Expert opinion on investigational drugs最新文献

Introduction: Chronic graft-versus-host disease (cGVHD) is the most common cause of late non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Rho-associated coiled-coiled kinases (ROCK) inhibitors have been shown to balance the pro-inflammatory and regulatory T-cell subsets in addition to reducing fibrosis in cGVHD, resulting in the development of multiple ROCK2 inhibitors including belumosudil.

Areas covered: We describe the pathophysiology of cGVHD and the role of ROCK2 in cGVHD. This includes a review of the current and ongoing clinical data with belumosudil, and an overview of current ROCK2 inhibitors in development for cGVHD, including rovadicitinib, zelasudil, and GV-101.

Expert opinion: Many of the recent novel agents with unique mechanisms such as ROCK2 inhibitors (i.e. belumosudil) provide high response rates but rarely yield complete responses in cGVHD. The future of management of cGVHD will rely on investigating combination therapy upfront that may achieve deeper complete responses, developing newer preventative therapies, and advancements in biomarker detection/risk stratification for cGVHD.

Background: BI 764198 is a selective, oral transient receptor potential cation channel, subfamily C, member 6 inhibitor under investigation for focal segmental glomerulosclerosis.

Research design and methods: Phase I study in 44 Japanese male volunteers. Single dose part: BI 764198 20 mg (n = 6) vs. placebo (n = 2); multiple dose part: BI 764198 40, 80, or 160 mg (n = 9 each) or placebo (n = 9) as a single dose then multiple daily dosing for 2 weeks. Primary endpoint: participants with drug-related adverse events (DRAEs); secondary endpoints: pharmacokinetic.

Results: DRAEs were reported in 20.5% (9/44) of participants (total BI 764198 21.2% [7/33]; placebo 18.2% [2/11]), mostly diarrhea (total BI 764198 15.2% [5/33]; placebo 18.2% [2/11]) and headache (BI 764198 80 mg 11.1% [1/9]; BI 764198 160 mg 33.3% [3/9]). BI 764198 exposure increased near dose proportionally to 80 mg and was slightly higher than anticipated with 160 mg. Pharmacokinetics were similar in Asians and non-Asians after accounting for body weight. Limitations include small sample size per dose and short trial duration.

Conclusions: BI 764198 was well tolerated; exposure increased near dose proportionally to 80 mg, as previously observed in predominantly White volunteers.

Clinical trial registration: This study was registered on Clinical Trials.gov, identifier NCT04665700.

Introduction: GPRC5D is a promising myeloma-associated antigen, and several GPRC5D-targeted therapies are under active investigation, including CAR T cells, bispecific and trispecific antibodies, and antibody-drug conjugates. This class of agents is poised to transform the landscape of multiple myeloma treatment.

Areas covered: Here, we review the biology of GPRC5D, the current and emerging uses of talquetamab in relapsed/refractory multiple myeloma, the landscape of investigational GPRC5D-targeted drugs, and how these agents are likely to be implemented into future clinical practice.

Expert opinion: Talquetamab is currently the only approved GPRC5D-targeted therapy, primarily used for BCMA-refractory multiple myeloma, but there is no biological reason BCMA therapies must be exhausted before targeting GPRC5D; utilizing GPRC5D in innovative ways will be key to fully realizing its therapeutic potential. Newer trials are exploring more aggressive approaches combining multiple immunotherapy targets within a single line to prevent resistance and potentially achieve a cure. While GPRC5D-targeted therapies are highly effective, they also pose significant toxicity risks including oral, skin, nail, and cerebellar toxicity. In addition to improving efficacy, future research must also focus on optimizing dosing, identifying biomarkers for toxicity, and developing better strategies for managing adverse events to optimize the risk-benefit profile of these therapies.

Introduction: The KRAS (Kirsten rat sarcoma viral oncogene homolog) gene is recognized as the most frequently mutated oncogene in advanced non-small cell lung cancer (NSCLC). The most prevalent mutation within this gene is G12C, formally known as KRAS G12C, which leads to the substitution of glycine with cysteine at position 12 of the KRAS protein.

Areas covered: Recent advancements in research have developed effective therapies designed to inhibit activated KRAS signaling. As a result, the first two accelerated FDA-approved KRAS inhibitors, sotorasib, and adagrasib have been successfully introduced to the market for locally advanced or metastatic KRAS G12C mutated NSCLC who progressed after prior therapy. A second generation of KRAS inhibitors is currently being tested in clinical trials, and in combination with immunotherapy and chemotherapy.

Expert opinion: Future research is crucial to determine the optimal timing for treatment with KRAS G12C inhibitors. Additional studies are needed to identify biomarkers that predict which patients will benefit most. This review discusses and analyzes both completed and ongoing clinical trials of first and second-generation KRAS inhibitors. It also addresses mechanisms of resistance to KRAS inhibition, potential therapeutic strategies to overcome this resistance, biomarkers, side effects, and its role in central nervous system metastatic disease.

Introduction: Zelenectide pevedotin (BT8009) is a novel Bicycle Toxin Conjugate targeting nectin-4, designed to overcome the limitations of already existing anti-nectin-4 antibody-drug conjugates such as enfortumab vedotin (EV). Its innovative molecular design enhances tumor penetration, minimizes systemic toxicity, and achieves therapeutic efficacy independent from internalization.

Areas covered: This review evaluates the preclinical rationale and clinical data for BT8009, focusing on its pharmacokinetic properties, safety, and efficacy compared to EV. Key findings from the ongoing phase I/II Duravelo-1 trial are analyzed alongside challenges in the design of the phase II/III Duravelo-2 trial and their potential implications for future clinical development.

Expert opinion: Preliminary data on BT8009 reveal an intriguing clinical profile, with promising efficacy and a notable safety profile. However, the design of ongoing trials raises concerns, particularly due to the use of outdated control arms and the lack of direct comparisons to EV. These limitations could delay its clinical adoption and regulatory approval, impacting on its positioning in an increasingly competitive therapeutic landscape. Nonetheless, if ongoing and future trials confirm its efficacy and safety advantages, BT8009 could represent a valuable advancement for the treatment of nectin-4 expressing solid tumors such as urothelial carcinoma, warranting further investigation in more robust comparative studies.

Background: BI 764198 could reduce podocyte injury in focal segmental glomerulosclerosis (FSGS).

Research design and methods: Four Phase 1 BI 764198 trials: single rising dose (SRD) and multiple rising dose (MRD)/drug-drug interaction trials in healthy volunteers; relative bioavailability (rBA) study (food and formulations effects on pharmacokinetics; PK); and kidney impairment (KI) PK study.

Results: SRD trial: 4/54 BI 764198-treated participants (7.4%) had ≥ 1 investigator-defined drug-related adverse event (DRAE): headache (n = 3; 5.6%); diarrhea (n = 1; 16.7%). BI 764198 PK was approximately linear. MRD trial: DRAEs occurred in 5/32 (15.6%) participants receiving BI 764198 and 1/8 (12.5%) receiving placebo. Once-daily BI 764198 80 mg (10 days) did not alter midazolam PK. All BI 764198 formulations tested had similar rBA; food did not affect PK. KI study: geometric mean ratios for area under the plasma concentration-time curve were 147.8% and 177.7% for participants with moderate and severe KI, respectively (vs. without). Limitations include typically small Phase 1 sample sizes and open-label design for the rBA and KI trials.

Conclusions: BI 764198 was well tolerated and could be taken with/without food; evaluation in FSGS is ongoing.

Clinical trial registration: The trials are registered at www.clinicaltrials.gov with codes NCT03854552; NCT04102462; NCT04656288; NCT04176536.

Introduction: Most of the current treatment modalities for sickle hemoglobinopathy are disease-modifying rather than curative. Therefore, there is a need for effective treatment of complications of sickle cell disease (SCD) that impair quality of life. This need drives the evaluation of preclinical therapeutics in search of new treatment modalities.

Areas covered: Interventions are likely to progress from research to clinical practice, their potential impact, and future directions in SCD care: HbF inducers, pyruvate kinase activators, anti-selectin P monoclonal antibodies, allosteric Hb modifiers, proactive treatment of cerebral artery conditional blood velocity, multimodal, and gene therapy. Established treatment modalities (e.g with hydroxyurea) are not included because these have advanced well beyond the preclinical stage of therapeutics. Information dated 2025 backward was obtained from Medline, PubMed, and other public sources.

Expert opinion: Places for the conduct of preclinical studies ought to include areas of high SCD prevalence. Limited resources currently hinder universal accessibility of curative SCD therapies in these places. The recent approval of non-viral gene therapy for SCD and the number of preclinical therapeutics in development bring realistic expectation that curative and disease-modifying interventions, such as multimodal therapy and proactive treatment of cerebral artery conditional blood velocity to prevent stroke, will become standard care.

Introduction: Urothelial carcinoma (UC) is frequently associated with a poor prognosis in patients with advanced disease. A strong biological rationale supports the investigation of combining antibody-drug conjugates (ADCs) with immunotherapy to overcome the occurrence of resistance and improve patient outcomes.

Areas covered: In this review, we illustrate the mechanisms of action of pembrolizumab and enfortumab vedotin (EV) and the immune and biological rationales underlying their synergy in mUC patients.

Expert opinion: The results of the combination of EV and pembrolizumab represent a ray of light in the therapeutic scenario of mUC patients. A deeper understanding of the mechanisms underlying the synergistic effects of these agents will be crucial to reduce drug-resistance and further improve the outcome of mUC patients.

Introduction: Follicular lymphoma (FL) is the most common indolent lymphoma. Patients with advanced-stage FL typically respond to therapy, then follow a relapsing/remitting course, with shorter progression-free survival with each subsequent line of therapy. Whilst existing CD19-directed therapies such as CAR T-cell therapy have shown promising efficacy in the management of relapsed/refractory FL, immune-mediated adverse events, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), are well described. AZD0486 is a fully human bispecific (CD19×CD3) T-cell engager (TCE) that induces T cell-mediated cytotoxicity but with low-affinity binding of CD3, resulting in a reduction in cytokine release.

Areas covered: In this review, we describe the key preclinical data for AZD0486 and evaluate in detail the available clinical data from the ongoing phase 1 first-in-human study, including safety, efficacy, pharmacokinetics, and future development plans.

Expert opinion: Bispecific TCEs are among the most promising novel therapies in use for the management of relapsed/refractory B-cell lymphomas. AZD0486 results in high complete response rates with low incidence of high-grade immune-mediated toxicity compared to alternative TCE therapies. Importantly, it remains active in patients with lymphomas that have lost CD20 expression, an important mechanism of treatment failure following CD20 targeting TCEs.

Background: This randomized clinical pharmacology trial investigated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of KN056 following single-dose subcutaneous administration in healthy Chinese participants.

Methods: Thirty healthy male subjects were randomized to receive a single dose of KN056 (0.5, 1.0, 3.0, 6.0, or 12.0 mg) or placebo. PK and PD parameters, as well as safety and tolerability, were assessed.

Results: KN056 exposure increased proportionally with dose, with a half-life ranging from 141 to 188 hours. KN056 was well-tolerated, with gastrointestinal adverse events being the most common, particularly at the highest dose (12.0 mg). In the oral glucose tolerance test, KN056 dose-dependently decreased the AUC on the glucose versus time (gAUC) from baseline within 144 hours post-dosing. Specifically, the maximum reduction was 29.9% (occurring at the 72-hour mark). Body weight decreased within seven days of administration, correlating with dose levels, with a mean reduction of -1.68 kg in the 12.0 mg group; however, no significant change in body weight was observed by the end of the study.

Conclusions: KN056 demonstrated favorable PK, PD, and safety profiles in healthy Chinese participants, supporting its potential for once-weekly dosing.