Expert opinion on investigational drugs最新文献

Introduction: Obsessive-compulsive personality disorder (OCPD) is a common psychopathological condition that generally causes a significant maladjustment in affected individuals. Despite its prevalence, there are no univocal and defined guidelines for the treatment of this condition, and the literature evidence on this topic is scant and controversial.

Areas covered: This narrative review synthesizes clinical trials, case reports, and experimental proposals for OCPD treatment in the light of the most recent neurobiological models. We aimed to review current therapeutic evidence for the disorder and evaluate their effectiveness, proposing potential rationales to guide future strategies.

Expert opinion: Although no guidelines are available for OCPD, given the paucity of controlled studies, a possibility to overcome this gap might rely on identifying among the currently available and emerging therapies those that may appear most promising for improving the outcome of the disorder and suggesting novel therapeutic targets. In this way, this paper might represent a sort of 'call to action' to the scientific deepening of the mode of action of those treatments that could be of help to improve the detrimental quality of life of OCPD patients.

Introduction: Multidrug-resistant Pseudomonas aeruginosa infections have disseminated globally and are associated with high mortality due to the considerable virulence of the pathogen and the limited therapeutic options. This has led to efforts to develop new treatment options for such infections.

Areas covered: This review evaluated the most recent literature on the relevant traditional and non-traditional antibiotics currently being developed in Phases 1, 2, and 3 clinical trials. We conducted a PubMed literature search, as well as a backward citation search of relevant studies. Traditional agents in clinical development include β-lactam/β-lactamase inhibitors (funobactam, taniborbactam, QPX2014-xeruborbactam), aminoglycosides (apramycin), polymyxin derivatives (upleganan, MRX-8, and SPR741), fluoroquinolones (MP-376), and lipopolysaccharide transport inhibitors (murepavadin). Non-traditional antibiotics in clinical development include anti-virulence agents (fluorothiazinone), monoclonal antibodies (INFEX-702, TRL-1068, and CMTX-101), bacteriophages (AP-PA02, YPT-01, BX004-A, and WRAIR-PAM-CF1), and miscellaneous agents (AR-501, PLG-0206, SNSP-113, OligoG CF-5/20, and ALX-009).

Expert opinion: A considerable number of antimicrobial agents, some with novel mechanisms of action, are in clinical phases of development for treating Pseudomonas aeruginosa infections. The urgent need for more therapeutic options necessitates the rapid optimization of progress to introduce new agents into clinical practice.

Introduction: Colorectal cancer, a significant global challenge, requires innovative treatment strategies. DNA topoisomerase I inhibitors, which disrupt DNA replication in rapidly proliferating cancer cells, have shown great potential. Natural product derivatives, such as camptothecin (CPT), and emerging compounds for CRC treatment have made significant progress.

Areas covered: This review article summarizes the state of the art in the development of selective topoisomerase I inhibitors, which show in vitro and in vivo activity against colorectal cancer in preclinical and early stage clinical trials. The compounds are classified into natural compounds and derivatives and new synthetic compounds classified according to their cyclic structure.

Expert opinion: Despite the success of CPT derivatives like irinotecan, topotecan and belotecan (approved drugs), drawbacks such as lactone instability have led to the development of modified compounds. Structural modifications in CPT derivatives, like derived homocamptothecins, show enhanced efficacy and reduced toxicity. Additionally, synthetic compounds like indenoisoquinolines and quinolines have emerged as potent TOP1 inhibitors. Dual inhibitors, combination therapies, integration with immunotherapy and personalized medicine further enhance treatment efficacy. Ongoing preclinical studies offer hope for improved CRC management.

Introduction: The addition of the anti-CD38 monoclonal antibody isatuximab to standard therapies is transforming the care of patients with newly diagnosed multiple myeloma (NDMM), as previously seen in the relapsed/refractory setting. This is particularly important for patients with NDMM as early treatment with effective, well tolerated therapies may ensure better clinical outcomes.

Areas covered: Here, we examine recent results from pivotal Phase 3 and 2 clinical trials that demonstrate efficacy and safety of isatuximab across multiple combinations, for both transplant-ineligible and transplant-eligible NDMM patients. We then evaluate long-term outcomes from the IKEMA and ICARIA-MM trials as well as real-world evidence emerging from analyses conducted in patients with relapsed/refractory MM (RRMM). Further, we address current approaches to optimize treatment with isatuximab-based combinations involving changes in bortezomib or dexamethasone dosing. Lastly, we review current findings with new administration modalities developed to optimize delivery of isatuximab in the clinic.

Expert opinion: Supported by multiple lines of high-level evidence, isatuximab in combination with standard-of-care backbone therapies produces triplet or quadruplet regimens with enhanced efficacy and consistent safety for the treatment of patients with NDMM and RRMM.

Introduction: Lung cancer is a leading cause of cancer-related mortality. Brain metastasis (BM) has a high incidence in non-small cell lung cancer (NSCLC) and represents a devastating complication associated with poor prognosis and symptoms that significantly reduce the quality of life (QOL) in patients. Managing and controlling BM is critical for prolonging survival and improving QOL. Surgical resection, stereotactic radiosurgery, and whole-brain radiation therapy are key treatment modalities for patients with NSCLC and BM.

Areas covered: Molecular targeted drugs developed against driver gene mutations and immune checkpoint inhibitors have shown efficacy against BM. This review examines newly approved therapies by conducting a literature search on these topics. Therefore, it is essential to determine the most appropriate local and systemic therapies and the optimal timing to maximize overall survival and QOL.

Expert opinion: Despite the effectiveness of new drugs, a high mortality rate persists. We discuss future strategies for overcoming resistance and progression.

Introduction: AXL, a member of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases, controls pro-tumorigenic signaling cascades and cancer-immunological functions, and promotes drug resistance. Due to AXL's multifaceted role and therapeutic activity in preclinical studies, a variety of AXL inhibitors are being developed and tested in clinical trials for cancer treatment. Some clinical studies are showing promising results for AXL inhibitors as monotherapy and in combination with standard of care therapeutics. Currently, no selective AXL-targeting therapy has reached FDA-approval, but several compounds have entered phase II and III studies.

Area covered: We elaborate on the role of AXL in cancer progression and suppressing anti-cancer immunity at both the molecular level and immune cell interaction level. Additionally, we review pre-clinical and clinical data of AXL-targeting agents.

Expert opinion: Preclinical and several early clinical trials demonstrated the safety of AXL-targeting monotherapies with some evidence of efficacy. Additionally, multiple novel combination regimens including AXL-targeting agents to overcome resistance mechanisms are being actively examined with some promising results. However, patient selection and companion biomarkers may be critical for the success of AXL-targeting therapies.

Introduction: Xanomeline-trospium chloride (Cobenfy, KarXT) received FDA approval on September 26, 2024, for the treatment of adults with schizophrenia. Xanomeline-trospium chloride is the first muscarinic M1, M4 acetylcholine receptor partial agonist approved to treat schizophrenia. Preliminary evidence also indicates that xanomeline-trospium chloride improves measures of cognition in Alzheimer's disease and schizophrenia.

Areas covered: Acetylcholine's physiology as well as evidence implicating disturbance in acetylcholine availability and/or its canonical receptors in mania and cognitive impairment in bipolar disorder is synthesized. Extant efficacy, safety and tolerability data for xanomeline-trospium chloride in adults with schizophrenia are reviewed. Xanomeline-trospium chloride's clinical and pharmacological profile provides rationale for investigating its efficacy, safety and tolerability in the treatment of manic episodes, mixed features and cognitive impairment associated with bipolar disorder.

Expert opinion: Xanomeline-trospium chloride is a mechanistically novel treatment for schizophrenia targeting cholinergic receptors as opposed to dopamine receptors and may have transdiagnostic efficacy in mania, mixed features and/or cognitive impairment in bipolar disorder. Xanomeline-trospium chloride is safe and generally well tolerated and does not have depressogenic effects and/or increased suicidality in adults with schizophrenia. Whether other investigational muscarinic agonists (e.g. positive allosteric modulator [PAM] or orthosteric agonism of M4) are potentially efficacious in mania and/or cognitive impairment in bipolar disorder is a priority future research avenue.