System for DNA-Guided Optimization and Personalization of Statin Therapy

DNA 引导的他汀类药物治疗优化和个性化系统

• 批准号: 8124566
• 负责人: GUALBERTO RUANO
• 金额: $ 60.55万
• 依托单位: GENOMAS, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124566
• 关键词: Accounting; Adverse effects; Algorithms; American; Biological Assay; Biometry; California; Cardiology; Cardiovascular Diseases; Cardiovascular system; Characteristics; Cholesterol; Clinical; Clinical Data; Clinical Management; Clinical Markers; Collaborations; Country; Creatine Kinase; Crestor; DNA; Data; Decision Support Systems; Development; Diagnostic; Doctor of Medicine; Doctor of Philosophy; Dose; Drug Prescriptions; Equilibrium; Funding; Genes; Genetic; Genetic Markers; Genome; Genomics; Genotype; Goals; Health; Hospitals; Human; Individual; Injury; Institutes; Journals; LDL Cholesterol Lipoproteins; Laboratories; Lipids; Longitudinal Studies; Marketing; Medical; Medical Informatics; Medical center; Medicine; Modeling; Monitor; Muscle; Muscle Cramp; Myalgia; Myopathy; New York; Observational Study; Outcome; Patients; Performance; Pharmaceutical Preparations; Phase; Physicians; Population; Presbyterian Church; Prevention; Production; Prospective Studies; Publications; Publishing; Qualifying; Research; Research Institute; Risk; Safety; San Francisco; Serum; Simvastatin; Single Nucleotide Polymorphism; Small Business Innovation Research Grant; Specialist; Staging; System; Therapeutic; Toxic effect; Universities; Validation; abstracting; atorvastatin; base; cardiovascular disorder risk; commercialization; cost; cost effective; gene discovery; genome-wide; lipid disorder; medical schools; neuromuscular; novel; patient population; programs; response; rosuvastatin; success; tool; treatment strategy; validation studies; zocor

DESCRIPTION (provided by applicant): Currently 30 million Americans with elevated cholesterol receive statin therapy, making statins the most prescribed drug class in the U.S. Statin Induction and Neuro-Myopathy (SINM), the balance of potency and safety, is the main clinical management challenge of these drugs, particularly when treatment targets are aggressive requiring LDL cholesterol levels below 100 mg/dl. In medical practice, Neuro-Myopathy presents as a constellation of neuromuscular side effects, including myalgia (muscle aches, cramps, weakness) and myopathy (muscular injury monitored by serum creatine kinase (CK) elevation). Neuro-myopathy is more frequent at the higher doses required for treating advanced cardiovascular disease and varies in extent between individual statins and from patient to patient. Statin usage is ultimately limited by toxicity. Clearly there is an urgent need to simultaneously avert side effects and optimize lipid lowering at the outset of treatment to bolster success in lowering cardiovascular disease risk in literally millions of patients. Recognizing that clinicians balance safety with efficacy when prescribing statins, our research group and others have established genetic markers that are valid candidates for a panel of safety and efficacy markers. The SINM PhyzioType System is the first diagnostic tool to integrate statin safety and efficacy markers for clinical use. The SINM PhyzioType system can predict the safety and efficacy of the pre-eminent statin drugs (namely, atorvastatin [Lipitor(R)], simvastatin [Zocor(R)], and rosuvastatin [Crestor(R)]-which together account for 85% of the U.S. market share8) according to the genome of each patient, enabling selection of the optimal drug for each patient. Alternatively if a patient's genomic profile proves to be incompatible with statins, the clinician can opt to prescribe another drug class. This Phase II Renewal Program is entitled SYSTEM FOR DNA-GUIDED OPTIMIZATION AND PERSONALIZATION OF STATIN THERAPY. Our previous Fast-Track SBIR Program enabled the discovery of gene markers and configuration of predictive bioclinical algorithms, and it advanced the clinical development of the SINM PhyzioType product closer to commercialization. The proposed Phase II Renewal Program will validate the performance of the SINM PhyzioType product in a prospective study of an independent population of 400 patients naove to statin therapy or who had not received statins for at least 3 months. Allocated funds will be used to validate the product for personalized clinical management of statins, to develop a medical informatics interface enabling use of the product by clinicians (Personalized Health Portal) and to prepare the SINM PhyzioType for commercialization. With this project, Genomas will continue to enlist some of the most highly qualified lipid clinical specialists in the world, including Paul D. Thompson, M.D., of Hartford Hospital's Division of Cardiology, John P. Kane, M.D., of the Cardiovascular Research Institute at University of California at San Francisco, and Bruce Gordon, M.D., of the Rogosin Institute at New York Presbyterian Medical Center for this Program. Theodore Holford, Ph.D., of the Yale School of Medicine will serve as a consultant in biostatistics. The expected outcome is final development of the Genomas product SINM PhyzioTypeTM System, that predicts the variable lipid-altering efficacy and the risk of drug-induced neuromuscular side effects that arise in the substantial segment of patients receiving statins. With data collected Phase II Renewal funding, Genomas will be able to serve confirmatory proof that the PhyzioType product is a reliable, reproducible and cost-effective product enabling physicians to optimize treatment strategies in lipid disorders while avoiding neuromyopathy. The goal is to enable clinicians to deploy a genetic decision support system to manage statins, prescribe these drugs on a DNA-guided, personalized basis and effectively lower the risk of cardiovascular disease for each patient. PUBLIC HEALTH RELEVANCE: In the proposed Phase II Renewal Program, the SINM PhyzioTypeTM System for optimization and personalization of statin therapy will be validated through a prospective study to finalize the product ahead of commercialization. This validation study will serve confirmatory proof that the SINM PhyzioTypeTM System is a reliable, reproducible and cost-effect product enabling physicians to optimize treatment strategies in lipid disorders and minimize detrimental neuromuscular side effects. This pioneering product, which represents the first tool to integrate statin safety and efficacy markers for clinical use, will advance the practice of personalized medicine and reduce side effects while elevating therapeutic benefits of the country's most popular drugs that are already on the market.

描述（由申请人提供）：目前有3000万胆固醇升高的美国人接受他汀类药物治疗，使他汀类药物成为美国最常用的处方药物类别。他汀类药物诱导和神经肌病（SINM），效力和安全性的平衡，是这些药物的主要临床管理挑战，特别是当治疗目标要求LDL胆固醇水平低于100 mg/dl时。在医疗实践中，神经肌病表现为一系列神经肌肉副作用，包括肌痛（肌肉疼痛、痉挛、无力）和肌病（通过血清肌酸激酶（CK）升高监测的肌肉损伤）。神经肌病在治疗晚期心血管疾病所需的较高剂量下更常见，并且在个体他汀类药物之间以及患者之间的程度不同。他汀类药物的使用最终受到毒性的限制。显然，迫切需要在治疗开始时同时避免副作用和优化降脂，以支持在数百万患者中成功降低心血管疾病风险。认识到临床医生在处方他汀类药物时平衡安全性和有效性，我们的研究小组和其他人已经建立了遗传标记，这些标记是一组安全性和有效性标记的有效候选者。SINM PhyzioType系统是第一个整合他汀类药物安全性和疗效标志物用于临床的诊断工具。SINM PhyzioType系统可以根据每个患者的基因组预测卓越的他汀类药物（即阿托伐他汀[Lipitor（R）]、辛伐他汀[Zocor（R）]和瑞舒伐他汀[Crestor（R）]--它们共同占美国市场份额的85% 8）的安全性和有效性，从而为每个患者选择最佳药物。或者，如果患者的基因组图谱被证明与他汀类药物不相容，临床医生可以选择开另一类药物。本II期更新计划的标题为DNA引导的他汀类药物治疗优化和个性化系统。我们之前的快速跟踪SBIR计划实现了基因标记的发现和预测生物临床算法的配置，并推动了SINM PhyzioType产品的临床开发更接近商业化。拟议的II期更新计划将在一项前瞻性研究中验证SINM PhyzioType产品的性能，该研究包括400名未接受他汀类药物治疗或至少3个月未接受他汀类药物治疗的独立患者。分配的资金将用于验证他汀类药物个性化临床管理的产品，开发一个医学信息学接口，使临床医生能够使用该产品（个性化健康门户网站），并为商业化准备SINM PhyzioType。在这个项目中，Genomas将继续招募一些世界上最高质量的脂质临床专家，包括Paul D。汤普森，医学博士，哈特福德医院心脏病科的John P. Kane，医学博士，和布鲁斯·戈登医学博士，纽约长老会医学中心罗戈辛研究所的负责人。西奥多霍尔福德博士，耶鲁医学院的一位教授将担任生物统计学顾问。预期的结果是Genomas产品SINM PhyzioTypeTM系统的最终开发，该系统预测了接受他汀类药物的大部分患者中出现的可变脂质改变疗效和药物诱导的神经肌肉副作用的风险。通过第二阶段更新资金收集的数据，Genomas将能够提供确认性证据，证明PhyzioType产品是一种可靠，可重复和具有成本效益的产品，使医生能够优化脂质紊乱的治疗策略，同时避免神经肌病。其目标是使临床医生能够部署遗传决策支持系统来管理他汀类药物，在DNA指导的个性化基础上开这些药物，并有效降低每位患者的心血管疾病风险。 公共卫生相关性：在拟议的II期更新计划中，用于优化和个性化他汀类药物治疗的SINM PhyzioTypeTM系统将通过前瞻性研究进行验证，以在商业化之前完成产品。该验证研究将提供确证性证据，证明SINM PhyzioTypeTM系统是一种可靠、可重复和具有成本效益的产品，使医生能够优化血脂紊乱的治疗策略，并最大限度地减少有害的神经肌肉副作用。这一开创性的产品是第一个将他汀类药物的安全性和有效性标志物整合到临床使用中的工具，它将推动个性化医疗的实践，减少副作用，同时提高该国最受欢迎的药物的治疗效果。