Drugs最新文献

Inavolisib (Itovebi^™) is an orally administered, phosphatidylinositol-3-kinase alpha (PI3Kα) inhibitor being developed by Genentech, a member of the Roche group, for the treatment of solid tumours. On 10 October 2024, inavolisib received its first approval in the USA in combination with palbociclib and fulvestrant for the treatment of adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. In the EU and other countries worldwide, regulatory review of inavolisib is currently underway. This article summarises the milestones in the development of inavolisib leading to this first approval for endocrine-resistant, PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

Buprenorphine is an agonist at the mu opioid receptor (MOR) and antagonist at the kappa (KOR) and delta (DOR) receptors and a nociceptin receptor (NOR) ligand. Buprenorphine has a relatively low intrinsic efficacy for G-proteins and a long brain and MOR dwell time. Buprenorphine ceiling on respiratory depression has theoretically been related multiple factors such as low intrinsic efficacy at MOR, binding to six-transmembrane MOR and interactions in MOR/NOR heterodimers. Buprenorphine reduces analgesic tolerance by acting as a delta opioid receptor (DOR) antagonist. As a kappa opioid receptor (KOR) antagonist, buprenorphine reduces craving associated with addiction. Buprenorphine is a model opioid for the ordinal bifunctional analogs BU10038, BU08028 which have been shown to be potent analgesics in non-human primates without reinforcing effects and little to no respiratory depression.

Type 1 diabetes mellitus (T1DM) is characterized by the progressive, autoimmune-mediated destruction of β cells. As such, restoring immunoregulation early in the disease course is sought to retain endogenous insulin production. Nevertheless, in the more than 100 years since the discovery of insulin, treatment of T1DM has focused primarily on hormone replacement and glucose monitoring. That said, immunotherapies are widely used to interdict autoimmune and autoinflammatory diseases and are emerging as potential therapeutics seeking the preservation of β-cell function among those with T1DM. In the past 4 decades of diabetes research, several immunomodulatory therapies have been explored, culminating with the US Food and Drug Administration approval of teplizumab to delay stage 3 (clinical) onset of T1DM. Clinical trials seeking to prevent or reverse T1DM by repurposing immunotherapies approved for other autoimmune conditions and by exploring new therapeutics are ongoing. Collectively, these efforts have the potential to transform the future of diabetes care. We encapsulate the past 40 years of immunotherapy trials, take stock of our successes and failures, and chart paths forward in this new age of clinically available immune therapies for T1DM.

Neurotrophic keratitis is a rare eye condition characterised by reduced or absent corneal sensation. This leads to impaired corneal healing through a loss of protective mechanisms such as blinking. The cornea becomes vulnerable to persistent epithelial defects, ulceration, infection and ultimately, vision loss or loss of the eye. Treatment strategies aim to protect the corneal surface and promote re-epithelialisation. Established treatments include specialised eye drops such as blood serum eye drops and topical nerve growth factor. In some cases, surgical interventions or procedures such as amniotic membrane transplantation or corneal neurotisation may be necessary. Emerging therapeutic drug options include insulin drops, BRM424, CSB-001 and varenicline. The aim of this Current Opinion is to introduce and review this field for the general reader, paying particular attention to emerging drug therapies for neurotrophic keratitis.

The rise of antimicrobial resistance represents a significant global health threat, driven by the diminishing efficacy of existing antibiotics, a lack of novel antibacterials entering the market, and an over- or misuse of existing antibiotics, which accelerates the evolution of resistant bacterial strains. This review focuses on innovative therapies by highlighting 19 novel antibacterials in clinical development as of June 2024. These selected compounds are characterized by new chemical scaffolds, novel molecular targets, and/or unique mechanisms of action, which render their potential to break antimicrobial resistance particularly high. A detailed analysis of the scientific foundations behind each of these compounds is provided, including their pharmacodynamic profiles, current development state, and potential for overcoming existing limitations in antibiotic therapy. By presenting this subset of chemically novel antibacterials, the review highlights the ability to innovate in antibiotic drug development to counteract bacterial resistance and improve treatment outcomes.

The human microbiome exerts profound influence over various biological processes within the body. Unlike many host determinants, it represents a readily accessible target for manipulation to promote health benefits. However, existing commercial microbiome-directed products often exhibit low efficacy. Advancements in technology are paving the way for the development of novel microbiome therapeutics, across a wide range of indications. In this narrative review, we provide an overview of state-of-the-art technologies in late-stage development, examining their advantages and limitations. By covering a spectrum, from fecal-derived products to live biotherapeutics, phage therapy, and synthetic biology, we illuminate the path toward the future of microbiome therapeutics.

The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.

Lysosomal storage disorders (LSDs) are rare inherited metabolic disorders characterized by defects in the function of specific enzymes responsible for breaking down substrates within cellular organelles (lysosomes) essential for the processing of macromolecules. Undigested substrate accumulates within lysosomes, leading to cellular dysfunction, tissue damage, and clinical manifestations. Clinical features vary depending on the degree and type of enzyme deficiency, the type and extent of substrate accumulated, and the tissues affected. The heterogeneous nature of LSDs results in a variety of treatment approaches, which must be tailored to patient presentation and characteristics. The treatment landscape for LSDs is rapidly evolving. An up-to-date discussion of current evidence is required to provide clinicians with an appropriate overview of treatment options. Therefore, we aimed to review current and ongoing trials pertaining to the treatment of common LSDs.

Liposomal irinotecan (Onivyde^®), also known as liposomal pegylated irinotecan, has been developed with the intent of maximising anti-tumour efficacy and minimising drug-related toxicities compared with conventional formulations of this topoisomerase 1 inhibitor. In combination with fluorouracil, leucovorin and oxaliplatin (NALIRIFOX), liposomal irinotecan is approved in the USA and the EU for first-line therapy of eligible patients with metastatic pancreatic adenocarcinoma. In a phase III clinical trial, NALIRIFOX significantly improved overall survival (OS) and progression free survival (PFS) compared with gemcitabine plus nanoparticle albumin bound paclitaxel (nab-paclitaxel) as first-line treatment of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). The safety profile of NALIRIFOX was generally manageable, with diarrhoea, hypokalaemia and neutropenia being the most common grade ≥ 3 treatment-emergent adverse events. Although further analyses will help position the liposomal irinotecan-containing regimen NALIRIFOX in first-line treatment of metastatic pancreatic adenocarcinoma, current evidence indicates that it is a useful addition to treatment options in this patient population.

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of hormone-receptor positive (HR+), HER2 negative (HER2-) metastatic breast cancer, and are now also established agents in the treatment of high-risk and intermediate-risk HR+ early breast cancer. Several strategies regarding CDK4/6i combinations or continuation beyond progression have been successfully evaluated in the metastatic setting, and are considered a standard of care. Mechanism of action of and resistance mechanisms against CDK4/6i in addition to endocrine resistance represent an important research topic, important for the treatment of HR+ breast cancer. Clinically, CDK4/6i are efficient substances that are usually well tolerated. However, side effects differing between the substances have been reported, and might lead to treatment discontinuation, including in the early disease setting. In the adjuvant setting, the addition of palbociclib to standard endocrine treatment has not improved outcomes, whereas large randomized phase III trials have demonstrated significant disease-free survival benefit for the addition of ribociclib (NATALEE trial) and abemaciclib (monarchE trial). Patient selection, treatment duration, endocrine backbone therapy, and other study details differ between these pivotal trials. This review focuses on both the scientific background as well as all available clinical data of CDK4/6i, with particular emphasis on their use in early breast cancer.