Mina Amin

Review of phase III trial data on IL-23 inhibitors tildrakizumab and guselkumab for psoriasis

The development of monoclonal antibodies targeting IL‐12 and IL‐23 has enhanced the therapeutic options available for psoriasis patients. Recent research suggests that IL‐23 alone plays a role in the pathogenesis of psoriasis. The objective was to review the phase III clinical trial data for the anti‐IL‐23 agents to evaluate the safety and efficacy profile of each agent. We reviewed the results of the phase III clinical trials for the anti‐IL‐23 agents tildrakizumab and guselkumab. The results of phase III trials on risankizumab have not yet been reported. By week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was >60% among the most efficacious dose of each agent. The percentage of patients achieving PASI 90 at week 16 was the primary endpoint for the phase III trials for guselkumab, which was above 70%. The safety profiles of the agents were comparable, with the most commonly reported adverse events of nasopharyngitis and upper respiratory tract infections. The anti‐IL‐23 agents demonstrated a rapid clinical improvement that is similar or superior to the improvement seen with currently marketed IL‐17 inhibitors with a favourable short‐term safety profile. The results of the phase III trials support the notion that IL‐23 is a potential target in psoriasis treatment.

Drug survival of biologic treatments in psoriasis: a systematic review

Abstract Drug survival measures the length of time until discontinuation of a drug. The length of time a patient remains on a biologic drug is impacted by several factors such as tolerability, side effects, safety profile and effectiveness. To evaluate the long-term drug survival, data of the most commonly prescribed biologic medications used in the treatment of psoriasis, a systematic review was conducted. A literature search using PubMed, the Cochrane Library and the Cumulative Index to Nursing and Allied Health Literature from January 1 2010 to October 28 2016 identified 3734 abstracts. Of which, 36 publications with over 40,000 patients met the inclusion criteria. The median overall drug survival for ustekinumab, adalimumab, infliximab and etanercept was 38.0, 36.5, 26.6 and 24.7 months, respectively. The mean annual drug survival rate of TNF inhibitors was 70%, 57%, 51%, 45% and 41% at years-1, 2, 3, 4 and 5, respectively. The 5-year mean annual drug survival rate of ustekinumab was 87%, 78%, 70%, 71% and 51%, respectively. Based on our findings, ustekinumab appears to have a longer drug survival with lower rates of discontinuation compared to tumor necrosis factor inhibitors.

Drug survival of apremilast in patients treated for psoriasis in a real-world setting

UCB Pharma. Dr Lacour has received honoraria and travel expenses from Abbvie, Amgen, Janssen, Celgene, LEO Pharma, Lilly, MSD, Novartis, Pfizer, and UCB Pharma. Dr Passeron has received honoraria and travel expenses from Abbvie, Celgene, Janssen, LEO Pharma, Lilly, MSD, Novartis, and Pfizer. Dr Montaudi e has received honoraria and travel expenses from Abbvie, Celgene, Lilly, Merck, Pfizer, ROCHE, and BMS. Dr Kelati has no conflicts of interest to disclose.

Review of IL-17 inhibitors for psoriasis

Abstract Background: The development of biologic agents directed against distinct cytokines and receptors has advanced the therapeutic options available for psoriasis patients. Evidence from preclinical studies suggests that IL-17 may contribute to the pathogenesis of psoriasis. Objective: The objective was to review the safety and efficacy profile for each IL-17 inhibitor by evaluating phase III clinical trial data. Methods: We reviewed the results of phase III clinical trials for the IL-17 inhibitors secukinumab, ixekizumab, and brodalumab. Results: At week 12, the proportion of patients reaching Psoriasis Area and Severity Index (PASI 75) was above 60% for the most efficacious dose of each agent with favorable and comparable safety profiles. The most commonly reported adverse events were nasopharyngitis, headache, and upper respiratory tract infection. Conclusions: The clinical improvement among psoriasis patients on IL-17 inhibitors is similar or superior to the improvement seen with commercially produced biologic agents available accompanied by a favorable short-term safety profile. The results of the phase III trials indicate that IL-17 inhibitors are effective therapeutic options for psoriasis patients.

Drug survival of secukinumab for psoriasis in a real-world setting.

Secukinumab, an IL-17 inhibitor, is effective for psoriasis and psoriatic arthritis but may have lower drug survival than other biologics in clinical practice (1,2). We retrospectively examined drug survival in 48 patients treated with secukinumab for psoriasis at Kaiser Permanente Los Angeles Medical Center dermatology clinic from January 21, 2015 to January 19, 2018 (Table 1), 12 of whom also had psoriatic arthritis (PsA). Secukinumab failure was defined as adding an oral medication or phototherapy or switching to a different oral or biologic agent. Failure date was set as the date at which the therapy was changed. Kaplan-Meier methodology was used to calculate drug survival probability in the cohort (persistence groups were censored) and provide a comprehensive survival duration. Twenty of 48 (41.7%) of patients persisted on secukinumab therapy throughout the study period (range 74 to 1004, Table 1), eighteen of whom were biologic-experienced. The remaining patients failed therapy after an average of 291 days and median of 198 days of treatment; all but one were biologic-experienced. Of patients with concurrent PsA, 10 of the 12 failed therapy after an average of 316 days. Mean and median drug survival durations (Figure 1) were 512 days (95% confidence interval 216–436 days) and 198 days, respectively.

Rates of latent tuberculosis infection in patients treated with TNF inhibitors for psoriasis: a retrospective chart review

Abstract Background: Although tuberculosis screening guidelines for psoriasis patients on TNF inhibitors exist, few studies have reported the prevalence of latent tuberculosis infection (LTBI) and conversion rates in this population. Objective: To determine the incidence of LTBI and active tuberculosis in patients with psoriasis receiving TNF inhibitor therapy. Methods: A total of 138 patients were included in our retrospective study of patients treated from September 2004 to September 2017. Tuberculin skin test was considered positive with an induration of greater than 5 mm. History of Bacillus Calmette-Guérin vaccination, follow-up tests and prophylaxis were recorded. Results: Among 99 biologic-naïve patients, 14 had LTBI before starting biologic therapy and five developed LTBI during TNF inhibitor therapy. One biologic-naïve patient developed LTBI, then active tuberculosis. Among 39 non-biologic-naïve patients, three had LTBI before starting any biologic therapy, and one developed LTBI during treatment. Limitations: Limitations include small sample size and limited information documented in the medical chart. Conclusions: LTBI appears to be prevalent among psoriasis patients. Screening for LTBI in patients on biologics may reduce risk of active tuberculosis; however, current methods may not be fully effective. Clinicians may need to use other tools including risk factor assessment to fully evaluate risk.

Adalimumab use in patients with psoriasis and hepatitis B: a case series

Tumor necrosis factor (TNF) inhibitors neutralize the biologic activity of TNF-alpha, a key cytokine involved in both the pathogenesis of psoriasis and host immune response in suppressing microbial proliferation.1 It is well known that chronic hepatitis B virus (HBV) carriers are at high risk of HBV reactivation when using immunosuppressive medications, chemotherapy, and TNF inhibitors.2-4 However, HBV reactivation in patients with resolved HBV infection using TNF inhibitors is exceedingly rare, and to our knowledge has not been reported in the psoriasis literature. This article is protected by copyright. All rights reserved.

Dynamics and spatial genomics of the nascent transcriptome in single mESCs by intron seqFISH

Recent single cell experiments have revealed significant heterogeneities at the levels of transcription, DNA methylation and chromosome organization in individual cells. However, existing method of profiling mRNAs effectively averages transcriptional dynamics over many hours due to hours-long life time of most mRNAs. To capture the instantaneous activity of the transcriptome that reflects the rapid regulatory changes in cells, we imaged up to 10,421 nascent transcription active sites (TAS) in single mouse embryonic stem cells using seqFISH followed by multiple rounds of single molecule FISH and immunofluorescence. We observed that nascent transcription active sites appear to be distributed on the surface of individual chromosome territories and are dispersed throughout the nucleus. In addition, there are significant variability in the number of active transcription sites in single cells, representing globally more active to quiescent states. These states interconverted on the time scale of 2 hours as determined by a single cell pulse-chase experiment. Thus, transcriptome level seqFISH experiments provide an unprecedented spatial and dynamic view of chromosome organization and global nascent transcription activity in single cells.

Interpreting Clinical Trial Data

Effective interpretation of clinical trial data allows for the integration of high-quality clinical research into clinical practice. Evidence from clinical trials directly impacts clinical decision making, which ultimately guides patient management (Page, Int J Sports Phys Ther 9: 726, 2014). The purpose of this chapter is to provide an overview of fundamental aspects of clinical trials, such as study designs, analyses, and methods of handling missing data along with potential sources of bias and uncertainty. Subject withdrawal can make statistical analysis difficult as studies are aimed to determine the impact of an intervention from beginning to end. The different approaches to account for missing data are presented: last observation carried forward (LOCF), nonresponder imputation (NRI), as-observed data analysis, and anytime analysis (Langley and Reich, Br J Dermatol 169:1198–1206, 2013). Identifying sources of error and understanding limitations of these methods helps clinicians evaluate the validity of clinical data, ultimately enhancing clinical decision making and patient care.

Risk of aortic aneurysm in patients with psoriasis: a retrospective cohort study

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