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Bluebird’s Gene Therapy Shows Promise in Rare Brain Disease

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die from complications, and further that graft-versus-host occurs in some form in half of patients who get a transplant. Those patients get rashes, gastrointesintal issues, and other potentially fatal problems, according to Amber Salzman, the president of the Stop ALD Foundation, and the CEO of gene therapy startup Annapurna Therapeutics. (Salzman is not involved with Bluebird, but she indirectly helped get the company involved with CALD several years ago via an academic study of a gene therapy in France, as I wrote in 2014)

“These kids, a lot of them [who get bone marrow transplants] go through hell and then they die,” says Salzman, who adds that parents know that the transplant is the only option. “But when they see sometimes what [the kids] go through, they really regret it,” she says.

Still, these transplants often work. According to Ross, historical data Bluebird has accrued shows that 80 percent of the patients who survive a transplant don’t suffer a major disability from their disease within two years. To that point, Salzman’s son Spencer got a transplant at two years old, and even though he didn’t have a matched donor, the procedure was so effective it stabilized his disease. Fourteen years later, he’s a healthy 16-year-old who plays lacrosse. Her nephew got a transplant at about six years old, also without a matched donor, and while he’s wheelchair bound, his disease also stabilized—albeit after a difficult battle with graft-versus-host disease. “He’s a perfect case for why you’d want gene therapy,” Salzman says.

The 80 percent figure of patients who emerge from the post-transplant danger is important because Bluebird’s trial is a single-arm study that compares Lenti-D to historical numbers, not an active control. Ross won’t say that Bluebird needs to match or top 80 percent with Lenti-D, but  “if we’re way off that number,” he says, “that’s a problem.”

So far, Bluebird is on track. At the end of March, none of the 17 patients in its trial had any new major disabilities. Three of them have gone at least two years after Lenti-D treatment, which is the main goal of the trial. Bluebird’s secondary goals include brain damage measured by MRI scans and a test of neurological function. Ross says the data so far are encouraging.

Still, “we need more numbers, and we need more time,” Salzman says, after a look at the data. Indeed, how long will the effects last, who will respond, and who won’t are some of the biggest unknowns for Lenti-D and for gene therapy overall. The patient-to-patient variability of a therapy cropped up in a trial of one of Bluebird’s other treatments, LentiGlobin, in beta-thalassemia patients.

And with Lenti-D, for instance, some patients have seen fluctuations in an MRI marker of brain inflammation called “gadolinium enhancement”—a telltale sign of CALD—as time has progressed. Ross says it’s unclear if the changes are related to disease progression, particularly since none of those patients have suffered new major disabilities along the way. “We have to follow this over time and see what happens,” he says, “but we may be seeing fluctuations that may not have a clinical impact.”

Bluebird doesn’t know yet if this early CALD study, known as “Starbeam,” will be enough to win regulatory approval. It may have to run another trial. Ross would only say Bluebird is in “ongoing conversations” with the agency.

The company will host a conference all later today to discuss the data.

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