Expert opinion on investigational drugs最新文献

Background: This first-in-human study compared the pharmacokinetics, safety, and immunogenicity of candidate biosimilar CT-P55 to both European Union (EU)-approved and United States (US)-licensed secukinumab in healthy participants.

Research design and methods: Three-arm, double-blinded, parallel-group, single-dose, Phase 1 study conducted across four centers in Japan over 22 weeks. Healthy adult males were randomized (1:1:1) to a single 150-mg subcutaneous dose of CTP55, EU-approved, or US-licensed secukinumab. Primary endpoints were area under the concentration - time curve from time zero to infinity (AUC_0-inf) and maximum serum drug concentration (C_max).

Results: Baseline characteristics were comparable across groups (CT-P55 [n = 57], EU-approved secukinumab [n = 59], and US-licensed secukinumab [n = 56]). The 90% confidence intervals for the geometric least squares mean ratios of AUC_0-inf and C_max were within the equivalence margin (80-125%). Safety profiles were comparable. 218 treatment-emergent adverse events were reported for 110 (65.5%) participants; most were Grade 1/2. One serious adverse event was reported (US-licensed secukinumab group). The low immunogenic profile of CT-P55 was comparable to both reference secukinumab groups, with no neutralizing antibodies detected.

Conclusions: CT-P55 exhibited equivalent pharmacokinetics as well as comparable safety and immunogenicity to both EU-approved and US-licensed secukinumab in healthy Japanese males. Generalizability may be limited beyond Asian males.

Trial registration: The study is registered at Clinicaltrials.gov (NCT07054970).

Introduction: Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) driven by recurrent acquired somatic mutations in hematopoietic stem cells and characterized by progressive bone marrow fibrosis, cytopenias, and extramedullary hematopoiesis. Janus kinase inhibitors (JAKi) improve splenomegaly and MF symptom burden but without achieving molecular remission or clear disease course modification. Novel therapies targeting epigenetic dysregulation through bromodomain and extra-terminal domain (BET) proteins have emerged as a key therapeutic approach, aimed at reducing pro-inflammatory and oncogenic transcription to deepen clinical responses in combination with JAKi therapy.

Areas covered: This review summarizes the biology, preclinical data, and emerging clinical data in the development of novel BET inhibitor (BETi). Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein.

Expert opinion: BET protein inhibition is a promising therapeutic target complementing JAK inhibition by co-targeting inflammatory pathways, fibrosis, and clonal proliferation. Pelabresib is a pan-BETi furthest in development demonstrating clinical benefit with ongoing trials. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies is ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined.

Introduction: Head and neck squamous cell carcinoma (HNSCC), has still a high mortality rate even if several multimodal treatments have been developed in the advanced stages.

Areas covered: In recent years, immunotherapy was introduced for the treatment of advanced and metastatic HNSCC with favorable effects on survival and quality of life. Currently, pembrolizumab plus or less chemotherapy is recommended in patients with CPS > 1 in metastatic HNSCC, while nivolumab is used in the second line setting for platinum-refractory disease. However, despite the benefits of these agents, most patients progress after immunotherapy. New approaches to overcome HNSCC immune escape are ongoing, involving antibodies against other immunological locks such as LAG-3, TIGIT, TIM-3, and CD134 (OX40). Moreover, T-lymphocyte activators like GITR and vaccine strategies based on peptides, DNA and RNA against HPV-positive HNSCCs, tumor-associated antigens, dendritic cells, and personalized cancer vaccines have been recently developed.

Expert opinion: Future research is crucial to determine the optimal setting for treatment with immunological checkpoint inhibitors through the use of new prognostic biomarkers. This review discusses both completed and ongoing clinical trials with PD-1/PDL-1 and new checkpoint inhibitors and immunotherapies. It also addresses mechanisms of resistance to immunotherapy, potential therapeutic strategies to overcome this resistance, biomarkers and side effects.

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.

Background: Rifaquizinone (RQZ, TNP-2092) is a novel drug for treating hepatic encephalopathy (HE). This study assessed the safety, pharmacokinetics (PK), and efficacy of RQZ capsules in healthy participants and cirrhosis patients with hyperammonemia.

Research design and methods: We conducted three double-blind, randomized, placebo-controlled trials. Trials 1 and 2 enrolled healthy participants, while Trial 3 involved 36 cirrhosis patients with hyperammonemia.

Results: In healthy participants and liver cirrhosis patients with hyperammonemia, RQZ was safe and well tolerated. Adverse events were generally mild or moderate. Both food and liver cirrhosis disease status increased the exposure of RQZ, which was around 1% of that of the corresponding doses after intravenous administration. The effect in lowering blood ammonia was dose-dependent. The changes from baseline in blood ammonia levels at day 15 were -14.1 and 0.5 μmol/L in 600 mg and placebo cohort. The percentage of achieving normal blood ammonia during treatment were 31.9% and 7.4% in 600 mg and placebo cohort.

Conclusions: Although this study enrolled a relatively small cohort of cirrhotic patients with hyperammonemia, RQZ demonstrated an excellent safety profile as an intestinally restricted agent and showed promising potential for lowering blood ammonia and treating hepatic encephalopathy.

Introduction: Cardiogenic shock (CS) is the most severe manifestation of acute heart failure (AHF), which is associated with one-year mortality rates of up to 60%. Inotropes are a cornerstone of CS treatment, as they improve central hemodynamics and provide time to address the underlying etiology. Therefore, their early administration, before CS progresses to the neurohumoral and inflammatory phase, is of great importance. Currently used inotropes are associated with adverse events, including tachycardia, ischemia, hypotension, and arrhythmias, and novel medications with a safer and more effective profile are needed. One of promising medications is istaroxime, characterized by a lower risk of malignant arrhythmias and a unique ino-lusitropic mechanism of action.

Areas covered: This study aimed to describe the mechanism of action of istaroxime and present results from phase II clinical trials on its effectiveness and safety in patients with early CS.

Expert opinion: Phase II clinical trials demonstrated that istaroxime is effective in the management of early CS (hemodynamic effect). Its advantages stem from a favorable safety profile compared with traditional inotropes, along with proven efficacy in raising systolic blood pressure (SBP) and enhancing central hemodynamics. These effects are mediated through its unique ino-lusitropic mechanism, achieved without increasing heart rate.

Introduction: Specifically Targeting the ABL1 Myristoyl Pocket inhibitors (STAMPi) have reshaped the management of chronic myeloid leukemia (CML). Yet, major challenges remain, including resistance and compound mutations, cross-intolerance, and long-term toxicities. Asciminib has shown efficacy in heavily pretreated patients and in the first-line setting, but resistance and limited benefit after ponatinib highlight the need for new therapeutic options.

Covered areas: This review summarizes preclinical and early clinical evidence on next-generation STAMPi. TGRX-678 exhibits potent activity against wild-type and mutant ABL1, including T315I, synergism with orthosteric tyrosine kinase inhibitors (TKIs), central nervous system (CNS) penetration, and encouraging phase Ia/Ib clinical activity in heavily pretreated CML. Early but promising data are also emerging for TERN-701 from the CARDINAL trial.

Expert opinion: Next-generation STAMPi may extend therapeutic options beyond asciminib by addressing resistant mutations and enabling rational dual-site inhibition. TGRX-678 ability to achieve CNS exposure raises potential in blast phase CML and Ph+ acute lymphoblastic leukemia. Key questions regarding durability, long-term safety, and optimal integration with ATP-competitive TKIs remain open. Ongoing trials will define the clinical role of these STAMPi and their potential to advance cure-directed strategies, including treatment-free remission.

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.