SAN DIEGO (EGMN) – In a phase II study of patients with advanced heart failure, gene therapy with MYDICAR was found to be safe and was associated with benefit in clinical outcomes, symptoms, functional status, and cardiac structure.

Deficiency of the protein SERCA2a is central to the progression of heart failure, resulting in abnormal calcium transfer and impairing myocardial relaxation and contraction, Dr. Barry H. Greenberg said at the annual meeting of the Heart Failure Society of America.

MYDICAR, manufactured by Celladon Corp., is an enzyme replacement therapy that is designed to restore levels of SERCA2a. A recombinant adeno-associated viral vector is used to deliver the SERCA2a gene.

The objectives of the phase II study, known as CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease), were to evaluate safety and feasibility and to explore the activity and efficacy of MYDICAR in patients with advanced heart failure, said Dr. Greenberg, professor of medicine and director of the Advance Heart Failure Treatment Program at the University of California, San Diego.

To be eligible for the trial, patients had to be 18-75 years old, have New York State Heart Association class III or IV heart failure caused by an ischemic or nonischemic etiology, have a maximal oxygen consumption of 20 mL/kg per minute or less, have a left ventricular fraction of 35% or less, and be on a stable, optimized heart failure regimen for 30 days.

Dr. Greenberg and his associates randomized 39 patients to one of three doses of MYDICAR or to placebo, and all were treated via single intracoronary infusion. All patients were observed for 12 months, with a primary analysis after 6 months of therapy.

The mean age of patients was 61 years, 87% were male, 87% were white, half had heart failure resulting from ischemic cardiomyopathy, and all had NYHA class III heart failure.

Safety measurements included physical examination, electrocardiogram, adverse events, complete blood count, serum chemistries, urinalysis, creatine kinase myocardial band, troponin T, and enzyme-linked immunospot testing for cellular immune response against viral proteins.

Efficacy domains included symptomatic changes in NYHA class and the MLHF (Minnesota Living With Heart Failure) questionnaire; functional changes based on 6-minute walk test and maximal oxygen consumption; changes in N-terminal prohormone brain natriuretic peptide; and evidence of remodeling based on ejection fraction scores and end systolic volume.

CUPID’s primary efficacy end point was defined as evidence of success in one of four areas: group-level analysis, individual analysis, time-to-event analysis, and duration of cardiovascular-related hospitalization analysis. All were deemed statistically significant (P less than .2).

CUPID met the primary efficacy end point for high-dose MYDICAR treatment group vs. placebo in three of the four areas. In the group-level analysis, significant improvements were seen in the treatment group, compared with the placebo group, in improvements in the 6-minute walk test and end systolic volume, with no clinically significant worsening in any end point and numerical superiority to placebo in all other end points.

In the individual analysis, the mean efficacy “score” for the treatment was significantly greater than that of the placebo group.

In the time-to-death analysis, the treatment group scored numerically better than the placebo group, but this difference did not reach statistical significance.

In the duration of cardiovascular-related hospitalization analysis, the duration of stay was significantly shorter for patients in the treatment group, compared with the placebo group (mean, 2 fewer days).

Dr. Greenberg reported that there were no statistically significant differences between the treatment groups and the placebo groups in the proportion of adverse events or serious events.

“These encouraging results support further studies to determine the value of genetically targeted enzyme replacement of SERCA2a in advanced heart failure,” Dr. Greenberg concluded.

The meeting’s invited discussant, Dr. Michael R. Bristow, president and CEO of ARCA Biopharma Inc., described it as “a big deal to have done gene therapy on this number of patients who are this sick and see absolutely no evidence of safety concern. I believe there’s definite evidence of an efficacy signal ... [and] that CUPID will serve as a catalyst for the development of other gene therapies for heart failure.”

Disclosures: Celladon Corp. funded the trial. Dr. Greenberg said that he had no relevant financial disclosures to make.

Copyright (c) 2010 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

圣迭哥(EGMN)——在美国心力衰竭协会年会上公布的一项对晚期心力衰竭患者所做的Ⅱ期研究表明，MYDICAR基因疗法安全并有助于改善患者的临床转归、症状、功能状态及心脏结构。

 

这项Ⅱ期研究为CUPID研究(经皮心肌转导钙上调基因疗法治疗心脏病研究)，由圣迭戈加州大学的Barry H. Greenberg博士带领完成，旨在评估对晚期心力衰竭患者采用MYDICAR(由Celladon公司生产的一种酶替代治疗药物，可恢复SERCA2a蛋白的水平)治疗的安全性和可行性，并探讨其活性和疗效。其纳入标准包括：年龄介于18~75岁，心力衰竭(病因不限)的NYHA分级为Ⅲ或Ⅳ级，心肌最大耗氧量≤20 ml/(kg·min)，左室射血分数≤35%，持续接受了30天心力衰竭优化治疗方案。最终纳入的受试者平均年龄为61岁，87%为男性，87%为白种人，半数受试者的心力衰竭系缺血性心肌病所致，所有患者的心力衰竭均为NYHA Ⅲ级。

 

39例患者被随机分配至3个MYDICAR剂量中的1个剂量组或安慰剂对照组，并接受单纯的冠状动脉内输注治疗，观察持续12个月，在治疗6个月后进行初步分析。

 

安全性测定包括体格检查、心电图、不良事件、全血细胞计数、血清化学检查、尿检、肌酐激酶心肌带、肌钙蛋白T以及酶联免疫斑点试验(测定针对病毒蛋白的细胞免疫应答)。疗效范畴包括NYHA分级和明尼苏达心力衰竭生活质量调查表 (MLHF) 中的症状性改变；功能改变(根据6 min步行试验和最大耗氧量判定)；N末端脑钠肽激素原的变化；重构的征象(根据射血分数和收缩末期容积判定)。主要疗效终点为以下4个方面之一有成功的表现：组间分析、个体分析、事件发生时间分析以及心血管相关的住院时间分析。

 

研究结果发现，高剂量MYDICAR治疗组与安慰剂对照组相比，在其中3个方面达到主要疗效终点：组间分析表明，与安慰剂对照组相比，治疗组在6 min步行试验和收缩末期容积方面有显著改善，而在其他所有终点方面均无临床上显著加重的表现或数量上的优势；个体分析显示，治疗组的平均疗效“评分”显著大于安慰剂对照组；在死亡时间分析中，治疗组的评分优于安慰剂对照组，但此差异未达到统计学意义；在心血管相关的住院时间分析方面，治疗组的住院时间相对于安慰剂对照组明显缩短(平均缩短2天)。治疗组与对照组之间在不良事件或严重事件发生率方面的差异无统计学意义。

 

大会的特邀评论员认为，该研究未显示MYDICAR治疗有任何安全隐患，而且有对心力衰竭有效的明确证据，大大推进了对其他心力衰竭基因疗法的研发进程。

 

本研究由Celladon公司资助。Greenberg博士无相关的经济利益冲突披露。

 

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