Clinical Trials

Date: 2015-04-26

Type of information: Results

phase: 2b

Announcement: results

Company: Celladon (USA - CA)

Product: Mydicar®

Action mechanism:

• gene therapy/ enzyme replacement therapy. Mydicar® is a genetically-targeted enzyme replacement therapy for advanced heart failure. It uses gene therapy to selectively target and restore SERCA2a enzyme levels by transferring the SERCA2a gene directly into cardiac muscle cells, which improves the heart's ability to pump blood. Mydicar® utilizes a non-pathogenic recombinant adeno-associated virus (AAV) and is delivered directly to the heart in a routine outpatient procedure, similar to an angiogram, in a cardiac catheterization laboratory.
• Results of a 39-patient Phase 2a CUPID 1 clinical trial of a single intracoronary infusion of high-dose Mydicar® in patients with advanced heart failure due to a systolic dysfunction showed the therapy was safe and well-tolerated in the study. In the Phase 2a CUPID 1 clinical trial, Mydicar® reduced heart failure-related hospitalizations and improved patients\\\' symptoms, quality of life and key markers of cardiac function predictive of survival, such as elevated levels of natriuretic peptides and left ventricular end systolic volume. Long-term follow-up results from the Phase 2a CUPID 1 clinical trial showed that in the additional two-year follow-up period, the durability of reduced cardiovascular and terminal events previously observed in the MYDICAR high-dose cohort at 12 months was maintained. The risk of recurrent cardiovascular events in the presence of terminal events over three years of follow up was reduced by 82 percent in the high-dose group compared with the placebo group (p=0.048). No safety concerns were noted during the three-year follow-up period for patients who received Mydicar®.

Disease: advanced heart failure

Therapeutic area: Cardiovascular diseases

Country: Belgium, Denmark, Germany, Hungary, Israel, The Netherlands, Poland, Sweden, UK, USA

Trial details:

• CUPID2 is a Phase 2b, randomized, double-blind, placebo-controlled, multinational trial evaluating a single intracoronary infusion of the cardiovascular gene therapy agent  Mydicar®  versus placebo added to a maximal, optimized heart failure regimen. The study included 250 adult patients who had stable NYHA (New York Heart Association) class II to IV ischemic or non-ischemic heart failure despite optimal therapy, reduced left ventricular ejection fraction (? 35%) and a high risk for recurrent heart-failure hospitalizations. CUPID2 enrolled only patients with heart failure with reduced ejection fraction (HF-REF). The statistical analysis for the primary endpoint was performed on the modified intent to treat population (mITT), comprising all patients who, after randomization, underwent cardiac catheterization and drug or placebo administration.
• The primary endpoint was time to recurrent heart failure related events (defined as heart failure-related hospitalizations or ambulatory treatment for worsening heart failure), using a statistical analysis methodology called joint frailty modeling. The secondary efficacy endpoint was time to first terminal event (defined as all-cause death, heart transplant or placement of a mechanical circulatory support device), analyzed simultaneously with the primary endpoint using joint frailty modeling. (NCT01643330)

Latest news:

• • On April 26, 2015, Celladon announced that its Phase 2b CUPID2 trial did not meet its primary and secondary endpoints. CUPID2 is a randomized, double-blind, placebo-controlled, multinational trial evaluating a single, one-time, intracoronary infusion of the cardiovascular gene therapy agent Mydicar® (AAV1/SERCA2a) versus placebo added to a maximal, optimized heart failure drug and device regimen. In the study, the primary endpoint comparison of  Mydicar® to placebo resulted in a hazard ratio of 0.93 (0.53, 1.65 95%CI) (p=0.81), defined as heart failure-related hospitalizations or ambulatory treatment for worsening heart failure. The secondary endpoint comparison of  Mydicar®  to placebo, defined as all-cause death, need for a mechanical circulatory support device, or heart transplant, likewise failed to show a significant treatment effect. The efficacy endpoint analyses were performed on the (n=243) modified intent to treat population (mITT), which excludes clinical events that occurred in patients who did not receive  Mydicar®  or placebo, or which occurred prior to dosing. All other exploratory efficacy endpoints (improvement in New York Heart Association classification, 6 Minute Walk Test, and Quality of Life) were also inconsistent with a treatment effect. No safety issues were noted. "We are surprised and very disappointed that  Mydicar®  failed to meet the endpoints in the CUPID2 trial, and we are rigorously analyzing the data in an attempt to better understand the observed outcome. We would like to express our sincere gratitude to our investigators and patients who participated in the study," said Krisztina Zsebo, Ph.D., CEO of Celladon. "At the same time we are evaluating our other programs in order to determine the best path forward to maximize shareholder value."

Is general: Yes