Drugs

Ji, Changyi; Sigurdsson, Einar M.

doi: 10.1007/s40265-021-01546-6pmid: 34101156

Tau immunotherapies have advanced from proof-of-concept studies to over a dozen clinical trials for Alzheimer’s disease (AD) and other tauopathies. Mechanistic studies in animal and culture models have provided valuable insight into how these therapies may work but multiple pathways are likely involved. Different groups have emphasized the importance of intracellular vs extracellular antibody-mediated clearance of the tau protein and there is no consensus on which pool of tau should ideally be targeted. Likewise, various normal and disease-selective epitopes are being targeted, and the antibody isotypes either favor phagocytosis of the tau-antibody complex or are neutral in that aspect. Most of the clinical trials are in early stages, thus their efficacy is not yet known, but all have been without any major adverse effects and some have reported target engagement. A few have been discontinued. One in phase I, presumably because of a poor pharmacokinetic profile, and three in phase II for a lack of efficacy although this trial stage is not well powered for efficacy measures. In these phase II studies, trials with two antibodies in patients with progressive supranuclear palsy or other primary tauopathies were halted but are continuing in patients with AD, and one antibody trial was stopped in early-stage AD but is continuing in moderate AD. These three antibodies have been reported to only work extracellularly and tau is not increased in the cerebrospinal fluid of primary tauopathies, which may explain the failures of two of them. In the discontinued AD trial, there are some concerns about how much of extracellular tau contains the N-terminal epitope that is being targeted. In addition, extracellular tau is only a small part of total tau, compared to intracellular tau. Targeting only the former may not be sufficient for functional benefits. Given these outcomes, decision makers within the pharmaceutical companies who green light these trials should attempt to target tau not only extracellularly but also intracellularly to increase their chances of success. Hopefully, some of the ongoing trials will provide some functional benefits to the large number of patients with tauopathies.

Lin, Eric Y; Adamson, Paul C; Klausner, Jeffrey D.

doi: 10.1007/s40265-021-01530-0pmid: 34097283

Neisseria gonorrhoeae is the second most common bacterial sexually transmitted infection in the world after Chlamydia trachomatis. The pathogen has developed resistance to every antibiotic currently approved for treatment, and multidrug-resistant strains have been identified globally. The current treatment recommended by the World Health Organization is ceftriaxone and azithromycin dual therapy. However, resistance to azithromycin and ceftriaxone are increasing and treatment failures have been reported. As a result, there is a critical need to develop novel strategies for mitigating the spread of antimicrobial-resistant N. gonorrhoeae through improved diagnosis and treatment of resistant infections. Strategies that are currently being pursued include developing molecular assays to predict resistance, utilizing higher doses of ceftriaxone, repurposing older antibiotics, and developing newer agents. In addition, efforts to discover a vaccine for N. gonorrhoeae have been reignited in recent years with the cross-protectivity provided by the N. meningitidis vaccine, with several new strategies and targets. Despite the significant progress that has been made, there is still much work ahead to combat antimicrobial-resistant N. gonorrhoeae globally.

Jin, Zhaosheng; Daksla, Neil; Gan, Tong J.

doi: 10.1007/s40265-021-01532-ypmid: 34106456

Postoperative nausea and vomiting (PONV) are the second most frequent adverse events after surgery second only to postoperative pain. Despite the advances in antiemetics and implementation of multimodal prophylactic interventions, the clinical management of PONV remains problematic. Neurokinin-1 (NK-1) receptor is a tachykinin receptor found throughout the central and peripheral nervous systems, with a particular affinity towards substance P. NK-1 receptors interact with several parts of the neuronal pathway for nausea and vomiting. This includes the chemoreceptor trigger zone, the gastrointestinal tract, and dorsal motor nucleus of the vagus. NK-1 antagonists are thought to prevent nausea and vomiting by downregulating the emetogenic signals at those points. As more head-to-head trials are conducted between the various anti-emetics, there is emerging evidence that NK-1 antagonists may be more effective in preventing PONV than several other antiemetics currently in use. In this review, we will discuss the pharmacology of NK-1 antagonists, their efficacy in clinical practice, and how they could fit into the framework of PONV management.

Hasegawa, Sho; Yoneda, Masato; Kurita, Yusuke; Nogami, Asako; Honda, Yasushi; Hosono, Kunihiro; Nakajima, Atsushi

doi: 10.1007/s40265-021-01545-7pmid: 34142342

Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.

Lee, Arnold; Shirley, Matt

doi: 10.1007/s40265-021-01544-8pmid: 34196946

Remimazolam (Byfavo™) is a benzodiazepine sedative that is indicated for the induction and maintenance of procedural sedation in adults. Remimazolam was efficacious in three phase III trials in patients requiring endoscopies. Significantly higher procedure success rates (composite of the completion of the procedure, top-up doses of study drug within predefined limits and no requirement for rescue therapy) were observed with remimazolam than with placebo, with the majority of placebo recipients requiring rescue midazolam. Furthermore, remimazolam significantly reduced times to onset of sedation and recovery in comparison with placebo (plus rescue). Remimazolam is generally well tolerated, with hypotension and hypertension the most common adverse drug reactions. Higher doses of concomitant fentanyl with remimazolam may increase the incidence of adverse drug reactions and deep sedation events. However, no correlation was observed between depth of sedation and vital signs. In summary, remimazolam is a useful option for the induction and maintenance of procedural sedation. Although pharmacoeconomic analyses for remimazolam are not yet available, the rapid induction of sedation and short recovery times with remimazolam may be beneficial in improving patient throughput in clinics.

Blair, Hannah A.

doi: 10.1007/s40265-021-01551-9pmid: 34228280

Prolonged-release (PR; as ascribed in the EU) or extended-release (as ascribed in the USA) bupivacaine/meloxicam (HTX-011; hereafter referred to as bupivacaine/meloxicam PR; Zynrelef®) is a synergistic fixed-dose combination (FDC) of the local anaesthetic bupivacaine and the NSAID meloxicam. It is approved in the EU and the USA to treat postoperative pain. After needle-free application at the surgical site, the novel polymer technology allows simultaneous diffusion of bupivacaine and meloxicam over 72 h. In clinical trials, bupivacaine/meloxicam PR significantly reduced postoperative pain and opioid consumption relative to bupivacaine hydrochloride (HCl) and placebo in patients undergoing bunionectomy, herniorrhaphy or total knee arthroplasty (TKA). When used as the foundation of a scheduled non-opioid multimodal analgesia (MMA) regimen, bupivacaine/meloxicam PR further improved pain control and reduced the need for opioids following surgery. Bupivacaine/meloxicam PR was generally well tolerated, with a lower incidence of opioid-related adverse events than bupivacaine HCl and placebo. Although additional data would be beneficial, current evidence indicates that bupivacaine/meloxicam PR is a promising non-opioid treatment option for the management of postoperative pain.

Markham, Anthony

doi: 10.1007/s40265-021-01539-5pmid: 34106455

Dostarlimab (Jemperli™; GlaxoSmithKline) is a humanized monoclonal antibody programmed death-1 (PD-1) receptor antagonist being developed for the treatment of various cancers. Based on preliminary results from the GARNET trial dostarlimab has recently been approved in the EU and USA for the treatment of adult patients with mismatch repair deficient recurrent or advanced endometrial cancer. This article summarizes the milestones in the development of dostarlimab leading to these first approvals.

Lee, Arnold

doi: 10.1007/s40265-021-01541-xpmid: 34118019

Fuzuloparib (AiRuiYi®, 艾瑞颐; formerly fluzoparib) is a small molecule, orally active PARP inhibitor being developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. (formerly Jiangsu Hengrui Medicine Co., Ltd.) for the treatment of solid cancers. Fuzuloparib has been approved in China for the treatment of ovarian cancer (including fallopian tube cancer or primary peritoneal cancer), and phase II and III trials are investigating fuzuloparib for the treatment of other solid cancers, including cancers of the pancreas, breast, prostate and lungs. This article summarizes the milestones in the development of fuzuloparib leading to this first approval for the treatment of platinum-sensitive recurrent ovarian cancer, fallopian tube cancer or primary peritoneal cancer in patients with germline BRCA mutation who have undergone second-line or above chemotherapy.

Lee, Arnold

doi: 10.1007/s40265-021-01570-6pmid: 34245448

Lee, Arnold

doi: 10.1007/s40265-021-01550-wpmid: 34143407

Loncastuximab tesirine (loncastuximab tesirine-lpyl; ZYNLONTA™) is an antibody-drug conjugate being developed for the treatment of B cell lymphomas by ADC Therapeutics SA. Loncastuximab tesirine consists of a pyrrolobenzodiazepine DNA-alkylating warhead covalently attached via a cleavable linker to an anti-CD19 antibody that binds to B cells. It is currently approved in the US for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL), and is being developed for the treatment of mantle-cell lymphoma, follicular lymphoma and acute lymphoblastic leukaemia. This article summarizes the milestones in the development of loncastuximab tesirine leading to this first approval for relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including DLBCL not otherwise specified (NOS), DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma.