Expert opinion on investigational drugs最新文献

{"title":"Phase 1 trials of BI 764198, a transient receptor potential channel 6 inhibitor, in healthy volunteers and participants with kidney impairment.","authors":"Armin Schultz, Atef Halabi, Friedeborg Seitz, Katrien Lemmens, Hauke S Wülfrath, Maximilian T Lobmeyer, Silke Retlich, Wansuk Choi, Nima Soleymanlou","doi":"10.1080/13543784.2025.2510673","DOIUrl":"10.1080/13543784.2025.2510673","url":null,"abstract":"<p><strong>Background: </strong>BI 764198 could reduce podocyte injury in focal segmental glomerulosclerosis (FSGS).</p><p><strong>Research design and methods: </strong>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.</p><p><strong>Results: </strong>SRD trial: 4/54 BI 764198-treated participants (7.4%) had ≥ 1 investigator-defined drug-related adverse event (DRAE): headache (<i>n</i> = 3; 5.6%); diarrhea (<i>n</i> = 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.</p><p><strong>Conclusions: </strong>BI 764198 was well tolerated and could be taken with/without food; evaluation in FSGS is ongoing.</p><p><strong>Clinical trial registration: </strong>The trials are registered at www.clinicaltrials.gov with codes NCT03854552; NCT04102462; NCT04656288; NCT04176536.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"415-423"},"PeriodicalIF":4.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198646","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}

{"title":"Preclinical therapeutics for sickle cell disease: modern developments and future considerations.","authors":"Iheanyi Okpala, Charles Nonyelu, Ebele Muoghalu, Ikechukwu Anigbogu, Chinenye Onodugo, Udoka Ilechukwu, Uwaoma Fidelis-Ewa, Augustine Duru, Helen Okoye","doi":"10.1080/13543784.2025.2500289","DOIUrl":"https://doi.org/10.1080/13543784.2025.2500289","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Areas covered: </strong>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.</p><p><strong>Expert opinion: </strong>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.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":"34 4","pages":"301-315"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001869","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}

{"title":"A phase 1, randomized, double-blind, placebo-controlled trial investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of KN056 (a recombinant human GLP-1 variant Fc fusion protein) in healthy Chinese participants.","authors":"Yuan-Fang Qin, Wen-Hua Zhang, Hao-Nan Zhang, Yu-Wei Li, Wen-Qiao Huang, Jin-Lian Xie, Shuang Yang, Lan-Ni Li, Chang Cui, Qi Pei, Jie Huang, Guo-Ping Yang","doi":"10.1080/13543784.2025.2500303","DOIUrl":"10.1080/13543784.2025.2500303","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>KN056 demonstrated favorable PK, PD, and safety profiles in healthy Chinese participants, supporting its potential for once-weekly dosing.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":"34 4","pages":"329-337"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980693","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}

{"title":"Unlocking the mechanisms underlying the activity of pembrolizumab plus enfortumab vedotin in patients with urothelial carcinoma.","authors":"Matteo Santoni, Alessandro Rizzo, Francesco Massari","doi":"10.1080/13543784.2025.2473695","DOIUrl":"10.1080/13543784.2025.2473695","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Areas covered: </strong>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.</p><p><strong>Expert opinion: </strong>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.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"259-265"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515091","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}

{"title":"The bispecific antibody AZD0486: an overview of the clinical journey to date with a focus on follicular lymphoma.","authors":"Harry Hambleton, Chan Y Cheah","doi":"10.1080/13543784.2025.2500290","DOIUrl":"https://doi.org/10.1080/13543784.2025.2500290","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Areas covered: </strong>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.</p><p><strong>Expert opinion: </strong>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.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":"34 4","pages":"245-252"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005268","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}

{"title":"Endothelin receptor antagonists for diabetic kidney disease: back to the future?","authors":"Panagiota Anyfanti, Marieta Theodorakopoulou, Fotini Iatridi, Pantelis Sarafidis","doi":"10.1080/13543784.2025.2500294","DOIUrl":"https://doi.org/10.1080/13543784.2025.2500294","url":null,"abstract":"<p><strong>Introduction: </strong>Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide. Endothelin-1 (ET-1) is a potent vasoconstrictor secreted by vascular endothelial cells, actively involved in the pathophysiology of numerous cardiovascular diseases. Based on the differential downstream effects of ET-1 binding to its two distinct types of receptors (ET_A/ET_B) within the kidney, selective ET_A receptor blockade has been long proposed as a promising treatment modality for DKD.</p><p><strong>Areas covered: </strong>This review aims to examine the available evidence base for the use of ERAs in the treatment of DKD, by critically reappraising available landmark trials and discussing their possible position in the context of current treatment of this disease.</p><p><strong>Expert opinion: </strong>Despite early enthusiasm and widespread expectations, endothelin receptor antagonists (ERAs) faded into obscurity following the release of the first randomized controlled trials (RCTs). More recent RCTs using different compounds have re-introduced ERAs as a promising treatment in the growing pharmaceutical armamentarium of DKD. While the future of DKD management will be based on a more personalized approach, new, robust evidence from appropriately designed RCTs is eagerly anticipated to clearly define the role of ERAs in DKD.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":"34 4","pages":"317-327"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976790","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}

{"title":"Chronic lymphocytic leukemia: what clinical progress have we seen in the last five years?","authors":"Elżbieta Iskierka-Jażdżewska, Bartosz Puła, Krzysztof Jamroziak, Tadeusz Robak","doi":"10.1080/13543784.2025.2500288","DOIUrl":"https://doi.org/10.1080/13543784.2025.2500288","url":null,"abstract":"<p><strong>Introduction: </strong>Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. Although treatment has shifted from immunochemotherapy to novel targeted drugs over the last 10 years, novel therapies remain under investigation, particularly in relapsed and refractory patients.</p><p><strong>Areas covered: </strong>This review describes the use of approved targeted drugs and novel therapies in treatment-naïve and relapsed or refractory CLL. Particular attention is paid to the management of double-refractory patients, and the discovery of novel drugs in the last five years.</p><p><strong>Expert opinion: </strong>Targeted drugs are effective and well-tolerated in the treatment of CLL. In the last five years, several novel agents have been investigated in preclinical studies and clinical trials, including combinations of approved drugs, novel BTK and BCL2 inhibitors, BTK degraders, bispecific antibodies and CAR-T cells. It is anticipated that some should be approved in the near future.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":"34 4","pages":"267-285"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994351","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}

{"title":"Pharmacokinetic equivalence and comparative safety, tolerability, and immunogenicity of Biocon's ustekinumab (Bmab-1200) with EU-approved and US-licensed reference ustekinumab in healthy subjects: results from the Study to Test pharmacokinetic BioEquivalence of BiosimiLar ustekinumab to SteLARa (STELLAR-1).","authors":"Jonathan Ackroyd, Sarika S Deodhar, Subramanian Loganathan, Gursharan Singh, Ashwani Marwah, Kuldeep Kumar, Jayanti Panda, Sandeep Nilkanth Athalye","doi":"10.1080/13543784.2025.2500334","DOIUrl":"10.1080/13543784.2025.2500334","url":null,"abstract":"<p><strong>Background: </strong>This study assessed the pharmacokinetics (PK) equivalence, safety, tolerability, and immunogenicity of Bmab-1200 versus the reference product ustekinumab (EU-approved and US-licensed Stelara).</p><p><strong>Research design & methods: </strong>This 20-week, randomized, double-blind, three-arm, parallel-design, Phase-1 study enrolled healthy male and female subjects (<i>n</i> = 258; 18-55 years). A single, 45-mg subcutaneous injection of Bmab-1200, EU-approved Stelara, or US-licensed Stelara was administered in a 1:1:1 ratio. Subject stratification was performed by ethnicity, body weight range, and gender. Primary PK endpoints included AUC_0-inf and C_max. Secondary endpoints included additional PK parameters, immunogenicity, and safety and tolerability.</p><p><strong>Results: </strong>All three pairwise comparisons of Bmab-1200 versus US-Stelara, Bmab-1200 versus EU-Stelara, and US-Stelara versus EU-Stelara were equivalent for AUC_0-inf (90% confidence intervals [CIs] of the geometric least squares mean [GLSM] ratio: 0.9975-1.1657, 0.9959-1.1685, and 0.9223-1.0921, respectively) and C_max (90% CIs of the GLSM ratio: 0.9478-1.0732, 0.9136-1.0376, and 0.9012-1.0267, respectively). All secondary analyses supported the primary results.</p><p><strong>Conclusion: </strong>Three-way PK equivalence between Bmab-1200, US-Stelara, and EU-Stelara was demonstrated. A single, 45-mg dose of Bmab-1200 was safe and well tolerated, and, overall, the number of AEs was similar among the groups. Diversity limited to White and Japanese groups did not impact the study results.</p><p><strong>Clinical trial registration: </strong>This study was registered with www.isrctn.com; identifier: ISRCTN11424009.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":"34 4","pages":"349-357"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958615","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}

{"title":"Safety, tolerability, pharmacokinetics, and pharmacodynamics of SHR-2010, a novel anti-MASP-2 antibody, in healthy volunteers: a randomized, double-blind, placebo-controlled phase 1 study.","authors":"Pingping Lin, Chenjing Wang, Xiaotong Hu, Lin Fang, Hongda Lin, Feifei Sun, Rong Huang, Rongxin Ban, Sheng Feng, Zhenyan Gao, Kai Shen, Yu Cao","doi":"10.1080/13543784.2025.2500291","DOIUrl":"10.1080/13543784.2025.2500291","url":null,"abstract":"<p><strong>Background: </strong>This first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of SHR-2010, a novel humanized IgG4 monoclonal antibody targeting mannan-binding lectin serine protease-2, in healthy adults.</p><p><strong>Research design and methods: </strong>In this randomized, double-blind, phase 1 study, eligible participants were randomly assigned to single ascending doses of SHR-2010 or placebo (32 via intravenous drip: 6:2; 0.3, 1.5, 4.0, and 8.0 mg/kg; 29 via subcutaneous injection: 8:2; 4.0, 8.0, and 12.0 mg/kg). The primary endpoints were safety and tolerability.</p><p><strong>Results: </strong>SHR-2010 was well tolerated. Treatment-related adverse events (TRAEs) were similar in SHR-2010 groups (55.3% [26/47]) and placebo groups (78.6% [11/14]). No deaths or severe TRAEs were reported. In the intravenous dose groups, the C_max increased proportionally with the dose, while the AUC increased slightly more than the dose increment. In the subcutaneous injection groups, C_max and AUC demonstrated a linear relationship with dose. SHR-2010 demonstrated a notable inhibitory effect on lectin pathway, with the mean maximum inhibition rates exceeding 80.0% across the tested doses, compared to 6.7% with placebo.</p><p><strong>Conclusions: </strong>SHR-2010 was safe and well tolerated after a single dose and exhibited robust blockade of the lectin pathway, supporting further development.</p><p><strong>Trial registration: </strong>The trial is registered at ClinicalTrials.gov (NCT05398510).</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":"34 4","pages":"339-348"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985640","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}

{"title":"Neuropathic pain management: a focused review of current treatments and novel data from main ongoing clinical trials.","authors":"Nikola Andrejic, Ivo Božovic, Hadi Moradi, Rojin Tataei, Nebojsa Nick Knezevic","doi":"10.1080/13543784.2025.2473692","DOIUrl":"10.1080/13543784.2025.2473692","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Areas covered: </strong>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.</p><p><strong>Expert opinion: </strong>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.</p>","PeriodicalId":12313,"journal":{"name":"Expert opinion on investigational drugs","volume":" ","pages":"287-299"},"PeriodicalIF":4.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523028","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}