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FDA advisers offer a vote of confidence for gene therapies

The endorsement of Bluebird Bio’s treatments offers hope for the industry.

Cambridge based Bluebird Bio is developing gene therapies for rare genetic conditions including the blood disease beta-thalassemiaScott Lowden

Gene therapy companies are sorely in need of good news, and they finally got some earlier this month when an advisory committee for the US Food and Drug Administration voted unanimously in favor of recommending Bluebird Bio’s two gene therapies for approval. The FDA committee’s full-throated assurance that the therapies’ benefits outweigh their risks — including the possibility of blood cancer — was a better outcome than many in the industry had hoped for.

The FDA itself still gets the final say on whether Bluebird’s therapies will be approved, and its decision is expected in the next few months. “Although it doesn’t translate directly to an FDA approval, a unanimous vote from the panel is as strong of an endorsement as you can get,” said Kyle O’Neil, a consultant at Back Bay Life Science Advisors, a consulting and investment banking firm in Boston.


Bluebird was once a marquee example of the potential of gene therapy, but a failed product launch in Europe and a few cases of cancer that arose in people receiving its experimental therapies has sent the Cambridge company’s stock down 98 percent over the past three years. It barely has enough cash to last another year.

“We’ve had our hiccups, but this was an enormously gratifying moment for us,” said Bluebird chief executive Andrew Obenshain. The advisory committee’s decision also bodes well for the gene therapy field at large, he added, since the “first whiff of a cancer” shouldn’t necessarily kill a gene therapy program now. “The risk-benefit is really being taken into account.”

Over the past couple of years, investor interest in gene therapy companies has soured as the FDA has grown increasingly concerned about the safety of the experimental treatments designed to correct genetic diseases. Many gene therapy stocks have fallen more than 90 percent amidst the broader biotech market slump, forcing firms to shed employees and trim their drug pipelines in order to stay afloat.


“Gene therapy has been under the winds in the last two years,” said Dr. Gaurav Shah, chief executive of the New Jersey gene therapy firm Rocket Pharmaceuticals. “And a lot of people — patients, physicians, and other stakeholders — were becoming nervous about whether this was actually a viable path.”

The advisory committee’s unanimous vote of support sets a precedent that is “hugely positive” for companies developing similar therapies, Shah added. “We will hopefully start to see the turning of the tide here.”

Both of Bluebird’s therapies require harvesting a person’s blood stem cells and then using engineered viruses called lentiviral vectors to deliver a therapeutic gene into the cells. The altered stem cells are then infused back into the patient, where the newly added gene compensates for a broken one.

Because lentiviruses integrate the therapeutic gene into DNA, the benefits of the treatment could last a lifetime. But the potential permanence of gene therapy is also its greatest risk. Depending on where in the genome the lentivirus integrates, it can heighten the risk of cancer.

“The challenge is it oftentimes isn’t something that we see right away,” said Dr. Jatin M. Vyas, an immunologist and infectious disease specialist at Massachusetts General Hospital. Although Bluebird followed some patients for seven years, Vyas said a more cautious approach would be to look for cancer risks 10, 15, or 20 years after treatment.


“That obviously has to be balanced by the fact that patients have diseases now and there are opportunities for therapies now,” he said.

Bluebird’s first treatment, eli-cel, helped children with a lethal neurodegenerative disease called cerebral adrenoleukodystrophy live longer by supplying them with a gene that’s crucial for the proper functioning of brain cells. Although three children in the trial developed blood cancers, the advisory committee said that certain death from the disease itself or dangerous immune system reactions from standard stem cell transplants made the risks of eli-cel worth it.

“It is such a terrible condition,” said Dr. Terence Flotte, dean of the University of Massachusetts T.H. Chan School of Medicine and a gene therapy researcher. “I think the advisory committee did the right thing. The risk-benefit is strongly in favor of offering it to these children.”

Other companies making lentiviral gene therapies — including Avrobio, Mustang Bio, Orchard Therapeutics, and Rocket Pharmaceuticals — emphasize that not all lentiviral vectors are created equal. A segment of DNA called the promoter controls how the therapeutic gene is turned on or off. Some promoters, such as the one used in eli-cel, crank the gene up high all the time, which increases the chance of mistakenly turning on cancer-promoting genes.

Bluebird’s second therapy, beti-cel, uses a different promoter that doesn’t seem to have the same degree of cancer risk as eli-cel. “For that to be understood and validated is very important,” said Geoff MacKay, president and chief executive of the Cambridge gene therapy firm Avrobio.


Beti-cel helped people with the rare blood disease beta-thalassemia stay off blood transfusions by supplying them with a gene needed to ferry oxygen throughout the body.

“It is extremely exciting. With a single administration of these gene-modified cells, you have the opportunity to potentially cure a disease,” said Dr. Bobby Gaspar, chief executive of the London- and Boston-based Orchard Therapeutics, which like Bluebird, has suffered a massive stock drop and layoffs.

“Seeing these therapies approved will, hopefully, restore some faith and energy and interest in the field,” Gaspar said. “We need these kinds of successes from Bluebird and ourselves to rejuvenate the market.”

The committee’s vote of confidence briefly lifted Bluebird’s struggling stock, but had little immediate impact on the value of other gene therapy firms. A negative vote from the committee might have been more harmful than a positive vote was helpful.

“If they had said no, that could have been a death knell to lentiviruses,” said Dr. Stuart Orkin, a scientist at the Harvard Stem Cell Institute and a physician at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

The FDA’s final decision is due by mid-August for beti-cel and by mid-September for eli-cel, but an FDA approval in no way guarantees successful commercialization. In fact, beti-cel and eli-cel are already approved in Europe, but Bluebird shut down its commercial operations there last year after it was unable to convince payers to cover the $1.8 million cost of beti-cel.

Obenshain said that Bluebird hasn’t decided on prices for the treatments in the US yet. Experts expect the products could cost between $2 million and $3 million. The Institute for Clinical and Economic Review, a Boston drug pricing watchdog, recently said that beti-cel could be considered cost-effective in that price range.


Gene therapy firms are eagerly waiting to see if Bluebird can get insurers to cover its therapies at premium prices, which would be a true bellwether for investors to feel confident that other firms can command similarly high prices.

“The pricing is something that is going to apply to the entire gene therapy field,” said Dr. Manuel Litchman, chief executive of Mustang Bio. “Because there are so few precedents for pricing, the pricing here is going to be really critical,” he added.

“If they get premium pricing that will do something far more important for the industry than the actual approval” of the Bluebird therapies, he said.

Ryan Cross can be reached at ryan.cross@globe.com. Follow him on Twitter @RLCscienceboss.