Drugs

Marchetti Calônego, Marco Antônio; Sikandar, Shafaq; Ferris, Frank D.; Moreira de Barros, Guilherme Antonio

doi: 10.1007/s40265-020-01342-8pmid: 32533500

Pain is associated with emotional and physical suffering that severely impacts quality of life. Many guidelines for the treatment of moderate to severe cancer pain indicate the use of opioids. For a small proportion of the global population, opioids are readily accessible, but are consequently also subject to risk of overuse and misuse. On the other hand, many regions provide limited access to licensed opioid therapeutics and patients struggle for better pain management. The use of prescription opioids for treatment of severe cancer and acute pain is well established, but opioid use in chronic non-cancer pain is controversial and not supported by the literature. The opioid crisis and the increasing overdose fatalities in some countries have resulted in a resurgence of opiophobia in these countries, but even worse, amplified opiophobia in countries with lower opioid consumption. In this narrative review, we highlight how the opioid crisis of overuse in some countries can negatively impact appropriate access to opioids elsewhere. The availability of opioids for clinical and recreational use differs between countries worldwide—this is an important factor in determining the occurrence of a ‘crisis of recreational use of opioids’ or a ‘crisis of under-prescription of opioids’ for pain management.

Kichler, Adam; Jang, Sunguk

doi: 10.1007/s40265-020-01360-6pmid: 32647920

Chronic pancreatitis is a clinical entity that results from the progressive inflammation and irreversible fibrosis of the pancreas resulting from the cumulative injury sustained by the pancreas over time. It is an illness with variable presentations that can severely impact quality of life, while its long-term complications such as exocrine pancreatic insufficiency (EPI), diabetes mellitus, and risk of pancreatic cancer can become life threatening. The diagnosis of chronic pancreatitis can be challenging as despite the recent advancements in imaging technology, the radiographic findings do not become prominent until late stages of disease. Thus, the physicians’ clinical acumen in obtaining thorough history taking focusing on risk factors, clinical symptoms, in addition to high-quality imaging, often guide to the accurate diagnosis of chronic pancreatitis. Endoscopy also plays a pivotal role in the diagnosis and management of chronic pancreatitis. Endoscopic ultrasound (EUS) is believed to be the most sensitive modality for diagnosing chronic pancreatitis. Despite efforts, however, natural history studies have demonstrated that 61% of individuals with chronic pancreatitis will require at least one endoscopic intervention, while 31% will require a surgical procedure as part of their management strategy. Recent advancements in genomic studies have furthered our understanding of the genetic polymorphisms that are associated with the pathogenesis of chronic pancreatitis. Genetic testing offers the potential to reveal treatable pancreatitis-related disorders, and can inform decision making with regard to radical therapies for persistent or severe disease such as total pancreatectomy with islet autotransplantation (TPIAT). The management of patients suffering from chronic pancreatitis often requires a multi-disciplinary approach, addressing pertinent symptoms as well as the sequelae of chronic inflammation and fibrosis. Abdominal pain is the prevailing symptom and most common complication of chronic pancreatitis, and impairs quality of life. Although heavily dependent on a wide range of analgesia, endoscopic treatment such as endoscopic retrograde cholangiopancreatography (ERCP) and surgical intervention can offer long-lasting relief of symptoms. For EPI, treatment with pancreatic enzyme supplements offers marginal-to-moderate relief. The most feared complication of chronic pancreatitis—the development of pancreatic cancer—has no known prevention measure to date.

Hirsch, Laure; Flippot, Ronan; Escudier, Bernard; Albiges, Laurence

doi: 10.1007/s40265-020-01327-7pmid: 32601914

Immune checkpoint inhibitors (ICIs) in combination with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have become a new standard of care in treatment-naïve patients with advanced renal cell carcinoma (RCC). The rationale for these combinations relies on the interplay between the immune and angiogenic systems. The angiogenic factors and their receptors can promote an immunosuppressive tumor microenvironment by a direct effect on the innate immune cells and adaptive immune cells, and by an indirect effect through their influence on endothelial cells. Antiangiogenic therapies counteract these immunosuppressive effects by increasing tumor infiltration of mature dendritic cells and effector T cells, and decreasing tumor infiltration of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. The immunomodulatory properties of antiangiogenic therapies combined with ICIs may provide enhanced activity through various mechanisms of action. Different associations with ICIs such as programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors and antiangiogenic therapies such as VEGFR-TKI or bevacizumab have been tested and led to the approval of pembrolizumab plus axitinib and avelumab plus axitinib in the first-line treatment of patients with advanced RCC. Other VEGFR axis inhibitors and ICI combinations are currently being tested with promising results. More combinations of immune agents, including cancer vaccines and immunostimulatory agents, are also being evaluated in association with VEGFR-TKI. Defining the best combination for each patient as well as the optimal therapeutic sequence will be essential to guide treatment decisions in clinical practice.

Harigai, Masayoshi; Honda, Suguru

doi: 10.1007/s40265-020-01349-1pmid: 32681420

Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors to the nucleus. Recently developed JAK inhibitors (JAKinibs) inhibit JAKs non-selectively or selectively and down-regulate the effects of corresponding ligands (i.e. cytokines and growth factors). JAKinibs are efficacious against rheumatoid arthritis and other immune-mediated inflammatory diseases and are being increasingly prescribed clinically. Regarding safety, JAKinib use is associated with common or unique changes in laboratory parameters; however, incidence rates of serious adverse drug reactions (ADRs) associated with these changes are low. Opportunistic and other infections, including tuberculosis, are the most critical ADRs of treatment with JAKinibs, and screening and monitoring of patients should be carefully performed. Incidence rates of herpes zoster (HZ) in patients receiving JAKinibs are high in Japan and Korea, and modestly high in other countries. Filgotinib may not be associated with an elevated risk for HZ, but long-term safety data are lacking. Data from clinical development programmes and post-marketing surveillance have indicated no increased risk for malignancy or serious cardiac events; however, long-term observational studies are necessary. Despite the non-elevated risk of gastrointestinal perforations, patients with older age and/or a history of diverticulitis or receiving non-steroidal anti-inflammatory drugs should be carefully evaluated to determine the risk-benefit balance. The incidence rates of venous thromboembolism with all approved doses are similar to that expected in the population, although there are discrepancies in the placebo-controlled portion of the baricitinib clinical development programmes. Regulatory agencies in the USA and Europe suggested a higher risk for thrombotic events in patients receiving JAKinibs. Pharmacokinetic studies demonstrated that dose adjustment should be considered for JAKinib use in patients with moderate-to-severe renal or hepatic dysfunction, depending on the metabolism of each drug. Long-term observational studies enrolling patients with diverse clinical backgrounds are required to strike a risk-benefit balance in clinical settings.

Trojan, Jörg

doi: 10.1007/s40265-020-01361-5pmid: 32671719

Cabozantinib (Cabometyx®) is a potent multikinase inhibitor targeting the vascular endothelial growth factor (VEGF) receptor 2, the mesenchymal-epithelial transition factor (MET) receptor, and the “anexelekto” (AXL) receptor tyrosine kinase. It is approved for the treatment of advanced hepatocellular carcinoma (HCC) after failure of sorafenib in Europe (since November 2018) and in the USA (since January 2019). The approval of cabozantinib was based on results of the randomized, placebo-controlled, phase 3 CELESTIAL trial in patients with unresectable HCC, who received one or two prior lines of treatment including sorafenib. At the second planned interim analysis, the trial was stopped, because the primary end point overall survival was clearly in favor for cabozantinib. Additionally, median progression-free survival was superior to placebo. The most common ≥ grade 3 relevant adverse events in patients with HCC treated with cabozantinib were palmar–plantar erythrodysesthesia, hypertension, fatigue, and diarrhea. In this review, current data on cabozantinib for the treatment of patients with advanced HCC, with a focus on the management of common adverse events and ongoing clinical trials, are discussed.

Sneyers, Barbara; Duceppe, Marc-Alexandre; Frenette, Anne Julie; Burry, Lisa D.; Rico, Philippe; Lavoie, Annie; Gélinas, Céline; Mehta, Sangeeta; Dagenais, Maryse; Williamson, David R.; Perreault, Marc M.

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Blair, Hannah A.

doi: 10.1007/s40265-020-01357-1pmid: 32632826

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.

Scott, L. J.

doi: 10.1007/s40265-020-01358-0pmid: 32666425

The global spread of antibacterial-resistant strains, especially methicillin-resistant Staphylococcus aureus (MRSA) for acute bacterial skin and skin structure infections (ABSSSIs), has driven the need for novel antibacterials. Delafloxacin [Quofenix™ (EU); Baxdela® (USA)], a new fluoroquinolone (FQ), has a unique chemical structure that enhances its antibacterial activity in acidic environments such as occurs in ABSSSIs (including S. aureus infections). Delafloxacin (intravenous and oral formulations) is approved in several countries for the treatment of adults with ABSSSIs (featured indication). In intent-to-treat analyses in pivotal phase 3 trials in adults with ABSSSIs, including those with comorbid disease, intravenous delafloxacin monotherapy (± oral switch after six doses) twice daily was noninferior to intravenous vancomycin + aztreonam for primary endpoints, as specified by the FDA (objective response rate at 48–78 h after initiation of therapy) and the EMA [investigator-assessed clinical cure rate at the follow-up visit at day 14 (± 1 day)]. Delafloxacin was generally well tolerated, with most treatment-related adverse events mild to moderate in severity and few patients discontinuing treatment because of these events. Relative to vancomycin + aztreonam (a non-FQ regimen), delafloxacin treatment was not associated with an increased risk of FQ-associated AEs of special interest. Given its unique chemical structure that confers novel properties relative to other FQ and its broad spectrum of activity against common clinically relevant Gram-positive pathogens, including against MRSA strains (± FQ-resistance mutations), and Gram-negative pathogens, intravenous delafloxacin (± oral switch) provides a novel emerging option for the treatment of adult patients with ABSSSIs.

Frampton, James E.

doi: 10.1007/s40265-020-01370-4pmid: 32729016

Inebilizumab (Uplizna™; inebilizumab-cdon in the USA) is a humanised anti-CD19 monoclonal antibody being developed by Viela Bio for the treatment of a range of autoimmune diseases associated with CD19-expressing B cells. Inebilizumab targets and depletes CD19-expressing B cells through antibody-dependent cell-mediated cytotoxicity. In June 2020, inebilizumab received its first global approval in the USA for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are seropositive for immunoglobulin G autoantibodies against aquaporin-4 (AQP4-IgG). The drug is also undergoing clinical evaluation for kidney transplant desensitization, myasthenia gravis, and IgG4-related disease. This article summarizes the milestones in the development of inebilizumab leading to this first approval for the treatment of AQP4-IgG seropositive NMOSD.

Lee, Arnold; Blair, Hannah A.

doi: 10.1007/s40265-020-01366-0pmid: 32700064

The article Dexamethasone Intracanalicular Insert: A Review in Treating Post-Surgical Ocular Pain and Inflammation, written by Arnold Lee and Hannah A. Blair, was originally published electronically in SpringerLink on 25 June 2020 without Open Access.