Drugs

Favalli, Ennio Giulio; Maioli, Gabriella; Caporali, Roberto

doi: 10.1007/s40265-024-02059-8pmid: 38949688

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis.

Toyoda, Task; Mankia, Kulveer

doi: 10.1007/s40265-024-02061-0pmid: 38954266

Early intervention has been the cornerstone of improving outcomes in patients with rheumatoid arthritis. Over the past decade, the boundaries have been pushed in an attempt to achieve effective prevention strategies in those who are at high risk of developing rheumatoid arthritis. Core risk factors including the presence of serum anti-citrullinated protein antibodies, arthralgia and subclinical inflammation on imaging are highly predictive of arthritis development. The influence of air pollution, diet and the role of microbiome on disease progression are less clear. In turn, therapeutic focus has shifted to an earlier pre-arthritis phase of the disease continuum where the clinically apparent arthritis may potentially be intercepted. Seven proof-of-concept interventional trials in at-risk individuals have been conducted so far. Whether true prevention of rheumatoid arthritis is possible remains elusive. Promising signals towards permanent disease modulation and improvement in symptom burden were seen with some immunomodulatory therapies, whilst others were unsuccessful. Long-term follow-up is required to ascertain a true effect. Looking forward, a better understanding of the natural history and underlying biological mechanisms of arthritis development and more accurate, validated risk stratification is needed.

Sasegbon, Ayodele; Cheng, Ivy; Labeit, Bendix; Lapa, Sriramya; Rommel, Nathalie; Hamdy, Shaheen

doi: 10.1007/s40265-024-02064-xpmid: 38954267

Despite swallowing being a frequently performed daily function, it is highly complex. For a safe swallow to occur, muscles within the head, neck, and thorax need to contract in a concerted pattern, controlled by several swallowing centers at multiple levels of the central nervous system, including the midbrain, cerebral cortex, and cerebellum in addition to five cranial nerves. Dysphagia, or difficulty swallowing, is caused by a long list of pathologic processes and diseases, which can interfere with various stages along the swallowing sensorimotor pathway. When present, dysphagia leads to increased mortality, morbidity, hospital length of stay, and reduced quality of life. Current dysphagia management approaches, such as altering the texture and consistency of foods and fluids and teaching patients rehabilitative exercises, have been broadly unchanged for many years and, in the case of texture modification, are of uncertain effectiveness. However, evidence is emerging in support of new medication-based and neuromodulatory treatment approaches. Regarding medication-based therapies, most research has focused on capsaicinoids, which studies have shown are able to improve swallowing in patients with post-stroke dysphagia. Separately, albeit convergently, in the field of neuromodulation, there is a growing and positive evidential base behind three non-invasive brain stimulation techniques: repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (TDCS), and pharyngeal electrical stimulation (PES). Should some or all of these emerging therapies fulfill their promise, dysphagia-related patient outcomes may be improved. This paper describes the current state of our understanding regarding new medication and neuromodulation-based neurogenic oropharyngeal dysphagia treatments.

Horváth, Luděk; Mráz, Miloš; Jude, Edward B.; Haluzík, Martin

doi: 10.1007/s40265-024-02029-0pmid: 38970626

A global obesity pandemic is one of the most significant health threats worldwide owing to its close association with numerous comorbidities such as type 2 diabetes mellitus, arterial hypertension, dyslipidemia, heart failure, cancer and many others. Obesity and its comorbidities lead to a higher rate of cardiovascular complications, heart failure and increased cardiovascular and overall mortality. Bariatric surgery is at present the most potent therapy for obesity, inducing a significant weight loss in the majority of patients. In the long-term, a substantial proportion of patients after bariatric surgery experience a gradual weight regain that may, in some, reach up to a presurgical body weight. As a result, anti-obesity pharmacotherapy may be needed in some patients after bariatric surgery to prevent the weight regain or to further potentiate weight loss. This article provides an overview of the use of anti-obesity medications as an augmentation to bariatric surgery for obesity. Despite relatively limited published data, it can be concluded that anti-obesity medication can serve as an effective adjunct therapy to bariatric surgery to help boost post-bariatric weight loss or prevent weight regain.

Cao, Zhiying; Han, Kaiyue; Lu, Hanting; Illangamudalige, Sandalika; Shaheed, Christina Abdel; Chen, Lingxiao; McLachlan, Andrew J.; Patanwala, Asad E.; Maher, Christopher G.; Lin, Chung-Wei Christine; March, Lyn; Ferreira, Manuela L.; Mathieson, Stephanie

doi: 10.1007/s40265-024-02065-wpmid: 38937394

Background and ObjectiveAlthough paracetamol (acetaminophen) combined with other analgesics can reduce pain intensity in some pain conditions, its effectiveness in managing low back pain and osteoarthritis is unclear. This systematic review investigated whether paracetamol combination therapy is more effective and safer than monotherapy or placebo in low back pain and osteoarthritis.MethodsOnline database searches were conducted for randomised trials that evaluated paracetamol combined with another analgesic compared to a placebo or the non-paracetamol ingredient in the combination (monotherapy) in low back pain and osteoarthritis. The primary outcome was a change in pain. Secondary outcomes were (serious) adverse events, changes in disability and quality of life. Follow-up was immediate (≤ 2 weeks), short (> 2 weeks but ≤ 3 months), intermediate (> 3 months but < 12 months) or long term (≥ 12 months). A random-effects meta-analysis was conducted. Risk of bias was assessed using the original Cochrane tool, and quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE).ResultsTwenty-two studies were included. Pain was reduced with oral paracetamol plus a non-steroidal anti-inflammatory drug (NSAID) at immediate term in low back pain (paracetamol plus ibuprofen vs ibuprofen [mean difference (MD) − 6.2, 95% confidence interval (CI) −10.4 to −2.0, moderate evidence]) and in osteoarthritis (paracetamol plus aceclofenac vs aceclofenac [MD − 4.7, 95% CI − 8.3 to − 1.2, moderate certainty evidence] and paracetamol plus etodolac vs etodolac [MD − 15.1, 95% CI − 18.5 to − 11.8; moderate certainty evidence]). Paracetamol plus oral tramadol reduced pain compared with placebo at intermediate term for low back pain (MD − 11.7, 95% CI − 19.2 to − 4.3; very low certainty evidence) and osteoarthritis (MD − 6.8, 95% CI − 12.7 to −0.9; moderate certainty evidence). Disability scores improved in half the comparisons. Quality of life was infrequently measured. All paracetamol plus NSAID combinations did not increase the risk of adverse events compared to NSAID monotherapy.ConclusionsLow-to-moderate quality evidence supports the oral use of some paracetamol plus NSAID combinations for short-term pain relief with no increased risk of harm for low back pain and osteoarthritis compared to its non-paracetamol monotherapy comparator.

Hoy, Sheridan M.

doi: 10.1007/s40265-024-02063-ypmid: 39004659

Mavorixafor (XOLREMDI™) is an oral, selective C-X-C chemokine receptor 4 (CXCR4) antagonist developed by X4 Pharmaceuticals that blocks the binding of C-X-C chemokine ligand 12 (also known as stromal derived factor-1) to CXCR4. In April 2024, it became the first therapy to be approved for WHIM syndrome (named by an acronym for its observed characteristics of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis) in the USA, where it is indicated for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes. Clinical development of mavorixafor is ongoing for chronic neutropenic disorders. This article summarizes the milestones in the development of mavorixafor leading to this first approval for use in patients aged ≥ 12 years with WHIM syndrome to increase the number of circulating mature neutrophils and lymphocytes.

Keam, Susan J.

doi: 10.1007/s40265-024-02056-xpmid: 38967717

Zolbetuximab (VYLOY™), a recombinant, chimeric, anti-claudin 18.2 (CLDN18.2) monoclonal antibody (mAb), is being developed by Astellas Pharma Inc. for the treatment of patients with HER2-negative (HER2-), CLDN18.2-positive (CLDN18.2+) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma and CLDN18.2+ advanced pancreatic adenocarcinoma. In March 2024, zolbetuximab was approved in Japan for the treatment of patients with HER2-, CLDN18.2+ unresectable, advanced/recurrent gastric cancer (the gastric cancer indication includes GEJ cancer). Zolbetuximab is also undergoing regulatory review for HER2-, CLDN18.2+ advanced gastric or GEJ adenocarcinoma in the USA, the EU, China, Australia and several other countries. This article summarizes the milestones in the development of zolbetuximab leading to this first approval for the treatment of patients with CLDN18.2+ gastrointestinal malignancies.

Dhillon, Sohita

doi: 10.1007/s40265-024-02069-6pmid: 38967715

Tovorafenib (OJEMDA™) is a once-weekly oral, selective, brain-penetrant, type II RAF kinase inhibitor being developed by Day One Biopharmaceuticals, Inc., under a license from Takeda Oncology, for the treatment of paediatric low-grade glioma (pLGG) and solid tumours. Most pLGGs harbour alterations in the MAPK pathway, such as a BRAF mutation or BRAF fusion, which result in aberrant intracellular signalling. Tovorafenib is an inhibitor of mutant BRAF V600E, wild-type BRAF and wild-type CRAF kinases and BRAF fusions. In April 2024, tovorafenib received its first approval in the USA for the treatment of patients aged ≥ 6 months with relapsed or refractory pLGGs harbouring a BRAF fusion or rearrangement, or BRAF V600 mutation. It received accelerated approval for this indication based on the response rate and duration of response achieved in this population in the ongoing, pivotal, phase 2 FIREFLY-1 study. Clinical development of tovorafenib is underway in numerous countries worldwide. This article summarizes the milestones in the development of tovorafenib leading to this first approval for relapsed or refractory pLGG with an activating BRAF alteration.

Dhillon, Sohita

doi: 10.1007/s40265-024-02070-zpmid: 39023700

Tarlatamab (tarlatamab-dlle: IMDELLTRA™) is a first-in-class, half-life extended bispecific delta-like ligand 3 (DLL3)-directed CD3 T-cell engager being developed by Amgen for the treatment of small cell lung cancer (SCLC) and neuroendocrine prostate cancer. Tarlatamab binds to DLL3 on the surface of tumour cells and CD3 on the surface of cytotoxic T lymphocytes (CTLs), resulting in T-cell activation, release of inflammatory cytokines and CTL-mediated cell death of DLL3-expressing tumour cells. In May 2024, tarlatamab received its first approval in the USA for the treatment of adults with extensive stage SCLC (ES-SCLC) with disease progression on or after platinum-based chemotherapy. Tarlatamab received accelerated approval for this indication based on overall response rate and duration of response in the pivotal phase 2 DeLLphi-301 study, and continued approval may be contingent on the demonstration of clinical benefit in a confirmatory trial(s). Tarlatamab is under regulatory review in Brazil, Canada, Israel and the UK, and clinical studies are underway in multiple countries. This article summarizes the milestones in the development of tarlatamab leading to this first approval for ES-SCLC with disease progression on or after platinum-based chemotherapy.

Keam, Susan J.

doi: 10.1007/s40265-024-02072-xpmid: 39034326

Tunlametinib (科露平®) is an oral, selective, mitogen-activated protein kinase kinase 1 and 2 (MEK 1/2) inhibitor being developed by Shanghai KeChow Pharma, Inc. for the treatment of solid tumours with RAS and RAF mutations, including melanoma, non-small cell cancer (NSCLC), colorectal cancer (CRC) and neurofibromatosis type 1 (NF1) plexiform neurofibromas. In March 2024, tunlametinib was granted conditional approval in China (based on surrogate endpoints) for use in patients with NRAS-mutated advanced melanoma who have failed anti-PD-1/PD-L1 treatment. This article summarizes the milestones in the development of tunlametinib leading to this first approval for the treatment of solid tumours with RAS and RAF mutations.