FDA Grants “Breakthrough Therapy” Status for Gene Therapy to reduce Systolic Heart Failure

Celladon Corporation (Nasdaq:CLDN), a clinical-stage biotechnology company developing novel therapies for patients with heart failure and other diseases characterized by SERCA enzyme deficiencies, announced that its lead product candidate, MYDICAR®, has been granted breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) for reducing hospitalizations for heart failure in NYHA class III or IV chronic heart failure patients who are NAb negative. This designation is intended to expedite the development and review of drugs for serious or life-threatening conditions and where preliminary clinical evidence suggests it provides a substantial improvement over existing therapies. Celladon is developing MYDICAR as a novel, first-in-class therapy for patients with chronic heart failure due to systolic dysfunction. MYDICAR uses genetic enzyme replacement therapy to correct the deficiency in the enzyme SERCA2a, which is an enzyme that becomes deficient in heart failure patients and results in inadequate pumping of the heart. Celladon has developed a companion diagnostic to identify the patients who are AAV1 NAb negative and therefore eligible for MYDICAR treatment.

MYDICAR® is Genetically-Targeted Enzyme Replacement Therapy for Advanced Heart Failure. The goal of the MYDICAR® treatment is to restore the enzyme SERCA2a, which is deficient in heart failure, to normal levels.

“We are looking forward to working with the senior staff at the FDA to determine the most expeditious path to bring MYDICAR to patients with advanced heart failure. This breakthrough therapy designation validates MYDICAR’s unique characteristics and clinical data to date and underscores the urgent need for new treatments for heart failure,” said Krisztina Zsebo, Ph.D., president and CEO of Celladon. “MYDICAR has the potential to provide transformative disease-modifying effects with long-term benefits in heart failure patients with a single administration. Our goal is to bring MYDICAR to market as quickly as possible in the United States, where we estimate approximately 350,000 heart failure patients with currently limited remaining treatment options could be eligible for therapy.”

Celladon is currently evaluating MYDICAR in the Phase 2b CUPID 2 trial to determine its efficacy in reducing the frequency of and/or delaying heart failure-related hospitalizations. This randomized, double-blind, placebo-controlled, multinational trial is evaluating a single intracoronary infusion of MYDICAR versus placebo added to a maximal, optimized heart failure regimen in patients with NYHA class III or IV symptoms of chronic heart failure due to systolic dysfunction. Patient enrollment has been completed and 250 patients have been randomized in this trial. The Company expects to report results in April 2015.

Heart failure is the inability of the heart to pump blood efficiently due to weakening and enlargement of the ventricles. Nearly 6 million individuals are currently diagnosed with heart failure in the United States according to the American Heart Association (AHA). Despite optimal guideline-directed therapies employing a wide range of pharmacologic, device and surgical options, many heart failure patients deteriorate over time. The long-term prognosis associated with heart failure is worse than that associated with the majority of cancers, with a mortality rate of approximately 50 percent at five years following initial diagnosis. In the United Sates, over 1 million primary heart failure-related hospitalizations and over 280,000 heart failure-related deaths occur annually. The estimated direct cost of heart failure in the United States in 2012 was greater than $60 billion, over half of which was related to repeated hospitalizations. The one- and six-month readmission rates after heart failure-related hospitalization are close to 25 and 50 percent, respectively, and there is growing pressure on hospitals to reduce readmissions for heart failure.

In patients with heart failure, SERCA2a, an enzyme critical to the contraction of the cardiac muscle cell, becomes deficient. Numerous 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. MYDICAR is designed to restore levels of an enzyme known to play a key role in the progression of heart failure. Repairing this molecular defect in preclinical studies reversed the disease and restored cardiac function. In the Phase 2 CUPID clinical trial in 39 patients, the frequency of death, worsening heart failure, heart failure-related hospitalizations, heart transplant, and need for a mechanical heart pump was dramatically lower and sustained for patients on high-dose MYDICAR compared with placebo. Furthermore, patients’ ability to exercise, symptoms of heart failure and quality of life improved.

MYDICAR’s molecular target is an enzyme found in the sarcoplasmic reticulum (SR) that is critical to the contraction of the cardiac muscle cell. 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 enables the re-loading of the SR with Ca2+ is the enzyme SERCA2a. Numerous human studies have established a clear association between depleted SERCA2a enzyme in cardiac cells and the progression of end-stage heart failure.

Role of SERCA2a in Heart Failure

SERCA2a’s role in heart failure was scientifically validated in the 1990s and immediately became a focus of pharmaceutical industry discovery efforts. However, due in part to ineffective screening technologies, SERCA2a proved to be an elusive target and to date no other company has been successful in targeting SERCA2a using traditional discovery methods.

Heart failure is characterized by abnormalities in the various steps of the heart muscle pumping process. Intracellular calcium movements in the heart are tightly regulated at various levels within the heart’s cells. An organelle called the sarcoplasmic reticulum, or SR, plays an important role in orchestrating the movement of calcium during each contraction and relaxation.

During contraction, calcium is released from the SR, activating the myofilaments leading to muscle contraction. During relaxation, the majority of calcium is sequestered back into the SR by the SERCA2a enzyme leading to muscle relaxation. It is modulated through normal physiology via a protein known as phospholamban (PLB in the figure below), increasing activity when we exercise and decreasing activity when we rest. In advanced heart failure, SERCA2a enzyme levels are abnormally low, so patients cannot effectively modulate SERCA2a activity and increase their cardiac output even upon mild physical activity, such as walking or climbing stairs.

Even in end-stage human heart failure cardiac cells, correction of the SERCA2a deficiency is able to restore normal contractility, relaxation, and calcium cycling. This demonstrates the central importance of SERCA2a deficiency in heart failure, and the ability to reverse the abnormality in contraction and relaxation driving the pathogenesis of this serious medical condition.

MYDICAR for Systolic Heart Failure

MYDICAR was initially evaluated in Phase 1 of our CUPID 1 trial, which was an open-label, dose-escalation trial in which patients with heart failure received a single intracoronary infusion of MYDICAR on top of maximal optimized heart failure therapy. Of the 12 patients who received MYDICAR, several demonstrated improvements from baseline to month six across a number of parameters important in heart failure. Based on these results, we advanced MYDICAR to Phase 2a of our CUPID 1 trial. In this 39-patient trial, MYDICAR was found to be safe and well-tolerated, reduced heart failure-related hospitalizations, improved patients’ symptoms and quality of life, and improved key markers of cardiac function predictive of survival, such as elevated levels of natriuretic peptides and end systolic volume. We advanced MYDICAR to our CUPID 2 Phase 2b trial.

The primary objective of our ongoing CUPID 2 trial is to determine the efficacy of a single intracoronary infusion of MYDICAR compared to placebo, in conjunction with maximal optimized heart failure therapy, in reducing the frequency of and/or delaying heart failure-related hospitalizations in patients with systolic heart failure who are at increased risk of terminal events based on elevated levels of natriuretic peptides or a recent heart failure-related hospitalization. The dose being used in this trial is equivalent to the high-dose used in CUPID 1. Patients are randomized in parallel to MYDICAR or placebo in a 1:1 ratio. The primary efficacy endpoint is time-to-recurrent heart failure-related hospitalizations in the presence of terminal events at the time of primary analysis data cutoff. We completed the enrollment of 250 patients in February 2014 and expect to announce results in April 2015.

MYDICAR will also be evaluated in an investigator-initiated trial called AGENT-HF, an AAV1 NAb positive trial called CELL-005, and a viral shedding trial called CELL-006. The primary objective of the AGENT-HF trial is to determine whether treatment with MYDICAR leads to a reversal in the decline of left-ventricular function of the heart. The primary objective of the AAV1 NAb positive trial is to determine the safety of a single intracoronary infusion of high-dose MYDICAR in patients who test positive for NAbs who would otherwise be ineligible for treatment with MYDICAR. The viral shedding trial is required as part of the environmental risk assessment that must be included in a marketing application to regulatory authorities, both in the United States and in Europe.

MYDICAR in Additional Indications

We believe that the involvement of SERCA2 deficiencies in multiple diseases and conditions that are currently poorly managed by existing treatment options create “franchise” opportunities for our first-in-class gene therapy. Beyond our proposed lead indication of systolic heart failure, we also plan to develop MYDICAR for additional indications including the treatment of arteriovenous fistula (AVF) maturation failure and for the treatment of patients with advanced heart failure who are on a left-ventricular assist device, or LVAD. In addition to these two indications, we also plan to initiate development programs in diastolic heart failure and pulmonary arterial hypertension (PAH). Each of these diseases and/or conditions is characterized by a SERCA2a deficiency, and MYDICAR has demonstrated disease-modifying capability in preclinical models of these diseases

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