Pub Date : 2024-10-28DOI: 10.1080/13543784.2024.2422838
Anita Nelson, Marit Pearlman Shapiro
Introduction: Selective progesterone receptor modulators (SPRMs), such as mifepristone and ulipristal acetate (UPA), have demonstrated high efficacy and safety as single dose treatments for medication abortion and emergency contraception (EC). Other obstetrical and gynecologic applications have emerged, both for episodic and ongoing uses. The potential of these compounds to provide estrogen-free, ongoing contraception is promising; however, the rare, but serious, hepatic injury cases seen with UPA have put at least a temporary halt to further research in this area.
Areas covered: This paper reviews the biophysical impacts and clinical applications of SPRMs in women's reproductive health, with a focus on the roles of mifepristone and UPA in family planning. Given the political environment, especially in the United States where these applications may be threatened, extensive description is dedicated to mechanisms of action of these agents.
Expert opinion: Both mifepristone and ulipristal acetate are first-line options for single use applications. There continues to be a need for estrogen-free ongoing contraception that does not have unpopular impacts on bleeding caused by contraceptive methods and for treatments for heavy menstrual bleeding. However, current restrictions on UPA limit longer term use. Perhaps other SPRMs without hepatic impacts may emerge to fill this need.
{"title":"Promising selective progesterone receptor modulators: what's new in female contraception?","authors":"Anita Nelson, Marit Pearlman Shapiro","doi":"10.1080/13543784.2024.2422838","DOIUrl":"https://doi.org/10.1080/13543784.2024.2422838","url":null,"abstract":"<p><strong>Introduction: </strong>Selective progesterone receptor modulators (SPRMs), such as mifepristone and ulipristal acetate (UPA), have demonstrated high efficacy and safety as single dose treatments for medication abortion and emergency contraception (EC). Other obstetrical and gynecologic applications have emerged, both for episodic and ongoing uses. The potential of these compounds to provide estrogen-free, ongoing contraception is promising; however, the rare, but serious, hepatic injury cases seen with UPA have put at least a temporary halt to further research in this area.</p><p><strong>Areas covered: </strong>This paper reviews the biophysical impacts and clinical applications of SPRMs in women's reproductive health, with a focus on the roles of mifepristone and UPA in family planning. Given the political environment, especially in the United States where these applications may be threatened, extensive description is dedicated to mechanisms of action of these agents.</p><p><strong>Expert opinion: </strong>Both mifepristone and ulipristal acetate are first-line options for single use applications. There continues to be a need for estrogen-free ongoing contraception that does not have unpopular impacts on bleeding caused by contraceptive methods and for treatments for heavy menstrual bleeding. However, current restrictions on UPA limit longer term use. Perhaps other SPRMs without hepatic impacts may emerge to fill this need.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: NSCLC is the leading cause of cancer-related deaths globally, with a low survival rate primarily due to NSCLC frequently becoming chemoresistant. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in pathways regulating multiple processes in the cell, including survival, migration, and the TME, that contribute to both tumor progression and drug resistance. Recently, FAK inhibitors (FAKi) have shown promising potential for the treatment of NSCLC.
Areas covered: This narrative review aims to summarize key signaling pathways involving FAK that contribute to tumor progression and drug resistance. It will further provide an overview of FAKi currently in pre- and early-phase clinical trials for solid tumors, as well as the therapeutic potential of combining FAKi with chemotherapy, as this has emerged as a promising strategy to overcome chemoresistance in NSCLC.
Expert opinion: It is becoming increasingly clear that FAK is not an oncogenic driver but rather contributes to tumor progression and drug resistance. Hence, while FAKi have only demonstrated modest results in clinical trials when given by themselves, treatment regimens combining other therapies with FAKi have shown promising potential to overcome drug resistance. Lastly, of particular novelty are FAK-PROTACs (proteolysis-targeting chimaeras), which uniquely target both cytosolic and nuclear FAK.
{"title":"Targeting a key FAK-tor: the therapeutic potential of combining focal adhesion kinase (FAK) inhibitors and chemotherapy for chemoresistant non-small cell lung cancer.","authors":"Emma Geijerman, Francesca Terrana, Godefridus J Peters, Dongmei Deng, Patrizia Diana, Elisa Giovannetti, Geng Xu","doi":"10.1080/13543784.2024.2417762","DOIUrl":"https://doi.org/10.1080/13543784.2024.2417762","url":null,"abstract":"<p><strong>Introduction: </strong>NSCLC is the leading cause of cancer-related deaths globally, with a low survival rate primarily due to NSCLC frequently becoming chemoresistant. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase involved in pathways regulating multiple processes in the cell, including survival, migration, and the TME, that contribute to both tumor progression and drug resistance. Recently, FAK inhibitors (FAKi) have shown promising potential for the treatment of NSCLC.</p><p><strong>Areas covered: </strong>This narrative review aims to summarize key signaling pathways involving FAK that contribute to tumor progression and drug resistance. It will further provide an overview of FAKi currently in pre- and early-phase clinical trials for solid tumors, as well as the therapeutic potential of combining FAKi with chemotherapy, as this has emerged as a promising strategy to overcome chemoresistance in NSCLC.</p><p><strong>Expert opinion: </strong>It is becoming increasingly clear that FAK is not an oncogenic driver but rather contributes to tumor progression and drug resistance. Hence, while FAKi have only demonstrated modest results in clinical trials when given by themselves, treatment regimens combining other therapies with FAKi have shown promising potential to overcome drug resistance. Lastly, of particular novelty are FAK-PROTACs (proteolysis-targeting chimaeras), which uniquely target both cytosolic and nuclear FAK.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Although immunoglobulin A nephropathy (IgAN) had been discovered more than 50 years ago, 30-40% of IgAN patients still have primary glomerular disease that progresses to end-stage renal disease. However, various treatment strategies for IgAN have rapidly expanded in recent years to include endothelin (ET) receptor antagonists.
Areas covered: In this review, we discuss the role of the ET-1/ETA receptor axis in the development of IgAN, especially focusing on the potential of sparsentan, a dual ET and angiotensin receptor antagonist as a novel therapy for IgAN.
Expert opinion: Evaluation of the MEST-C score at the time of renal biopsy in IgAN is important in determining treatment strategies. If lesions are mainly in the acute phase, such as crescents, steroid therapy should be continued. However, if lesions are mainly in the chronic phase, such as glomerulosclerosis, sparsentan rather than steroid or angiotensin II receptor blocker alone may improve renal outcomes. Although further clinical studies are needed to back up these assumptions, appropriate combination of new drugs containing sparsentan and conventional drugs for IgAN treatment at the appropriate disease stage is expected to further inhibit the progression of renal damage.
简介尽管免疫球蛋白A肾病(IgAN)早在50多年前就已被发现,但仍有30%-40%的IgAN患者患有原发性肾小球疾病,并发展为终末期肾病。然而,近年来IgAN的各种治疗策略已迅速扩展,包括内皮素(ET)受体拮抗剂:在这篇综述中,我们讨论了 ET-1/ETA 受体轴在 IgAN 发病过程中的作用,尤其关注了 sparsentan(一种 ET 和血管紧张素受体双重拮抗剂)作为 IgAN 新型疗法的潜力:专家意见:在 IgAN 肾活检时评估 MEST-C 评分对于确定治疗策略非常重要。如果病变主要发生在急性期,如新月体,则应继续使用类固醇治疗。但是,如果病变主要处于慢性期,如肾小球硬化,则单用司帕生坦而非类固醇或血管紧张素 II 受体阻滞剂可能会改善肾脏预后。尽管还需要进一步的临床研究来支持这些假设,但在适当的疾病阶段,将含有 sparsentan 的新药与用于 IgAN 治疗的传统药物适当结合,有望进一步抑制肾损害的进展。
{"title":"Dual blockade of endothelin A and angiotensin II type 1 receptors with sparsentan as a novel treatment strategy to alleviate IgA nephropathy.","authors":"Hajime Nagasawa, Hitoshi Suzuki, Seiji Ueda, Yusuke Suzuki","doi":"10.1080/13543784.2024.2414902","DOIUrl":"https://doi.org/10.1080/13543784.2024.2414902","url":null,"abstract":"<p><strong>Introduction: </strong>Although immunoglobulin A nephropathy (IgAN) had been discovered more than 50 years ago, 30-40% of IgAN patients still have primary glomerular disease that progresses to end-stage renal disease. However, various treatment strategies for IgAN have rapidly expanded in recent years to include endothelin (ET) receptor antagonists.</p><p><strong>Areas covered: </strong>In this review, we discuss the role of the ET-1/ET<sub>A</sub> receptor axis in the development of IgAN, especially focusing on the potential of sparsentan, a dual ET and angiotensin receptor antagonist as a novel therapy for IgAN.</p><p><strong>Expert opinion: </strong>Evaluation of the MEST-C score at the time of renal biopsy in IgAN is important in determining treatment strategies. If lesions are mainly in the acute phase, such as crescents, steroid therapy should be continued. However, if lesions are mainly in the chronic phase, such as glomerulosclerosis, sparsentan rather than steroid or angiotensin II receptor blocker alone may improve renal outcomes. Although further clinical studies are needed to back up these assumptions, appropriate combination of new drugs containing sparsentan and conventional drugs for IgAN treatment at the appropriate disease stage is expected to further inhibit the progression of renal damage.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-16DOI: 10.1080/13543784.2024.2417755
Vishwadeep Shelke, Neha Dagar, Maciej Lech, Anil Bhanudas Gaikwad
Introduction: To improve kidney disease treatments, it is crucial to understand how inflammaging affects patients´ longevity. We could potentially slow down kidney disease progression and enhance longevity by targeting specific pathways involved in inflammaging with potential drugs.
Areas of covered: This review offers an updated overview of 'anti-inflammaging' drugs currently in the kidney disease research pipeline, as well as those with potential for future therapeutic use. Furthermore, these drugs are categorized according to their mechanisms, including targeting inflammation, immune and metabolic regulation, oxidative stress, senescence, and autophagy, as demonstrated in preclinical and early clinical trials. Additionally, the review provides insights into key challenges and opinions for future advancements in this field.
Expert opinion: We reviewed recent advancements in applying different therapies to mitigate inflammaging in kidney diseases. We underscore the need for continued research to elucidate the complex pathways underlying inflammaging, which will be essential for the development of more precise and effective treatments. As research in this field advances, several emerging drugs appear promising for future investigation. While current findings are encouraging, further clinical studies are required to validate the therapeutic potential of these agents in kidney diseases, ultimately paving the way for more targeted and efficacious interventions.
{"title":"Management of inflammaging in kidney diseases: focusing on the current investigational drugs.","authors":"Vishwadeep Shelke, Neha Dagar, Maciej Lech, Anil Bhanudas Gaikwad","doi":"10.1080/13543784.2024.2417755","DOIUrl":"https://doi.org/10.1080/13543784.2024.2417755","url":null,"abstract":"<p><strong>Introduction: </strong>To improve kidney disease treatments, it is crucial to understand how inflammaging affects patients´ longevity. We could potentially slow down kidney disease progression and enhance longevity by targeting specific pathways involved in inflammaging with potential drugs.</p><p><strong>Areas of covered: </strong>This review offers an updated overview of 'anti-inflammaging' drugs currently in the kidney disease research pipeline, as well as those with potential for future therapeutic use. Furthermore, these drugs are categorized according to their mechanisms, including targeting inflammation, immune and metabolic regulation, oxidative stress, senescence, and autophagy, as demonstrated in preclinical and early clinical trials. Additionally, the review provides insights into key challenges and opinions for future advancements in this field.</p><p><strong>Expert opinion: </strong>We reviewed recent advancements in applying different therapies to mitigate inflammaging in kidney diseases. We underscore the need for continued research to elucidate the complex pathways underlying inflammaging, which will be essential for the development of more precise and effective treatments. As research in this field advances, several emerging drugs appear promising for future investigation. While current findings are encouraging, further clinical studies are required to validate the therapeutic potential of these agents in kidney diseases, ultimately paving the way for more targeted and efficacious interventions.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1080/13543784.2024.2416982
Sabina Antoniu, Setfan Rascu
Introduction: Chronic obstructive pulmonary disease (COPD) is characterized by progressive inflammation during therapy. Cystic fibrosis (CF), alpha-one antitrypsin deficiency (AATD), and non-CF bronchiectasis are also chronic respiratory disorders with inflammation and progression that share many similarities with COPD. Therefore, various anti-inflammatory approaches are currently being investigated, and protein phosphatase 2A (PP2A) activators may represent one such approach.
Areas covered: Systematic review of papers published from 2000-to date on the anti-inflammatory role of endogenous PP2A, the consequences of its inhibition by smoking, and the beneficial effects of its activation in COPD.
Expert opinion: PP2A activation is a plausible therapeutic approach in COPD and related disorders, such as CF, AATD, and non-CF bronchiectasis, although the available evidence is still mostly experimental. Metformin repurposing and consideration of inhalation for some of the molecules discussed in this study are promising approaches.
{"title":"Protein phosphatase 2A activators under investigation for smoking-related chronic obstructive pulmonary disease and related disorders.","authors":"Sabina Antoniu, Setfan Rascu","doi":"10.1080/13543784.2024.2416982","DOIUrl":"https://doi.org/10.1080/13543784.2024.2416982","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic obstructive pulmonary disease (COPD) is characterized by progressive inflammation during therapy. Cystic fibrosis (CF), alpha-one antitrypsin deficiency (AATD), and non-CF bronchiectasis are also chronic respiratory disorders with inflammation and progression that share many similarities with COPD. Therefore, various anti-inflammatory approaches are currently being investigated, and protein phosphatase 2A (PP2A) activators may represent one such approach.</p><p><strong>Areas covered: </strong>Systematic review of papers published from 2000-to date on the anti-inflammatory role of endogenous PP2A, the consequences of its inhibition by smoking, and the beneficial effects of its activation in COPD.</p><p><strong>Expert opinion: </strong>PP2A activation is a plausible therapeutic approach in COPD and related disorders, such as CF, AATD, and non-CF bronchiectasis, although the available evidence is still mostly experimental. Metformin repurposing and consideration of inhalation for some of the molecules discussed in this study are promising approaches.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1080/13543784.2024.2414119
Luca Filippi, Cristina Ferrari, Giuseppe Rubini
Introduction: Sarcomas encompass a highly diverse range of malignancies, characterized by varied morphological and molecular profiles. Treatment options in case of therapy-refractory or advanced disease are limited. In this context, theranostics emerges as an innovative platform seamlessly integrating diagnosis and therapy, offering promising prospects.
Areas covered: This special report delves into the initial clinical applications of theranostic-based approaches in sarcomas. Specifically, it examines various strategies targeting biomarkers associated with sarcomas, including fibroblast activation protein (FAP), prostate-specific membrane antigen (PSMA), C-X-C chemokine receptor type 4 (CXCR4) and somatostatin receptor 2 (SSTR2).
Expert opinion: The heterogeneous uptake of the CXCR4-targeted radioligand in lesions, along with its poor correlation with immunohistochemistry data, diminishes the attractiveness of this theranostic approach in the sarcoma oncological setting. SSTR2-targeted approaches in sarcoma, although potentially effective, are limited to a single case. Early experiences with FAP inhibitors in sarcoma patients have shown particularly promising outcomes, indicating effective disease control with minimal toxicity. While PSMA presents an enticing target for theranostic approaches in sarcomas, its utilization remains anecdotal and requires further investigation. Prospective and well-designed clinical trials are imperative to delineate the potential impact of FAPI- and PSMA-based approaches on sarcoma therapeutic landscapes, offering innovative and personalized treatment options.
{"title":"Theranostic strategies in sarcoma: preliminary clinical evidence.","authors":"Luca Filippi, Cristina Ferrari, Giuseppe Rubini","doi":"10.1080/13543784.2024.2414119","DOIUrl":"10.1080/13543784.2024.2414119","url":null,"abstract":"<p><strong>Introduction: </strong>Sarcomas encompass a highly diverse range of malignancies, characterized by varied morphological and molecular profiles. Treatment options in case of therapy-refractory or advanced disease are limited. In this context, theranostics emerges as an innovative platform seamlessly integrating diagnosis and therapy, offering promising prospects.</p><p><strong>Areas covered: </strong>This special report delves into the initial clinical applications of theranostic-based approaches in sarcomas. Specifically, it examines various strategies targeting biomarkers associated with sarcomas, including fibroblast activation protein (FAP), prostate-specific membrane antigen (PSMA), C-X-C chemokine receptor type 4 (CXCR4) and somatostatin receptor 2 (SSTR2).</p><p><strong>Expert opinion: </strong>The heterogeneous uptake of the CXCR4-targeted radioligand in lesions, along with its poor correlation with immunohistochemistry data, diminishes the attractiveness of this theranostic approach in the sarcoma oncological setting. SSTR2-targeted approaches in sarcoma, although potentially effective, are limited to a single case. Early experiences with FAP inhibitors in sarcoma patients have shown particularly promising outcomes, indicating effective disease control with minimal toxicity. While PSMA presents an enticing target for theranostic approaches in sarcomas, its utilization remains anecdotal and requires further investigation. Prospective and well-designed clinical trials are imperative to delineate the potential impact of FAPI- and PSMA-based approaches on sarcoma therapeutic landscapes, offering innovative and personalized treatment options.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-09DOI: 10.1080/13543784.2024.2414126
Xuan L Tang, Amanda J Hooper, John R Burnett
{"title":"Assessing the clinical potential of plozasiran, an <i>APOC3</i> siRNA therapy for severe hypertriglyceridemia.","authors":"Xuan L Tang, Amanda J Hooper, John R Burnett","doi":"10.1080/13543784.2024.2414126","DOIUrl":"10.1080/13543784.2024.2414126","url":null,"abstract":"","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-26DOI: 10.1080/13543784.2024.2393867
Qi Shen, Lingzhi Li, Weilin Qian, Xue Dong, Manchen Bao, Rong Huang, Na Li, Zi Ye, Gang Cheng, Quanren Wang, Kai Shen, Zhu Luo
Background: This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.
Research design and methods: In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability.
Results: HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (Tmax) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged Tmax but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration.
Conclusions: HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation.
{"title":"A four-in-one first-in-human study to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and concentration-QTc relationship of HRS-1780, a selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.","authors":"Qi Shen, Lingzhi Li, Weilin Qian, Xue Dong, Manchen Bao, Rong Huang, Na Li, Zi Ye, Gang Cheng, Quanren Wang, Kai Shen, Zhu Luo","doi":"10.1080/13543784.2024.2393867","DOIUrl":"10.1080/13543784.2024.2393867","url":null,"abstract":"<p><strong>Background: </strong>This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.</p><p><strong>Research design and methods: </strong>In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability.</p><p><strong>Results: </strong>HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (T<sub>max</sub>) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged T<sub>max</sub> but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration.</p><p><strong>Conclusions: </strong>HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov (NCT05638126).</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01Epub Date: 2024-08-22DOI: 10.1080/13543784.2024.2391837
Tingting Ma, Zuyi Weng, Bei Cao, Yanli Dong, Chanjuan Deng, Lei Huang, Yuanxun Yang, Yuqi Wang, Chenxi Shen, Lei Wang, Kai Shen, Juan Li
Background: Inhibiting the coagulation factor XI (FXI) is a novel strategy for prevention and treatment of thromboembolism without affecting extrinsic coagulation pathways. SHR-2004 is a humanized monoclonal antibody that selectively binds to FXI and factor XIa (FXIa).
Research design & methods: This randomized, double-blind, dose-escalation, placebo-controlled study evaluated SHR-2004 administered either intravenously (i.v.; Part A) or subcutaneously (s.c.; Part B). In Part A, 24 subjects received a single i.v. dose of SHR-2004 (0.1, 0.3, or 1.0 mg/kg) or placebo. In Part B, 40 subjects received a single s.c. dose of SHR-2004 (0.5, 1.0, 3.0, or 4.5 mg/kg) or placebo.
Results: SHR-2004 was well tolerated. Plasma exposure to SHR-2004 increased in a dose-dependent manner. The geometric mean half-time ranged from 11.6 to 13.0 days. FXI activity decreased, and the activated partial thromboplastin time (APTT) was prolonged after i.v. and s.c. administration in a dose- and time-dependent manner. FXI activity was nearly completely abolished immediately after administering the highest i.v. dose, with the average APTT prolonged to nearly three times of baseline.
Conclusion: SHR-2004 is a promising candidate for further development as an anticoagulant drug that exerts effective anticoagulation with minimal risk of bleeding.
Clinical trial registration: www.clinicaltrials.gov identifier is NCT05369767.
{"title":"The first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the factor XI monoclonal antibody SHR-2004 in healthy subjects.","authors":"Tingting Ma, Zuyi Weng, Bei Cao, Yanli Dong, Chanjuan Deng, Lei Huang, Yuanxun Yang, Yuqi Wang, Chenxi Shen, Lei Wang, Kai Shen, Juan Li","doi":"10.1080/13543784.2024.2391837","DOIUrl":"10.1080/13543784.2024.2391837","url":null,"abstract":"<p><strong>Background: </strong>Inhibiting the coagulation factor XI (FXI) is a novel strategy for prevention and treatment of thromboembolism without affecting extrinsic coagulation pathways. SHR-2004 is a humanized monoclonal antibody that selectively binds to FXI and factor XIa (FXIa).</p><p><strong>Research design & methods: </strong>This randomized, double-blind, dose-escalation, placebo-controlled study evaluated SHR-2004 administered either intravenously (i.v.; Part A) or subcutaneously (s.c.; Part B). In Part A, 24 subjects received a single i.v. dose of SHR-2004 (0.1, 0.3, or 1.0 mg/kg) or placebo. In Part B, 40 subjects received a single s.c. dose of SHR-2004 (0.5, 1.0, 3.0, or 4.5 mg/kg) or placebo.</p><p><strong>Results: </strong>SHR-2004 was well tolerated. Plasma exposure to SHR-2004 increased in a dose-dependent manner. The geometric mean half-time ranged from 11.6 to 13.0 days. FXI activity decreased, and the activated partial thromboplastin time (APTT) was prolonged after i.v. and s.c. administration in a dose- and time-dependent manner. FXI activity was nearly completely abolished immediately after administering the highest i.v. dose, with the average APTT prolonged to nearly three times of baseline.</p><p><strong>Conclusion: </strong>SHR-2004 is a promising candidate for further development as an anticoagulant drug that exerts effective anticoagulation with minimal risk of bleeding.</p><p><strong>Clinical trial registration: </strong>www.clinicaltrials.gov identifier is NCT05369767.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Introduction: Over the past 20 years, significant progress has been made in anti-leishmanial therapy. Three new drugs/formulations are available for the treatment of various forms of leishmaniasis, namely oral miltefosine, paromomycin and liposomal amphotericin B. However, these advances in drug development have added considerable complexity for clinicians including toxicity, emergence of resistance and decreased sensitivity of available drugs. The development of newer drugs with less toxicity and more efficacy is urgently needed.
Areas covered: This review comprehensively examines the latest developments and current status of antileishmanial drugs for the treatment of leishmaniasis across the world. Several new investigational drugs that showed anti-leishmanial activity under in vitro or in vivo conditions and either underwent the phase-I/II clinical trials or are on the verge of entering the trials were reviewed. We also delve into the challenges of drug resistance and discuss the emergence of new and effective antileishmanial compounds.
Expert opinion: The available treatments for leishmaniasis are limited in number, toxic, expensive, and demand extensive healthcare resources. Every available antileishmanial drug is associated with several disadvantages, such as drug resistance and toxicity or high cost. Miltefosine is potentially teratogenic. New antileishmanial drugs/treatment modalities are sorely needed for expanding future treatment options.
{"title":"Investigational new drugs for the treatment of leishmaniasis.","authors":"Shyam Sundar, Vishal Kumar Singh, Neha Agrawal, Om Prakash Singh, Rajiv Kumar","doi":"10.1080/13543784.2024.2400139","DOIUrl":"10.1080/13543784.2024.2400139","url":null,"abstract":"<p><strong>Introduction: </strong>Over the past 20 years, significant progress has been made in anti-leishmanial therapy. Three new drugs/formulations are available for the treatment of various forms of leishmaniasis, namely oral miltefosine, paromomycin and liposomal amphotericin B. However, these advances in drug development have added considerable complexity for clinicians including toxicity, emergence of resistance and decreased sensitivity of available drugs. The development of newer drugs with less toxicity and more efficacy is urgently needed.</p><p><strong>Areas covered: </strong>This review comprehensively examines the latest developments and current status of antileishmanial drugs for the treatment of leishmaniasis across the world. Several new investigational drugs that showed anti-leishmanial activity under <i>in vitro</i> or <i>in vivo</i> conditions and either underwent the phase-I/II clinical trials or are on the verge of entering the trials were reviewed. We also delve into the challenges of drug resistance and discuss the emergence of new and effective antileishmanial compounds.</p><p><strong>Expert opinion: </strong>The available treatments for leishmaniasis are limited in number, toxic, expensive, and demand extensive healthcare resources. Every available antileishmanial drug is associated with several disadvantages, such as drug resistance and toxicity or high cost. Miltefosine is potentially teratogenic. New antileishmanial drugs/treatment modalities are sorely needed for expanding future treatment options.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}