Exploratory Evaluation of Biomarkers Associated With Treatment Response to Cosentyx (Secukinumab) in Psoriasis Patients

Psoriasis Vulgaris Clinical Trial

— BIOMARKER  

Official title:

Exploratory Evaluation of Biomarkers Associated With Treatment Response to Cosentyx (Secukinumab) in Psoriasis Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03149900
• Other study ID #: CAIN457ADE02T
• Status: Completed
• Start date: October 2016
• Est. completion date: July 25, 2019

Study information

• Verified date: August 2019
• Source: University of Luebeck
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

To identify possible genetic associations of clinical response to anti-IL-17A (Secukinumab) treatment in psoriasis using a combined gene association study and gene expression analysis.

To investigate the influence of IL-17A on the cutaneous microbial flora and to analyse cutaneous antimicrobial peptide expression in the skin of patients with psoriasis prior to, and during, treatment with Secukinumab to determine the extent to which the microbial flora is associated with response to treatment, as determined by the PASI75, PASI90, PGA- and DLQI improvement.

Description:

Psoriasis vulgaris is a chronic inflammatory skin disease which is characterized by raised, well-demarcated, erythematous plaques and affects approximately 2% of the Caucasian population.

Patients suffering from moderate-to-severe psoriasis may be treated with a variety of systemic agents and treatment modalities, including retinoids, phototherapy and/or immunomodulatory drugs, including methotrexate, ciclosporin and fumarates. Patients are regularly monitored to determine the efficacy of treatment and to detect signs of systemic toxicity. Indeed, lack of efficacy and/or therapeutic toxicity are factors which require a re-evaluation of therapy. In addition to the conventional systemic treatments, systemic "biologic" therapies are playing an increasingly important role in the management of moderate to severe psoriasis.These treatments have resulted from advances in the understanding of the patho-physiology of psoriasis, combined with advances in molecular biology, in order to provide a more targeted therapy. Biologics include drugs targeting the production or signal transduction of tumour necrosis factor alpha (TNFα), and more recently, agents which target specific cytokines known to play an important role in the disease, including interleukin (IL) 12/23.

Despite these advances in psoriasis therapy, a relatively small number of patients initially fail to respond to biological psoriasis treatment or relapse during treatment. In fact, treatment with TNFα inhibitors and IL-12/23 monoclonal antibodies fails to induce disease control (PASI 75) in approximately 20-30% of the patients.

An alternative biological therapy, recently licensed for the management of moderate to severe psoriasis is Secukinumab (Cosentyx®). Secukinumab binds to human IL-17A and neutralizes the bioactivity of this cytokine. IL-17A is increasingly recognized as one of the principal pro-inflammatory cytokines in immune mediated inflammatory diseases, including psoriasis. A recombinant, high-affinity, fully human monoclonal anti-human IL-17A antibody of the IgG1/κ class, Secukinumab treatment has reportedly resulted in disease response rates of up to almost 80%, as measured by a 90% improvement in the Psoriasis Area and Severity Index measure (PASI). Moreover, treatment with Secukinumab was associated with superior improvements in quality of life indices (Dermatology Life Quality Index (DLQI) when compared to treatment with the IL12/23 inhibitor Ustekinumab. Given that treatment with biologics is reportedly associated with a loss of response over time, the development of novel classes of biologics, including those targeting IL-17, has been welcomed in terms of expanding the psoriasis treatment armamentarium.

Despite the clinical data supporting the use of Secukinumab in the management of moderate to severe psoriasis, there are currently no molecular tools to identify which patients are likely to respond to treatment. Identifying biomarker(s) of disease response would not only facilitate optimized and personalized treatment, but would also ensure that patients who are unlikely to respond are not exposed to the risks associated with biologic treatments, principally derived from long-term immunosuppression. In addition, given that psoriasis is often associated with several inflammatory diseases, including psoriatic arthritis and inflammatory bowel disease, such biomarkers may also serve a key role in predicting treatment response of those co-morbid conditions to biological therapy.

An interesting potential type of biomarker is the presence of single nucleotide polymorphisms (SNPs). Such polymorphisms are alterations in (i) genes which may be associated with genetic susceptibility to particular diseases or (ii) genes which are important in molecular pathways involved in disease and/or treatment response. Many respective genes in these pathways have been implicated by genome-wide association studies. For example, in terms of psoriasis, SNPs have been identified in cellular methotrexate efflux transporters which may influence both treatment response and the risk of methotrexate toxicity. On the other hand, variations in the genes important to the intracellular metabolism of methotrexate did not predict treatment response to methotrexate. Interestingly, variations in the IL17A and IL17A receptor gene are reportedly not associated with psoriatic arthritis susceptibility, although such variations remain to be systematically examined specifically in patients with psoriasis.

An additional potential type of biomarker is the cutaneous expression of anti-microbial peptides (AMPs). Initially identified in frog skin, AMP expression in human psoriatic skin, specifically human beta defensin 2, was identified almost two decades ago. Since then it has become clear that a range of AMPs are highly expressed in the involved skin of psoriatic patients compared to normal skin. These proteins serve a protective antimicrobial function in the skin, but at the same time they may also play an immunomodulatory role. Therefore, it is conceivable that they may influence the pathophysiology of psoriasis. Indeed, the AMP cathelicidin (LL37) was shown to modulate proinflammatory keratinocyte responses in vitro, leading the authors to speculate that LL37 "may promote IL17/IL22 and IL6 associated psoriasis.". Thus, it is at least possible that treatment with IL17-targetting biologics not only influences the cutaneous expression of AMPs, but also alters the cutaneous inflammatory milieu, which may in result in profound changes in the cutaneous bacterial flora which the skin supports.

To this end, a third promising type of biomarker is the presence and composition of the cutaneous bacterial flora; the skin microbiome. The term "cutaneous microbiome" describes the microbiological flora which colonizes human skin. There is evidence that the flora may be regulated in a time-, sex-, and medication-dependent manner. Indeed, describing and understanding the cutaneous microbiome is now the focus of intense research efforts to determine the role it may play in several skin diseases, including atopic dermatitis and bullous diseases.

Whilst several studies have suggested shifts in the microbiological composition in associated with psoriasis, relatively few studies have addressed longitudinal changes in the microbiome under therapy. Indeed, at present there are no studies which have specifically sought to identify changes in the cutaneous microbiome under IL17 targeted therapy. Given the importance of IL17 in the pathophysiology of psoriasis, this important gap in our knowledge needs to be urgently addressed.

Therefore, in summary, this study aims to identify and describe the presence of genetic variations governing susceptibility to psoriasis and response to treatment with secukinumab. This genetic data will be complemented by functional data determining gene expression before and during treatment and correlated with the expression of AMPs and the composition of the cutaneous microbiome. Using both genetic and phenotypic data we aim to identify novel biomarkers which can be rigorously tested and validated in subsequent studies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: July 25, 2019
• Est. primary completion date: July 25, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subjects must be able to understand and communicate with the investigator and comply with the requirements of the study and must give written, signed and dated informed consent before any study related activity is performed.

2. Chronic moderate to severe plaque type psoriasis for at least 6 months prior to baseline with a PASI score = 10 and BSA = 10 as per German guidelines.

3. Subjects must be at least 18 years of age at time of enrollment

4. Patients starting treatment with Secukinumab and for whom the clinical decision has been made prior to participation in the study.

5. Initiation of Secukinumab therapy, in patients who are not biologic naïve will be carried out according to a published consensus paper (Mrowietz et al. 2014)

Exclusion Criteria:

1. Exclusion criteria will comply with the licensed product specifications for Cosentyx (Secukinumab)

2. Patients incapable of giving full informed consent.

3. Forms of psoriasis other than chronic plaque-type at enrollment

4. Oral or topical antibiotic therapy within the month prior to enrollment

5. Phototherapy (UVB/PUVA) within the month prior to enrollment

6. Allergy to local anaesthetic or latex

7. Pregnancy/Lactation

Related Conditions & MeSH terms

• Psoriasis
• Psoriasis Vulgaris

Intervention

Drug:
• Secukinumab
See Arm Description

Locations

Country	Name	City	State
Germany	University Clinic Schleswig-Holstein	Lubeck	Schleswig-Holstein

Sponsors (2)

Lead Sponsor	Collaborator
Diamant Thaci	Novartis

Country where clinical trial is conducted

Germany, 

References & Publications (21)

Alekseyenko AV, Perez-Perez GI, De Souza A, Strober B, Gao Z, Bihan M, Li K, Methé BA, Blaser MJ. Community differentiation of the cutaneous microbiota in psoriasis. Microbiome. 2013 Dec 23;1(1):31. doi: 10.1186/2049-2618-1-31. — View Citation

Batycka-Baran A, Maj J, Wolf R, Szepietowski JC. The new insight into the role of antimicrobial proteins-alarmins in the immunopathogenesis of psoriasis. J Immunol Res. 2014;2014:628289. doi: 10.1155/2014/628289. Epub 2014 May 8. Review. — View Citation

Catanoso MG, Boiardi L, Macchioni P, Garagnani P, Sazzini M, De Fanti S, Farnetti E, Casali B, Chiarolanza I, Nicoli D, Luiselli D, Salvarani C. IL-23A, IL-23R, IL-17A and IL-17R polymorphisms in different psoriatic arthritis clinical manifestations in the northern Italian population. Rheumatol Int. 2013 May;33(5):1165-76. doi: 10.1007/s00296-012-2501-6. Epub 2012 Sep 7. — View Citation

Chen X, Takai T, Xie Y, Niyonsaba F, Okumura K, Ogawa H. Human antimicrobial peptide LL-37 modulates proinflammatory responses induced by cytokine milieus and double-stranded RNA in human keratinocytes. Biochem Biophys Res Commun. 2013 Apr 19;433(4):532-7. doi: 10.1016/j.bbrc.2013.03.024. Epub 2013 Mar 20. — View Citation

Chen YE, Tsao H. The skin microbiome: current perspectives and future challenges. J Am Acad Dermatol. 2013 Jul;69(1):143-55. doi: 10.1016/j.jaad.2013.01.016. Epub 2013 Mar 13. Review. — View Citation

Gläser R, Harder J, Lange H, Bartels J, Christophers E, Schröder JM. Antimicrobial psoriasin (S100A7) protects human skin from Escherichia coli infection. Nat Immunol. 2005 Jan;6(1):57-64. Epub 2004 Nov 28. — View Citation

Gupta Y, Möller S, Zillikens D, Boehncke WH, Ibrahim SM, Ludwig RJ. Genetic control of psoriasis is relatively distinct from that of metabolic syndrome and coronary artery disease. Exp Dermatol. 2013 Aug;22(8):552-3. doi: 10.1111/exd.12192. — View Citation

Harder J, Bartels J, Christophers E, Schröder JM. A peptide antibiotic from human skin. Nature. 1997 Jun 26;387(6636):861. — View Citation

Johnson-Huang LM, Lowes MA, Krueger JG. Putting together the psoriasis puzzle: an update on developing targeted therapies. Dis Model Mech. 2012 Jul;5(4):423-33. doi: 10.1242/dmm.009092. Review. — View Citation

Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C; ERASURE Study Group; FIXTURE Study Group. Secukinumab in plaque psoriasis--results of two phase 3 trials. N Engl J Med. 2014 Jul 24;371(4):326-38. doi: 10.1056/NEJMoa1314258. Epub 2014 Jul 9. — View Citation

Mrowietz U, de Jong EM, Kragballe K, Langley R, Nast A, Puig L, Reich K, Schmitt J, Warren RB. A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis. J Eur Acad Dermatol Venereol. 2014 Apr;28(4):438-53. doi: 10.1111/jdv.12118. Epub 2013 Feb 26. — View Citation

Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR; Collaborative Association Study of Psoriasis. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet. 2009 Feb;41(2):199-204. doi: 10.1038/ng.311. Epub 2009 Jan 25. — View Citation

Rich P, Sigurgeirsson B, Thaci D, Ortonne JP, Paul C, Schopf RE, Morita A, Roseau K, Harfst E, Guettner A, Machacek M, Papavassilis C. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol. 2013 Feb;168(2):402-11. doi: 10.1111/bjd.12112. — View Citation

Rothstein B, Gottlieb A. Secukinumab for treating plaque psoriasis. Expert Opin Biol Ther. 2016;16(1):119-28. doi: 10.1517/14712598.2016.1121986. Epub 2015 Dec 14. Review. — View Citation

Schön MP, Boehncke WH. Psoriasis. N Engl J Med. 2005 May 5;352(18):1899-912. Review. — View Citation

Srinivas G, Möller S, Wang J, Künzel S, Zillikens D, Baines JF, Ibrahim SM. Genome-wide mapping of gene-microbiota interactions in susceptibility to autoimmune skin blistering. Nat Commun. 2013;4:2462. doi: 10.1038/ncomms3462. — View Citation

Statnikov A, Alekseyenko AV, Li Z, Henaff M, Perez-Perez GI, Blaser MJ, Aliferis CF. Microbiomic signatures of psoriasis: feasibility and methodology comparison. Sci Rep. 2013;3:2620. doi: 10.1038/srep02620. — View Citation

Thaçi D, Blauvelt A, Reich K, Tsai TF, Vanaclocha F, Kingo K, Ziv M, Pinter A, Hugot S, You R, Milutinovic M. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015 Sep;73(3):400-9. doi: 10.1016/j.jaad.2015.05.013. Epub 2015 Jun 17. — View Citation

Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, Ding J, Li Y, Tejasvi T, Gudjonsson JE, Kang HM, Allen MH, McManus R, Novelli G, Samuelsson L, Schalkwijk J, Ståhle M, Burden AD, Smith CH, Cork MJ, Estivill X, Bowcock AM, Krueger GG, Weger W, Worthington J, Tazi-Ahnini R, Nestle FO, Hayday A, Hoffmann P, Winkelmann J, Wijmenga C, Langford C, Edkins S, Andrews R, Blackburn H, Strange A, Band G, Pearson RD, Vukcevic D, Spencer CC, Deloukas P, Mrowietz U, Schreiber S, Weidinger S, Koks S, Kingo K, Esko T, Metspalu A, Lim HW, Voorhees JJ, Weichenthal M, Wichmann HE, Chandran V, Rosen CF, Rahman P, Gladman DD, Griffiths CE, Reis A, Kere J; Collaborative Association Study of Psoriasis (CASP); Genetic Analysis of Psoriasis Consortium; Psoriasis Association Genetics Extension; Wellcome Trust Case Control Consortium 2, Nair RP, Franke A, Barker JN, Abecasis GR, Elder JT, Trembath RC. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012 Dec;44(12):1341-8. doi: 10.1038/ng.2467. Epub 2012 Nov 11. — View Citation

Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN, Worthington J, Griffiths CE. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol. 2008 Aug;128(8):1925-9. doi: 10.1038/jid.2008.16. Epub 2008 Feb 7. — View Citation

Warren RB, Smith RL, Campalani E, Eyre S, Smith CH, Barker JN, Worthington J, Griffiths CE. Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. Br J Dermatol. 2009 Feb;160(2):438-41. doi: 10.1111/j.1365-2133.2008.08898.x. Epub 2008 Oct 25. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in skin microbiome composition	Investigation of skin microbiome composition associated with treatment response in psoriasis patients treated with Secukinumab	from baseline to week 24
Primary	Change in antimicrobial peptide composition	Investigation of antimicrobial peptide composition associated with treatment response in psoriasis patients treated with Secukinumab	from baseline to week 24
Primary	Change in gene expression	Investigation of gene expression in RNA and DNA associated with treatment response in psoriasis patients treated with Secukinumab	from baseline to week 24