After years of research and billions of dollars spent, Bluebird bio is on the cusp of a milestone only a few drugmakers have ever reached.
Two gene therapies it’s developed are under review by the Food and Drug Administration and, if approved, would become only the third and fourth cleared by the agency for use in treating inherited diseases.
But Bluebird, a pioneer in the field, simultaneously faces financial peril. The Massachusetts-based biotech is quickly running out of cash and earlier this year warned investors that it may struggle to stay solvent. It’s already cutting costs.
Most importantly, FDA clearances would bring new treatment options for patients with few. One of Bluebird’s therapies treats the rare blood condition beta thalassemia, which in its severe form requires blood transfusions every few weeks for life. The other is meant to halt the progression of a devastating neurological disorder called CALD, or cerebral adrenoleukodystrophy, that affects young boys.
On Thursday and again on Friday, the FDA will convene a panel of outside experts to review Bluebird’s data and advise it on the treatments’ respective benefits and risks. Documents published Tuesday indicate agency scientists are cautiously supportive of the beta thalassemia treatment, called beti-cel, but are more skeptical of the CALD therapy, eli-cel.
The FDA is due to make its decisions by Aug. 19 and Sept. 16, respectively. Its verdicts could determine Bluebird’s fate, shape how other gene therapies are developed and, potentially, change how two genetic diseases are treated.
“I think there really is a spotlight on how this is handled by the FDA,” said Christine Duncan, a physician at Boston Children’s Hospital and medical director of the gene therapy program there.
Bluebird’s rocky road
Four years ago, Bluebird was riding high. The biotech’s progress developing gene therapies for rare genetic diseases early last decade had helped propel the field forward, and Bluebird, as a result, had become one of the industry’s most valuable companies.
That January, Nick Leschly, Bluebird’s longtime CEO, took the stage at the pharmaceutical industry’s most closely watched conference and told the gathered crowd his company would soon ask regulators for approval of three experimental drugs.
It was a noteworthy declaration, meant to signal Bluebird’s coming transition into a commercial-stage drugmaker after nearly three decades of laboratory and clinical research. Leschly’s forum, the grand ballroom of the Westin St. Francis at that year’s J.P. Morgan Healthcare Conference, seemed to match the moment, and reflect Bluebird’s ascension.
“We believe we're in a leadership position in an important field that's emerging,” Leschly said, according to a transcript of his 2018 speech by market data firm Koyfin.
But Bluebird’s transition has been rockier than anticipated. While the company did win milestone approvals of beti-cel and eli-cel in Europe, manufacturing hurdles and difficulties securing reimbursement forced Bluebird to later pull both from market and shut down its operations there. Only a handful of patients received either treatment.
In the U.S., disagreements with the FDA over production tests twice delayed Bluebird’s plans to seek approval of beti-cel, and slowed progress with another gene therapy for the blood condition sickle cell. The FDA also initially refused Bluebird and partner Bristol Myers Squibb’s application for the third drug referred to by Leschly, a cell therapy for multiple myeloma, before eventually approving it in early 2021.
“It’s the challenge of being [on] a frontier. You hit all the waves first,” Leschly said in a February interview, a few months after leaving to head 2seventybio, a new biotech that Bluebird created by spinning out its oncology business. (Andrew Obenshain, formerly Bluebird’s genetic disease head, succeeded Leschly as Bluebird’s CEO.)
Other gene therapy developers have struggled to cross the FDA’s finish line as well, or have run into unexpected roadblocks with their products
“What’s happening to them is not unique to Bluebird,” said Nicole Paulk, an assistant professor of AAV gene therapy at the University of California, San Francisco. “Any gene therapy company you can name off the top of your head … they’re all facing the same problems around manufacturing and [production controls].”
For Bluebird, though, the delays and setbacks have been especially costly. Its market value, near $10 billion in early 2018, has dwindled to just above $250 million currently. The company moved its headquarters from Cambridge to Somerville, Massachusetts to save money and in April said it will lay off about a third of its employees.
The cost-cutting might not be enough, either. Bluebird, which regularly records quarterly losses totaling hundreds of millions of dollars, now has just $267 million in available funds. In March and again in May, the biotech warned there was “substantial doubt” it will be able to stay afloat for the next year.
Bluebird’s survival may come down to whether the FDA clears beti-cel and eli-cel. Approval of either would give Bluebird the chance to make money not only from commercial sales, but also from special regulatory vouchers the FDA awards that typically sell for about $100 million each.
Yet Bluebird’s treatments aren’t a sure bet to win the FDA’s blessing. Looming over both are safety concerns that have cropped up over the past year.
Last February, Bluebird suspended testing of its sickle cell gene therapy after a study participant developed a form of leukemia. While no cases were reported for beti-cel, which uses similar technology, the FDA subsequently placed study “holds” on both therapies.
An investigation by the company found no clear link between treatment and the leukemia case, and in June the FDA lifted its mandated trial pauses.
But then in August Bluebird reported a case of myelodysplastic syndrome, a cancer-like condition of the bone marrow that can evolve into leukemia, in a CALD patient treated with eli-cel.
Two more eli-cel patients were subsequently diagnosed with myelodysplastic syndrome, or MDS. Two of the cases were directly linked to treatment, while the third was judged highly likely to be related.
In documents published Tuesday, FDA scientists made clear their concerns, noting that, as all three cases occurred long after treatment, they expect more to emerge from recently treated study participants. Laboratory testing also revealed troubling genetic signs in many of the other patients that could portend — but not necessarily cause — future cancer.
Both eli-cel and beti-cel, as well as Bluebird’s sickle cell treatment, are based around a similar therapeutic concept. Stem cells are taken from each patient and, in a laboratory, genetically modified using a type of virus known as a lentivirus. Once reinfused, the engineered stem cells mature and express proteins that replace ones mutated or missing in beta-thalassemia, CALD and sickle cell.
“The question is whether the insertion of the virus into the genome of the cells has resulted in the clonal expansion of that population of cells and, potentially, evolution towards leukemia,” said Paul Orchard, a pediatric transplant specialist at the University of Minnesota who helped run a study of eli-cel.
Benefit versus risk
The FDA and its advisers will have to weigh the therapies’ safety risks against their benefits. In the case of eli-cel, the treatment’s effectiveness was primarily measured as the percent of treated patients who survived two years without major functional disabilities like tube-feeding or wheelchair dependence.
Twenty-nine of the 32 study participants assessed reached this goal, a rate that’s near what Bluebird found for similar CALD patients treated with donor-derived stem cell transplants in two natural history studies.
Donor, or allogeneic, transplants can be an effective treatment for CALD, but work best when the stem cells come from a sibling. Unfortunately, only about 30% of boys with CALD have matched sibling donors, according to the FDA.
“Aside from donor factors, it is unclear if there is a CALD population for whom the benefit of treatment with eli-cel outweighs the significant and unknown long-term risk of MDS,” FDA staff wrote in the documents.
Duncan, of Boston Children’s, agrees the tradeoffs are difficult to weigh but argues that, for some at least, eli-cel would be a needed additional option.
“It’s not black and white,” said Duncan, who is an investigator in an eli-cel study and will present to the FDA’s advisers Thursday on behalf of Bluebird. “This is an area of gray in that for some patients, if they don’t have an allogeneic stem cell transplant match, they don’t have a choice. Their disease progresses, they’re neurologically devastated and they die.”
The FDA appears more supportive of beti-cel, which in testing showed a powerful ability to free beta thalassemia patients from needing regular blood transfusions. Agency staff agreed the data show it to provide a meaningful benefit for those patients and noted treatment could reduce serious health risks associated with chronic transfusions.
Even so, the FDA is asking its advisers to weigh the cancer risk observed in testing of eli-cel and Bluebird’s sickle cell therapy, and whether that should impact its decision on beti-cel.
Gene therapy catalyst
Neither eli-cel or beti-cel, if approved, are expected to become top-selling drugs, despite expectations that Bluebird could price them similarly to other gene therapies available in the U.S. and Europe that cost more than $1 million.
Bluebird estimates there are between 1,000 and 1,300 beta thalassemia patients in the U.S. who require regular blood transfusions. The number of boys with CALD is far less, perhaps as few as 50 in the U.S, according to analysts from RBC Capital Markets.
But the impact of each treatment could still be significant, both for patients that might receive them and for the broader gene therapy field.
Only two gene therapies for inherited diseases are approved in the U.S. — Luxturna for a form of childhood blindness and Zolgensma for the neurodegenerative disease spinal muscular atrophy. (Six CAR-T cell therapies, which are sometimes classified as gene therapy, are also approved for a range of blood cancers.)
Previously FDA officials had predicted that, by 2025, they’d be reviewing between 10 and 20 gene and cell therapies each year — a figure that now looks likely to be an overestimate. The agency also appears to be moving cautiously as more safety concerns beyond Bluebird emerge, freezing a number of gene therapy studies over the past year.
“We need a catalyst moment … to bring us out of this sentiment slump,” said Paulk.
FDA approval of beti-cel and eli-cel could provide one. If the agency decides to hold off, expectations for more gene therapy clearances in the near future might be further tempered.
For Bluebird, the consequences are clearer. The FDA’s decisions could determine whether the company remains around long enough to provide either therapy to patients.
“It would be extremely unfortunate to get to the point where [we’ve] developed efficacious therapies and then the companies don’t have the finances to move forward,” said Orchard, of the University of Minnesota.