Gene therapy has never lived up to two decades of hype, but some intriguing new evidence for the technology emerged over the weekend at a medical meeting in Berlin. That was where San Diego-based Celladon unveiled results from a clinical trial—albeit a small one—that offers the first sign that gene therapy might help people suffering from heart failure.
Celladon hinted about what was coming in late April when it issued a vague statement saying that its gene therapy hit the main goal in a trial of 39 patients, demonstrating its superiority over a placebo. It turns out the trial, called “Cupid,” showed that a high dose of Celladon’s gene therapy offered a 50 percent lower risk of serious cardiovascular event like death, or a heart transplant, when compared with those who got a placebo. The Celladon treatment, called Mydicar, didn’t appear to cause any serious side effects, researchers said. Details were presented at the Heart Failure Association of the European Society of Cardiology.
“To see a signal like this in a small number of patients is promising,” says Barry Greenberg, a researcher at UC San Diego and an investigator on the study. “But you have to be realistic and say it is a small number of patients. It still needs to be re-produced in a larger study.”
That said, this data is sure to stir up hope in a long-struggling field. 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, and many companies abandoned the field over the past decade. After all those years, no gene therapy has won FDA approval.
Celladon, as I explained back in April, had a clear strategy on why it thought its approach would work. Older gene therapy techniques used common adenoviruses or retroviruses to deliver genes into 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 to shuttle genes into cells without causing illness. Congestive heart failure was thought to be a promising field to study, partly because it’s a gravely 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 to the heart, and doesn’t need to circulate through the body-a distribution challenge that has plagued gene therapies before.
So what did researchers really learn from this “Cupid” study? The primary goal of the study looked at a whole kitchen sink of important questions for the health of heart failure patients—how far they could walk in a six-minute period, how well their hearts pumped blood, how much time they spent in the hospital, and whether biomarkers could confirm these clinical readings at the molecular level.
Specifically, over the six-month study period, patients on the high dose of Celladon’s treatment spent an average of 0.2 days in the hospital, compared with 2.1 days for those on placebo. Patients who completed the six-minute walk test were able to walk one extra meter after six months of taking the Celladon treatment, compared with an 87-meter decline in walking distance for those on placebo, researchers said. Patients on the Celladon treatment had an improved score after six months on a common blood biomarker of heart failure, while they got worse on that reading if they took a placebo. The same pattern was true when researchers look at quality of life questionnaires—patients on the Celladon treatment said they felt better, and the placebo said they felt worse.
Any single one of those data points in isolation could be dismissed as a fluke, Greenberg says. But the fact that all of these readings reinforced each other in a positive way ought to be an encouraging sign that these results can be duplicated in an even more rigorous Phase III clinical trial, he says.
The main objection to this study will be its small size, Greenberg says. There were low, medium, and high-dose groups on Celladon’s Mydicar, plus a placebo group—meaning that in a study of 39 patients, only about 10 people were in each cohort. Such small numbers mean it couldn’t be proven to be statistically significant, but it did appear that people who got the higher dose of Celladon’s drug did better than those who got a lower dose—always an important sign. And when asked about side effects, he had nothing to report.
“We saw nothing in patients treated with meds that seems unusual. The drug didn’t appear to be doing anything untoward,” Greenberg says.
For Celladon as a business, this translates into a whole set of new options. CEO Krisztina Zsebo knows she needs 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. That will take money. It could come via a partnership, more venture capital, or an acquisition, Zsebo has said. It will be interesting to see which door Celladon and its backers—Venrock Associates, Enterprise Partners Venture Capital, and Johnson & Johnson Development Corporation—choose to open.