Bluebird’s Gene Therapy Shows Promise in Rare Brain Disease

Xconomy Boston — 

Cerebral adrenoleukodystrophy is a rare, crippling neurological disease that leaves its patients, typically boys, severely disabled and ultimately dead in a matter of years. Only painful, dangerous bone marrow transplants can stop the progression of CALD. But while the transplants are effective in many cases, they can also be deadly for the patients who get them.

For years, Cambridge, MA-based Bluebird Bio (NASDAQ: BLUE) has been working on another solution—gene therapy, in which a virus, modified to carry specific genetic instructions, is infused into a patient’s body. The goal is to produce a one-time, long-lasting treatment that halts the progression of CALD without the safety hazards of a bone marrow transplant.

Bluebird has a long way to go to make that claim. But today, at the American Association of Neurology’s annual meeting in Vancouver, BC, the company unveiled the first data from patients taking that therapy, known as Lenti-D. And the results, while early and in just a handful of patients, are promising.

The headline number: None of the 17 patients who have received Lenti-D so far have developed a major disability—such as losing the ability to walk or talk—or had a serious safety problem, like graft-versus-host disease or death that can occur with a transplant. Three of the patients were treated more than two years ago, with the effects of treatment still holding up.

“We’re cautiously optimistic,” says Bluebird senior VP of clinical development Robert Ross. “But we need all the patients [in the study] to be through two years before we can say with some confidence that we’ve achieved our goal.”

To understand why such small sample sizes of data are potentially important, a little background helps. CALD is caused by a mutation to the ABCD1 gene that causes a shortage of the protein, ALD. Without that protein, long chains of fatty acids build up in the brain, leading to an abnormal immune response that destroys myelin, the coating that protects part of the brain’s neurons.

CALD is the most severe and common form of adrenoleukodystrophy, afflicting about 30 to 40 percent of patients with the disease. People stricken with CALD lose their ability to walk, communicate, or function properly. They often die or are permanently disabled within five years of diagnosis, according to the nonprofit Stop ALD Foundation. The disease is estimated to affect roughly one in every 20,000 babies born, though Ross says those numbers may increase as newborn screening for the disorder becomes more prevalent.

Stem cell transplants—either from a donor’s bone marrow or umbilical cord blood—are the only proven method to treat CALD. The 1992 film Lorenzo’s Oil described two desperate parents’ search for a cure for their CALD-stricken son Lorenzo, leading to the discovery of a concoction made from two cooking oils. Still, almost 25 years after the movie’s release, it’s unclear whether that mixture, named “Lorenzo’s Oil,” has any real therapeutic benefit for patients with CALD. Ross says the data surrounding it are “pretty mixed” and added that there’s nothing conclusive as to whether it “actually reverses or changes the disease itself.” Here’s more on the topic.

With its Lenti-D gene therapy, Bluebird essentially wants to recreate a successful transplant, but with a patient’s own cells rather than a donor’s. It harvests stem cells from a patient’s bone marrow, and uses a modified virus—known as a viral “vector”—to insert a healthy version of the ABCD1 gene into those cells. The altered cells are infused back into the body, where they help create new cells with the ability to make the crucial ALD protein these patients lack.

Bluebird hopes Lenti-D is safer than a transplant. Patients can die from the transplant itself or afterwards get graft-versus-host disease, when the donor cells mount an attack against the patient. Ross says 5 to 10 percent of CALD patients can 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.