in patients with moderate to severe psoriasis has been completed, but the results were not available at the time of publication (NCT01490632).

Talarozole (CYP26 Inhibitor)

Talarozole (formerly known as R115866)(GlaxoSmithKline) is a selective oral CYP26 inhibitor that could serve to regulate the degradation of all-trans retinoic acid in the management of conditions such as acne and psoriasis. One phase 2 nonrandomized, open-label study (NCT00725348) and another phase 2 randomized, placebo-controlled, double-blind, dose-dependent trial examining the effectiveness and safety profile of 12-week talarozole treatment in patients with severe plaque psoriasis have been completed, but the results were not available at the time of publication (NCT00716144).

R3421 or BCX-4208 (PNP Inhibitor)

R3421 or BCX-4208 (BioCryst Pharmaceuticals, Inc/Hoffman–La Roche) is an oral PNP inhibitor that may help regulate apoptosis of T cells and B cells.³⁵ A randomized, placebo-controlled, double-blind, dose-dependent phase 2 trial in patients with moderate to severe psoriasis has been completed, but the results were not available at the time of publication (NCT00504270).

RWJ-445380 (Cathepsin S Inhibitor)

RWJ-445380 (Alza Corporation, DE) is an oral cathepsin S inhibitor. Cathepsin S is produced by antigen-presenting cells and activates CD4⁺ T cells via presentation of antigen by class II major histocompatibility complex.³⁶ A randomized, placebo-controlled, double-blind, dose-dependent phase 2 trial evaluating the tolerability, safety, pharmacodynamics, and pharmacokinetics of RWJ-445380 in patients with plaque psoriasis has been completed, but the results were not available at the time of publication (NCT00396422).

SRT2104 (Sirtuin 1 Activator)

SRT2104 (GlaxoSmithKline) is a selective oral NAD⁺-dependent deacetylase sirtuin 1 activator. Sirtuins help regulate apoptosis, inflammation, and other important cellular mechanisms.³⁷ A randomized, open-label phase 1 trial examining drug bioavailability (NCT01702493) and a randomized, placebo-controlled, double-blind, dose-dependent phase 2 trial studying the efficacy, tolerability, and safety of SRT2104 in patients with moderate to severe psoriasis have been completed (NCT01154101), but the results were not available at the time of publication.

VB-201 (Oxidized Phospholipid)

VB-201 (VBL Therapeutics) is an orally administered oxidized phospholipid analogue with anti-inflammatory effects.³⁸ Oxidized phospholipids are another element in the intricate spectrum of inflammatory mediators. A randomized, placebo-controlled, double-blind, dose-dependent phase 2 trial of VB-201 20 mg or 80 mg daily in patients with moderate to severe psoriasis was completed, but the results were not available at the time of publication (NCT01001468). Another randomized, placebo-controlled, double-blind, dose-dependent phase 2 trial of VB-201 80 mg and 160 mg twice daily in patients with moderate to severe psoriasis has been completed, but the results were not available at the time of publication (NCT01837420).

Conclusion

We are living in an exciting time in the treatment of psoriasis and PsA, with promising novel therapies afforded by the discovery of new therapeutic targets. In this 3-part series, we have reviewed topical, systemic, and biologic therapies that currently are in phase 2 through phase 4 clinical trials or have recently been approved by the US Food and Drug Administration for the management of psoriasis and PsA. These treatments offer patients and their caregivers the prospect of more targeted therapeutic regimens that offer enhanced clinical outcomes with more favorable side-effect profiles. As clinicians and researchers build upon this knowledge in the years to come, we can offer psoriasis patients an increasingly diverse and powerful therapeutic armamentarium.