Expert opinion on investigational drugs最新文献

Introduction: The Centers for Disease Control and Prevention (CDC) estimates that Clostridioides difficile infection (CDI) results in 250,000 hospitalizations yearly in the U.S.A. an annual mortality of 12,800 and recurrence in 15-30% of patients. Consequently, new approaches and agents are needed to treat CDI. We review the current developmental pipeline for various categories of CDI therapies.

Areas covered: We searched various data bases to identify relevant data.

Expert opinion: Ibezapolstat, CRS3123, and ridinilazole were identified with unique mechanisms of action and narrow spectrums of activity that result in gut microbiome preservation and reduced recurrent CDI (rCDI) rates. One cannot predict the potential efficacy of these new agents under study until further studies are done. Some may emerge as only supplemental therapies, while others may fail or be shelved and hopefully at least one will emerge as a primary CDI therapy and to prevent rCDI. Some have the ability to restore the microbiome (VE303) or preserve intestinal integrity (e.g. REC-3964, LMN-201, AQ). Regardless, patients and clinicians need new agents. CDI is a significant burden to the healthcare system and the quality of life for patients who suffer from CDI and rCDI. Further development of these investigational agents to prevent this cycle are of upmost importance.

Introduction: The additions of letermovir and maribavir to the cytomegalovirus (CMV) armamentarium have markedly changed the landscape of CMV prevention and treatment in transplant recipients. However, their currently approved indications remain relatively restricted, and there is still a definite need for additional interventions to limit the impact of CMV in both immunocompromised and immunocompetent persons. The development of novel antivirals, vaccines, and immunotherapy-based strategies would represent significant steps toward this goal.

Areas covered: This review examines anti-CMV agents in early stage (Phase I or II) clinical trials, including expanding indications for existing agents, novel agents, vaccines, and immune-based therapies.

Expert opinion: Despite recent advances in CMV chemoprevention and treatment in transplant recipients, there remains a need for a broader, more diversified approach to mitigating the impact of CMV infection in both transplant and non-immunocompromised persons. Intravenous brincidofovir would provide an important alternative option to current antivirals in the right clinical setting. Several promising vaccine candidates are in various stages of clinical development. A safe and effective vaccine may also expand preventative strategies beyond transplant recipients and into healthy persons, specifically for the prevention of maternal-to-fetal transmission. The therapeutic possibilities of VST and TCR therapy represent important potential adjuncts to antivirals.

Background: This phase I study aimed to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of MG-ZG122, an anti-thymic stromal lymphopoietin mAb, in a healthy Chinese population.

Methods: A randomized, double-blind, placebo-controlled, and dose-escalation design was used. Four dose cohorts (52.5, 105, 210, and 420 mg) with 10 participants each were randomized to receive subcutaneously (SC) a single dose of MG-ZG122 or placebo (8:2), except for the 52.5 mg with 4 participants (2:2).

Results: Among participants who received MG-ZG122 (n = 26/34), most treatment-emergent adverse events (TEAEs) were grade 1 or 2. A single dose of MG-ZG122 exhibited a dose-dependent increase in the serum concentration ranging from 52.5 to 420 mg. It showed a half-life of up to 80 days and is intended to support a once-every-6-month administration. Dose-dependent reductions in peripheral blood eosinophil counts were observed in the 210 and 420 mg dose cohorts, with a greater decrease at the 420 mg and a sustained response through day 211.

Conclusions: MG-ZG122 was safe and well-tolerated with favorable PK profiles after a single SC injection in healthy Chinese at doses ranging from 52.5 to 420 mg, providing preliminary evidence for further evaluation.

Clinical trial registration: This study was registered with ClinicalTrials.gov, NCT05659927.

Introduction: Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma and has a rapidly evolving treatment landscape. For patients at increased risk of primary treatment failure and those with relapsed/refractory disease, emerging therapeutic classes have significantly improved outcomes.

Areas covered: This review describes the most important trials evaluating treatment for DLBCL in frontline and the relapsed/refractory setting for both fit patients and patients ineligible for intensive therapy. Particular attention is paid to rational treatment sequencing and selection for CAR-T, bispecific antibodies and molecularly targeted therapies.

Expert opinion: In modern DLBCL therapy, it is critical to identify individuals at increased risk of primary treatment failure with R-CHOP, who may then be offered the addition of Polatuzumab Vedotin or other targeted therapies in frontline. CAR-T is now a treatment standard in second line for patients with primary refractory or early relapsed disease, with ASCT reserved for eligible patients with later relapse, who may subsequently receive CAR-T in third-line. ASCT ineligible patients also face improved outcomes with CAR-T and enhanced therapies incorporating novel agents. Molecular and genomic tumor profiling is likely in the future to direct optimal treatment for patients by identifying biologically distinct lymphomas sensitive to distinct targeted agents.

Introduction: Lipoprotein(a) [Lp(a)] is an independent, inherited risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. Lp(a) is an LDL-like particle containing apoB-100 and apo(a). Lifestyle changes and statin therapy lower LDL-cholesterol and apoB, but do not reduce Lp(a), whereas PCSK9 inhibitors exert a modest effect. There are currently no approved Lp(a)-lowering drugs, although several are at various phases of clinical development.

Areas covered: We discuss the role of Lp(a) as a therapeutic target, describe the development, pharmacodynamics, pharmacokinetics, and metabolism of zerlasiran, a small interfering RNA (siRNA) targeting Lp(a), and report the findings of recent clinical trials.

Expert opinion: The GalNAc-conjugated siRNA zerlasiran reduces Lp(a) by targeting hepatic apo(a) synthesis and subsequent assembly of Lp(a), with comparable efficacy to other Lp(a)-lowering therapies in phase II development. Its long half-life, infrequent dosing, and potentially lower cost, together with its favorable safety and tolerability profile, make zerlasiran a promising candidate. However, long-term studies are needed to assess its impact on major adverse cardiovascular events and safety in diverse patient populations, and across different clinical settings. The phase III cardiovascular outcome study has not commenced.

Introduction: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease characterized by progressive bile duct destruction that can lead to liver cirrhosis and liver failure. While ursodeoxycholic acid (UDCA) remains the first-line treatment, up to 40% of patients show an inadequate response. In such cases, second-line therapies are explored. Obeticholic acid (OCA), a farnesoid X receptor agonist, was initially approved but recently lost its marketing authorization in the EU due to an unfavorable risk-benefit balance. Fibrates, particularly bezafibrate and fenofibrate, have shown promising results in improving biochemical markers and reducing pruritus, although they remain off-label.

Areas covered: We here focus on new FDA- and EMA-approved therapies, including the PPAR agonists elafibranor and seladelpar, which demonstrate improved biochemical response and, in the case of seladelpar, a significant reduction in pruritus. Additional investigational agents include NOX inhibitors such as setanaxib, IBAT inhibitors like linerixibat and odevixibat, and golexanolone, targeting fatigue through modulation of GABAergic neurotransmission.

Expert opinion: Despite advances, challenges remain in treatment personalization, access to new drugs, and identification of robust endpoints beyond ALP normalization, including quality of life improvements. Future directions emphasize a personalized approach, long-term outcome studies, and broader access to effective therapies.

Introduction: All human cells have the capacity to respond to damage or danger through conserved signaling pathways that converge on interleukin-1 receptor-associated kinases (IRAKs). IRAKs are a family of kinases that play central roles in innate immunity and inflammation and are increasingly implicated in the development and progression of cancer.

Areas covered: IRAKs are tightly regulated by multiple mechanisms to prevent aberrant activation. Dysregulated IRAK function has been increasingly recognized for its role in cancer initiation, progression, and therapy resistance, extending beyond its canonical function in inflammatory signaling. While much of the research to date has focused on IRAK signaling in hematologic malignancies, emerging evidence suggests that IRAKs are also activated and therapeutically relevant in solid tumors. As a result, several small-molecule inhibitors targeting one or more IRAK family members are now approved, in clinical trials, or under preclinical development. In this review, we summarize the current understanding of IRAK biology in cancer, with a particular focus on therapeutic strategies and the translational potential of IRAK-targeted therapies.

Expert opinion: IRAK inhibitors and degraders are promising treatments for a variety of cancers. Future clinical success will depend on optimizing kinase selectivity profiles and identifying biomarkers to guide patient selection and combination strategies.

Introduction: Prostate cancer (PC), including castration-resistant disease (CRPC), remains largely driven by dysregulated androgen receptor (AR) signaling. While androgen deprivation therapy (ADT) combined with next-generation AR inhibitors improves survival, resistance inevitably arises through mechanisms such as AR amplification, mutations, and splice variants. Additionally, chronic AR suppression induces significant metabolic, musculoskeletal, and cardiovascular toxicities, highlighting the need for novel therapies that overcome resistance while minimizing systemic adverse effects.

Areas covered: This review outlines the pivotal role of AR signaling in PC pathogenesis and evaluates the clinical impact and limitations of current AR-targeted therapies. In addition, it examines emerging therapeutic strategies aimed at modulating AR activity, disrupting androgen biosynthesis, and degrading the AR protein itself. Finally, we explore novel approaches targeting alternative oncogenic pathways involved in resistance and lineage plasticity, with the goal of advancing more effective and durable treatment paradigms.

Expert opinion: Novel strategies such as bipolar androgen therapy (BAT), selective androgen receptor modulators (SARMs), and AR degraders like PROTACs offer context-specific or mechanistically distinct ways to overcome resistance to traditional AR antagonism in prostate cancer. These approaches, along with CYP11A1 inhibitors and resistance pathway targeting (e.g. PI3K/AKT, EZH2), mark a shift toward more personalized therapies aimed at improving efficacy while minimizing toxicity.

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.