Expert opinion on investigational drugs最新文献

Introduction: Effective skin-directed therapies (SDT) are the cornerstone for managing early-stage Cutaneous T-cell Lymphoma (CTCL). However, standard treatments like PUVA phototherapy and topical mechlorethamine carry significant drawbacks, including mutagenic risk and treatment-limiting skin reactions. This unmet need has driven demand for safer options. Topical photodynamic therapy with synthetic hypericin (research name: SGX301; trade name: HyBryte™) has emerged as a novel agent addressing this gap.

Areas covered: This review details synthetic hypericin's evolution and its unique non-mutagenic, light-activated mechanism. It generates singlet oxygen, preferentially inducing apoptosis in malignant T-cells. We analyze key clinical trials, including the pivotal Phase III FLASH study, to establish its efficacy and safety in patch- and plaque-stage mycosis fungoides, comparing it to other SDTs.

Expert opinion: Topical synthetic hypericin is a significant advancement for early-stage CTCL. Its excellent safety profile, proven efficacy, and non-mutagenic mechanism position it as a valuable first-line option. Minimal local adverse events and limited systemic absorption offer a key long-term safety advantage over conventional phototherapies. Its effectiveness in both patch and plaque lesions makes it a versatile tool, improving outcomes and quality of life for patients.

Introduction: Macrophages are attractive targets for novel cancer immunotherapy approaches since they can infiltrate into the tumor microenvironment and have the capacity to engulf and destroy cancer cells by phagocytosis. The CD47/SIRPα axis is a key immune checkpoint that regulates macrophages' ability to attack cancer cells and has been the subject of intense preclinical and clinical investigation.

Areas covered: We review the scientific rationale for developing CD47/SIRPα-targeting therapies, and we summarize results of recent clinical trials that tested anti-CD47 antibodies, SIRPα-Fc fusion proteins, or anti-SIRPα antibodies in patients with lymphoma. We review signs of efficacy, opportunities for combination strategies, and challenges such as on-target hematologic toxicity and an 'antigen sink' that exists due to CD47 expression on blood cells.

Expert opinion: Multiple CD47/SIRPα-targeting therapeutics and multiple clinical trials have demonstrated encouraging results in patients with non-Hodgkin lymphoma, where objective responses have been observed in combination with rituximab and other anti-cancer agents. Next-generation approaches, such as bispecific antibodies and engineering efforts to reduce blood cell binding, are now under clinical development and may be successful strategies to unlock the extraordinary potential of the CD47/SIRPα immune checkpoint.

Introduction: Graft-versus-host disease (GVHD) remains the primary barrier to successful allogeneic hematopoietic cell transplantation, contributing significantly to non-relapse mortality. With approximately 50% of patients developing GVHD despite prophylaxis, there is an urgent need for effective alternatives. Janus kinase (JAK) inhibitors have emerged as a promising class of targeted immunomodulators to address this clinical challenge.

Areas covered: This review examines the mechanistic rationale for JAK inhibition in GVHD and summarizes key preclinical and clinical data. We evaluate the efficacy and safety of selective and nonselective agents, including ruxolitinib, baricitinib, itacitinib, pacritinib, and rovadicitinib. Furthermore, the review analyzes recent advancements in peri-transplant prophylaxis, biomarker-driven strategies, and the comparative landscape of FDA-approved therapies for acute and chronic GVHD.

Expert opinion: The future of GVHD management is shifting from broad immunosuppression toward precision medicine. We anticipate a transition from the current 'steroid-first' paradigm to risk-stratified algorithms utilizing biomarker profiling and novel combination strategies. While ruxolitinib is the current cornerstone, the development of highly selective inhibitors and the resolution of financial access barriers will be crucial for establishing JAK inhibitors as the frontline standard of care over the next decade.

Introduction: Microtubules are essential to cancer therapy as key cytoskeletal components that regulate cell division, intracellular transport, and mitotic spindle formation. Tubulin polymerization inhibition is a critical target in anticancer drug development. This review evaluates tubulin polymerization inhibitors (TPIs) in early clinical stages. Using pertinent keywords on tubulin polymerization inhibitors and related trials, literature from January 2018 to January 2026 was obtained from PubMed, Scopus, Embase, Web of Science, ClinicalTrials.gov, and Google Scholar.

Area covered: TPIs are classified by their tubulin binding sites into colchicine, vinca alkaloid, and taxane categories. Preclinical data demonstrate strong antiproliferative activity, tumor regression in models, and synergism with DNA-damaging agents, targeted therapies, and immunotherapy. Clinical investigations assess efficacy, identify dose-limiting toxicities, and guide biomarker-based patient selection. Challenges such as drug resistance and pharmacokinetics are addressed through nanoparticle delivery and combination strategies.

Expert opinion: TPIs are evolving from traditional cytotoxic agents to precision medicines that exploit molecular differences between cancerous and normal tissues. Advances such as βIII-tubulin as a predictive biomarker enable personalized therapy. Despite challenges, integrating nanotechnology and immunotherapy offers transformative potential. TPIs are emerging as potent agents in precision oncology with enhanced efficacy and reduced toxicity, marking a pivotal shift in targeted cancer treatment.

Introduction: Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It accounts for ~15% of breast cancer diagnoses, and disproportionally affects young women and those of African and Hispanic ancestry.

Areas covered: This review encompasses recent advances in the management of early and advanced-stage TNBC. The identification of distinct molecular subtypes of TNBC has allowed for the optimization of systemic therapy. Distinct drivers of TNBC have been identified, resulting in the regulatory approval of targeted therapies for early and advanced stage disease, including immunotherapy, PARP inhibitors, and antibody-drug conjugates. Literature search was performed using PubMed, and included publications between 01/2010 to 11/2025.

Expert opinion: Until recently, the only treatment available for TNBC was chemotherapy. Advances in the molecular characterization of TNBC has revealed distinct subtypes, enabling the development and approval of targeted therapies, including PARP inhibitors, immunotherapy, and antibody-drug conjugates. Treatment options for both early and advanced-stage TNBC are improving, although it remains the subtype with the poorest outcomes. Ongoing trials are focused on personalizing treatment through predictive biomarkers, response-adaptive strategies, and novel agents, with the goal of maximizing efficacy while minimizing toxicity.

Introduction: IMNN-001 is designed for local and durable delivery of a pluripotent anti-tumor cytokine, IL-12, using an expression plasmid and a synthetic lipopolymer delivery system. IMNN-001, delivered intraperitoneally in combination with chemotherapy, is currently in a Phase 3 trial for the front-line treatment of advanced epithelial ovarian cancer.

Areas covered: This report details IMNN-001 preclinical and clinical development, demonstrating local and durable production of IL-12, minimal systemic exposure and manageable safety profile, as well as its antitumoral effects in a total of six completed trials in ovarian cancer. In the OVATION-2 Phase 2 randomized trial, neo- and adjuvant chemotherapy combined with IMNN-001 produced a numerical 13 month increase in overall survival, with even greater benefit in tumors that lacked DNA homologous repair activity. In translational studies, IMNN-001-induced changes in the tumor microenvironment are consistent with the observed induction of IL-12 and IFN-γ levels at the tumor site and support the hypothesis that IMNN-001 treatment alters the tumor microenvironment in favor of broad immune stimulation and inhibition of immunosuppressive mechanisms.

Expert opinion: IMNN-001 gene therapy could add clinically meaningful IL-12-driven immunotherapy to newly diagnosed ovarian cancer patients. IMNN-001 holds promise for synergistic combinations with immunotherapies requiring intrinsic immune activity.

Insomnia is common. Seltorexant (JNJ-42847922), a selective orexin-2 receptor antagonist, was originally trialed in major depression. In a repurposing, seltorexant has been tested in a phase 2b trial for insomnia. This trial represents a new approach to treat insomnia. The primary efficacy endpoint was latency to persistent sleep (LPS) on night 1, which was shortened with seltorexant. In addition to shortening the time to go to sleep in subjects with insomnia, Seltorexant prolonged sleeping time before waking. Comparison showed more benefit and less adverse effects with seltorexant than with zolpidem, an established treatment for insomnia. The findings that (i) the effects of seltorexant may diminish with time, depending on dose and (ii) that the overall incidence of treatment-emergent adverse effects was lower with seltorexant than with placebo, need explanation. A phase 3 trial of seltorexant in depression and insomnia is underway. As seltorexant is showing promise in insomnia, further trials are needed. However, at present, there are no phase 3 clinical trials registered for the treatment of insomnia by seltorexant alone or in comparison with zolpidem, and such trials need consideration.

Introduction: Phase II studies provide signals that guide therapeutic development for advanced NSCLC. This is particularly important for certain categories of patients, such as those who have already undergone immunotherapy and those with oncogene-addicted disease. However, promising results in phase II often do not translate into equally positive outcomes in phase III and the reason may be related to assay variability, sample heterogeneity, inadequate comparators or optimistic endpoints.

Areas covered: This paper provides an overview of treatments for advanced NSCLC and identifies settings where phase II evidence plays a decisive role: post-PD-(L)1/-chemotherapy, post-TKIs, frail patients or patients with brain disease. It also analyzes the reasons behind the failure of phase II success in phase III and proposes what makes a robust signal in phase II, while recognizing the limitations of surrogate endpoints. We take stock of the therapeutic classes that are gaining the most ground and provide a critical assessment of ongoing clinical programs.

Expert opinion: At present, a convincing phase II trial in NSCLC is possibly randomized, guided by biomarkers detected by standardized tests, with durable systemic and cerebral activity, inclusion of PROs, and is already in alignment with confirmatory study design and regulatory endpoints.

Introduction: Narcolepsy is a debilitating chronic neurological disorder, and currently, there is no cure. Activation of the histaminergic system through the blockade of histamine 3 (H3) autoreceptors promotes wakefulness. Blockade of H3 heteroreceptors modulates adrenergic, serotonergic, cholinergic, and dopaminergic systems. These properties of H3 receptors may offer therapeutic options for managing the symptoms of narcolepsy. Samelisant is an investigational H3 receptor inverse agonist/antagonist being developed for the treatment of hypersomnia disorders.

Areas covered: This review includes an evaluation of the nonclinical and clinical profiles of samelisant.

Expert opinion: Samelisant's inverse agonism property at the H3 receptor may be ideal for addressing challenges associated with the constitutive activity. A key distinguishing feature of samelisant is its cleaner drug-drug interaction and cardiovascular safety profile compared to existing treatments. This is particularly important for women of childbearing potential, considering the known interactions of current treatments (e.g. pitolisant and modafinil) with hormonal contraceptives, as well as the common occurrence of polypharmacy and comorbidities in narcolepsy. Additionally, as samelisant may act downstream of orexinergic pathways, it presents an opportunity to complement orexin-based therapies. The potential of samelisant in combination with other narcolepsy treatments represents an important area for future research.

Introduction: KAT6A and its paralog KAT6B (KAT6) are part of the MYST family of histone acetyltransferases. KAT6 is involved in regulating multiple cellular processes by acetylating different lysine residues on histone H3. While KAT6A is overexpressed in various solid tumors, KAT6 is best characterized for its role in ESR1 transcription in estrogen receptor-positive (ER+) breast cancer.

Areas covered: Prifetrastat (PF-07248144), a first-in-class KAT6A/B inhibitor, has been tested in a phase I trial, mainly for patients with ER+ breast cancer, and demonstrated promising efficacy with a favorable safety profile, albeit frequent dysgeusia. Prifetrastat in combination with fulvestrant is now being evaluated in a phase III trial for pretreated ER+ advanced breast cancer. In parallel, numerous KAT6 catalytic inhibitors and degraders have entered preclinical and clinical development.

Expert opinion: A phase III study of prifetrastat will provide initial data on the clinical significance of KAT6 inhibitors. The application of Prifetrastat and other KAT6 inhibitors to wider breast cancer subpopulations and other solid tumors is anticipated. Additionally, mitigation strategies for dysgeusia and clinically available response-predictive biomarkers should be developed. KAT6 inhibitors with different target spectra, including KAT6A-selective and KAT6/7 inhibitors, may exhibit differential efficacy and safety profiles, offering deeper insights into KAT6-targeted therapy.