Celladon believes it is positioned to succeed where others have failed in attempting to treat heart failure by targeting a deficiency of cytosolic calcium ions (Ca). While other programs have sought to isolate small-molecule compounds to increase enzymatic activity, Celladon is using an enzyme replacement gene-therapy approach.

The La Jolla, Calif.-based biotech currently is moving its drug Mydicar through Phase II with an approach that attaches copies of the SERCA2a gene to a non-pathogenic virus in order to deliver it directly to a patient's heart via percutaneous injection, similar to an outpatient cardiac catheterization procedure.

In an interview, Celladon CEO and President Krisztina Szebo noted that Ca deficiency has a widely recognized and validated role in advanced heart failure. The enzyme deficiency reduces the heart's contractility - its ability to pump blood adequately throughout the body - and while current products (so-called positive inotropic drugs) meant to increase contractility work, they have a negative effect on long-term survival.

"The primary issue is that [Ca is] a membrane-bound enzyme inside the cell and it's very difficult to target," Szebo explained. "Mydicar increases the enzyme activity by simply correcting the genetic defect, i.e., correcting the deficiency. We insert the gene and we make more of the enzyme in cardiac muscle."

Celladon believes its approach can reduce the costs of caring for advanced heart failure patients while improving their prognosis and quality of life. Unlike positive inotropic drugs - such as Orion's Simdax (levosimendan) and GlaxoSmithKline's Lanoxin (digoxin) -Celladon believes Mydicar also offers the potential to improve survival.

The weakened cardiac muscle typically found in terminal-stage heart failure patients means sufficient blood isn't pumped through the body to prevent accumulation of fluid in the lungs, which is the primary reason these patients become hospitalized, Szebo explained. Annual claims costs for such patients are around $35,000 and many are eligible for a heart transplant or left ventricular assist device, both of which cost over $200,000.

"When you increase the contractility of the heart, you can improve blood flow and reduce dyspnea, the shortening of breath," Szebo said. "And that's basically what we hope will keep patients out of the hospital."

Clinical data to date shows improvement in cardiac function

Phase I trial data in New York Heart Association Class III and Class IV patients - the most serious stages of heart failure - showed Mydicar increased participants' exercise ability and improved their symptomatic quality of life and independent measures of cardiac function as assessed by echocardiography, she added.

Now, the firm has Mydicar in Phase II study in the same class of patients, looking at composite endpoints involving worsening heart health, myocardial infarction, need for transplant or left ventricular assist device implantation, and death. The trial will involve only 39 subjects and the company hopes to unveil preliminary data next month at the European Society of Cardiology meeting in Berlin.

Whereas clinical studies for beta blockers typically require thousands of patients, Mydicar can be studied in a small population, Szebo explained, "because the types of endpoints that we're looking at are so severe and are so frequent at this stage that an intervention that has a significant impact will be able to demonstrate significance with a fairly small number of patients."

Mydicar will be delivered via attachment to a recombinant adeno-associated virus - approximately 90 percent of the U.S. population has been exposed to AAV already, typically in adolescence, without harm. In 2005, Celladon in-licensed the rAAV vector technology from Targeted Genetics, which contributed a small amount of development funding and is eligible for downstream revenue sharing via development milestones and royalties ([See Deal]). As of 2008, Targeted Genetics had realized $8.9 million in revenue from the partnership.

Celladon anticipates that Mydicar not only will treat advanced heart failure, but that it also will reverse the disease's progression.

"One of the things that happens when the heart muscle continues to weaken is the heart literally gets larger and larger," Szebo said. "It just turns into a very large, thin balloon-like structure. And reversing the course of the disease refers to basically shrinking that and strengthening the muscle. It's determined by a particular echocardiography parameter which measures the volume of the heart, and we hope to demonstrate, based on animal data and also data from our Phase I, that we can actually reverse this trajectory of the muscle continuing to weaken."

Celladon open to a variety of partnership structures

In terms of its business plan, Celladon appears well funded to continue moving the Mydicar program forward, plus launch a second clinical program for a small-molecule approach to treating hospital-based acute heart failure through SERCA biochemistry.

The privately-held company has raised nearly $64 million in cash during its history from a variety of venture capital and corporate venture partners, including Johnson & Johnson Development Corporation, the Big Pharma's venture capital subsidiary. Celladon raised nearly $22 million in a Series C round in 2008 and 2009, which it augmented last year with the sale of $3 million in convertible debt.

Szebo said her company is open to a variety of partnering options for Mydicar, such as co-development and/or commercialization collaborations and even merger or acquisition. Despite the fact that some large companies have de-emphasized the cardiovascular space in their business plans, Celladon has received interest from a wide variety of potential partners, she added.

"It's very interesting because we obviously read the same news as [everyone else], however, in private discussions we get a response something like 'if you can make an impact in this disease, in this severe population, we don't care whether the product comes from Mars, we're interested,'" Szebo said. "I think the data if strong enough may rekindle some interest from some of the players who have de-emphasized this."

One factor that may attract a potential partner or even an acquirer is the way Celladon holds down costs by operating as a virtual company, even six years after its inception (Also see "Celladon Corp." - Scrip, 1 March, 2006.). Szebo said the company's "core team" consists of about 10 to 12 people, some of whom are full-time contractors, rather than employees.

"We also work closely with CROs, manufacturing partners, etc.," she said. "We basically utilize a number of external collaborations and contracts. We look for best-in-class wherever we can find it [but] don't have to hire the people and move them to La Jolla, Calif."

-Joseph Haas (j.haas@elsevier.com)

Celladon Hopes To Bring Gene-Therapy Solution To Heart Failure Patients

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