Elivaldogene Autotemcel (Bluebird Bio)

Bluebird bio revealed in its third-quarter report Thursday that it remains in a tight financial position and needs to secure more funds in order to avoid running out of cash by early 2025 — casting a shadow over otherwise encouraging signs of commercial progress for its gene therapy portfolio.The announcement puts pressure on the company to garner additional financing within the next few months to bridge the gap to its projected cash flow break-even in the second half of next year."Based on our current forecasts, which assumes continued cost saving initiatives, successfully renegotiating key contracts and continued collaborative engagement from Hercules, we expect our existing cash and cash equivalents will enable us to fund our operations into the first quarter of 2025," stated Chief Financial Officer James Sterling during the company's earnings call.This past March, bluebird inked a $175-million, five-year term loan facility with Hercules Capital, securing funding that the company said was expected to extend its cash runway for 24 months. Bluebird later announced it would let go of about a quarter of its staff in an effort to scale back operating expenses by 20% as its trio of gene therapies struggled to get off the ground.The company ended September with $118.7 million in cash and cash equivalents, including $48 million in restricted cash — a stark contrast to its 2018 position when it held $1.6 billion (see – Vital Signs: The last flight of the bluebird).Seventeen starts for LyfgeniaThe update comes amid a backdrop of third-quarter momentum. Bluebird reported 57 patient starts completed to date in 2024 across its three approved gene therapies: 35 for Zynteglo in beta-thalassemia, 17 for sickle cell disease treatment Lyfgenia (compared to only four in Q2), and 5 for Skysona in cerebral adrenoleukodystrophy. An additional 17 starts are scheduled through year-end.Tom Klima, chief commercial and operating officer, highlighted strong early indicators for 2025, noting "30 patient starts already scheduled in 2025," with the "vast majority" of those in the first quarter. He also pointed to a near-perfect conversion rate from scheduled to treated patients. "So far, it's very high… Essentially, 100% are converting to a start. The only variable is just the time."He added, "We have plans to double capacity for Lyfgenia in 2026 based on anticipated demand."Meanwhile, the company's network of qualified treatment centres (QTCs) has more than 70 locations in the US, with approximately 30 having initiated for one of its therapies. "I think the most exciting part of that is we have about 40 QTCs that are looking to start their first patients. So, I think it's a nice indicator of growth ahead," Klima said.

Seven young boys treated with bluebird bio’s gene therapy for a rare neurological disease have been diagnosed with blood cancer months or years after treatment, according to data published on Wednesday in the New England Journal of Medicine . Researchers have long known that therapies developed with lentiviral vectors could, in some cases, cause cancer, but they have been seeking to understand why Skysona comes with a seemingly greater risk. The cases may relate to the design of the lentiviral vector used in the treatment, scientists hypothesize. Bluebird’s eli-cel was approved in 2022 under the brand name Skysona to treat cerebral adrenoleukodystrophy, also known as CALD. The condition mostly affects young boys and progresses rapidly without treatment, leading to neurological decline or death. Skysona was approved in 2022 with a black box warning for hematologic malignancy, and the FDA updated its label in April to disclose that there had been six cases of the cancer out of 67 patients dosed in clinical studies. An additional case has been diagnosed since then, according to new data published in NEJM. The patients received Skysona when they were between 5 and 13 years old, with the cancer diagnoses occurring 14 to 92 months later, according to the data. In an editorial published alongside the data, Cynthia Dunbar, a hematologist at the NIH’s National Heart, Lung and Blood Institute, wrote that more cases may appear over time. “Unfortunately, I think she’s right,” Christine Duncan, lead author of the NEJM study and Boston Children’s Hospital senior physician, told Endpoints News. “ Patients are being followed very closely. The families are being very educated. They all know about all of these cases.” Duncan and her team hypothesized that the cases may have been driven by the design of the lentiviral vector used in Skysona. CALD is caused by a mutation in a gene called ABCD1. Skysona works by using a lentivirus to insert a functioning form of the ABCD1 gene. Skysona’s lentiviral vector was designed with the use of a viral promoter, intended to help drive strong expression of the gene. But a risk of that type of promoter is oncogenesis, or driving the development of cancer, Duncan explained. “We’re relatively confident that that promoter in the design of the vector is driving this,” she said. “The question then is, in my mind, is it driving it alone, or are there other factors that contribute?” Duncan noted that patients in one study, ALD-102, which has reported only one case of hematologic cancer, received a stronger chemotherapy regimen as part of preparation for treatment than another study, ALD-104, which reported the other six cases. But at this time, it remains unclear whether that made a difference, or whether other factors were involved. “Is it a combination of conditioning regimen and the vector?” she asked. “We can’t know for certain.” Duncan added that the risk-benefit analysis for Skysona may vary from patient to patient. Some patients may be eligible for allogeneic stem cell transplant, but that process comes with its own risks — and just 20% of CALD patients have an available matched donor, according to the NEJM editorial. “We recognize that families of children diagnosed with CALD face urgent treatment decisions, and bluebird is committed to ensuring that treating physicians have access to the most up-to-date safety information to support informed decision making,” bluebird said in a statement. Leaving CALD untreated is the greatest risk, Duncan said. “Both allogeneic stem cell transplant, so the traditional therapy, and gene therapy, they both have things that are good about them, they both have things that are bad about them. And for any individual patient, it’s not the same scale,” Duncan said. “At the end of the day, I think it is very valuable, very important that families have choices that they can personalize with their caregivers and their providers.” Researchers noted there have been no cases of lentivirus-caused cancer reported with bluebird’s sickle cell and beta thalassemia therapy, which used a different lentiviral vector called BB305, and none with Orchard Therapeutics’ metachromatic leukodystrophy therapy Lenmeldy. Lei Lei Wu contributed reporting.