Emerging Therapies in the Evolving Biologic Platform for Psoriasis Treatment
In the last decade, biologic therapy has emerged as a critical treatment modality for moderate to severe psoriasis. During that time, long-term studies for have confirmed the safety profiles for TNF inhibitors such as such as etanercept (Enbrel, Amgen) and adalimumab (Humira, AbbVie). More recently, discoveries involving various interleukin (IL) pathways have led to the development of several new agents, notably the IL-12/23 inhibitor ustekinumab (Stelara, Janssen). This has led to a flurry of new activity in the biologic pipeline for psoriasis treatment. Ahead, I will examine the latest advances in the growing treatment armamentarium and offer a glimpse of what the psoriasis treatment arena may look like in coming years.
SMALL IMMUNOSUPPRESSANT MOLECULES
Already FDA-approved for psoriatic arthritis, the oral agent apremilast (Otezla, Celgene) is an inhibitor of phosphodiesterase. This results in an increase in intracellular cyclic adenosine monophosphate (cAMP), which is known to decrease the amount of pro-inflammatory molecules that are produced. By increasing cAMP, apremilast decreases TNF IL-17 in dendritic cells, neutrophils, T-cells, macrophages. In one study, 33 percent of patients receiving apremilast 30mg BID achieved PASI 75 after 16 weeks of treatment, while 54 percent of patients achieved PASI 50.1 Over 28 weeks, patients receiving apremilast saw a 60 percent improvement in PASI, which was maintained through 52 weeks. Thus, although short-term efficacy data for apremilast is moderate, long-term data is potentially significant.
In addition, apremilast is remarkably safe. The most notable side effects are early disturbing flatulence and loose stools, which can be minimized by decreasing early dosage. Moreover, abnormal labs in clinical trials were so negligible compared to placebo that no lab monitoring is necessary in the treatment of psoriatic arthritis, not even PPDs.2
Therapies in the Pipeline. The next two oral small molecules— baricitinib and tofacitnib—act via Janus Kinase (JAK) inhibition. JAK, when activated, results in phosphorylation of STAT (Signal Transducer and Activator of Transcription). This results in the protein synthesis of pro-inflammatory molecules such as IL-22, IL-23, IL12, and IL-6. These two molecules block JAK from phosphorylating STAT, hence decreasing the production of these two interleukins.
In one study, 50 percent of patients treated with the investigational agent baricitinib 10mg BID achieved PASI 75 by week 12 and maintained these results through 24 weeks. Moreover, 35 percent of patients achieved PASI 90.3
Tofacitinib has also shown promise in early trials. In one study, 63 percent of patients achieved PASI 75 at 12 weeks, compared to 58 percent of patients receiving etanercept.4 However, several serious infections were reported, and since STAT is involved in heamatopoiesis, patients will probably need their white blood cell counts and hemoglobins monitored.
IL-23
With the 2009 approval of the anti-IL12/23 agent ustekinumab, a new pathway in treating psoriasis treatment was opened. In the last five years, researchers and physicians have learned much about the role of interleukin pathways in the systemic inflammation of psoriasis. Specifically, we have learned that IL-23 induces the proliferation of Th-17 cells, the upshot of which is the release of IL-17 and IL-22, which both are more specifically involved in the hyperproliferation of the epidermis than other interleukins or chemokines. The discovery of Th17 cells that were different from Th1 or Th2 cells led to the shift in thought away from Th1-induced TNF as the driving force in psoriasis. Th17 cells produce IL-17 and IL-22, which are both involved in the stimulation of keratinocyte proliferation, an excess of which results in the abnormal epidermis seen in psoriasis.5
There is an increased expression of IL-23 as noted by an excess of p19 subunit in the lesional skin of psoriatic plaques but not that of the p35 subunit.6 One part of the initial trigger is keratinocyte-mediated expression of IL-1B, IL-6, and TNF alpha, resulting in activation of antigen-presenting cells that in turn produce IL-23 and proliferation of Th-17 cells via the activation of the innate immune system through dendritic cell activation.
As we have learned more about IL-23, we have also refined our knowledge of TNF and its role in psoriatic disease. TNF is more broadly active at multiple points in the inflammatory cascade. Macrophages, mast cells, keratinocytes, and lymphocytes produce TNF, which is involved in the recruitment of T-cells from lymph nodes and helps halt their proliferation. TNF Il-17A and INF gamma also stimulate keratinocytes to produce antimicrobial peptides and chemokines. Moreover, genetic analyses have linked IL-23 and IL-17 to psoriasis susceptibility.7
Therapies in the Pipeline. Two monoclonal antibodies to IL-23 are currently in development. The first is guselkumab (Janssen), which in Phase II trials has shown to be comparable to ustekinumab in head to head studies. Recent data presented at the American Academy of Dermatology meeting in Denver, CO, found that 85 percent of patients receiving guselkumab 100mg every eight weeks achieved a PGA score of 0 or 1 by 16 weeks, with 78 percent of patients also achieving PASI 75. Moreover, at the 40-week mark, nearly 90 percent of patients in the 100mg group achieved PASI 75.8 However, early safety markers did show some major adverse cardiac events.
The other IL-23 agent under investigation is tildrakizumab, also known as MK-322 (Merck), which is currently in Phase III trials, the results of which are expected in 2015. In preliminary findings, 75 percent of patients receiving tildrakizumab achieved PASI 75 at 12 weeks.9
IL-17 AND IL-22
More recently, researchers have learned of the importance of the IL-17 cytokine family, which has six subtypes—IL-17A through IL-17F.10 There are numerous IL-17 receptors expressed in the skin, lungs, kidneys, liver, and spleen. IL-17 is involved in acute inflammation and has been shown to be important in the host defense against extracellular pathogens, i.e. Staph and Candida, whereas Thl (TNF and IFN) are involved in host defense against intra-cellular pathogens, i.e. tuberculosis (TB) and salmonella. IL-17 released from Th17 cells or innate immune cells acts on keratinocytes to cause hyperproliferation and the release of antimicrobial peptides attract neutrophils, which produce more IL-17.11
IL-22 produced from Th17 cells also contributes to keratinocyte hyperproliferation and expression of antimicrobial peptides acting synergistically with IL-17A. Therefore we have developed the notion that IL-17 is one of the key drivers in the pathogenesis in psoriasis.
Therapies in the Pipeline. Three new agents are in development to interfere with IL-17.
Brodalumab (Amgen) is a monoclonal antibody against the IL-17 RA receptor and 5/6 IL-17 receptors. In one study, PASI 75, 90, 100 responses at week 12 were 83, 75, and 63, respectively (210mg QO week).12 Another study found showed that patient reported symptoms were decreased significant after 12 weeks of treatment.13 Maintenance of response was essentially maintained through 48 weeks. Brodalumab has shown benefit in treating psoriatic arthritis, with one study showing patients achieving ACR 20 of 64 at 24 weeks, and an ACR 50 of 43, which may be even better than previous TNF data.14 In terms of adverse events, two cases of asymptomatic neutropenia were observed that came back to normal after discontinuation of the drug. Early data indicating that brodalumab clears almost two-thirds of all patients with severe psoriasis within 12 weeks is a previously unseen and potential breakthrough in efficacy.
Secukinumab is the first of the IL-17 antibodies to complete phase III clinical trials.The ERASURE study showed a PASI 75 of 81.6 percent, 71.6 percent, and 4.5 percent for secukinumab 300mg,150mg, and placebo, respectively, at 12 weeks.15
The FIXTURE study evaluating secukinumab 300mg, 150mg, etanercept 50mg 2x/week, and placebo, showed a PASI 75 at week 12 of 77.1 percent, 67 percent, 44 percent, and 4.9 percent respectively.16 This study also demonstratedrapidly improved physical functioning and sustained responses in patients with PsA through week 52.17
The SCULPTURE trial evaluated patients who on either secukinumab 150mg or 300mg achieved a PASI 75 at week 12 and were then re-randomized to receive monthly injections at the same dose every 4 weeks or prn treatment (when there was a ≥ 20 percent loss of maximum improvement and a loss of PASI 75 response). The percentage of patients maintaining PASI 75 trough week 52 monthly 300 mg secukinumab, 150mg vs 300mg, 150mg prn was 78.2 percent, 62.1 percent and 67.7 percent, 52.4 percent respectively.18
In regards to safety, analysis of a sub-set of pooled safety data from 10 clinical studies of psoriasis patients with a prior history of IBD treated with secukinumab revealed no exacerbation in the placebo or in the etanercept groups, and 3 in the secukinumab group. However, the overall exposure-adjusted incidence rates of IBD were similar between secukinumab (0.33) and etanercept (0.34) and 0 for placebo. The authors conclusions were that these data were not indicating a relationship between treatment with secukinumab and IBD; however, more data is required.
Safety data in sub-group analyses of ERASURE study showed 4 cases of candidiasis in non previously biologically treated subjects, 2 cases of oral candidiasis, 1 case of esophageal candidiasis in the 300 mg group and 1 case of vulvovaginal candidiasis in the placebo group.19
In view of the fact that neutrophils produce IL-17, an inhibition of IL-17 could result in neutropenia. In the same pooled analysis of 10 psoriasis clinical trials, grade 1 and 2 abnormalities occurred in 6.5% and 1.5% of the cases treated with secukinumab compared to 9.4% and 3.2% in cases treated with etanercept and 2.3% and 0.3% in placebo, respectively. No dose effect of secukinumab was evident with regard to overall neutropenia.20
AN EVOLVING TREATMENT PLATFORM
From the development of several small systemic molecules to the continued focus on IL pathways, the psoriasis pipeline is brimming with potential. Although the small molecules such as apremilast, tofacitinib, and baricitinib do not appear to offer the efficacy of larger biologic molecules, they may eventually fill therapeutic niche between those of baseline topical intervention and more complex biologic therapies. Moreover, the new IL agents under investigation show even greater potential from an efficacy perspective, with more patients in clinical trials achieving PASI 100 and PASI 90 than we have seen on any previous biologic agents. While the efficacy data on these agents is quite promising, much work remains on the safety front to ensure that the adverse event profiles of these agents are favorable.
There is little doubt that the growing number of agents under investigation is a reflection of our increasing knowledge regarding the systemic nature of psoriasis. As we learn more about the IL pathways, it is highly likely that we will see a continued evolution in the understanding and application of systemic immunosuppressant and biologic therapies.
Dr. Bagel has served as consultant, researcher, or speaker for Amgen, AbbVie, Janssen, Eli-Lilly, Novartis, Celgene, and Pfizer.
Jerry Bagel, MD, FAAD, is director of the Psoriasis Treatment Center of Central New Jersey.
- 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 Derm. 2013;12(8):888-897.
- Papp K, Cather JC, Rosoph L, et al. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet 2012;380(9843):738-741.
- Poster Presentation. AAD Annual Meeting 2014.
- Menter A, Papp KA, Tan H, Tyring S, Wolk R, Buonanno M. Efficacy of tofacitinib, an oral janus kinase inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions. J Drugs Derm. 2014;13(3):252-256.
- Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199(1):125-130.
- Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496-509.
- Martin DA, Towne JE, Kricorian G, et al. The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings. J Invest Dermatol. 2013;133(1):17-26.
- Sofen H, Smith S, Matheson RT, et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy Clin Immun. 2014;133(4):1032-1040.
- Tausend W, Downing C, Tyring S. Systematic Review of Interleukin-12, Interleukin-17, and Interleukin-23 Pathway Inhibitors for the Treatment of Moderate-to-Severe Chronic Plaque Psoriasis: Ustekinumab, Briakinumab, Tildrakizumab, Guselkumab, Secukinumab, Ixekizumab, and Brodalumab. J Cut Med Surg. 2014;18:1-14.
- Elloso MM, Gomez-Angelats M, Fourie AM. Targeting the Th17 pathway in psoriasis. J Leukoc Biol. 2012;92(8):556-567.
- Girolomoni G, Mrowietz U, Paul C. Psoriasis: rationale for targeting interleukin-17. Br J Dermatol. 2012;167(4):717-724.
- Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181-1189.
- Gordon KB, Kimball AB, Chau D, et al. Impact of brodalumab treatment on psoriasis symptoms and health-related quality of life: use of a novel patient-reported outcome measure, the Psoriasis Symptom Inventory. Br J Dermatol. 2014;170(3):705-715.
- . Spuls PI, Hooft L. Brodalumab and ixekizumab, anti-interleukin-17-receptor antibodies for psoriasis: a critical appraisal. Br J Dermatol. 2012;167(4):710-715
- Elewski B, Lebwohl M, Papp K, et al. Secukinumab in Patients with Moderate-to-Severe Plaque Psoriasis: Results from the Efficacy of Response And Safety of 2 fixed Secukinumab Regimens in Psoriasis (ERASURE), a Pivotal Phase 3 Study [poster]. Presented at Maui Derm on January 26-30, 2014 in Maui, Hawaii.
- Langley R, Reich K, Griffiths C, et al. Secukinumab compared with placebo and etanercept: A head-to-head comparison of two biologics in a phase 3 study of moderate-to-severe plaque psoriasis (FIXTURE). Poster presented at the 22nd European Academy of Dermatology and Venereology Congress; October 2-6, 2013; Istanbul, Turkey.
- Philipp S, Fretzin S, Notter M, et al. Secukinumab effect on functional ability in subjects with moderate-to-severe plaque psoriasis and concomitant psoriatic arthritis: A subanalysis of the FIXTURE study [poster]. Presented at: 72nd Annual Meeting of the American Academy of Dermatology (AAD); March 21-25, 2014; Denver, Colorado, USA. ePoster 8098.
- Mrowietz U, Leonardi C, Girolomoni G, et al. Secukinumab `Fixed-Interval vs. `Retreatment-as-Needed Regimen for Moderate-to-Severe Plaque Psoriasis: A Study Comparing Secukinumab Use in Long-Term Psoriasis Maintenance Therapy (SCULPTURE). Poster presented at: 22nd Congress of the European Academy of Dermatology and Venereology; October 2-6 2013; Istanbul, Turkey.
- Ward N, Sands B, Guettner A, Cooper S. Secukinumab safety and tolerability in subjects with moderate-to-severe plaque psoriasis: A pooled subgroup analysis of 10 clinical studies evaluating
- Griffiths et al Behavior of Neutrophil Count During 52 Weeks of Treatment with secukinumab P8266 AAD Denver 3/18-24.2014
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