Expert opinion on investigational drugs最新文献

Objective: HE009, a novel selective sphingosine-1-phosphate receptor-1 (S1P1) modulator, was evaluated in healthy Chinese subjects to assess its pharmacokinetics, pharmacodynamics, and safety profile.

Research design and methods: This randomized, placebo-controlled phase I study comprised single ascending dose (SAD, 0.05-4.0 mg), multiple ascending dose (MAD, 0.5-3.0 mg), dose titration, and food effect components.

Results: HE009 exhibited dose-proportional exposure, with T_maxof 4-6 h and t_1/2 of 16-24 h, supporting once-daily dosing. Steady-state was achieved by day 7 with minimal accumulation (1.7-2.0 fold). A clear concentration-effect relationship was observed, with maximum lymphocyte count reductions of 58% (SAD) and 70-80% (MAD). Notably, HE009 demonstrated a favorable cardiac safety profile, with transient, asymptomatic bradycardia mitigated by dose titration. No events related to hypertension were observed during the study period.

Conclusion: These findings suggest HE009 offers potential advantages in efficacy, safety, and dosing flexibility compared to existing S1P receptor modulators for treating autoimmune disorders like systemic lupus erythematosus.

Trial registration: The trial was registered on the Chinese Clinical Trial Registry, (Identifier No. ChiCTR2200066345), Registered December 1, 2022.

Introduction: Although innovative ways of treating epilepsy that is resistant to standard therapy are actively being researched, not many have demonstrated sufficient efficacy and safety in clinical research to obtain marketing authorization.

Areas covered: The article aims to provide a concise overview of the most important investigational treatments for epilepsy that have achieved breakthroughs in clinical studies in terms of efficacy and safety. Relevant studies published between 2020 and 2025 were searched for in PubMed and Google Scholar databases, without language restrictions.

Expert opinion: Although the first clinical breakthroughs have been achieved in the causal therapy of epilepsy using cell therapy and antisense oligonucleotides, larger clinical and observational studies are needed after the wider application of these therapeutic methods to evaluate their true place in epilepsy therapy. Symptomatic antiseizure medication has achieved significantly greater success in clinical practice by acting through several different mechanisms, and in the future, the reduction of the number of patients who will not respond favorably to any form of antiseizure medication could be expected.

Introduction: Gliomas are tumors that arise from glial cells in the central nervous system. Radiation provides local control for low-grade gliomas and improves survival for patients with high-grade gliomas; however, recurrence is common and treatment can be associated with long-term toxicities. Several strategies are under development to improve the anti-tumor efficacy of radiation and limit possible side effects. Novel molecular imaging agents can help diagnose new gliomas, delineate tumors for more accurate radiation planning, and differentiate tumor recurrence from treatment response changes on imaging. Radiotherapeutics provide an alternative method of delivering targeted radiation to tumors by leveraging molecular targets. New generation of radiosensitizers that target DNA damage response and cell cycle pathways aim to enhance radiation-induced cytotoxicity.

Areas covered: This review summarizes emerging molecular imaging agents, radiotherapeutics, and radiosensitizers in glioma with a focus on agents currently in the early phase of clinical trials.

Expert opinion: The development of new diagnostic and therapeutic agents has the potential of improving outcomes for glioma patients. As new agents are tested in clinical trials, it will be critical to consider questions regarding standardization of methodology in use/interpretation of molecular imaging techniques, appropriate dosimetry of radiotherapeutics, and cumulative toxicities with radiosensitizers.

Introduction: Alzheimer's disease (AD) is characterized by the formation of senile plaques composed of amyloid-beta (Aβ) peptides and the intraneuronal accumulation of neurofibrillary tangles composed of abnormal, hyperphosphorylated tau proteins. These act in concert to drive cognitive decline, but it is widely held that tau spread correlates better with cognitive decline than does amyloid burden. Control of AD neuropathologies with active immunizations is studied as a potential therapeutic avenue because it could build innate immunity. Although most active immunization studies have focused on Aβ targets, tau and other targets continue to be explored.

Areas covered: This study aimed to identify and describe non-Aβ active immunization trials for AD treatment. A narrative review was conducted to analyze the current status of non-Aβ active immunization for AD using PubMed as the research database.

Expert opinion: The potential of active immunization beyond Aβ was explored as a therapeutic strategy for AD with a focus that targets tau and provides insights into its effectiveness, associated challenges, and limitations. Results from preclinical and clinical studies were examined, highlighting the progress and the hurdles that exist. Active immunization against non-Aβ targets, such as tau, for the treatment of AD remains a promising and expanding field.

Introduction: Tirzepatide is a once-weekly injectable dual glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist. GIP and GLP-1 are incretins promoting insulin release from pancreatic β-cells. Results from clinical trials have confirmed that tirzepatide exerts favorable effects on glucose metabolism and insulin resistance, reduces food intake and has been approved for the treatment of adults with type 2 diabetes, and who are overweight/obese or who have weight-related comorbidities.

Areas covered: Results from SYNERGY-NASH, a phase 2 study involving patients with biopsy-proven MASH and stage 2 or 3 fibrosis, have shown that tirzepatide achieved MASH resolution with no worsening of fibrosis in a significantly higher percentage of patients than placebo. Additionally, more patients in the tirzepatide group in comparison to placebo achieved a 1-stage or greater fibrosis improvement without worsening of MASH, but the study was not powered to detect this change, and noninvasive biomarkers of fibrosis were not significantly improved.

Expert opinion: While these results suggest a potential role for tirzepatide in MASH treatment given its ability to improve insulin sensitivity and reduce food intake, factors already shown to be beneficial in reducing livers steatosis and fibrosis, larger clinical trials are needed.

Introduction: Sickle cell disease (SCD) is a monogenic disorder caused by a point mutation in the HBB gene, leading to the production of sickle hemoglobin (HbS). Under hypoxic or acidic conditions, HbS polymerizes within erythrocytes, leading to a series of downstream events resulting in tissue ischemia. Acute chest syndrome (ACS) is a severe and often life-threatening complication of SCD and the leading cause of intensive care unit admission and mortality in children.

Areas covered: This review covers the latest understanding of ACS pathology involving infectious triggers, pulmonary fat embolism, endothelial activation, hypercoagulability, and sterile inflammation. We discuss the role of neutrophil extracellular traps, inflammasomes, and platelet - leukocyte aggregates in pulmonary microvasculature causing tissue infarction, ventilation perfusion mismatch, and respiratory failure. We explore the emergence of targeted therapies in preventing and treating ACS.

Expert opinion: Although understanding of ACS pathogenesis has improved, current treatments are mainly supportive, with hydroxyurea as the primary preventive therapy. Newer treatments focus on specific mechanisms such as heme scavenging, P-selectin inhibition, toll-like receptor blockade, nitric oxide pathway modulation, and anti-thrombotic strategies. Given ACS's complex nature, a multi-drug targeted approach is likely needed. Scaling up hydroxyurea use remains essential to improving outcomes for millions affected globally by this life-threatening condition.

Introduction: Neurofibromatosis type 1 (NF1) is an autosomal-dominant cancer predisposition syndrome that leads to the development of plexiform neurofibromas (PNs), which can cause significant morbidity and are at risk to transform into malignant peripheral nerve sheath tumors (MPNSTs). Targeted therapies such as mirdametinib, a selective oral MEK1/2 inhibitor, have offered new treatment options for patients with symptomatic, inoperable PNs.

Areas covered: This review summarizes the pathophysiology of NF1, the role of MEK inhibition, and the development of mirdametinib as a treatment for NF1-associated plexiform neurofibromas. Relevant literature was identified through PubMed searches using keywords related to NF1, plexiform neurofibromas, MEK inhibition, and mirdametinib. Key aspects discussed include mirdametinib's pharmacologic properties, clinical efficacy, safety profile, and comparison with other MEK inhibitors.

Expert opinion: Mirdametinib offers an effective, targeted, and orally available treatment for NF1-associated plexiform neurofibromas, with the added advantage of CNS penetration and durable clinical benefit. However, resistance and toxicity remain challenges, and future research should focus on optimizing patient selection and developing combination strategies to further expand its role in NF1-PN management.

Introduction: Carbapenem-resistant Acinetobacter baumannii (CRAB) infections have become common in healthcare settings worldwide, yet current therapeutic options are limited. A pipeline of new antibiotics and non-traditional antimicrobial agents is being developed to address the urgent need for efficacious therapeutic options for patients with CRAB infections.

Areas covered: At the time of this writing, 13 traditional antibiotics are in clinical development for CRAB infections, some with a novel mechanism of action. Specifically, 9 antibiotics are in Phase 1 (R-327, xeruborbactam/QPX-7728, upleganan/SPR-206, MRX-8, QPX-9003, zifanocycline/KBP-7072, apramycin/EBL-1003, zosurabalpin/RG-6006, and ANT-3310), two in Phase 2 (BV-100, OMN-6), and two in Phase 3 (zidebactam/WCK-5222, funobactam/XNW-4107) clinical trials. Additionally, there are six non-traditional antimicrobial agents in Phase 1 or 2 clinical trials for treating CRAB infections. In particular, two monoclonal antibodies (TRL-1068, CMTX-101), a phage therapy (Phagebank), an immune-modulating agent (recombinant human plasma gelsolin/Rhu-pGSN), a microbiome-modulating agent (SER-155), and an engineered cationic antibiotic peptide (PLG-0206).

Expert opinion: Several agents with promising characteristics against CRAB infections are in clinical development (Phases 1, 2, and 3). The urgent need for therapeutic options against CRAB infections necessitates optimizing efforts and time for introducing successfully studied agents into clinical practice.

Introduction: Pancreatic neuroendocrine tumors (pNETs), a group of endocrine tumors that arise in the pancreas from the hormonal cells of the islets of Langerhans, are among the most common gastroenteropancreatic neuroendocrine tumors. The incidence of pNETs has increased in recent years to about 1.5 per 100,000 population and prognosis correlates with histologic grade.This review aims to provide an overview of the newly approved or currently developing drugs over the past five years that have shown a significant improvement in prognosis for patients affected by this rare disease.

Areas covered: The literature search was conducted using PubMed, focusing on English-language publications from 2020 to 2025. Keywords included 'pancreatic neuroendocrine tumors,' 'new treatments,' 'targeted therapy,' and 'clinical trials.' Studies selected for inclusion comprised clinical trials, systematic reviews, and meta-analyses reporting data on treatment efficacy, safety, and patient quality of life.

Expert opinion: Future research holds great potential, especially in improving personalized treatment predictions. Therefore, it is not easy to define a 'definitive endpoint' for research, as discoveries and technological innovations continue to evolve.

Introduction: Ischemic heart disease (IHD) constitutes the most prevalent form of cardiac disease in the general population. Although current therapeutic interventions have significantly improved both quality of life and survival rates, no available treatment can reverse the loss of cardiomyocytes resulting from ischemic injury. Existing therapies are limited to attenuating myocardial damage, reducing its extent, and mitigating its clinical consequences.

Area covered: Advances in pharmacological and biomedical research have paved the way for novel therapeutic modalities. Tissue engineering, gene therapy, microRNAs (miRNAs), small interfering RNAs (siRNAs), and stem cell-based approaches represent promising avenues for promoting myocardial regeneration. In the present review, we aim to provide a succinct yet comprehensive review of the principal areas of current scientific investigation in this evolving field.

Expert opinion: Although current scientific evidence remains limited, primarily due to the lack of large-scale clinical trials in vivo, the prospects of these therapeutic strategies are highly promising, particularly for patients with limited conventional treatment options. It remains to be determined when and how these approaches may be effectively implemented in clinical practice.