Shares of Bluebird Bio fell more than 20% in premarket trading Thursday after the gene therapy developer announced that the FDA is hitting the company with quality-control demands not unlike those that have delayed other pioneers in the fast-growing space.
Specifically, the FDA wants Bluebird to provide additional information on the manufacturing process it will use as it transitions the product, LentiGlobin, from clinical trials to commercial production, the company said during its third-quarter earnings announcement.
The FDA requested “an analytical comparability strategy,” which will require Bluebird to manufacture the product from cells taken from both sickle cell patients and healthy donors “as well as commercial lentiviral vector to demonstrate drug product comparability.”
That will push the timing of the company’s FDA filing back a full year, to late 2022. The delay is certainly a disappointment for Bluebird, which, after 27 years of development, finally got LentiGlobin approved last year in Europe, where it’s called Zynteglo. But that approval, to treat transfusion-dependent beta thalassemia, was also plagued with manufacturing issues, which delayed the launch of the product by several months.
For the FDA, the issue is “chemistry, manufacturing and control,” or CMC in industry jargon. The exercises it is demanding from Bluebird are meant to ensure that as the company scales up the production process, the commercial-grade LentiGlobin will be comparable to that used in clinical trials.
As for why the FDA is demanding that Bluebird manufacture the product from cells taken from sickle cell patients in addition to healthy donors, the presumption is that the healthy donor cells “don’t allow us to check the actual potency of the drug product,” Derek Adams, Ph.D., chief technology and manufacturing officer, said during a conference call with analysts after the earnings announcement.
LentiGlobin has both fast-track and breakthrough-therapy designations from the FDA in transfusion-dependent beta thalassemia and is on track to complete that submission in mid-2021, the company said. But it’s the sickle cell indication that analysts expect will push the product into blockbuster territory.
When Bluebird got the thumbs-up for LentiGlobin in Europe last year, analysts at Jefferies estimated total sales of the product in beta thalassemia would peak at $696 million. But if it succeeds in sickle cell, that would push sales to $1.1 billion in 2027, the analysts said at the time.
In a note to investors today, Jefferies analysts called the delay “disappointing” in light of the fact that sickle cell “is the biggest revenue component in our model,” and they noted that the COVID-19 pandemic would only make complying with the FDA demands more difficult for Bluebird.
“Given the multifaceted inquiry from FDA on [manufacturing], we think commercial readiness may need extra time,” they wrote.
This is not Bluebird’s first run-in with the FDA on manufacturing worries. In May, the agency refused to review the approval request for ide-cel (bb2121), a CAR-T therapy for multiple myeloma that Bristol Myers Squibb is developing with Bluebird. The problem? The two companies didn’t provide enough detail on CMC, Bluebird CEO Nick Leschly and BMS CEO Giovanni Caforio said at the time.
In September, the FDA accepted ide-cel for priority review, setting a decision date of March 27. That’s cutting it close for investors who bought contingent value rights (CVRs) as part of BMS’ $74 billion purchase of Celgene, which was Bluebird's original development partner for ide-cel. The approval of the product by March of 2021 was one of three regulatory milestones that would have to be met for that CVR to pay off for investors.
Indeed, the FDA is quickly developing a track record for raising concerns about the manufacturing of gene and cell therapies. In October, the agency slapped a hold on Voyager Therapeutics’ gene therapy for Huntington's disease due to CMC concerns.
During Bluebird’s conference call, analysts pressed Leschly for hints that the company might be able to submit LentiGlobin to the FDA in sickle cell earlier than late 2022. But he made no promises and admitted he’s frustrated by the extended timeline.
“There’s going to be an ongoing dialog with the agency,” he said, adding, “for now we’re going to deliver what they ask. But at the same time, as we’re developing the CMC package here, we’re certainly going to engage with them, and hopefully, as that data continues to be clear to us and clear to them, then we can potentially figure out a way to navigate this a little bit more … flexibly.”