Bluebird Bio has helped catalyze gene therapy’s recent renaissance with snippets of human data that hint of a long-lasting, perhaps even one-time fix for a crippling blood disorder known as beta-thalassemia. However, the Cambridge, MA-based company released data today that dampen the hopes for a long-term fix for some of the folks with the most severe form the rare disease.
About 288,000 people worldwide have beta-thalassemia, and an estimated 60 to 80 percent of them have the most dire form, known as beta-thalassemia major. These people, who have a faulty gene that leads to severe anemia, are the ones Bluebird aims to treat with a gene therapy known as LentiGlobin. But the data Bluebird released today cast some doubt on LentiGlobin’s effectiveness in about a third of beta-thalassemia major patients.
The data Bluebird (NASDAQ: BLUE) released today are taken from a broader report the company will roll out at the American Society of Hematology’s annual meeting next month. The data, which include updates on seven beta-thalassemia patients and one sickle cell disease patient on its gene therapy, are mixed.
On the positive side, four of the seven beta-thalassemia patients no longer rely upon the transfusions they’d typically need to fend off the potentially deadly anemia that is a hallmark of their disease. These patients have been monitored for at least six months, and haven’t needed transfusions for at least 90 days. The length of time these patients have been off transfusions ranges from 171 days to 396, with a median of 287.
To put that in context, these patients typically need a blood transfusion every month. “It’s a remarkable outcome,” says Bluebird chief medical officer David Davidson.
There is similar good news for the sickle cell patient, Bluebird’s first-ever, who also hasn’t yet needed hospitalization for any sickle cell-related complications—like strokes, bouts of excruciating pain, or anemia. When the patient began the gene therapy, he needed chronic blood transfusions, but began the process of weaning off those transfusions after 37 days. He received his last transfusion 88 days after treatment.
This patient also continues to produce higher levels of healthy hemoglobin, the red blood protein that ferries oxygen from the lungs to the rest of the body. In sickle cell disease, a genetic mutation in hemoglobin causes red blood cells to form a sickle shape and impede blood flow. The Bluebird patient is producing about 51.5 percent anti-sickling hemoglobin nine months after treatment—more than the 45 percent Bluebird disclosed at the European Hematology Association’s annual meeting in June. While this is only one patient, that number is important, because Bluebird has said based on historical data, patients who have greater than 30 percent of anti-sickling hemoglobin have the potential to be rid of the severe complications of sickle cell disease.
Additionally, no serious gene therapy-related side effects have emerged in any of the sickle cell or beta-thalassemia patients so far.
Results like these the past few years have helped both establish Bluebird as a leading gene therapy company, and boost the field overall. They’re small examples of real, tangible evidence that gene therapy, after so many ups and downs, might be able to make a real difference for healthcare.
But the news isn’t all good for Bluebird this time. Two of the three other beta-thalassemia patients treated so far have needed one transfusion, and the other one, according to the company, remains “transfusion dependent.” These patients have two copies of a genetic mutation—each called b0—that prevents them from producing any beta globin, which is a subunit of hemoglobin.
By comparison, the four patients who remain transfusion-free have only one copy of the b0 mutation, and as such produce at least some beta globin on their own. That means b0/b0 patients need more beta-globin than others—or as CEO Nick Leschly puts it, “these patients are clinically the highest hurdle.”
This doesn’t mean that LentiGlobin is having no effect on these b0/b0 patients. Chief medical officer Davidson says there is “evidence of a reduction in transfusion requirements,” but he wouldn’t be more specific. Those details—among them how long after treatment these patients needed infusions—will emerge when Bluebird presents all the data next month at ASH.
Still, these new insights could, at least potentially, curtail the reach for LentiGlobin. According to Leschly, about one third of patients with beta-thalassemia major have two copies of the b0 mutation.
Leschly acknowledges that this is a learning exercise for Bluebird. Up to this point, Bluebird had essentially had a 100 percent success rate—albeit in a small sample size—of eliminating the need for chronic blood transfusions in beta-thalassemia patients, a major milestone for gene therapy. Now, a “genotype separation,” Leschly says, of one patient group from another, seems to be affecting the power of the gene therapy. Bluebird has to test more patients, and do more follow-up, to understand exactly how LentiGlobin affects these patients, and what type of utility it might have as a treatment.
“We’re not ready to declare it doesn’t work in those patients,” he says.
Understanding what impact LentiGlobin actually has in these patients will help Bluebird figure out its next steps. The company already came to an agreement with the FDA earlier this year on what it’ll need to do to get LentiGlobin to market. That includes running two additional studies with the goal of freeing patients from blood transfusions for 12 months. Leschly says that Bluebird’s overall regulatory strategy “very much still holds,” though there are now “some nuances” that the company will have to figure out and discuss with the FDA.
To treat beta-thalassemia patients with its LentiGlobin gene therapy, Bluebird harvests stem cells from a patient’s bone marrow and inserts into them a healthy version of the beta-globin gene. The healthy gene is carried into the cell by HIV viruses that have been genetically modified to be harmless. Once modified, the stem cells are 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 normal levels of hemoglobin. That’s the theory, at least.
Bluebird has been using this approach on beta-thalassemia, sickle cell disease, and childhood cerebral adrenoleukodystrophy, or CCALD. The first patient data from the CCALD study should come next year, Leschly says.
The firm went public with a splash in 2013, and even amidst biotech’s recent swoon, Bluebird’s shares as of Thursday afternoon were still worth more than five times their $17 IPO price. Thanks to its high valuation and positive drips and drabs of data released the past few years, Bluebird has been able to raise hundreds of millions of dollars in follow-on offerings—it had more than $900 million in the bank as of Sept. 30. The company has also expanded into fields such as gene editing and cellular immunotherapy for cancer. It’ll present preclinical data on a multiple myeloma immunotherapy partnered with Celgene at ASH.
“We’re just getting our mojo here, that’s our view,” Leschly says.