Expert opinion on investigational drugs最新文献

Introduction: 'Maximum tolerated dose' (MTD) was historically used to maximize clinical efficacy. However, there is a drive to optimize dose selection to improve safety/tolerability, while maintaining efficacy. This paradigm is increasingly important in oncology clinical development, leading to a focus on careful early-phase trial design to ensure that appropriate dose - or exposure-response data are obtained to guide dose selection.

Areas covered: We describe the development pathway and risk-benefit considerations for clinical dose selection for giredestrant, a next-generation, highly potent, non-steroidal oral selective estrogen receptor antagonist and degrader, under development for estrogen receptor-positive breast cancer. This included evaluating low-grade adverse events to potentially improve tolerability, long-term compliance, and giredestrant combination therapy use; using pharmacodynamic markers for early drug activity assessment; and testing multiple dose levels during dose-escalation and -expansion phases. Data were leveraged from preclinical and phase I/II studies in metastatic and early breast cancer, as a single agent with palbociclib, to inform giredestrant dose selection.

Expert opinion: Our learnings challenge the MTD paradigm in drug development, particularly in targeted therapies, and demonstrate the importance of basing dose selection on the totality of evidence, including preclinical data, and may help inform the clinical development of future targeted therapies.

Introduction: Allergic rhinitis (AR) is a prevalent IgE-mediated inflammatory disease with significant global health and economic burdens. Common treatments include pharmacotherapy and allergen-specific immunotherapy (AIT), but challenges remain in managing some of the moderate-to-severe patients, driving development on targeted biologics.

Areas covered: This review covers recent advances in AR management, including optimized pharmacotherapy, biologics targeting type 2 inflammation and innovations in AIT.

Expert opinion: The management toward AR should fully consider the phenotypic and endotypic characteristics of the patients and develop stepwise, comprehensive, and personalized care pathways that combine pharmacotherapy, AIT, and biologics. Further studies are needed to validate long-term efficacy and safety and optimize precision medicine approaches.

Introduction: Cytokines are important immunomodulatory proteins for therapeutic applications but display several limitations due to their pleiotropic nature, sometimes systemic toxicities, and suboptimal pharmacokinetics. Recent advances in protein engineering have enabled the development of antibody-derived cytokine mimetics which elicit cytokine-like signaling by targeting specific cytokine receptor subunits.

Areas covered: In this special report, we summarize our current knowledge of antibody-based cytokine mimetics. We discuss antibody-derived mimetics for several cytokines such as IL-2 an IL-18 and put emphasis on IL-12 receptor agonists with biased cell subset specificities. Furthermore, we provide an overview of next-generation engineering possibilities, including conditionally active cytokine mimetics which convert an anti-inflammatory stimulus into a pro-inflammatory agonism.

Expert opinion: Antibody-derived cytokine mimetics represent an emerging class of immunomodulatory agents in a bi- or multispecific architecture which might complement conventional cytokine engineering approaches. While these entities can be highly tailor-made for precise receptor engagement, enabling the modulation of downstream signaling, cell-type specificity, and functional bias, challenges remain, such as potential immunogenicity, preclinical model limitations, and differences in receptor binding affinities compared with natural cytokines.

Introduction: Chromosomal instability (CIN), a hallmark of over 90% of solid tumors, presents both a vulnerability and an opportunity in cancer therapy. KIF18A, a kinesin motor protein essential for mitotic fidelity, becomes critical for CIN cancer cells, where it suppresses lethal mitotic errors. This selective dependency makes KIF18A an attractive therapeutic target.

Areas covered: This review explores the structural and functional biology of KIF18A, its role in maintaining chromosomal alignment, and how its inhibition leads to mitotic failure specifically in cancer cells exhibiting high CIN. We summarize the development of small-molecule inhibitors, from early compounds like BTB-1 to second-generation agents including Sovilnesib and VLS-1488, the latter currently in Phase I/II trials. Clinical data show manageable toxicity and promising antitumor activity, particularly in high-grade serous ovarian cancer. New entrants like ATX-295 and GH2616 further expand the landscape. We also highlight efforts to refine KIF18A targeting through structural studies and emerging AI-driven drug discovery.

Expert opinion: KIF18A inhibition represents a mechanistically grounded, tumor-selective strategy for treating CIN-driven cancers. As clinical trials progress, optimizing patient stratification and exploring synergistic combinations will be crucial. Broadening the range of druggable sites on KIF18A, especially beyond the motor domain, could mitigate resistance and help expand therapeutic potential.

Introduction: Endoglin has been extensively studied as an anti-angiogenic target, with preclinical work highlighting its critical role in tumor vasculature. TRC105 (carotuximab), a monoclonal antibody against endoglin, progressed through multiple clinical trials and was well tolerated, yet outcomes were disappointing, revealing a gap between preclinical findings and patient benefit. Recent insights into endoglin biology in the tumor microenvironment suggest that more precise, informed strategies are needed to fully realize its therapeutic potential.

Areas covered: This review summarizes key advances in endoglin biology, including its endothelial and non-endothelial roles and context-dependent effects across tumor and stromal compartments. We discuss preclinical therapeutic strategies and clinical trial experience with TRC105 and examine the translational challenges and future considerations needed to achieve potential clinical benefit.

Expert opinion: Preclinical studies have greatly advanced our understanding of endoglin biology, but the key challenge lies in identifying the biologic context where endoglin drives tumor progression. Future progress requires a deeper mechanistic resolution of endoglin's roles across tumor type and disease stage, along with the development of biomarkers incorporating spatial expression patterns. Successful translation will depend on matching endoglin-targeted therapy to patients and tumor ecosystems most likely to benefit, shifting from broad anti-angiogenic application to precision stromal targeting.

Background: Avenciguat, a potent nitric oxide-independent activator of soluble guanylyl cyclase, is being evaluated in chronic kidney disease and systemic sclerosis. We assessed avenciguat absolute bioavailability and mass balance.

Research design and methods: Open-label Phase 1 trial in healthy men. Doses: Part A, 3 mg [¹⁴C]-avenciguat single dose (oral solution); Part B, 3 mg unlabeled avenciguat (tablet) then 30 µg [¹⁴C]-avenciguat (intravenous). Primary endpoints: Part A, mass balance and recovery of [¹⁴C] radioactivity in excreta; Part B, absolute bioavailability. Safety and pharmacokinetics were evaluated.

Results: In Part A (N = 6), geometric mean recovery of [¹⁴C] radioactivity was 90.0% (range 80.6-96.0%). Elimination was mainly via feces (geometric mean 85.3%; range 76.5-91.3%); urine (4.66%; range 4.10-5.31%). In Part B (N = 6), the absolute bioavailability of avenciguat was 83.0%. In pooled plasma, the predominant drug-related component was avenciguat (mean 86.8%); the acyl glucuronide metabolite represented 5.2% of radioactivity. Drug-related adverse events (AEs) occurred in 33.3% (4/12) of participants, mostly mild, with one moderate presyncope event. No AEs leading to discontinuation were reported.

Conclusions: Avenciguat was generally well tolerated and was primarily excreted unchanged in feces and minimally excreted in urine. After oral administration, avenciguat has high oral bioavailability.

Clinical trial registration: ClinicalTrials.gov (NCT05515328).

Introduction: Menin inhibitors are a relatively new class of drugs that reverse oncogenesis and induce leukemic cell differentiation by blocking the interaction between the MEN1 gene product (menin) and lysine (K)-methyltransferase 2 (KMT2A). This is relevant in 50-70% of acute myeloid leukemia (AML) subsets driven by overexpression of the HOXA9/MEIS1 pathway. These patients have dismal outcomes with current options, especially in the relapsed/refractory setting.

Areas covered: Here, we discuss menin pathobiology, the available and emerging clinical data for menin inhibitors, clinical nuance related to their use, and the current unmet needs that may guide future endeavors for this drug class. A literature search was conducted using PubMed/MEDLINE, Embase, and Web of Science databases. The search included articles published in English up to 25 August 2025. Keywords and Medical Subject Headings (MeSH) related to 'menin inhibitors' were combined using Boolean operators (AND, OR). Additionally, abstracts from major hematology conferences were reviewed, and the clinicaltrials.gov registry was queried for active trials as well.

Expert opinion: Menin inhibitor approval/use is expanding into other HOX-driven subtypes (e.g. NPM1, NUP98r), as a frontline option and in combination settings. Monitoring for differentiation syndrome, QT interval prolongation, recognizing pseudo-progression, and supportive care needs remains essential to maximize patient benefit.

Introduction: Current standard-of-care for idiopathic pulmonary fibrosis is limited to nintedanib and pirfenidone, which only slow the progressive loss of lung function and have significant adverse effects that are intolerable to many patients. There is therefore a significant unmet need for alternative treatments for this incurable disease.

Areas covered: This review describes emerging evidence implicating dysregulation of the renin-angiotensin system in IPF pathogenesis, and both pre-clinical and recent clinical data supporting activation of the anti-fibrotic AT₂R as a promising therapeutic strategy. The efficacy of AT₂R agonists across pre-clinical models of both IPF and relevant lung diseases is discussed, with a particular focus on favorable findings with the AT₂R agonist C21 (buloxibutid), leading to its current clinical trials for IPF.

Expert opinion: Rapid translation of C21 (now named buloxibutid), the first-in-class orally available AT₂R agonist, to early phase clinical trials for IPF have established its safety and disease-modifying potential. Ongoing development of novel, more highly selective AT₂R agonists may deliver the same clinical benefit as C21 with reduced off-target effects. The AT₂R drug class offers great promise as novel therapeutics, potentially extending beyond IPF to other inflammatory and fibrotic lung diseases.

Introduction: Endometriosis is a chronic, estrogen-dependent inflammatory disease affecting up to 10% of reproductive-aged women. Current therapies are predominantly hormone-based and offer symptomatic relief without correcting the immune dysregulation and inflammation that drive lesion persistence, pain, and infertility.

Areas covered: This review summarizes emerging strategies that directly target inflammatory pathways in endometriosis. Key mechanisms involved in lesion survival and symptom generation include cytokine signaling (TNF-α, IL-1, IL-6), oxidative stress, immune-checkpoint dysregulation, and activation of the JAK/STAT pathway. Therapeutic approaches discussed comprise biologic agents (infliximab, etanercept, adalimumab, anakinra, tocilizumab), small-molecule JAK inhibitors (tofacitinib), and antioxidant compounds such as N-acetylcysteine, resveratrol, and vitamins C and E.

Expert opinion: Targeting inflammation represents a promising shift in endometriosis management, particularly for women who do not respond to hormonal therapies or aim to conceive. Preclinical studies consistently demonstrate reductions in lesion size, inflammatory cytokines, oxidative stress, and neuroangiogenic signaling. Early clinical evidence - especially for TNF-α and IL-1 blockade and for N-acetylcysteine - suggests improvements in pain and, in selected cases, reproductive outcomes. Although preliminary, these findings support the rationale for inflammation-directed therapies. Future research should prioritize randomized trials, long-term safety and fertility assessment, and biomarker-guided patient stratification to identify responders and optimize precision use of these agents.