The story of gene therapy’s recent renaissance is well known at this point. Established pharma companies who abandoned the field a decade ago are returning and building up their own gene therapy divisions. Startups are getting backing from venture firms. Programs are advancing, and starting to produce real clinical data—without the safety setbacks that plagued the field in the past.
One of the symbols of this changing landscape has been Bluebird Bio (NASDAQ: BLUE). The Cambridge, MA-based company has almost tripled in value since going public last year, largely due to some indication—in a very small number of patients—that its gene therapy just might be remarkably effective at treating a crippling blood disease called beta-thalassemia.
Indeed, in June, Bluebird said that two patients with the disease were freed of the frequent blood transfusions they normally require to prevent anemia within just a few weeks of receiving the firm’s gene therapy. Today, at the American Society of Hematology’s annual meeting in San Francisco, it’s circling back with its first updates since then. And while the sample sizes remain small, the results remain promising.
Bluebird today is reporting additional interim results from two small studies of its gene therapy, LentiGlobin. The trials in the U.S. (named Northstar) and Europe (HGB-205) are enrolling patients with beta-thalassemia and sickle cell disease.
So far, eight total patients have been enrolled in these studies: five in the U.S. trial, and three in Europe. Bluebird is disclosing data today from two patients in each of those studies (the two patients in Europe are the same ones it detailed in June). Each of those patients have had at least three months of follow-up since being treated with LentiGlobin; Bluebird says it’s too early to assess the response of the other patients.
But Bluebird says that the four evaluable patients are all transfusion-free. For the Northstar patients, that’s three and five months, respectively, since their last transfusions. For the HGB-205 patients, it’s now nine and 12 months without transfusions.
“We were 2 for 2, and now it’s really a 4 for 4 story in the ultimate important clinical indicator in these patients, which is transfusions,” says Bluebird CEO Nick Leschly. “It’s really confirmation of the original patients from June.”
The big difference so far is for one patient in the Northstar study it took longer for Bluebird’s gene therapy to kick in and produce results. That patient’s last transfusion came 90 days after treatment, compared to less than a month for the other three patients.
“We’ve learned there’s variability in there,” Leschly says. “[But] at the end of the day when you’re talking about a potential one-time cure, what’s the real difference over the goodness of time between 10 days, and 1 month, 3 months, or even 6 or 12?”
Importantly, Bluebird hasn’t seen any serious gene-therapy related side effects in these patients as of yet. But it’s worth noting that Bluebird will likely have to follow these patients for several years to see if the newly corrected genes cause unintended problems.
That’s just one of the major hurdles Bluebird faces going forward. More proof from more patients, and durability of response without safety issues, are both critical, of course. But the biggest looming questions—assuming the data continue to hold up—are how much data are needed to make a case for approval to regulators? And what type of trial would best show it?
For one, the FDA has never approved a gene therapy. Only one gene therapy, UniQure’s tiparvovec (Glybera), has been approved, and that’s in Europe. And as Leschly says, a controlled, randomized trial—the gold standard for scientific testing that’s often used in registration studies—isn’t an option here for a variety of reasons. Leschly isn’t disclosing exactly what Bluebird’s regulatory strategy is (“the data are going to drive it,” he says), but acknowledges that it’s one of the most important decisions the company faces moving forward.
“We’re kind of shifting our mindset to not ‘if’ we have a product in beta-thalassemia, but ‘when,’” he says. “And what that really means is, how do you now really start thinking about this data as it continues to evolve? How do you design the best pivotal study in collaboration with the agencies? We have to understand some of these details and work together to put what is absolutely the most appropriate study in place so it has the right hurdle for success. We have to make sure we do that very thoughtfully.”
For those unfamiliar, gene therapy is a process by which corrective genes are transported, typically by a virus, into cells to fix a genetic defect that triggers disease. In the case of beta-thalassemia, patients inherit a faulty gene that codes for beta globin, a subunit of hemoglobin, the protein in red blood cells that carries oxygen. Without the ability to make hemoglobin, these patients get severe anemia and need frequent blood transfusions to survive. They also need iron chelation therapy to deal with the iron overload those transfusions cause; that buildup of iron often kills patients.
About 15,000 people in the U.S. and Europe and 280,000 worldwide are estimated to be living with the disorder, and a majority of them have beta-thalassemia major, the severe form, according to Bluebird.
The only cure for beta-thalassemia is a bone marrow transplant, but less than 25 percent of patients are eligible for them, they’re only offered to children, and the procedure is risky. LentiGlobin is supposed to essentially mimic the effects of a bone marrow transplant and restart hemoglobin production, but without the donor-matching limitations and safety risks.
The company takes stem cells harvested from a patient’s bone marrow. Then it uses HIV viruses that have been genetically modified to be harmless to insert a healthy version of the beta-globin gene into them. Those cells are then grown in a culture, and infused back into the patient in a one-time procedure. The cells then head to the bone marrow and divide, giving rise to more cells with the correct gene—and therefore, eventually (in theory) normal levels of hemoglobin.
Bluebird also recently enrolled a single patient with sickle cell disease, another inherited disorder caused by abnormal hemoglobin that causes red blood cells to become distorted into a sickle-like shape, causing pain, organ damage, and other potentially fatal complications. It’s a potentially huge opportunity for Bluebird. About 250,000 to 300,000 people globally are born with the disease every year, and some 20 million to 25 million currently live with it, according to the company (by comparison, 40,000 people every year are born with the serious form of beta-thalassemia). And like beta-thalassemia, the only curative treatment is a bone marrow transplant. Most treatments just alleviate the pain and other complications of the disorder.
Bluebird doesn’t have much of an update here though. It dosed the first sickle cell patient—the first ever to be given gene therapy—in October, and Leschly says it’s too early to draw any conclusions about the therapy’s effectiveness. That’s certain to be one of the most closely watched biotech stories over the next year or so.
“I honestly could not imagine exiting 2014 with any more exciting data,” Leschly says.