Expert opinion on investigational drugs最新文献

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: GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes.

Areas covered: This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration.

Expert opinion: The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.

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: 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: 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.

Introduction: The concept of insulin resistance has been a major topic for more than 5 decades. While there are several treatments that may impact insulin resistance, this pathology is uniquely addressed by mitochondrially directed thiazolidinedione (TZD) insulin sensitizers. Understanding of this mechanism of action and consideration of 'insulin resistance' as a consequence of metabolic inflammation allows a new paradigm for approaching chronic diseases.

Areas covered: We review evolving understanding of the mitochondrial pyruvate carrier (MPC) as a mitochondrial mechanism of action of the TZD insulin sensitizers and discuss how reprogramming of mitochondrial metabolism impacts pleotropic pharmacology in multiple tissues. Additional lines of investigation are proposed.

Expert opinion: A change in paradigm can facilitate rethinking of insulin sensitizers in clinical trials, specifically beyond the treatment of frank type 2 diabetes. There should be broader clinical evaluation of insulin sensitizers in combination with weight loss and lifestyle approaches across diseases/syndromes associated with insulin resistance. Finally, 'connecting all the dots' to unwind the interconnectedness of cell biology involved in the syndromes impacted by metabolic dysfunction and the efficacy of TZD insulin sensitizers may also uncover new molecular targets. New studies should facilitate the discovery and development of novel pharmacologic agents.

Introduction: Opioid use disorder and neonatal opioid withdrawal syndrome are persisting consequences of the opioid epidemic in the United States. Current pharmacologic approaches primarily utilize opioid replacement therapy, but non-opioid therapeutics could have advantages. Preclinical and clinical data suggest modulation of the serotonergic system as a novel therapeutic approach in relieving opioid withdrawal syndromes.

Areas covered: Serotonin receptors that have been reported to mediate opioid withdrawal signs based on preclinical findings are identified and described. Extant clinical studies assessing the modulation of these receptors on opioid withdrawal outcomes are then summarized.

Expert opinion: While medications that serve as agonists or antagonists to serotonin receptor subtypes have the potential for treatment of opioid withdrawal and neonatal opioid withdrawal syndrome, much of the evidence is tenuous. The supportive data are mainly derived from preclinical studies, and the measured clinical efficacy has been variable, but reductions in symptom severity are consistently noted. Serotonergic modulation offers a non-opioid pathway to relieving opioid withdrawal manifestations, which is especially useful for neonates as changes in neuroplasticity have been noted with postnatal opioid use. Potential benefits warrant additional studies to clarify the mechanisms for their effect and for measuring how effective these agents are in human disease.

Objectives: 22011 is an insulin degludec/insulin aspart co-formulation (IDegAsp) that shares an identical amino acid sequence with Ryzodeg, the originator IDegAsp. This study aimed to compare the pharmacokinetics (PK), pharmacodynamics (PD), and safety of 22011 with Ryzodeg.

Methods: In a single-center, randomized, open-label, two-treatment, two-period, two-sequence, crossover, euglycemic clamp study, healthy Chinese adults were randomized to receive 0.5 U/kg of 22011 and Ryzodeg under fasting conditions. PK was evaluated for up to 120 h and PD (represented by glucose infusion rate [GIR]) was assessed for up to 24 h.

Results: Of 46 subjects randomized, all completed both treatment periods and were included in the PK/PD and safety analysis set. Insulin exposure (AUC_{IDeg, 0-24 h}, AUC_{IAsp, 0-12 h}, and C_{max, IAsp}) and activity (GIR_max and AUC_{GIR, 0-24 h}) were comparable (estimates of treatment ratios 0.916 ~ 1.076 for primary PK parameters and 0.946 ~ 1.037 for primary PD parameters), with 90% confidence intervals for the ratios of least square means falling within the range of 0.80 ~ 1.25. Adverse events were similar for both products and no significant safety concerns were noted in the laboratory results, vital signs, or electrocardiogram.

Conclusion: This study demonstrated the PK/PD similarity of 22011 to Ryzodeg with a comparable safety profile.Trial Registration: http://www.chinadrugtrials.org.cn/index.html with an identifier of CTR20230678, registered 15 March 2023.