Celladon said yesterday its lead investigational product candidate, the cardiovascular gene therapy agent Mydicar® (AAV1/SERCA2a), did not meet its primary and secondary endpoints in the Phase IIb CUPID2 trial for systolic heart failure.
CUPID2 is a randomized, double-blind, placebo-controlled, multinational trial evaluating a single, one-time, intracoronary infusion of Mydicar versus placebo added to a maximal, optimized heart failure drug and device regimen.
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.
In the study, the primary endpoint comparison of Mydicar to placebo resulted in a hazard ratio of 0.93, defined as heart failure-related hospitalizations or ambulatory treatment for worsening heart failure. Mydicar showed only a statistically-insignificant 6% improvement compared to a placebo in reduction of the risk of heart-failure related hospitalization.
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 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. Celladon said 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.
All other exploratory efficacy endpoints were also inconsistent with a treatment effect, the company said, including improvement in New York Heart Association classification, 6 Minute Walk Test, and Quality of Life.
Mydicar is designed to work via infusion of the gene for the SERCA2a enzyme, which is deficient in heart failure, into the coronary arteries, where it restores SERCA2a enzyme production in cardiac cells to improve heart muscle contractions. In 2012, Celladon completed a $43 million equity financing to advance Mydicar development, led by new investor Pfizer Venture Investments with new investors Lundbeckfond Ventures, Novartis Venture Funds, H&Q Healthcare/Life Sciences Investors, and GBS Venture Partners.
CUPID2 assessed 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 CUPID 2 results came a year to the month that Mydicar won FDA’s Breakthrough Therapy designation. Mydicar was the third product candidate to receive this designation, after the agency determined that the CUPID 1 Phase I study provided preliminary clinical evidence that the gene therapy candidate may demonstrate substantial improvement over available therapies in a serious and life-threatening condition such as advanced heart failure.
“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,” Celladon CEO Krisztina Zsebo, Ph.D., said in a statement.
Dr. Zsebo added: “At the same time we are evaluating our other programs in order to determine the best path forward to maximize shareholder value.”
Investors responded with a sell-off that sent Celladon’s share price down 79%, to $2.87 as of 10:15 a.m., from a closing price on Friday of $13.68.
Analyst David Nierengarten at Wedbush downgraded Celladon to neutral from outperform, and slashed his 12-month stock price target to $3 from $29: “Given the company's uncertain future, we now value the company at cash,” he wrote in a note to clients, according to MarketWatch.