Clinical trial NCT03149900: Exploratory Evaluation of Biomarkers Associated With Treatment Response to Cosentyx (Secukinumab) in Psoriasis Patients
Official title: Exploratory Evaluation of Biomarkers Associated With Treatment Response to Cosentyx (Secukinumab) in Psoriasis Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Psoriasis Vulgaris
Lead sponsor: University of Luebeck
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2017-05-11
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study population will consist of 40 subjects (both male and female), aged 18 years and older, in whom treatment with Secukinumab is clinically indicated and according to the licensed product specifications. The study drug will be prescribed by a doctor who is independent of this study. Visit 1 will be carried out prior to the first injection of Secukinumab.

All patients will receive a number and the data will be recorded in a pseudo-anonymised form. No blinding is necessary for investigators or patients (open study), as all patients receive the same treatment (marketed product).

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in skin microbiome composition
timeFrame: from baseline to week 24
measure: Change in antimicrobial peptide composition
timeFrame: from baseline to week 24
measure: Change in gene expression
timeFrame: from baseline to week 24
Secondary outcomes:
Other outcomes:
Locations:
city: Lubeck
country: Germany
facility: University Clinic Schleswig-Holstein
state: Schleswig-Holstein
Study officials:
affiliation: University of Luebeck
name: Diamant Thaci, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
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