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Gene Therapy Flops in Heart Failure Study

Mid-stage trial fails to meet primary and secondary endpoints

The phase IIb CUPID2 trial has failed to meet its primary and secondary endpoints. The randomized, double-blind, placebo-controlled study evaluated a single, one-time, intracoronary infusion of the cardiovascular gene therapy agent Mydicar (AAV1/SERCA2a, Celladon Corporation) compared with placebo added to a maximal, optimized heart failure drug and device regimen.

In the study, the primary endpoint comparison of Mydicar versus placebo, defined as heart failure-related hospitalizations or ambulatory treatment for worsening heart failure, resulted in a hazard ratio of 0.93 (P = 0.81). The secondary endpoint comparison of Mydicar versus placebo, defined as all-cause death, the need for a mechanical circulatory support device, or a heart transplant, likewise failed to show a significant treatment effect.

The efficacy endpoint analyses were performed in 243 subjects with stable New York Heart Association (NYHA) class II to IV ischemic or nonischemic heart failure despite optimal therapy, a reduced left ventricular ejection fraction (less than or equal to 35%), and a high risk for recurrent heart-failure hospitalizations.

In patients with heart failure, SERCA2a, an enzyme critical to the contraction of cardiac muscle cells, becomes deficient. Human studies have established a clear association between depleted SERCA2a enzyme in cardiac cells and the progression of end-stage heart failure.

Mydicar treatment involves a one-time outpatient infusion in a cardiac catheterization laboratory, similar to undergoing an angiogram.

The treatment’s molecular target is an enzyme found in the sarcoplasmic reticulum (SR) that is critical to the contraction of cardiac muscle cells. The SR is a specialized part of a cell (cellular organelle) that regulates the contraction and relaxation of cardiac muscle cells by coordinating the outflow (contraction) and inflow (relaxation) of calcium ions (Ca2+). The heart muscle’s ability to contract, and thus to pump blood and maintain oxygenation of the body, is determined by a continual re-loading of the SR with Ca2+ to “stage” for the next cycle of contraction. The key factor that allows the re-loading of the SR with Ca2+ is the enzyme SERCA2a. Several human studies have established a clear association between depletion of the SERCA2a enzyme in cardiac cells and the progression of end-stage heart failure.

Sources: Celladon Corporation; April 26, 2015; and Mydicar; 2015.

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