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Bluebird’s Upgraded Gene Therapy Shows Promise For Sickle Cell Patients

Xconomy Boston — 

Bluebird Bio has new clinical data this morning that, while early and only from a handful of patients, are the most significant evidence to date that gene therapy might help people with sickle cell disease, a genetic disorder without an effective treatment that afflicts millions around the world.

The data, presented at the European Hematology Association meeting, come from a Phase 1 study called HGB-206, which evaluates the Bluebird (NASDAQ: BLUE) experimental therapy LentiGlobin. The broad takeaway: Bluebird’s recent manufacturing and other changes to the gene therapy, an effort to boost its effectiveness, seem to be working so far. Before Bluebird’s technical changes, LentiGlobin was not good enough to carry forward in sickle cell.

“Looking at the data, it’s quite evident the dramatic impact that [the changes] have had on clinical outcomes,” says chief medical officer David Davidson.

As with all early studies, especially those for gene therapy, the small sample size is a major caveat. Bluebird is reporting on four sickle cell patients who received the improved version of LentiGlobin. Three months after treatment, the four patients are producing a median of 39 percent of “anti-sickling,” healthy hemoglobin—the protein in red blood cells that carries oxygen—in their blood.

The hallmark of sickle cell disease is abnormal, crescent shaped red blood cells that can get stuck in the bloodstream and cause a host of problems—anemia, bouts of pain, organ damage and more. Bluebird has been aiming for a threshold of 30 percent anti-sickling in its study participants, says Davidson. Based on scientific literature, patients at that level should have a “substantially diminished rate” of the complications associated with the disease, he says.

One of those four patients was treated six months ago and has had the best response. More than 60 percent of the patient’s hemoglobin is anti-sickling. The patient’s hemoglobin levels came in at 14.2 g/dL of blood. The Mayo Clinic considers 13.5 to 17.5 g/dL normal for men, 12.0 to 15.5 g/dL for women.

Two other patients were recently treated; Bluebird doesn’t have any follow-up data on them as of yet.

The first sickle cell patient ever treated with the earlier version of LentiGlobin, in 2014, had such remarkable results that they were published as a case study in the New England Journal of Medicine in March 2017. But that patient proved to be an outlier; Bluebird has had much more modest data in sickle cell since. Long-term results from the next seven patients treated with the original version of LentiGlobin, also released this morning, show they have produced very little anti-sickling hemoglobin (5 percent) after a median of 24.2 months. The treatment wasn’t having enough impact. “That’s why we had to improve the product,” says CEO Nick Leschly.

Bluebird hasn’t disclosed specifics about safety yet, but only said in a statement LentiGlobin’s profile is “generally consistent with” bone marrow transplants.

Even after four years and two versions of LentiGlobin, Bluebird remains the only sickle cell developer to reach clinical studies and produce data with a gene modification. Sangamo Therapeutics (NASDAQ: SGMO) and partner Bioverativ (NASDAQ: BIVV) were cleared last month to enroll patients in a first study of their gene editing treatment. The FDA recently held up the first human test of a gene editing therapy from CRISPR Therapeutics (NASDAQ: CRSP) and Vertex Pharmaceuticals (NASDAQ: VRTX). (Xconomy’s Alex Lash has more today on the various treatments on the horizon and the questions they’ll face as they advance through clinical testing.)

Time will tell how long LentiGlobin can boost levels of anti-sickling hemoglobin long-term, and whether that translates into relief from the disease’s many crippling symptoms without unintended problems. But the FDA has signaled it doesn’t need to wait too long. In a speech last month, FDA commissioner Scott Gottlieb spoke of remaining “uncertainty” even after some gene therapies are approved. The question of how long they last, for instance, “can’t be fully answered in any reasonably sized pre-market trial,” Gottlieb said.

There are only two drugs approved to treat the symptoms of sickle cell. And the only available cure is a bone marrow transplant, a risky procedure that many patients can’t qualify for. Bluebird’s gene therapy is essentially meant to be a more accessible alternative to a transplant.

If current results hold up, it remains to be seen if Bluebird will have to run a new study to show LentiGlobin improves patients’ lives by lessening anemia, pain crises, or other complications; or if the surrogate marker of a boost in healthy hemoglobin would be enough for approval.

With the related genetic blood disease, beta-thalassemia—also a target of LentiGlobin—there is a direct connection between boosting hemoglobin levels, freeing people from the need for blood transfusions, and seeing a positive impact on their health. (Bluebird is also presenting updated LentiGlobin results in beta-thalassemia at EHA this morning.) The problem is, sickle cell disease is complicated, with many ways to hobble a patient.

Leschly says discussions with the FDA about its goals for sickle cell trials are underway, and there are “a range of possibilities.” Bluebird hopes to have an update later this year, he says. “Certainly the magnitude and consistency of the data perhaps open the door to more aggressive [FDA filing] approaches, but that depends how this data evolves.”