Celladon’s Gene Therapy Passes Heart Failure Trial; Maintains Suspense on Details

4/28/10Follow @xconomy

Celladon has some tantalizing news today for the world of gene therapy. The San Diego-based biotech company is announcing that its experimental treatment, which delivers a gene to help people with heart failure pump blood more efficiently, has met its primary goal of showing the treatment is more effective than a placebo.

The trial enrolled 39 patients with advanced heart failure who were randomly assigned to get a single-shot infusion of Celladon’s gene therapy, called Mydicar, or a placebo. The study, called Cupid, was designed to compare the drug to placebo on a mixture of important factors, like whether patients on the drug could get out of the hospital sooner, how often they need heart transplants or implants, how far they could walk for six minutes, and how long they lived. Patients were followed for as long as a year.

Celladon isn’t revealing any details in today’s announcement about how much better its treatment performed versus placebo, so it’s impossible to say with certainty how big a deal this is. But CEO Krisztina Zsebo said her company’s drug showed a statistically significant advantage over the placebo group on the study’s primary goal. And there was no greater rate of adverse events among patients who got the gene therapy than those in the placebo. Detailed results will be presented at European Society of Cardiology’s Heart Failure Congress in Berlin on May 30, and will be published soon in a top peer-reviewed journal, Zsebo says.

“We’re very excited. This has been a long, tough program, and a lot of translational science has gone into making it a success,” Zsebo says.

If the European cardiologists agree that this is an important finding, it will be a major milestone for gene therapy and for heart failure patients. Gene therapy was hyped in the early 1990s as a cure-all for diseases that resisted conventional drug treatment. The idea is to deliver properly functioning copies of genes into cells where they can replace missing or faulty genes at the root cause of certain diseases. The field was plagued by safety concerns in the late 1990s, and many companies abandoned the field altogether. Even today, no such treatment has yet won FDA approval.

Krisztina Zsebo

Krisztina Zsebo

But Celladon likes its chances for a few reasons: Older gene therapy techniques used common viruses as the delivery mode to get those genes inside cells, which often failed. Celladon sought out what it thought was a better delivery tool with adeno-associated virus technology from Seattle-based Targeted Genetics, which engineered the viruses so they would be efficient without causing illness. Congestive heart failure was thought to be an ideal testing ground for gene therapy, partly because it’s a serious illness that kills 300,000 people a year, who have few treatment options other than beta-blockers and diuretics. And Celladon’s therapy can be delivered via a direct infusion into the heart, and doesn’t need to circulate effectively through the body—a distribution challenge that has tripped up other gene therapies of the past.

The Celladon program began about five or six years ago, Zsebo says. The concept was to deliver a gene called SERCA2a into heart muscle cells. Once in the heart cells, it produces an enzyme that improves the heart’s ability to pump blood.

Everything is riding on the outcome of this trial for tiny Celladon, which has just five employees. The company raised $2.8 million when I last wrote about the company in September, which essentially was like adding a little gas in the tank so it could drive the car to this vital destination. The company has secured a total of $61 million since it first raised money in 2004, from investors that include Enterprise Partners Venture Capital, Venrock Associates, and Johnson & Johnson Development Corporation.

It’s kind of hard to ask about the next steps for Celladon when I can’t even see the data yet, but I asked anyway. The company is considering its options for getting more cash, which it will certainly need to run a pivotal, Phase III clinical trial that the FDA will require before the gene therapy can be sold to patients in the U.S. The options include a partnership, more venture capital, or an acquisition, Zsebo says.

Celladon has a clinical trial designed and is almost ready to approach the FDA and ask for regulators to agree on whether it’s a valid approach for the next phase of trials. The budget of this trial will depend on how many patients the company needs to enroll to satisfy the FDA. Celladon is hoping the agency won’t require huge numbers of patients—which would require more time and money—because it has already cleared a difficult statistical hurdle by showing a benefit in a small group of patients.

“We believe the data we have now are strong enough that we’ll get a priority review,” Zsebo says, meaning the FDA might offer a faster-than-usual six-month review cycle for this drug’s application. The FDA sometimes does that for treatments with life-saving potential.

No matter how much buzz the company generates in the scientific community, such a treatment is still a long way from being commercially available. Celladon hopes the pivotal trial could start sometime in the second quarter of 2011, Zsebo says, and it will require one year of patient follow up. Given how long it might take to fully enroll patients, she didn’t want to guess when the company would be ready to submit an application for FDA approval.

Zsebo, a biochemist by training who previously worked at Cell Genesys and Amgen, has heard every skeptical remark in the book about gene therapy. Can you deliver it efficiently throughout tissues where it needs to go? Can the gene get into cells, and properly express the functional protein? Is it safe?

She sounds ready to make her case on the potential benefit to patients and society at large, if this treatment can make it through the FDA. She pointed out that congestive heart failure costs the U.S. health system an estimated $39 billion a year. A lot of gene therapy products have been tested for rare genetic diseases, not a mass-market problem like this.

“This is by far the largest population for a gene therapy candidate,” Zsebo says. “This could have a very big footprint.”

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