Expert opinion on investigational drugs最新文献

Introduction: Neuropathic pain (NP) remains a significant challenge in clinical practice, requiring a sophisticated pharmacotherapeutic strategy for effective symptom management. This review provides a comprehensive analysis of the current pharmacological treatments for NP, focusing on their efficacy, mechanism of action, and therapeutic potential. Additionally, it evaluates ongoing clinical trials investigating novel drugs and therapeutic approaches, highlighting emerging trends and future directions in NP management.

Areas covered: This review examines first- to third-line therapeutic modalities for NP, critically analyzing their efficacy, safety profiles, and clinical applications. It also includes an overview of ongoing clinical trials exploring innovative pharmacological therapies. A thorough literature review was conducted using the MEDLINE database without temporal limitations, offering a detailed assessment of established and emerging treatments.

Expert opinion: While current pharmacological options offer significant symptom relief, their overall effectiveness in managing NP remains limited, highlighting the need for further therapeutic advancements. Staying informed about emerging therapies and clinical trials is vital to enhancing patient care and quality of life. The future of NP management lies in optimizing individualized treatment strategies, refining therapeutic approaches, and fostering interdisciplinary collaboration. Close monitoring of outcomes and continued research are essential for advancing understanding and improving the precision of NP therapies.

Introduction: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. While disease-modifying therapies have significantly improved the management of relapsing MS, progressive MS remains a major clinical challenge.

Areas covered: This review provides a general overview of recent and ongoing phase 2 clinical trials investigating treatments for MS, summarizing emerging results when available. The trials are categorized based on the desired therapeutic effect: immunomodulatory treatments, neuroprotection, and remyelination. A comprehensive literature search was conducted using databases such as PubMed and ClinicalTrials.gov to identify relevant studies, with a focus on promising therapies that address both inflammatory and neurodegenerative processes in MS.

Expert opinion: Despite promising results from phase 2 trials, many phase 3 trials fail to demonstrate significant efficacy. This discrepancy is partly due to limitations in biomarkers, which often lack disease specificity and fail to predict long-term outcomes. Additionally, smaller, narrowly focused phase 2 trials may overestimate efficacy, leading to challenges when transitioning to larger, more inclusive phase 3 trials. Recruitment of patients with less aggressive disease further complicates phase 3 success. Addressing these challenges requires the refinement of biomarkers, adoption of unified definitions for outcomes like progression independent of relapse activity (PIRA), and trial designs that better capture the complexity of MS progression.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited therapeutic options and poor overall survival. In recent years, advances in genomic profiling have revealed the complex molecular and cellular heterogeneity of PDAC, offering new avenues for therapeutic intervention.

Areas covered: This review explores emerging therapeutic strategies targeting dysregulated molecular pathways, along with the tumor microenvironment, that have shown promise in overcoming drug resistance. Novel immunotherapy strategies, such as immune checkpoint inhibitors and CAR T-cell therapies, are currently being explored in an attempt to modulate PDAC immugnosuppressive microenvironment. Additionally, we highlight recent clinical trials over the last 5 years and innovative therapeutic strategies aiming to improve outcomes in PDAC.

Expert opinion: Significant progress in genomic profiling, targeted therapies, and immunotherapy is shaping the treatment of PDAC. Despite challenges posed by its dense stroma and immune suppressive microenvironment, novel strategies such as IL 6 and CD137 inhibitors, CAR-T, and therapeutic cancer vaccines are promising. KRAS targeted therapies are expanding beyond G12C inhibitors, with novel drugs in development that will further improve treatment options. Additionally, tumor treating fields (TTF) are being investigated in locally advanced PDAC, with the PANOVA-3 trial potentially integrating this modality into future treatment strategies. Continued advancements in these areas will significantly enhance PDAC outcomes.

Introduction: Patients with Systemic Lupus Erythematosus (SLE) experience varied manifestations and unpredictable flares, complicating treatment and drug development. Despite these challenges, anifrolumab, voclosporin, and belimumab were approved by FDA. These treatments complement, but don't replace, traditional therapies like NSAIDs, corticosteroids, antimalarials, and immunosuppressives. Therefore, there remains an unmet need for more effective medications targeting excessive proinflammatory cytokines in SLE patients.

Areas covered: This review summarizes the clinical trial outcomes of four upcoming medications targeting cytokine activity: Litifilimab showed a 7-point reduction in CLASI-A in its phase II trial. Daxdilimab was unsuccessful in its phase II trial. Anifrolumab reduced SLE activity in both phase II and III trials. Deucravacitinib decreased disease activity by multiple measures in its phase II trial.

Expert opinion: High levels of IFN-I (type 1 interferon) are present in most SLE patients, making this pathway an attractive target for drug development. Litifilimab downregulates IFN-I by targeting BDCA2, while dexadilimab targets ILT7 to recruit effector cells, reducing IFN-I production by killing PDCs. Anifrolumab binds to the IFN-I receptor, blocking the activity of all IFN-Is, and deucravacitinib reduces IFN-I by inhibiting TYK2, thereby interfering with downstream signaling. Therapies that target IFN-I represents a promising class of medications for SLE patients.

Introduction: Over the past 20 years, the treatment landscape of HER2-amplified tumors has considerably evolved. Until now, no approved targeted therapies were available for patients with HER2-amplified metastatic colorectal cancer (mCRC). Tucatinib, a highly selective tyrosine kinase inhibitor, demonstrated significant efficacy in combination with trastuzumab in patients with refractory mCRC, leading to its approval by the Food and Drug Administration (FDA).

Areas covered: This review dives into the efficacy of tucatinib-based regimens in gastrointestinal malignancies, with a focus on the pivotal MOUNTAINEER trial, which led to the FDA approval of tucatinib plus trastuzumab in chemo-refractory HER2-amplified mCRC. Additionally, ongoing trials are exploring tucatinib in earlier treatment lines and across other gastrointestinal cancers, including biliary tract, gastric, and pancreatic malignancies. The mechanistic basis of dual HER2 inhibition and its implications for clinical practice are discussed.

Expert commentary: The future of tucatinib-based therapeutic strategies in GI malignancies depends on their integration into different treatment lines. Addressing acquired resistance using liquid biopsy-guided strategies and other TKIs like lapatinib will be paramount to improve outcomes.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) or glucagon receptor agonists have emerged as promising agents to treat metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). Although the beneficial effects of GLP-1RAs on glycemic control and weight are well-established, clinicians may be unfamiliar with other potential benefits of this class.

Areas covered: We examined the pleiotropic effects of GLP-1RAs and how they relate to gastroenterologists for MASLD/MASH treatment. Our narrative review of English articles included four GLP-1RAs (subcutaneous semaglutide, liraglutide, dulaglutide, and efpeglenatide), a dual GLP-1/GIP agonist (tirzepatide), a dual GLP-1/glucagon receptor agonist (survodutide), MASLD/MASH, related disorders, clinical management, treatment outcomes and landscape.

Expert opinion: In Phase I - III trials, GLP-1RAs are associated with clinically relevant hepatic improvements including MASH resolution, liver fat reduction, and preventing worsening fibrosis. Effects on cardiometabolic parameters align with type 2 diabetes/obesity Phase III data, comprising substantial improvements in glycemic, weight, and cardiovascular outcomes. Promising data also suggest benefits in common comorbidities, including obstructive sleep apnea, polycystic ovary syndrome, chronic kidney disease, and heart failure with preserved ejection fraction.GLP-1RAs represent a valuable pharmacotherapeutic option for gastroenterologists managing individuals with MASLD/MASH and cardiometabolic comorbid conditions.

Introduction: Mantle cell lymphoma is still a lymphoma subtype with productive clinical research. Recent published data on Bruton kinase inhibitors have changed the management of patients.

Areas covered: This review summarizes the most important trials evaluating the different treatment options in mantle cell lymphoma in the frontline and the relapsed/refractory setting in young and older patients, focusing on the role of Bruton kinase inhibitors in improving disease outcome and omitting consolidative autologous stem cell transplantation.

Expert opinion: Following the results of the TRIANGLE trial, the addition of ibrutinib to the induction and maintenance treatment should be considered and the omission of autologous stem cell transplantation is questionable in all patients. Minimal residual disease is a promising biomarker that would dictate our decision making especially in the maintenance setting. CAR-T cells remain the best option in the relapsed/refractory patients after Brutonkinase inhibitors.

Introduction: Glaucoma is a neurodegenerative disease that causes irreversible blindness worldwide. It results from retinal ganglion cell (RGC) loss and progressive optic nerve damage, mainly associated with elevated intraocular pressure (IOP). Current treatments focus on reducing IOP but do not directly delve into the underlying pathophysiological mechanisms of neurodegeneration. A mechanistic approach enables researchers to identify drugs that target these fundamental mechanisms rather than solely addressing symptoms such as elevated IOP.

Areas covered: This review explores mechanistic approaches to emerging preclinical agents, including those targeting trabecular meshwork function, neuroprotection, RGC survival, and ocular blood flow. We also review promising nutrients, gene therapies, and biologics currently under investigation, particularly agents that modulate oxidative stress and neuroinflammatory pathways.

Expert opinion: Recently, investigational drugs that protect the RGC and the optic nerve from further damage have become critical in treating glaucoma. For example, CNTF was shown to promote the survival and growth of photoreceptors and RGC in cell culture and animal models. Moreover, optimizing drug delivery is paramount to achieving tailored management and patient adherence. Meticulous clinical trials will pave the way for the potential reevaluation of glaucoma management, offering new hope for patients with this complex disease.

Introduction: Huntington's Disease (HD) is a progressive fatal neurodegenerative disease with an unmet need for disease-modifying therapies. Neuroinflammation, particularly astrogliosis, plays a crucial role in the pathogenesis of HD and modulation of this damaging activity and its downstream effects presents a promising therapeutic avenue. Pepinemab, a semaphorin 4D (SEMA4D) blocking antibody, has the potential to serve this purpose.

Areas covered: We review the proposed mechanisms of action of pepinemab, published safety and efficacy results from the 'SIGNAL' Phase 2 trial in HD and supporting data from a Phase 1 trial in multiple sclerosis (MS).

Expert opinion: Pepinemab's potential to reduce reactive gliosis and inflammation is a novel mechanism of action (MOA) that may be effective as a standalone therapy as well as one that may complement other strategies to reduce toxic disease associated processes. Pepinemab has demonstrated a favorable safety profile and treatment benefits in fluid biomarkers, imaging endpoints, and measures of cognitive function that encourage continued development in HD and other neurodegenerative diseases.