Topical application of a novel anti-interleukin-17A antibody fragment penetrates psoriatic skin: Results of a randomised, double-blind, placebo-controlled Phase Ib study.

Interleukin (IL)-17A underlies the pathogenesis of chronic plaque psoriasis (CPP). Well-tolerated, effective IL-17A inhibitors for mild-to-moderate CPP are needed. ZL-1102 is a novel antibody fragment targeting IL-17A. To assess the safety, tolerability, preliminary efficacy and skin penetration of a topical 1% ZL-1102 hydrogel in patients with mild-to-moderate CPP, a two-part, Phase Ib study was conducted. Open-label Part A: six patients received a single topical application of ZL-1102 onto a psoriatic plaque; double-blind Part B: 53 patients were randomised 1:1 to twice-daily ZL-1102 or vehicle for 4 weeks. Key primary endpoints included treatment-emergent adverse events (TEAEs), tolerability and changes in local psoriasis area and severity index (PASI). TEAEs occurred in two (33.3%) patients in Part A and in 16 (59.3%) and 13 (50.0%) patients in the ZL-1102 and vehicle arms, respectively, in Part B. No grade ≥3 TEAEs were seen with ZL-1102. ZL-1102 led to numerically greater changes in local PASI versus vehicle (-28.8% vs. -17.2%), with good local tolerability. The trend towards local PASI improvement was accompanied by biomarker changes based on RNA sequencing, indicative of ZL-1102 penetration into psoriatic plaques. Topical ZL-1102 showed good safety, local tolerability and a trend towards improved local PASI; skin penetration was observed without measurable systemic exposure. ACTRN12620000700932.

IL-17A inhibitors alleviate Psoriasis with concomitant restoration of intestinal/skin microbiota homeostasis and altered microbiota function.

Background: Disturbed gut microbiota and associated metabolic dysfunction exist in Psoriasis. Despite the growing use of interleukin-17 inhibitor (anti-IL17) therapy, the effect of anti-IL17 on gut/skin microbiota function is not fully understood in patients with Psoriasis. Objective: Therefore, we explored whether Psoriasis is associated with alterations in selected gut/skin microbiota in a study cohort, and a longitudinal cohort study to reveal the effects of IL-17A inhibitor treatment on gut microbiota in Psoriasis. Methods: In a case-control study, 14 patients with Psoriasis and 10 age, sex and body mass index-matched Healthy Controls were recruited. Longitudinal mapping of the gut microbiome was performed using 16S rRNA gene sequencing. Mouse models were used to further study and validate the interrelationship between the skin microbiome and the gut microbiome in Psoriasis. PICRUST2 was applied to predict the function of the bacterial community. Results: In Psoriasis patients, gut microbiota dysbiosis was present with increased heterogeneity: decreased Bacteroidota and increased Firmicutes as well as Actinobacteriota predominating in Psoriasis. Escherichia-Shigella enrichment was associated with reduction in serum levels of total bile acid and markers in Apoptotic pathways. After IL-17A inhibitor treatment in Psoriasis patients, longitudinal studies observed a trend toward a normal distribution of the gut microbiome and modulation of apoptosis-related metabolic pathways. Results from a mouse model showed dysregulation of the skin microbiota in Psoriasis characterized by Staphylococcus colonization. Conclusion: The psoriatic gut/skin microbiota exhibits loss of community stability and pathogen enrichment. IL-17A inhibitors restore microbiota homeostasis and metabolic pathways, reduce pro-inflammatory cytokine expression, and alleviate symptoms in patients with Psoriasis.

A case of herpetiform pemphigus mimicking bullous pemphigoid after using secukinumab and successfully treated with sulfasalazine.

Interleukin 17A (IL-17A) inhibitors, such as secukinumab, have been widely used as the mainstream treatment for chronic plaque psoriasis; however, cutaneous adverse events have been reported. Here, we report a 43-year-old Chinese man who developed herpetiform pemphigus (HP) during secukinumab treatment for his psoriasis. He presented with (1) clinical features of HP, which resembled bullous pemphigoid; histopathological features of intraepidermal blisters, eosinophilic/neutrophilic spongiosis, and liquefactive degeneration of the basal cell layer; (3) positive anti-desmoglein 1 antibody by enzyme-linked immunosorbent assay and cell surface IgG reactivity within the epidermis by indirect immunofluorescence assay; and (4) a satisfactory response to salicylazosulfapyridine (sulfasalazine). To the best of our knowledge, this is the first report of the development of HP after the use of secukinumab for psoriasis.

Two cases with bullous pemphigoid relapsed after using interleukin-17A inhibitors for psoriasis: A paradoxical reaction.

Biological drugs, including IL-17A inhibitors, have become the first-line treating options for moderate to severe psoriasis, and reports show a beneficial effect of IL-17A inhibitors on bullous pemphigoid. Here, we report two cases of bullous pemphigoid in remission that experienced severe flares during treatment with two major IL-17A inhibitors, i.e., ixekizumab or secukinumab for their psoriasis vulgaris. The patient with bullous pemphigoid induced by secukinumab became very recalcitrant to control the relapse. This is by far the first and paradoxical report on the IL-17A inhibitors having a negative effect on bullous pemphigoid patients in previously stable status. Our reports of these two cases alert clinicians to be careful when using IL-17A in pemphigoid patients. We also suggest that patients with psoriasis vulgaris should be asked for a detailed history of pemphigoid and its BP180 autoantibodies status be checked before using these biologicals.

Ixekizumab is effective in the long-term management in moderate-to-severe plaque psoriasis: results from an Italian retrospective cohort study (the LOTIXE study).

PURPOSE: Ixekizumab is a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A approved for the treatment of moderate-to-severe plaque psoriasis. The objective of this study was to describe the real-world long-term effectiveness of ixekizumab in patients with plaque psoriasis in Italy. MATERIALS AND METHODS: A retrospective study was conducted in patients affected by moderate-to-severe plaque psoriasis who were continuously treated with ixekizumab for at least 12 months. Patient data was obtained at 4-weeks, 12-weeks and 6-, 12-, 18- and 24-months after baseline (June 2017 and September 2019) from 10 sites. Results were analyzed by complete case approach, with sensitivity analysis performed to evaluate the impact of missing data. RESULTS: A total of 198 patients were enrolled in the study. At Month 24, 94.3% of patients achieved PASI75 response, while 85.1 and 71.8% achieved PASI90 and PASI100, respectively; and 91.1% of the patients achieved absolute PASI score ≤2. Patients experienced psoriasis improvement at 4 weeks after starting treatment, and improvement was maintained with continued ixekizumab use. The quality of life of patients also improved significantly starting at Week 12, with sustained effect in the long term. CONCLUSION: This 24-month observational cohort study confirmed that ixekizumab is effective in the long-term management of patients with moderate-to-severe plaque psoriasis.

Simultaneous Nail and Skin Clearance in Ixekizumab Head-to-Head Trials for Moderate-to-Severe Psoriasis and Psoriatic Arthritis.

INTRODUCTION: The lifetime incidence of nail psoriasis in patients with psoriasis is 80-90%, with 23-27% of patients having nail psoriasis at any given time. Nail psoriasis is even more prevalent in patients with comorbid psoriatic arthritis. Complete psoriasis clearance, an achievable therapeutic goal, should ideally include the resolution of nail psoriasis. Here, we assessed simultaneous skin and nail clearance in patients with psoriasis across five head-to-head trials comparing ixekizumab with other biologics. METHODS: Data were assessed in patients with moderate-to-severe psoriasis (with or without psoriatic arthritis) with nail psoriasis at baseline from the IXORA-R, IXORA-S, UNCOVER-2, UNCOVER-3, and SPIRIT-H2H trials. Ixekizumab patients received IXEQ2W to week 12 and IXEQ4W beyond week 12. PASI 100 depicted complete skin clearance, and PGA-F 0 (IXORA-R) or NAPSI 0 (all other trials) depicted complete nail clearance. Treatment comparisons were evaluated using the Cochran-Mantel-Haenszel test. Non-responder imputation was used for missing data. RESULTS: Ixekizumab achieved significantly greater simultaneous skin and nail complete clearance than etanercept (UNCOVER-2: p < 0.001 and UNCOVER-3: p < 0.001) at week 12, demonstrating an efficacious and rapid response. Across all five head-to-head trials, ixekizumab achieved a high rate of simultaneous skin and nail clearance (range: 28.6-45.9% of patients) by week 24 that was maintained up to week 52 (range: 40.5-51.4% of patients). Ixekizumab achieved numerically greater simultaneous complete clearance than guselkumab at week 24 (p = 0.079), but statistically significant greater simultaneous clearance compared to ustekinumab (p < 0.001) and adalimumab (p = 0.006) at week 24 and week 52 (p < 0.001 and p = 0.007, respectively). CONCLUSION: In five head-to-head trials, ixekizumab-treated patients had higher rates of simultaneous complete skin and nail clearance compared to etanercept, guselkumab, ustekinumab, and adalimumab, thereby reinforcing ixekizumab's ability to achieve high levels of efficacy in multiple domains of psoriatic disease. TRIAL REGISTRATION: NCT01474512, NCT01597245, NCT01646177, NCT03573323, NCT02561806, and NCT03151551.

Successful use of secukinumab in two melanoma patients with immune checkpoint inhibitor-induced inflammatory arthropathy.

Immune-related adverse events (irAEs) are a major concern when treating cancer patients with immune checkpoint inhibitor (ICI) therapy. Selecting the most appropriate management of irAEs remains an ongoing challenge because prolonged use of glucocorticoids come with their own side effects and may counteract the antineoplastic effects from immunotherapy. In this case report, we present two patients with metastatic melanoma who developed symptoms of inflammatory arthritis attributed to ICI therapy. We found that treatment with secukinumab, an anti-IL-17A inhibitor, effectively managed their symptoms and did not lead to tumor progression. Our study suggests that secukinumab can be a safe and effective treatment option for ICI-induced inflammatory arthropathy.

Immune-related adverse events (irAEs) are unwanted side effects commonly seen in cancer patients treated with immunotherapy. A frequently underreported irAE is inflammation of the joints (ankles, knees, shoulders, etc.), which is known as inflammatory arthropathy. Inflammatory arthropathy is frequently treated with steroids, but there is concern that it may counteract the anticancer effect from immunotherapy. Alternative treatments are needed to better treat this irAE without compromising the benefit of immunotherapy. In this case report, we present two patients with stage 4 melanoma who developed immunotherapy-induced inflammatory arthropathy and were successfully treated with secukinumab. We found that treating the inflammatory arthropathy was safe, effective, and did not lead to cancer progression in either patient.

Narrative Review of the Emerging Therapeutic Role of Brodalumab in Difficult-to-Treat Psoriasis.

Psoriatic involvement in areas of the body such as nails, palms and soles (palmoplantar), and scalp is associated with dramatically negative effects on quality of life relative to involvement elsewhere in the body. Although numerous evidence-based studies demonstrate the efficacy of biologics for overall skin clearance in moderate-to-severe plaque psoriasis (including tumor necrosis factor α [TNFα] inhibitors and interleukin [IL]-17A, IL-12/IL-23, IL-23, IL-17F, and IL-17A/F inhibitors), large, randomized, placebo-controlled clinical studies of psoriasis with nail, palmoplantar, and scalp involvement are needed to better inform decision-making in clinical practice. Moreover, biologic failure caused by drug ineffectiveness is a common occurrence in patients who do not respond, lose response, or are intolerant to treatment. Brodalumab is a fully human IL-17 receptor A antagonist that demonstrates high rates of skin clearance among the latest generation of biologic therapies for treatment of moderate-to-severe psoriasis. This review summarizes current literature on the efficacy of brodalumab and other therapies in difficult-to-treat psoriasis including psoriasis in difficult-to-treat locations (such as psoriasis with nail, palmoplantar, or scalp involvement) and psoriasis in patients whose disease did not respond to other biologics.

Role of secukinumab in ankylosing spondylitis with tubercular uveitis.

We present the case of a 32-year-old Indian male one-eyed individual with a history of unilateral panuveitis with HLA B 27 positive spondyloarthropathy on systemic immunosuppressant (Adalimumab). He developed recurrent inflammation in the same eye in a span of 2 years, later complicated with retinal vasculitis. On evaluation, he was diagnosed with tubercular uveitis and started on antitubercular treatment along with systemic steroids. Inview of Increased IOP due to steroid response, Inj. Secukinumab ( IL 17 A inhibitor) was started and significant improvement was noted.

Treatment of Psoriasis with Secukinumab in Challenging Patient Scenarios: A Review of the Available Evidence.

Psoriasis (PsO) is a common, systemic, chronic, inflammatory disease characterized by key clinical symptoms, including itching, pain, and scaling. PsO is associated with a high prevalence of comorbidities, including other autoimmune diseases and malignancies. Furthermore, special populations, such as pregnant, pediatric, and elderly patients, and those with erythrodermic PsO, are challenging to treat and require tightly monitored disease and treatment management. Because certain populations have demographic or clinical characteristics that can affect the presentation of PsO and complicate treatment responses, these patient populations are largely excluded from clinical trials; therefore, most clinical evidence for the treatment of these patients is derived from case reports and series. Secukinumab, a fully human monoclonal interleukin-17A antibody, has been shown in several clinical trials to be effective and safe for the treatment of PsO; however, these studies offer only limited data on the use of secukinumab in patients with chronic illnesses or in special populations. This review explores the use of secukinumab for PsO in special populations, including pregnant women, children, elderly people, patients with erythrodermic PsO, and those with chronic illnesses, including latent tuberculosis, hepatitis B and C, HIV, multiple sclerosis, and malignancies.

Ixekizumab for the treatment of psoriasis: an update on new data since first approval.

Introduction: Psoriasis is a chronic immune-mediated skin disease with a multifactorial etiology. Studies have shown that the inflammatory cytokine interleukin-17A (IL-17A) is a key mediator in the pathogenesis. Targeted biologics have changed the outcome for patients in a variety of diseases including psoriasis. Ixekizumab is a humanized monoclonal antibody directed against IL-17A and it has been approved for the treatment of moderate-to-severe plaque psoriasis, and recently also psoriatic arthritis. Areas covered: In this review, we summarize the latest clinical study results on ixekizumab. Long-term Phase III study data on efficacy and safety are now available for both plaque psoriasis and psoriatic arthritis. Additionally, new indications for ixekizumab are under investigation. Expert commentary: Overall, the efficacy and safety of ixekizumab are promising. In plaque psoriasis, the efficacy of ixekizumab was superior to etanercept and ustekinumab, while the efficacy was comparable to adalimumab in psoriatic arthritis. The safety profile has also been found very tolerable and similar to other biologics; however, vigilance regarding non-invasive Candida infections is necessary. Also, caution is advised when treating patients with concomitant inflammatory bowel disease, since ixekizumab could cause exacerbations. Long-term studies in real-life treatment settings are needed to decide the actual potential and safety of ixekizumab.

Budget impact analysis of secukinumab versus adalimumab in the treatment of ankylosing spondylitis.

BACKGROUND: Biologic treatments have enhanced the treatment outcomes of patients with active ankylosing spondylitis (AS). Until recently, TNF-alpha-inhibitors have been the only biologics approved for the treatment of active AS. The objective of this study was to assess the potential financial impact of the first non-TNF-alpha biologic secukinumab (fully human IL-17A-inhibitor) vs adalimumab (TNF-alpha-inhibitor) in the treatment of AS in Finland. MATERIALS AND METHODS: In this model-based budget impact analysis, patients were treated either with secukinumab (150 mg) or adalimumab (40 mg). The number of patients and market share of different biologics were based on national reimbursement registry data. Adalimumab was the most commonly used biologic treatment for AS, and in the base case analysis all adalimumab patients are assumed to switch to secukinumab. Response rates were based on a matching-adjusted indirect comparison between secukinumab and adalimumab. Patients not achieving response were switched to another biologic treatment. RESULTS: Treating AS patients with secukinumab instead of adalimumab leads to potential savings of 18.2 million euros within a 5-year time period. The total costs within the follow-up time were 59.5 million euros and 77.7 million euros with and without secukinumab, respectively. According to sensitivity analyses, a higher adoption rate of secukinumab corresponds to higher potential savings. CONCLUSIONS: Secukinumab is a cost-saving treatment option compared with adalimumab in the treatment of AS in Finland. More patients could be treated with a biologic by allocating resources more efficiently.

A Case of Recalcitrant Psoriatic Arthritis to TNF Inhibitors Improved After Administration of Secukinumab, an IL-17A Inhibitor.

Psoriatic arthritis (PsA) is a unique inflammatory arthritis due to the fact that patients have to deal not only with pain but also with their skin appearance, which may have a detrimental effect on their everyday lives and psychology. Treating a patient with PsA, improving both the musculoskeletal and skin symptoms is a challenge for the clinical rheumatologist. In this case, we present a patient of recalcitrant PsA to tumor necrosis factor inhibitors (TNFi) who had an exceptional improvement after administration of the interleukin-17A inhibitor (IL-17Ai) secukinumab.

Efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis: 52-week pooled results from two phase 3 studies.

AIM: To evaluate efficacy and safety of secukinumab in Asian patients with active ankylosing spondylitis (AS) via a pooled subgroup analysis from two phase 3 studies, MEASURE 1 (NCT01358175) and MEASURE 2 (NCT01649375). METHODS: In MEASURE 1, patients were randomized to intravenous secukinumab 10 mg/kg or placebo at baseline, Weeks 2 and 4, followed by subcutaneous (s.c.) secukinumab 150 mg, 75 mg or placebo every 4 weeks (q4w) at Week 8. In MEASURE 2, patients were randomized to s.c. secukinumab 150 mg, 75 mg or placebo at baseline, Weeks 1, 2 and 3, and q4w starting at Week 4. Efficacy outcomes were SpondyloArthritis International Society (ASAS) 20/40, high-sensitivity C-reactive protein (hsCRP), ASAS5/6, Bath Ankylosing Spondylitis Disease Activity Index, Short Form-36 physical component summary, AS quality of life (QoL), ASAS partial remission, and Ankylosing Spondylitis Disease Activity Score - CRP at Weeks 16 and 52. Due to lack of efficacy, the secukinumab 75 mg dose in MEASURE 2 was excluded from this pooled Asian subgroup analysis. Safety analysis included patients who received ≥ 1 dose of study treatment. RESULTS: Of 517 patients enrolled into the MEASURE studies, 69 (13.3%) were Asians: 46 in pooled secukinumab and 23 in placebo. At Week 16, ASAS20/40 responses in Asian patients were 69.6%/43.5% with pooled secukinumab versus 26.1%/17.4% with placebo, which were comparable with rates reported in the overall study population. Secukinumab improved predefined efficacy endpoints at Week 16, with responses sustained through Week 52. Secukinumab was well tolerated in Asian patients, with a safety profile consistent with that reported in the overall study population. CONCLUSION: Secukinumab improved signs and symptoms, physical function, and disease-specific QoL in Asian patients with active AS.

Treatment of novel IL17A inhibitor in glioblastoma implementing 3rd generation co-culture cell line and patient-derived tumor model.

Despite many treatment options, cancer remains a growing problem and has become the second leading cause of death globally. Here, we present fluorescence molecular tomography (FMT) data regarding the reversion of third generation co-cultured U87+DBTRG and patient-derived GBM tumor model after treatment with novel IL17A inhibitor named FLVM and FLVZ (organic derivatives of caffeic acid). FMT was used to determine tumor angiogenesis volume (assessment of number of blood vessel; the expression of angiogenic factors CD34 and other angiogenic cancer bio-markers) in U87+DBTRG and patient-derived gliomas. Immunohistochemistry was used to determine microvessel density [CD34], and cell proliferation [Ki67]. Western blot was used to assess the interleukin 17A [IL17A], vascular endothelial growth factor [VEGF] and hypoxia-inducible factor-1α [HIF-1α]. Antibody array was used to assess the cancer bio-markers in co-cultured U87+DBTRG gliomas. Animal survival was found to be significantly increased (P<0.0001) after FLVM treatment compared with control-IL17A. After FMT detection, FLVM, administered orally, was found to decrease tumor growth (P<0.0001). FLVM and FLVZ administration resulted in significant decreases in tumor hypoxia [HIF-1α (P<0.05)], angiogenesis [CD34 (P<0.05)], VEGF, IL17A and cell proliferation [Ki67 (P<0.05)] and caused a significant increase of Bax, caspase and FasL (P<0.05), compared with untreated animals. Additionally, Leptin, LPL (P<0.01), FFA (P<0.05) and adipogenesis were downregulated and no additive toxicity was found in mice except calorie-restriction like effect. Use of FLVM can be considered as a novel inhibitor of IL17A for the treatment of human gliomas.

Ixekizumab for treatment of adults with moderate-to-severe plaque psoriasis and psoriatic arthritis.

INTRODUCTION: The interleukin (IL)-17 family of cytokines has emerged as an important pro-inflammatory mediator of psoriasis and psoriatic arthritis (PsA). Ixekizumab is an IL17A inhibitor that has been approved for the treatment of chronic plaque psoriasis. Phase III studies of ixekizumab in treating of PsA demonstrated promise by minimizing disease severity and progression. Areas covered: This review focuses on the biologic properties, pharmacokinetics and key clinical trial results that demonstrated the safety and efficacy of ixekizumab in treating psoriatic disease. Expert commentary: Ixekizumab is a biologic that has been approved for the treatment of chronic plaque psoriasis. With respect to safety, ixekizumab is generally well tolerated with injection-site reactions, nasopharyngitis, and upper respiratory tract infections being the most common adverse events. Most patients with anti-drug antibodies have low antibody titer levels resulting in no meaningful interference in clinical response to ixekizumab.