Candidates For Systemic Therapy Research Articles

Guselkumab: the First Selective IL-23 Inhibitor for Active Psoriatic Arthritis in Adults

ABSTRACT Introduction Guselkumab is a subcutaneously administered human monoclonal antibody, selectively blocking IL-23 through binding to its p19 subunit. It was initially approved for the treatment of patients with moderate-to-severe plaque-psoriasis who are candidates for systemic therapy or phototherapy. Pubmed and Embase databases were searched for publications, using the following search terms: psoriasis, psoriatic arthritis, guselkumab, risankizumab, tildrakizumab, p19, interleukin 23, guidelines, treatment recommendations, DISCOVER, ECLIPSE, and VOYAGE. Areas covered Accumulating evidence suggests that the IL-23/Th17 pathway is important in the pathogenesis of both psoriasis and psoriatic arthritis. Following a successful development program in psoriasis, guselkumab was evaluated for its efficacy and safety in psoriatic arthritis in a comprehensive clinical trial program, comprising one phase-2 study and two phase-3 studies (DISCOVER-1 and −2). Complementary data on pharmacokinetics and safety exist from pre-clinical experiments and pooled analyses from two long-term studies in psoriasis (VOYAGE-1 and −2). Based on the DISCOVER-1 and −2 data, guselkumab was approved by the FDA for the treatment of active psoriatic arthritis in 2020. Expert Opinion Guselkumab is the first selective IL-23 inhibitor approved to treat adults with active psoriatic arthritis, broadening therapeutic options in the field through a novel mode of action.

Risankizumab: A Review in Moderate to Severe Plaque Psoriasis.

Risankizumab (Skyrizi®; risankizumab-rzaa) is a humanized immunoglobulin (Ig) G1 monoclonal antibody that specifically targets the p19 subunit of interleukin (IL)-23, thereby inhibiting IL-23-dependent cell signaling. Subcutaneous risankizumab is approved for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy (in the EU), those who are candidates for systemic therapy or phototherapy (in the USA) and those who have an inadequate response to conventional therapies (in Japan). In pivotal phase III trials (UltIMMa-1, UltIMMa-2, IMMvent and IMMhance), risankizumab was more effective than placebo, ustekinumab and adalimumab with regard to the proportion of patients achieving ≥ 90% improvement from baseline in Psoriasis Area and Severity Index score (PASI 90) and a static Physician’s Global Assessment score of 0 or 1 at week 16, with these benefits maintained over the longer term. In supportive head-to-head trials, risankizumab was also superior to secukinumab and fumaric acid esters in terms of PASI 90 response rate. In an ongoing open-label extension study (LIMMitless), risankizumab was associated with durable and improved efficacy after switching from ustekinumab or adalimumab, as well as durable maintenance of efficacy through > 2.5 years of continuous exposure. Treatment with risankizumab improved health-related quality of life and was generally well tolerated, both in the short- and longer-term. In conclusion, risankizumab represents a useful new treatment option for patients with moderate to severe plaque psoriasis.

LB972 IL-17 inhibitor-induced remission of guttate psoriasis

Effective, targeted treatments for guttate psoriasis are lacking. Drugs that block the interleukin-17 (IL-17) pathway are highly effective in the treatment of plaque psoriasis. Given the overlap of immunopathogenic features between guttate and plaque psoriasis, including an over activation of Th17 cells, it is plausible that IL-17A inhibition would be an effective treatment for guttate psoriasis. Ixekizumab, a humanized IgG4 monoclonal antibody that targets interleukin-17A (IL-17A) is FDA-approved for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy, but to our knowledge has never been reported in the treatment of guttate psoriasis. Here we report three cases of guttate psoriasis successfully treated with ixekizumab. Three patients presented with guttate psoriasis involving 15-40% body surface area (BSA) and with psoriasis physician global assessment (PGA) scores ranging from 3-6. Two patients developed lesions idiopathically, and one developed lesions after a documented episode of streptococcal pharyngitis. Lesions had been present for 7-90 days at the time of presentation, and prior ineffective treatment attempts across patients by primary care providers included courses of keflex, triamcinolone cream, betamethasone ointment, oral prednisone, oral acyclovir, and expectant management. Patients were treated with standard ixekizumab dosing regimens for plaque psoriasis. Starting doses of 160mg subcutaneous injection and induction doses of 80mg every two weeks thereafter were given. Two patients achieved complete clearance after 2 doses of ixekizumab (clearance documented in clinic at 42 and 86 days after treatment initiation), and the third achieved 1% BSA involvement and PGA score of 1 after 3 doses (documented 61 days after treatment initiation). No adverse effects of treatment were noted. This report provides strong evidence for the potential efficacy of IL-17 inhibition in guttate psoriasis. Additional follow-up to assess for duration of clinical remission and progression to plaque psoriasis, as well as larger, randomized, controlled studies are needed.

<p>Clinical Evaluation of Risankizumab-rzaa in the Treatment of Plaque Psoriasis</p>

Risankizumab-rzaa (Skyrizi®; AbbVie) is a humanized IgG monoclonal antibody directed against interleukin-23p19 (IL-23p19) indicated for the treatment of moderate-to-severe psoriasis in adults who are candidates for systemic therapy or phototherapy. Four pivotal Phase III trials: UltIMMa-1, UltIMMa-2, IMMhance, and IMMvent have demonstrated efficacy and safety in patients with moderate-to-severe plaque psoriasis. This review highlights important findings from these and other clinical trials that have evaluated risankizumab. In addition, we discuss the mechanism of action, pharmacokinetics/pharmacodynamics, dosing recommendations, drug interactions, other potential indications, and ongoing clinical trials.

Tumor Marker-Based Definition of the Transarterial Chemoembolization-Refractoriness in Intermediate-Stage Hepatocellular Carcinoma: A Multi-Cohort Study.

Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre- and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (ΔMoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ΔMoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ΔMoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

Recategorization of psoriasis severity: Delphi consensus from the International Psoriasis Council

Psoriasis severity categories have been important tools for clinicians to use in treatment decisions as well as to determine eligibility criteria for clinical studies. However, owing to the heterogeneity of severity classifications and their lack of consideration for the impact of psoriasis involvement of special areas or past treatment history, patients may be miscategorized, which can lead to undertreatment of psoriasis. To develop a consensus statement on the classification of psoriasis severity. A modified Delphi approach was developed by the International Psoriasis Council to define psoriasis severity. After completion of the exercise, 7 severity definitions were preferentially ranked. This most preferred statement rejects the mild, moderate, and severe categories in favor of a dichotomous definition: Psoriasis patients should be classified as either candidates for topical therapy or candidates for systemic therapy; the latter are patients who meet at least one of the following criteria: (1) body surface area >10%, (2) disease involving special areas, and (3) failure of topical therapy. This effort might have suffered from a lack of representation by all relevant stakeholders, including patients. The consensus statement describes 2 categories of psoriasis severity, while accounting for special circumstances where patients may require systemic therapy.

PB1792 AGE AS AN INDEPENDENT PREDICTIVE FACTOR IN SURVIVAL OUTCOMES OF MULTIMODALITY TREATMENTS FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A REVIEW FROM TERTIARY INSTITUTION

Background:Primary central nervous system lymphoma (PCNSL) is a rare malignancy with a median survival of less than 3 months, if untreated. Multimodality treatments with high‐dose methotrexate (HD‐MTX)‐based systemic therapy and/or whole brain irradiation for consolidation or salvage constitutes the most commonly used treatment approach. Due to severe treatment toxicity and aggressive course of the disease, not all patients benefit from this treatment approach.Aims:In this retrospective study, we aimed to identify various clinical parameters that predicted outcomes on survival, and response to various treatments in patients with PCNSL.Methods:Patients diagnosed with PCNSL between 2002 and 2017 were selected for analysis. Data on patient demographics, tumor characteristics and treatment were collected and analyzed for correlation with clinical outcomes. Survival curves were generated with the Kaplan‐Meier method and compared using log‐rank test. Multivariate analysis was performed where prognostic variables and patient outcome were correlated with Cox proportional hazard model.Results:A total of 82 patients were identified and selected for analysis. Median age at diagnosis was 68 years (range 30‐89 years) and median follow up was 3.7 years. The majority (86.6%) of tumors were identified as diffuse large B‐cell lymphoma on histology. Among the 82 patients, 10 (12.2%), 31 (37.8%) and 23 (28.0%) patients received systemic therapy (CT) only, radiotherapy (RT) only and systemic therapy followed by salvage radiotherapy (CRT), respectively, while 18 (22.0%) patients received supportive care (SC) only. Median time interval between diagnosis and treatment was 33 days for CT group and 63 days for RT group. Median overall survival (OS) of the entire cohort was 11.1 months (95% CI 6.1‐15.5 months), while median OS for RT, CRT and SC groups were 8.8 months (95% CI 4.5‐11.3 months), 30.1 months (95% CI 19.3‐41.0 months) and 3.3 months (95% CI 0.8‐5.8 months), respectively (median OS for CT group not reached). Multivariate analysis demonstrated that both the use of systemic therapy (hazard ratio [HR] 0.23, 95% CI 0.11‐0.49, p &lt; 0.001) and radiotherapy (HR 0.54, 95% CI 0.32‐0.92, p = 0.022) were associated with improved survival in the total population, while age (p = 0.48) or type of tumor (p = 0.88) did not demonstrate any statistical significance. Subgroup analysis showed that systemic therapy in patients younger than 70 years of age was associated with improved OS (HR 0.13, 95% CI 0.05‐0.32, p &lt; 0.001), whereas in elderly patient population (70 years of age or older), addition of radiotherapy was associated with improved OS (HR 0.45, 95% CI 0.21‐0.96, p = 0.039).Summary/Conclusion:Our results concur with the published literature demonstrating the survival benefit with the use of systemic therapy in younger patient population. Radiotherapy was independently associated with an improved overall survival in older patient population and therefore should be considered as palliative treatment of choice in the elderly population who may not be candidates for systemic therapy. Further prospective studies are required to validate our findings as well as optimization of radiotherapy in this population.

Conjunctivitis in dupilumab clinical trials.

SummaryBackgroundDupilumab blocks the shared receptor component for interleukin (IL)‐4 and IL‐13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate‐to‐severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate‐to‐severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate‐to‐severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo.ObjectivesTo characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials.MethodsWe evaluated randomized placebo‐controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47).ResultsIn most AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis.ConclusionsConjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab‐treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD).In most dupilumab AD trials, dupilumab‐treated patients had higher conjunctivitis incidence than those receiving placebo.Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare.Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials.Baseline disease‐related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation‐regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis.Patients who responded well to dupilumab had reduced incidence of conjunctivitis.Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab‐treated patients with AD.

Cells to Surgery Quiz: May 2019

Cells to Surgery Quiz: May 2019

Risankizumab.rzaa: an interleukin monoclonal antibody antagonist binding to the p19 subunit of human IL-23 cytokine.

Plaque psoriasis is the commonest form of psoriasis affecting about 85% of those patients with the condition. Risankizumab was developed as a high-affinity humanized monoclonal antibody specific for the p19 subunit of interleukin-23 (IL-23p19). Clinical trials demonstrated that risankizumab was very effective in patients with moderate to severe plaque psoriasis causing total clearing of the condition as evidenced by Psoriasis Scalp Severity Index (PSSI100) and static Physician's Global Assessment (sPGA) of 0 in more than 50% of patients after 52 weeks of treatment. Risankizumab has been approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy as a dose of 150 mg administered by subcutaneous injection at week 0, week 4 and every 12 weeks thereafter.

Top New Drug Approvals of 2018

Top New Drug Approvals of 2018

PSS7 - QUALITY OF LIFE IMPROVEMENTS IN PSORIASIS WITH SECUKINUMAB IN A DIFFICULT TO TREAT POPULATION OF ANTI-TNF ALPHA FAILURE PATIENTS FROM THE UK AND REPUBLIC OF IRELAND

Psoriasis can have a large impact on quality of life (QoL). Secukinumab, a fully human anti–interleukin-17A monoclonal antibody is licensed for the treatment of plaque psoriasis in adults who are candidates for systemic therapy. QoL results are presented from an open-label, non-comparator study that investigated the safety and efficacy of secukinumab in patients who previously failed anti-tumour necrosis factor (TNF) α biologic therapy. 235 eligible adults with active, moderate-to-severe, chronic plaque psoriasis from 53 sites in UK and Ireland were randomised 1:1 to receive secukinumab 300mg or 150mg subcutaneously for 72 weeks (dosing at weeks 0-4, then 4-weekly). Patients completed the Dermatology Life Quality Index (DLQI, range 0-30, higher scores reflecting worse QoL) and EuroQoL 5-Dimension Health Status Questionnaire (EQ-5D-5L) at baseline, weeks 12, 16, 24, 48 and 72. Results are presented for 118 patients on the dose of secukinumab licensed for psoriasis (300mg). At baseline, mean DLQI was 20.2 (SD=6.03). By week 16 this improved to 4.2 (SD=4.97). Improvements were maintained amongst patients remaining in the study; 4.2 (SD=5.90) at week 48 and 3.7 (SD=5.41) at week 72. Baseline EQ-5D-5L mean visual analogue score (VAS; range 0-100, lower scores reflecting worse QoL) was 54.9 (SD=24.84). By week 16 this improved to 76.3 (SD=21.58). Improvements were maintained amongst patients remaining in the study; 77.7 (SD=21.60) at week 48 and 78.2 (SD=19.80) at week 72. EQ-5D domains impacting the largest proportion of patients at baseline were pain/discomfort (90%; 106/118 patients) and anxiety/depression (77%; 91/118). By weeks 16, 48 and 72 respectively, fewer patients were reporting pain/discomfort; 53% (63/118), 43% (46/107) and 52% (43/83) and anxiety/depression; 38% (45/118), 36% (39/107) and 37% (31/83). These results demonstrate that secukinumab 300mg provides sustained QoL improvements even in a difficult to treat anti-TNFa failure population of psoriasis patients.

Targeted therapies for pediatric psoriasis.

Children who are recalcitrant to topical therapy for their moderate to severe plaque psoriasis and/or highly visible lesions may be candidates for systemic therapy. Methotrexate has been the most commonly used systemic agent in children. However, at least 25% of patients are now treated with biologics, especially tumor necrosis factor-α inhibitors, and their use is expanding as their availability, demonstrated safety and efficacy, and practitioner experience are increasing. In the United States, etanercept is Food and Drug Administration approved for ages 6 years and older and ustekinumab for 12 years of age and older. In Europe, adalimumab is also approved for pediatric psoriasis for 4 years of age and older. While biologics have the advantage of less frequent administration, greater and more rapid efficacy than methotrexate, fewer side effects, and a less rigorous need for monitoring, their cost is much higher than that of methotrexate and other systemic medications, concerns about the development of neutralizing antibodies necessitate continuous treatment, and their long-term safety profile remains to be determined.

Profile of tildrakizumab-asmn in the treatment of moderate-to-severe plaque psoriasis: evidence to date

Plaque psoriasis is an immune-mediated skin disease that affects roughly 3% of adults in the United States. Advances over the past 20 years in understanding the immune-mediated pathophysiology of psoriasis have led to the development of targeted biologic therapies for this condition. Currently, biologic medications approved for the treatment of plaque psoriasis include tumor necrosis factor α inhibitors, interleukin (IL)-17 or IL-17 receptor inhibitors, IL-12/23 inhibitors, and IL-23 inhibitors. Tildrakizumab-asmn is a monoclonal antibody that targets the p19 subunit of IL-23 and is approved for use in adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This article reviews the current pharmacologic, efficacy, and safety data on tildrakizumab-asmn.

Guselkumab for the treatment of plaque psoriasis

Guselkumab (Tremfya) is a monoclonal antibody against interleukin‐23 for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. This article discusses its efficacy, side‐effects and place in therapy.

Tildrakizumab: First Global Approval.

Merck & Company Inc. have developed tildrakizumab (tildrakizumab-asmn; Ilumya™), a high-affinity, humanised IgG1 κ monoclonal antibody that specifically targets interleukin-23 p19, as a treatment for chronic plaque psoriasis. The drug was recently approved for marketing by the US FDA based on positive results from the phase III reSURFACE clinical trial programme in patients with chronic plaque psoriasis. This article summarizes the milestones in the development of tildrakizumab leading to this first approval for the treatment of adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

Dupilumab for the treatment of atopic dermatitis

Dupilumab (Dupixent) is a new monoclonal antibody treatment licensed for use in adults with moderate to severe atopic dermatitis (eczema) who are candidates for systemic therapy. This article discusses its properties, efficacy and side‐effects.

Guselkumab for the treatment of moderate-to-severe plaque psoriasis

ABSTRACTIntroduction: Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis.Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis.Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.

Survival and prognostic factors for patients with melanoma brain metastases in the era of modern systemic therapy

Historically, the prognosis of patients with melanoma brain metastases is poor, with median overall survival (OS) of 4-6months. Little is known of OS in the era of modern systemic therapies and local therapy with stereotactic radiosurgery (SRS) or surgery. Patients diagnosed with melanoma brain metastases at Melanoma Institute Australia from January 2011 to December 2014 were included. OS and prognostic factors were analysed using Cox regression and Kaplan-Meier survival analyses.355 patients were included. The median OS was 7.1 months (95% confidence interval [CI] 6.0-8.1). Median OS differed by treatment modality: systemic therapy and SRS and/or surgery 14.9months (95% CI 10.7-19.0), SRS and/or surgery with or without whole brain radiotherapy (WBRT) 6.4months (95% CI 5.4-7.5), systemic therapy 5.4months (95% CI 3.1-7.7), systemic therapy and WBRT 5.2months (95% CI 4.1-6.4), WBRT 4.4months (95% CI 2.4-6.3), and best supportive care 1.8months (95% CI 1.2-2.3). OS for patients with melanoma brain metastases appears improved in the modern era, particularly for patients who are candidates for systemic therapy with SRS and/or surgery.

Targeted Therapy and Imaging Findings.

Non-small cell lung cancer (NSCLC) is usually diagnosed when it is not amenable to curative surgery or radiation. Many of these patients are candidates for systemic therapy. Median survival is only approximately 10 months, and, accordingly, treatment in advanced NSCLC is evolving toward a more personalized approach with the identification of genetic abnormalities based on biomarkers. For example, gene mutations in EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) lead to a cascade of pathways resulting in uncontrolled growth, proliferation, and survival of tumor cells. Targeted therapies are aimed at the products of these mutated genes and include agents such as erlotinib and gefitinib (in EGFR-mutant NSCLC) or crizotinib (in ALK-positive NSCLC). Antiangiogenesis agents such as bevacizumab are another category of targeted therapy that inhibits vascular endothelial growth factors. The imaging characteristics of advanced NSCLC with genetic abnormalities, the evolution of targeted therapies and their imaging manifestations will be discussed.