Small Molecules: An Overview of Emerging Therapeutic Options in the Treatment of Psoriasis
Melinda Gooderham, MD, MSc, FRCPC
Skin Centre for Dermatology, Peterborough, ON, Canada
Psoriasis is a chronic condition which requires ongoing management with therapies that have demonstrated favorable safety and efficacy profiles in long-term use. While biologics changed the way psoriasis is treated by providing effective targeted therapy, they are not without limitations. However, small molecules are emerging therapeutic options for the treatment of psoriasis. Several oral and topical small molecules, spanning different therapeutic classes, are proving to be promising treatment options in psoriasis. While studies to date have yielded positive results, further investigation of these agents are warranted for both safety and efficacy.
apremilast, baricitinib, dimethyl fumarate, fumaric acid esters, inflammation, JAK inhibitors, Janus kinases, phosphodiesterase 4 inhibitors, ponesimod, psoriasis, ruxolitinib, small molecules, sphingosine 1-phosphate receptor agonists, tofacitinib
Insights into the pathogenesis of psoriasis coupled with a detailed understanding of the action of cytokines and their associated transduction pathways have yielded a number of new therapeutic targets. Psoriasis is a chronic condition and, therefore, requires ongoing management with safe and effective therapy. The introduction of biological agents has changed the way we treat psoriasis, providing more efficacious and directed therapy for this complex disease. Although excellent treatment options, biological agents have limitations: side effect profile, immunogenicity, contraindication and lack or loss of efficacy in some patients. On the horizon are new therapeutic options for patients with psoriasis: small molecules including oral Janus kinase (JAK) inhibitors, tofacitinib (CP-690,550) (Pfizer), baricitinib (LY3009104) (Eli Lilly), ASP015K (Janssen), as well as a topical agent, ruxolitinib (INCB018424) (Incyte), which is also available in an oral form. Agents from other therapeutic classes are also being investigated, including two from the phosphodiesterase 4 inhibitor class, oral apremilast (CC-10004) (Celgene) and topical AN2728 (Anacor), one from the sphingosine 1-phosphate receptor agonist class, ponesimod (ACT-128800) (Actelion), and a fumaric acid ester, dimethyl fumarate (FP187) (Forward-Pharma GmbH).
JAK Inhibitors (Jakinibs)
The Janus kinases, a group of tyrosine kinases comprised of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2), are mainly found in hematopoietic cells. These kinases reside on the cytoplasmic side of Type I and II cytokine receptors. Kinases are invoked as part of signal transmission when cytokines bind to their cognate receptors. JAKs activate the intracellular transcription factors known as signal transducers and activators of transcription (STATs). The binding of STAT to an activated JAK results in phosphorylation and subsequent dimerization and translocation to the nucleus, where it directly modulates gene transcription.1-3
The JAKs play an important role in immune defense as we have learned from a series of mutant cell lines, mouse knock-out models and the clinical expression of JAK3 mutations, resulting in severe combined immunodeficiency. Inhibiting this pathway has been beneficial in treating immune-mediated diseases, including rheumatoid arthritis, inflammatory bowel disease and psoriasis, as well as preventing allograft rejection.3
The JAK inhibitors, or so-called jakinibs, uncouple cytokine receptor signaling from downstream STAT transcription activation and, thereby, modulate immune response in these disease states (Figure 1). The potential side effects of these agents are partially predictable and are directly related to their mode of action. These effects can include neutropenia and anemia, which are likely related to JAK2 inhibition. JAK2 is associated with the erythropoietin (EPO) receptor. Such effects are possibly doserelated and, to date, have been mild and appear not to be limiting usage. Not as well understood are some reports of hyperlipidemia (total cholesterol, LDL cholesterol and HDL cholesterol) similar to that seen with the interleukin (IL)-6 inhibitor, tocilizumab.3 This mechanism is still under investigation.
Figure 1: JAK inhibitors uncouple cytokine receptor signaling from downstream STAT transcription activation and thereby modulate immune response
STAT = signal transducers and activators of transcription; P = phosphate
One of the first JAK inhibitors used in humans was tofacitinib (formerly called tasocitinib), a potent inhibitor of JAK3, which was also found to have activity against JAK1 and to a lesser extent JAK2.1,3 It has been reported to be a safe and effective therapy for ulcerative colitis4 and rheumatoid arthritis, both with and without concomitant methotrexate therapy.5,6 Tofacitinib has been approved for use in rheumatoid arthritis in the US. For psoriasis, the initial Phase 1 trial was a randomized, doubleblind, placebo-controlled, dose-escalation study examining 5 mg, 10 mg, 20 mg, 30 mg, and 50 mg twice daily (BID) and 60 mg once daily (OD) for 14 days in 59 patients.7 Boy et al. (2009) found a significant dose-dependent decrease in erythema, induration and scaling using the Psoriatic Lesion Severity Sum (PLSS) from baseline to day 14 in all doses except 5 mg BID.7 Results of skin biopsies showed marked histological improvement at the higher dose of 30 mg BID with decrease in lesional thickness and K16 expression (a keratinocyte growth activation marker) to normal or near normal.7 In this initial study, adverse effects noted were an increase in total cholesterol, LDL cholesterol and triglyceride compared to placebo.
Papp et al. (2012) published results of the Phase 2b dose-ranging study in psoriasis.8 One hundred and ninety-seven patients with severe psoriasis were randomized to receive tofacitinib 2 mg, 5 mg, 15 mg or placebo BID and a clear dose-response was observed. A significant Psoriasis Area and Severity Index (PASI) 75 response was seen as early as week 4 and lasted through week 12. They reported a PASI 75 of 25% (2 mg, p<0.001), 40.8% (5 mg, p<0.0001) and 66.7% (15 mg, p<0.0001) in treated patients vs. 2% of patients in the placebo group.8 Patients treated with tofacitinib also demonstrated a significant and rapid improvement in pruritus compared to those receiving placebo.9
The most common adverse effect reported was infection and some dose-related changes in laboratory parameters were also observed. Mild reductions in hemoglobin and mean absolute neutrophil counts were noted starting at week 2 and were most pronounced in the 15 mg BID group; elevations in total cholesterol, HDL cholesterol and LDL cholesterol were also reported in a dose-related fashion similar to Phase 1 data.8 Currently, Phase 3 studies are evaluating the safety and efficacy of 5 mg and 10 mg BID dosing; as well, one comparator study is being conducted with etanercept.
As of October 2013, Pfizer announced that two of the five psoriasis Phase 3 studies have reported beneficial results as expected from Phase 2 data.10 The 12-week non-inferiority study comparing tofacitinib with high-dose etanercept and the 56-week retreatment investigation both met primary safety and efficacy endpoints, and further information should be published in the coming months.
A newer JAK inhibitor under investigation is baricitinib (Eli Lilly), which preferentially inhibits JAK2 over JAK1 and JAK3. Not much has yet been published on this molecule and it has just recently completed Phase 2 trials. The Phase 2b study was a randomized, double-blind, dose-escalation study evaluating 2 mg, 4 mg, 8 mg, and 10 mg BID vs. placebo (ClinicalTrials.gov, identifier NCT01490632). Phase 1 and 2 data have not yet been published.
ASP015K (Janssen, previously Astellas) is another oral JAK inhibitor that has shown selectivity of JAK1/JAK3 over JAK2 in cell-based assays. A Phase 2a randomized, placebo-controlled, sequential dose-escalation study of 10 mg, 25 mg, 60 mg, 100 mg BID or 50 mg OD was carried out over 6 weeks in patients with moderate to severe psoriasis. ASP015K demonstrated efficacy with dose-dependent reductions in body surface area (BSA) and mean PASI and Psoriasis Static Global Assessment (PSGA), and was generally well-tolerated.11 Janssen acquired ASP015K in October 2012, and there are no current plans to develop this drug in a psoriasis platform.
Topical JAK Inhibitors
In contrast to other biologics, due to their small size, these agents have also been demonstrated to be of benefit when applied topically. Topical tofacitinib has been studied (ClinicalTrials.gov, identifier NCT00678561) on 81 patients with OD or BID application of 0.02%, 0.2% and 2% ointment compared to vehicle for 28 days, although results are not yet published. A Phase 2b trial of topical tofacitinib comparing two dose strengths and two dose regimens is currently underway (ClinicalTrials.gov, identifier NCT01831466).
Ruxolitinib, the first US FDA-approved selective JAK1/JAK2 drug used orally for myelofibrosis,3 has also been investigated in its topical form (INCB018424, Incyte) for use in psoriasis. A Phase 2a trial comparing topical INCB018424 0.5%, 1% and 1.5% cream in a double-blind, vehicle-controlled fashion was shown to be safe and effective with improvement in total lesion score, PGA and PASI.12,13 This study compared topical INCB018424 with currently approved topical therapies, calcipotriene 0.005% cream and betamethasone diproprionate 0.05% cream13 (ClinicalTrials.gov, identifier NCT00820950).
Phosphodiesterase 4 (PDE4) Inhibitors
Cyclic adenosine monophosphate (cAMP) is the principal secondary messenger responsible for immune response regulation. PDE4 is the main cAMP degrading enzyme found in cells of the immune system and keratinocytes. Inhibitors of PDE4 can prolong or enhance effects of cAMP, resulting in suppression of both Th1 and Th2 immune responses (Figure 2).14 Due to these immune modulating effects, PDE4 inhibitors are currently under investigation for a variety of conditions including asthma, chronic obstructive pulmonary disease, atopic dermatitis, psoriasis, and psoriatic arthritis.14,15
Figure 2: Action of PDE4 inhibitors can prolong or enhance effects of cAMP and result in suppression of both Th1 and Th2 immune responses
G-protein coupled receptor = integral membrane proteins that respond to extracellular stimuli in a cAMP dependent fashion; AC = adenylate cyclase; PKA = protein kinase A
The PDE4 inhibitor, apremilast (CC-10004, Celgene Corporation), has been shown to inhibit production of the pro-inflammatory cytokines, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-12 and IL-23, which are major players in the pathogenesis of psoriasis. Apremilast was shown to have a range of anti-inflammatory effects on a variety of cell lines in vitro and reduce the psoriasiform response in a preclinical model of psoriasis in vivo,15 as well as demonstrate biologic activity in a pilot study in humans16.
A Phase 2, randomized, placebo-controlled trial demonstrated efficacy of apremilast 20 mg BID for 12 weeks in 259 patients.17 Apremilast at 20 mg BID achieved PASI 75 in 24.4% of patients compared to only 10.3% of patients in a placebo group. A doseresponsewas observed with a mean percent reduction in PASI from baseline of 17.4% for placebo, 30.3% for apremilast 20 mg OD, and 52.1% for apremilast 20 mg BID.17 Papp et al. (2012) reported results from the Phase 2b double-blind, randomized, placebocontrolled crossover trial in 352 patients, which compared apremilast 10 mg, 20 mg, 30 mg or placebo BID for 16 weeks, at which point patients receiving placebo were then randomized to 20 mg or 30 mg BID for up to 24 weeks. The primary endpoint of PASI 75 at 16 weeks was 11% for 10 mg, 29% for 20 mg, and 41% for 30 mg BID vs. 6% of patients on placebo.18
Patients treated with apremilast also demonstrated significant improvement on patient-reported quality of life outcomes with particular benefit noted at the 30 mg BID dose.19 Reported adverse effects were mild to moderate and included headache, nausea, urinary tract infection and diarrhea, but no significant changes in laboratory values were observed in any of the trials.
Phase 3 studies investigating the long-term safety and efficacy of the 30 mg BID dose are currently ongoing. The preliminary findings from ESTEEM-1, a Phase 3 trial including 844 patients receiving oral apremilast 30 mg BID, reported a PASI 75 response of 33% at week 16 compared to the placebo response of 5.3%.20
Topical PDE4 Inhibitors
The development of oral PDE4 inhibitors has been limited in some instances by systemic side effects, which prompted development of topical therapeutic options. This led to discovery of a novel boron-containing topical PDE4 inhibitor, AN2728 (Anacor Pharmaceuticals Inc.).21 Phase 1 and 2 trials on AN2728 have already been completed for psoriasis and Phase 2 trials are ongoing for use in atopic dermatitis. AN2728 was found to be both efficacious and well-tolerated in psoriasis.22 In a previously reported Phase 2b randomized, double-blind, vehicle-controlled 12-week bilateral comparison study on 145 adults who acted as their own controls, subjects were randomized to 2% or 0.5% ointment vs. vehicle ointment OD or BID. In patients with mild to moderate plaque psoriasis, AN2728 2% ointment BID provided most benefit and was well-tolerated with no safety concerns.23 Phase 3 trials in psoriasis have received clearance by the FDA, but have not yet been registered as Anacor is currently focusing the development of AN2728 in atopic dermatitis (http://www.anacor.com/an2728.php accessed October 7, 2013).
Sphingosine 1-Phosphate Receptor Agonists
Sphingosine 1-phosphate (S1P) is a sphingolipid required by lymphocytes to exit the lymphoid tissue and enter the bloodstream via a chemotactic gradient.24 Agonists of the S1P receptor cause a blockade of lymphocyte migration out of the lymph tissue through internalization of the receptor, resulting in a sequestration of lymphocytes. Recent development of S1P agonists involve utilizing these agents in the treatment of lymphocyte-mediated autoimmune conditions such as multiple sclerosis. Most recently, a drug from this class, fingolimod, was approved for the treatment of multiple sclerosis.25
The S1P1 agonist, ponesimod, has been studied in psoriasis vulgaris in a Phase 2, randomized, placebo-controlled trial (ClinicalTrials.gov, identifier NCT01208090) involving 326 patients who were randomized to receive ponesimod 20 mg, 40 mg or placebo for a 16-week induction period, followed by rerandomization to a 12-week maintenance period.26 At 16 weeks, 46% of the 20 mg group and 48.1% of the 40 mg group reached the primary endpoint of PASI 75 compared to 13% of patients receiving placebo. At week 28, the end of the maintenance period, the PASI 75 score further improved to 71% and 77% for the 20 mg and 40 mg groups, respectively, compared to 42% and 40% of patients who were re-randomized from ponesimod to placebo.26 Safety analysis revealed an expected decrease in lymphocyte counts, which returned to baseline values 2 weeks after discontinuation of therapy and was not associated with an increased risk of infection. Other notable effects include dyspnea, transaminitis, nasopharyngitis, headache and dizziness.26
Fumaric Acid Esters
Fumaric acid esters (FAEs) are a group of small molecules that have been used for many years in Germany to treat psoriasis. Initial use for psoriasis can be traced to 1959 by the German biochemist Schweckendiek who himself suffered from psoriasis. More recently, FAEs have gained attention as an immunomodulatory therapy for multiple sclerosis.27 Since 1994, FAEs have been available as a mix of dimethyl fumarate (DMF) and three salts of ethylhydrogenfumarate under the trade name Fumaderm® (Fumapharm/Biogen Idec) and widely used in some European countries.27,28 The mechanism of action is not completely understood, but one theory suggests that FAEs increase glutathione level in the cell, resulting in inhibition of nuclear factor-kappa B (NFκB) translocation into the nucleus and, thereby, a reduction of inflammatory cytokine production.27 Other immunologic effects are discussed in more detail elsewhere.28 The use of Fumaderm® has been limited by its gastrointestinal side effects in up to 30% of patients, thus, a newer formulation of DMF is being investigated.
Dimethyl Fumarate (FP187)
FP187 is a patented controlled-release erosion matrix tablet of DMF produced by Forward-Pharma GmbH. A pivotal Phase 2 study has been completed (ClinicalTrials.gov, identifier NCT01230138) which examined the safety and efficacy of different doses of FP187, but the results have not yet been reported. A Phase 3 study is registered to compare 500 mg of FP187 (250 mg BID) to the commercially available Fumaderm® at a dose of 720 mg (240 mg three times daily) over 20 weeks (ClinicalTrials.gov, NCT01815723) and is likely to start in the fourth quarter of 2013.
Psoriasis vulgaris is a chronic condition in which effective and safe therapies are needed for long-term use. To date, there have been promising results with small molecules for psoriasis including JAK inhibitors, PDE4 inhibitors, an S1P agonist, and DMF. The advantages of the small molecules are that they are amenable to both oral and topical use, do not require subcutaneous or parental administration, and avoid risk for immunogenicity. The mechanism of action of JAK inhibitors, PDE4 inhibitors and DMF provide downstream inhibition of the inflammatory cascade, resulting in blockade of multiple cytokines, which target cell types that are key players in psoriasis. The S1P agonists result in immunomodulation via sequestration of lymphocytes in lymphoid tissue. Time will tell whether any further new therapeutic targets are developed, such as TYK2, the final Janus kinase in the JAK family involved in cytokine signaling, which has not yet been investigated for psoriasis. TYK2 also appears to be a promising target as it associates with the receptors for IL-12/23 and IL-6, the major players in psoriasis pathogenesis. Another oral molecule to look out for is apilimod (STA-5326) (Synta Pharmaceuticals), which blocks the IL-12/23 pathway and has been studied in Phase 2 trials. Further investigations of these small molecules are warranted for both safety and efficacy, but we look forward to the possibility of new therapies as treatment options for our patients in the future.
The author gratefully acknowledges the medical editorial support from Flora Krasnoshtein in reviewing this manuscript.
- Laurence A, Ghoreschi K, Hirahara K, et al. Therapeutic inhibition of the Janus kinases. Inflammation and Regeneration. 2012 Jan;32(1):16-22.
- Kwatra SG, Dabade TS, Gustafson CJ, et al. JAK inhibitors in psoriasis: a promising new treatment modality. J Drugs Dermatol. 2012 Aug;11(8):913-8.
- Kontzias A, Kotlyar A, Laurence A, et al. Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease. Curr Opin Pharmacol. 2012 Aug;12(4):464-70.
- Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012 Aug 16;367(7):616-24.
- Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6): 495-507.
- van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):508-19.
- Boy MG, Wang C, Wilkinson BE, et al. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol. 2009 Sep;129(9):2299-302.
- 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 Sep;167(3):668-77.
- Mamolo C, Bushmakin A, Harness J, et al. An evaluation of the effect of tasocitinib (CP-690,550), an oral janus kinase inhibitor, on pruritus with plaque psoriasis. J Am Acad Dermatol. 2011 Feb;64(2 Suppl 1):AB146. (Poster abstract P3304) Presented at: 60th Annual Meeting of American Academy of Dermatology. February 4-8, 2011. New Orleans, LA.
- Pfizer Inc. press release dated October 9, 2013: Pfizer announces top line results of the first two of five Phase 3 clinical trials of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. Available at: http://www.pfizer.com/news/press-release/press-releasedetail/pfizer_announces_top_line_results_of_the_first_two_of_five_phase_3_clinical_trials_of_tofacitinib_in_adults_with_moderate_to_severe_chronic_plaque_psoriasis. Accessed October 15, 2013.
- Papp K, Pariser D, Wierz G, et al. Phase IIa randomized, double-blind, placebocontrolled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel janus kinase (JAK) inhibitor, in patients with moderate to severe psoriasis. (Abstract ID 2492991) Presented at: 3rd World Psoriasis and Psoriatic Arthritis Conference. June 27-July 1, 2012. Stockholm, Sweden.
- Callis Duffin K, Luchi M, Fidelus-Gort R, et al. Novel mechanism for topical treatment of plaque psoriasis – results of a randomized, doubleblind, concentration ranging, vehicle controlled 12 week study with JAK 1/2 inhibitor INCB018424 cream. J Invest Dermatol. 2010;130Suppl. (Abstract 261) Presented at: Society for Investigative Dermatology 2010 Annual Meeting. May 8-10, 2010. Atlanta, GA
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- Bäumer W, Hoppmann J, Rundfeldt C, et al. Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis. Inflamm Allergy Drug Targets. 2007 Mar;6(1):17-26.
- Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010 Feb;159(4):842-55.
- Gottlieb AB, Strober B, Krueger JG, et al. An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral antiinflammatory agent, apremilast. Curr Med Res Opin. 2008 May;24(5):1529-38.
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- Nazarian R, Weinberg JM. AN-2728, a PDE4 inhibitor for the potential topical treatment of psoriasis and atopic dermatitis. Curr Opin Investig Drugs. 2009 Nov;10(11):1236-42.
- Zane LT, Toledo-Bahena M, Hughes MH, et al. Safety and efficacy of AN2728 ointment in a phase 2b dose-ranging, bilateral study of mild-to-moderate plaque psoriasis. (Poster 505) Presented at: 71st Annual Meeting of the Society for Investigative Dermatology, May 4-7, 2011 Phoenix, AZ.
- Piali L, Froidevaux S, Hess P, et al. The selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation. J Pharmacol Exp Ther. 2011 May;337(2):547-56.
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- Chimenti S, Arenberger P, Karpati S, et al. A phase II study of ponesimod, an oral, selective sphingosine 1-phosphate receptor-1 modulator in chronic plaque psoriasis. (Poster 050) J Eur Acad Dermatol Venereol 2013;27 (Suppl 4):22.
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In this issue:
- Small Molecules: An Overview of Emerging Therapeutic Options in the Treatment of Psoriasis
- Chronic Urticaria and Autoimmunity
- Update on Drugs and Drug News - November-December 2013