IL-17 targeted therapies for psoriasis

Introduction: Psoriasis is a chronic, disabling, inflammatory skin disease whose pathogenesis still remains to be fully elucidated. Genetic and environmental factors induce an immune response mediated by several cytokines and chemokines, including IL-17A.

Areas covered: Emerging evidence now suggests that IL-17A is central in the pathogenesis of psoriasis. Three agents neutralizing IL-17 (i.e., secukinumab and ixekizumab) or antagonizing its receptor (i.e., brodalumab) are in development and are being studied in Phase III clinical trials to evaluate their overall efficacy and safety. However, Phase II results of IL-17 blockade with each of these agents has shown a marked improvement of disease severity, thus confirming the pathogenic relevance of IL-17 in mediating crucial inflammatory circuits in psoriasis.

Expert opinion: Anti-IL-17 agents are likely to become important future therapeutics in this disease and the may potentially impact on cardiovascular diseases, arthritis and other comorbidities associated with psoriasis.     

The safety of brodalumab for the treatment of psoriasis

ABSTRACT

Introduction: Brodalumab is a newly developed targeted biologic agent for the treatment of psoriasis that blocks IL-17 receptor A.

Areas covered: This review sought to provide a detailed overview on safety of brodalumab for the treatment of psoriasis. A PubMed search was conducted for relevant literature. Here we review the efficacy and safety data from key phase II, phase III and open-label extension clinical trials, as well as systematic reviews and meta-analyses.

Expert opinion: The unique mechanism of action of brodalumab offers advantages on efficacy over other targeted treatments, with a quick onset of action and long-term maintenance of treatment response. Brodalumab has a favorable safety profile, similar to other IL-17 inhibitors. Infections, especially mucocutaneous candidiasis, must be monitored. Suicidal ideation was detected in brodalumab trials, although a causal relationship has not been revealed. Brodalumab is a highly efficacious and comparably safe therapeutic choice in patients with moderate to severe psoriasis, especially when rapid control of the disease is desired.     

Pharmacokinetic drug evaluation of brodalumab for the treatment of psoriasis

Introduction: Psoriasis is now understood to also be under the driving influence of the IL-17/IL-23 axis, and the medical breakthrough of novel IL-17 inhibitor medications signals a paradigm shift in the way psoriatic patients are managed medically.

Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab.

Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association.

Expert opinion: Brodalumab provides an important new therapy for management of psoriasis, because there remains a significant unmet patient need for new agents that can provide novel mechanisms of action, rapid onset of effect, improved, and sustained total skin clearance, greater compliance, and minimization of drug-specific safety concerns.     

A review of emerging IL-17 inhibitors in the treatment of psoriasis focusing on preclinical through phase II studies

Introduction: Interleukin-17 has recently been identified as a key player in the pathogenesis of psoriasis. As such, several drugs targeting IL-17 are in various stages of clinical development.

Areas covered: In this review, the authors describe several emerging therapies and drug candidates targeting IL-17. The authors detail many biologic injectable drug candidates as well as numerous potential oral and topical small molecule drug candidates.

Expert opinion: Approval of IL-17 inhibitors has significantly improved the treatment options for psoriasis patients. Secukinumab and ixekizumab are approved in both Europe and the USA, and brodalumab is likely facing approval by the end of 2016. Numerous additional biologic and small molecule drug candidates are in the pipeline, and once deemed safe and effective will likely offer significant benefit to our psoriasis population.     

Emerging drugs for psoriatic arthritis

Introduction: The majority of Psoriatic Arthritis patients experience a good clinical response to anti-Tumor Necrosis Factor (TNF)-α therapies. However, treatment failure with anti-TNF-α can represent a relevant clinical problem.

Areas covered: We review the efficacy and safety profile of biological therapies that have been reported from randomized, controlled trials in phase II and phase III available in Pubmed Database for agents targeting IL-12/23p40 antibody (ustekinumab) and IL-17 (secukinumab), inhibitor of phosphodiesterase 4, (apremilast), and of JAK/STAT pathways (tofacitinib) and CTLA4 co-stimulation (abatacept) in Psoriatic Arthritis.

Expert opinion: In Psoriatic Arthritis, main emerging drugs are represented by the fully human monoclonal IL-12/23p40 antibody, ustekinumab, the agent targeting IL-17, secukinumab, and the inhibitor of phosphodiesterase 4, apremilast.

Results on T cell co-stimulation inhibition by abatacept are insufficient both in psoriasis and in PsA. In vitro investigations on JAK/STAT pathways in PsA suggest that tofacitinib could represent a further valuable therapeutic option.

Emerging biological treatments other than anti-TNF agents, ustekinumab, secukinumab and apremilast appear promising for Psoriatic Arthritis and recent studies have showed a good efficacy and an acceptable safety profile; however, further and long-term studies are advocated.     

Secukinumab:抗银屑病新药、白细胞介素-17抑制剂

Secukinumab是一种完全人源化的IgG1单克隆抗体,可以选择性地中和促炎性细胞因子白细胞介素17A(IL-17A),而IL-17和IL-23/T17轴在银屑病的发病机制中具有核心作用,因此,IL-17是银屑病治疗中的一个关键靶标。II期临床和III期临床试验研究表明secukinumab作为皮下注射的IL-17抑制剂,在中度至重度斑块型银屑病和银屑病关节炎(PsA)治疗中具有明显的优势,且安全性及耐受性良好。美国FDA于2015年1月已批准其作为治疗成人中度至重度斑块型银屑病的新药申请,是治疗该类疾病的第一个靶向IL-17的上市药物,预计到2020年其销售额将突破10亿美元。     

Adverse reactions to duloxetine in depression

Introduction: Untreated or inadequately treated depression is the largest risk factor for suicide. However, treatment with different antidepressants can have considerable adverse effects, including the increase of the frequency of suicidal thoughts and behavior. This review summarizes the frequency and severity of adverse events observed during the treatment of depression with duloxetine and considers their relevance to clinical practice.

Areas covered: A comprehensive review of the literature was conducted using PubMed and Medline databases listing data published until December 2010. Articles describing safety and tolerability of duloxetine were selected and reference lists of these articles were scrutinized for further relevant papers. In addition, US and EU Summaries of Product Characteristics were studied.

Expert opinion: Treatment with duloxetine was associated with mild to moderate adverse events; sexual dysfunction, nausea, headache, dry mouth, somnolence and dizziness being the most frequent among them. No increase in death from suicide and suicidal thoughts and behavior were detected as compared to placebo. So as to avoid discontinuation syndrome as a consequence of abrupt withdrawal of duloxetine, 2 weeks tapering has been recommended before discontinuation. Overall, duloxetine was found to be well tolerated and can be safely administered even in older patients and in those with concomitant illnesses.     

A safety assessment of biological therapies targeting the IL-23/IL-17 axis in inflammatory bowel diseases

Introduction: Many different compounds targeting the interleukin 23/17 axis have been developed and successfully studied in several autoimmune diseases, including inflammatory bowel diseases. Nevertheless, interfering with key immunological pathways raises potential safety concerns. This review focuses on the safety profile of these novel biological therapies.

Areas covered: A literature search until March 2017 was performed to collect safety data on different compounds targeting this pathway, with emphasis on ustekinumab and secukinumab. Firstly, the authors discuss briefly how genetics can inform about potential safety issues. Secondly, they extensively describe safety issues (common adverse events, infections, malignancies…), immunogenicity, exposure to ustekinumab in specific populations and provide advice for vaccination. Finally, they address safety profiles of secukinumab and other biological targeting the IL-23/17 axis in IBD.

Expert opinion: Current evidence suggests that ustekinumab therapy overweigh the potential drug-related risks. Additional safety data beyond randomized-controlled trials, derived from statistically powered, large prospective studies with long-term follow-up are urgently needed to assess the real-life ustekinumab-related risks and to establish the correct position of these novel class of biologicals in IBD treatment. Combining immunomodulators with ustekinumab seems to be safe, though prospective data specifically addressing this topic are currently missing. Similarly, the combination of different biological therapies still has to be studied.     

Emerging drugs for the treatment of axial spondyloarthritis

Introduction: The treatment of axial spondyloarthritis(axSpA) has been for nearly 15 years constricted to non-steroidal antirheumatic drugs and TNFα inhibitors. With the approval of secukinumab, a drug targeting the interleukin(IL)-17 axis became available. Nonetheless, an unmet need for further emerging therapeutic options remains.

Areas covered: This review summarizes the recent and ongoing clinical trials with novel drugs in axSpA. Besides secukinumab, further therapeutics directed against the IL-17A (e.g. ixekizumab) as well as the dual IL-17A and F inhibitor bimekizumab and the IL-17RA antibody brodalumab are in development. Furthermore, several drugs targeting the IL-12/-23 axis are being evaluated. Pan-JAK and JAK-1 inhibitors might offer another effective mode of action.

Expert opinion: The number of treatment options in axSpA is likely to be further extended in the coming years. Data of ongoing studies are needed to prove the efficacy of drugs directed against the IL-12/-23 axis as well as of JAK inhibition, whilst targeting the IL-17 axis was shown to be as effective as TNF inhibition by indirect comparison. There is an emerging need for trials aiming at identification of optimal treatment strategies in the scope of the treat-to-target concept in axSpA.     

Pharmacological treatment of children and adolescents with depression

Introduction: Despite an increasing number of studies, there is debate whether antidepressants have a favorable benefit/risk balance in depressed youth.

Areas covered: A systematic search identified 23 systematic reviews and meta-analyses published between 2010–2016. More than 30 controlled clinical trials were conducted in adolescents, but only a few in pre-pubertal patients. About one-third of the trials were severely statistically underpowered. Most studies failed to detect differences from placebo, but a few found fluoxetine effective. Although no suicide occurred in these studies, antidepressants increased suicidality risk (including suicidal ideation and behavior) versus placebo (OR = 2.39). Only two placebo-controlled trials with acceptable statistical power were publicly funded: both showed efficacy of fluoxetine, and one found a higher incidence of suicidality (OR = 3.7, 95% C.I. 1.00–13.7).

Expert opinion: In youth, antidepressants have, on average, a small therapeutic effect. The high placebo response is exacerbated by the large number of sites in many industry-funded studies. There is evidence that fluoxetine leads to greater and faster improvement than placebo or psychotherapy in adolescents. Considering both the high response to non-specific interventions and safety concerns, antidepressants should be used cautiously in youth, and limited to patients with moderate-to-severe depression for whom psychosocial interventions are either ineffective or not feasible.     

Topoisomerase II inhibitors in AML: past,present, and future

ABSTRACT

Introduction: Topoisomerase II inhibitors have long been used in the frontline and as salvage therapy for AML, with daunorubicin and idarubicin being prototypical agents in this therapeutic class, classically in combination with nucleoside analogs, e.g. cytarabine. Most recently, several other compounds from this drug class have or are being investigated.

Areas covered: The current paper reviews older and newer topoisomerase II inhibitors in clinical development for the treatment of AML. The authors discuss the clinical use of these agents, current trials involving them as well as their safety profile. Important side effects of these medications including therapy-related AML (t-AML) are also covered.

Expert opinion: Topoisomerase II inhibitors have helped improve outcomes in AML. Recently, the FDA approved several agents including CPX-351 for the treatment of secondary and t-AML. CPX-351 may have applicability in other high-risk myeloid diseases. Future directions include a combination of these agents with other targeted therapies. Finally, the authors believe that small molecule inhibitors, such as venetoclax and possibly immunotherapy options could also be incorporated to our treatment paradigm in selected patients.     

Targeting IL-6 for the treatment of rheumatoid arthritis: Phase II investigational drugs

Introduction: IL-6 is a key cytokine in the pathogenesis of rheumatoid arthritis (RA). The clinical efficacy of tocilizumab (TCZ), a humanized anti-IL6-receptor mAb, confirmed the value of IL-6 blockade in this disease. A number of new anti-IL-6 biologics are currently in Phase I – III of clinical development for RA.

Areas covered: This article reviews the available results from Phase II trials of investigational anti-IL-6 agents in RA. The authors discuss the potential relevance of alternative IL-6-blocking agents, with regard to their specific molecular targets in IL-6 signaling pathways and to the main open questions in the clinical research agenda for anti-IL-6 biologics.

Expert opinion: The results of Phase II trials of new anti-IL-6 biologics show promising results in terms of efficacy. The most frequently reported adverse events were not unexpected based on previous experience with TCZ. Further evidence is needed to appraise whether the difference in molecular structure or in the specific target of new anti-IL-6 biologics might result in added therapeutic value over TCZ. New data from Phase III trials that provides a head-to-head comparison against TCZ and anti-TNF agents with or without methotrexate background treatment are expected in the future.     

Comparative efficacy and safety of thirteen biologic therapies for patients with moderate or severe psoriasis: A network meta-analysis

PurposeThis network meta-analysis was aimed to enhance the corresponding evidence with respect to the efficacy and safety of biologic treatments.MethodsPubMed and EMBASE database searches were conducted. Odds ratios were used to evaluate multi-aspect comparisons. SUCRA was used to analyze the ranking of treatments in each endpoint. Psoriasis Area and Severity Index 50%, 75%, 90%, 100%, PGA, dermatology quality of life index were considered as outcomes while adverse events and discontinuation were adopted to evaluate safety.ResultsFor safety issues, briakinumab was associated with least headache and itolizumab had the lowest risk of infection. Ustekinumab performed best in discontinuation. SUCRA ranked briakinumab, brodalumab, Infliximab and ixekizumab as the favorable efficacy therapies, while briakinumab and brodalumab seemed to have mild side effects. No heterogeneity was observed between these comparisons.ConclusionsBriakinumab performed relatively stable under efficacy and safety outcome. Infliximab can be a good choice for its lower risk of infection. Brodalumab present very good potential in efficacy outcome like PASI and PGA. More clinical trials are required to supply more data about discontinuation of infliximab and infection of brodalumab and larger RCT for assessment of briakinumab.     

The safety of ixekizumab in psoriasis drug therapy

ABSTRACT

Introduction: Ixekizumab, a humanized IgG4 monoclonal antibody that selectively binds and neutralizes interleukin IL-17A, has been approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of moderate to severe plaque psoriasis (2016), active psoriatic arthritis (FDA 2017, EMA 2018), and active ankylosing spondylitis (FDA 2019).

Areas covered: This review evaluates the safety profile of ixekizumab for the treatment of moderate-to-severe psoriasis. A literature search was performed for articles published through November 2019.

Expert opinion: These studies show that ixekizumab demonstrates a favorable safety profile. Antidrug antibodies can be detected in up to 17% of patients but they do not significantly affect clinical response or safety of the treatment. Injection site reactions, erythema or pain, develop in up to 10% of the patients during the first 12 weeks of treatment, an incidence similar to that of etanercept. Infections overall do not cause a safety problem; mucocutaneous Candida infections, occur at a rate of in 1.9/100 patient-years, but are easily managed and usually do not determine treatment discontinuation. The occasional de novo appearance or exacerbation of preexistent inflammatory bowel disease remains a cause of concern, and requires close monitoring of patients at risk.     

Investigational luteinizing hormone releasing hormone (LHRH) agonists and other hormonal agents in early stage clinical trials for prostate cancer

Introduction: The treatment and management of prostate cancer continues to evolve; newer classes of agents and combination therapies are being developed and some are being investigated in early phase clinical trials.

Areas covered: We discuss investigational hormonal agents for the treatment of prostate cancer and focus primarily on luteinizing hormone releasing hormone (LHRH) agonists in early stage trials. We look at agents that target the hormonal axis, including anti-androgens, gonadotropins, estrogenic agents and progestogenic agents and other non-hormonal agents often used in combination with LHRH agonists. We review these candidates in the specific clinical niche in which they might find utility.

Expert opinion: Of all candidate compounds being evaluated in clinical trials, very few will receive FDA approval. Few, if any of the investigational agents discussed here will be used routinely in clinical practice for treating prostate cancer. Recognizing the reasons for the failure of agents to advance to later stage trials is important. Furthermore, a thorough understanding of the mechanisms underlying prostate cancer pathogenesis, including various points in the HGPA and parallel pathways, will help identify potentially actionable targets.     

Bedaquiline as part of combination therapy in adults with pulmonary multi-drug resistant tuberculosis

Introduction: Few innovative anti-microbial products have been brought to market in recent years to combat the global multidrug resistant-tuberculosis (MDR-TB) epidemic. Bedaquiline, a novel oral diarylquinoline, was approved by the US FDA as a part of combination therapy in adults with pulmonary MDR-TB based on phase II trials.

Area covered: Pubmed searches were conducted using search terms bedaquiline, diarylquinoline, R207910, and TMC207 was performed. Supplementary sources included World Health Organization, Clinicaltrial.gov, US Food and Drug Administration. Bedaquiline is an ATP synthase inhibitor specific for M. tuberculosis and some nontuberculous mycobacteria. It is metabolized by CYP3A4 and it’s drug exposure can be influenced by inducers and inhibitors of this enzyme. Phase II studies showed promising results on efficacy of bedaquiline when being used in combination with a background regimen for MDR-TB. Main safety concerns include QTc prolongation and hepatotoxicity. Phase III trials are ongoing to confirm efficacy findings from phase II studies and provide additional evidence of safety and efficacy.

Expert commentary: Critical data for long-term efficacy and safety are incomplete and scarce, supporting the cautious use of bedaquiline.     

Targeting IL-1 in depression

Introduction: Depression is associated with inflammation, Th1 and Th17 responses, oxidative and nitrosative stress (O&NS), autoimmune responses against neoantigenic determinants, and neuroprogression (i.e., neurodegeneration, impaired plasticity and reduced neurogenesis). These pathways involve increased monocytic activation and interleukin-1 (IL-1) levels.

Areas covered: This review will highlight the putative role of IL-1 in depression and the potential use of IL-1 signaling blockade as a treatment of depression. Electronic databases, i.e., Scopus, PUBMED and Google Scholar were employed using keywords: depression, depressive-like, interleukin-1, and interleukin-1 receptor antagonist (IL-1RA).

Expert opinion: Ample studies show that depression is accompanied by increased levels of IL-1 and IL-1RA, which attenuates the pro-inflammatory activities of IL-1. In some, but not all studies, antidepressant treatment decreased IL-1β levels. In translational models, IL-1β administration elicits depressive-like behaviors, neuroinflammation and neuroprogression, whereas treatment with IL-1RA yields antidepressant-like effects and attenuates neuroprogression. Anakinra, an IL-1RA, targets not only IL-1 signaling, but also Th1, Th17, O&NS and neuroprogressive pathways and therefore may be advanced to clinical Phase-II trials in depression due to medical conditions associated with an elevated IL-1/IL-1RA ratio.