For the first time in half a decade, the U.S. Food and Drug Administration’s Cellular, Tissue and Gene Therapies Advisory Committee will convene June 9-10 to address two therapies developed by bluebird bio in back-to-back meetings sure to draw the eyes of all companies developing lentiviral vectors as potential therapeutics for rare diseases.
For Cambridge, MA-based bluebird, the two-day meetings will be a huge moment in a watershed year for the beleaguered company that laid off nearly one-third of its employees in April. Not only will the advisory committee help shape the future for beti-cel and eli-cel, gene therapies that are already marketed in Europe, it could likely shape the future of the trailblazing company.
“Next week is going to be monumental, quite frankly,” Melissa Bonner, head of research at bluebird bio told BioSpace. “This is the first time a lentiviral vector will be considered in the United States. This will have a profound impact on the entire field of gene therapy because there are a lot of different products in development that use an LVV approach.”
Like a spelunker carefully exploring a newly-discovered cave, the bluebird team, along with the scientists who make up the advisory committee, will be navigating new regulatory territory in gene therapy. Because the discussions that will be had this week as eli-cel and beti-cel are carefully examined will have ripple effects across the industry, Bonner predicted the committee meeting will be closely watched by other companies following a similar program path.
“Everyone will tune in with their popcorn to see how this is going,” she quipped.
Eli-cel, also known as elivaldogene autotemcel, will be the first bluebird program discussed by the advisory committee. Eli-cel was previously approved in Europe under the brand name Skysona. It was approved last year as a treatment for juvenile patients with early cerebral adrenoleukodystrophy (CALD), a serious neurological disorder caused by mutations in the ABCD1 gene. CALD typically develops in a juvenile around the age of 7. The rare, progressive, x-linked disorder is ultimately fatal but not before sending the patient into a vegetative state.
Eli-cel uses ex vivo transduction with the Lenti-D lentiviral vector to add functional copies of the ABCD1 gene into a patient’s own hematopoietic stem cells (HSC). The addition of the functional ABCD1 gene allows patients to produce the ALD protein, which is thought to facilitate the breakdown of very long-chain fatty acids, which cause the breakdown of myelin, the protective sheath around nerve cells in the brain.
Throughout the course of its development, eli-cel has shown positive efficacy. But, at the same time, there have been some safety concerns, which the FDA advisory committee members will likely discuss in detail. The eli-cel study was hit with a clinical hold last year over safety concerns after a patient treated with the gene therapy developed a rare form of cancer, myelodysplastic syndrome.
Bonner said the company has been transparent about the safety of eli-cel. Throughout its development, three patients developed a malignancy that was likely related to the gene therapy. Bonner said the safety issues will have to be weighed against the overall positive efficacy seen throughout clinical development. The advisory committee members are expected to “have a lively discussion” to determine if the overall benefits of eli-cel outweigh the risks in a patient population that has few options beyond an allogeneic stem cell transplant from a matched donor.
“If you have a matched donor, your odds are good. If not, your odds are very different,” she said. “This is a life-saving therapy. We think there’s a positive benefit-risk.”
On day two, the advisory committee will assess beti-cel, which is being developed for the blood disorder beta-thalassemia. Beti-cel is marketed as Zynteglo in Europe. Pointing to the clinical data, Bonner said with beti-cel there have not been the same safety concerns seen with eli-cel, and also noted that it has had positive efficacy data that she called “transformative.” Beti-cel is one-time gene therapy intended to treat beta-thalassemia in patients who need regular transfusions of red blood cells. In Phase III trials of beti-cel, 89% of patients who could be evaluated achieved transfusion independence.
As the advisory committee meeting looms closer, Bonner said the bluebird team will prepare as well as possible for all potential questions brought up by the committee members. While the meeting is a new experience for bluebird, Bonner noted this is also a new experience for the advisory committee members who have not met since the 2017 meeting before the approval of Spark Therapeutics’ Luxturna, a gene therapy for a rare form of blindness.
Although Bonner admitted the advisory committee meetings are stress-inducing, especially given the recent layoffs at bluebird, she shared her hope for the vast potential gene therapies have for rare disease patients. There are approximately 7,000 known rare diseases that impact between 25 million and 30 million Americans. The vast majority of those rare diseases do not have any therapeutic options or have insufficient ones.
“This type of technology (lentiviral vectors) can be pretty useful for these patients. That’s why this will be such a momentous occasion,” she said.
https://www.biospace.com/article/bluebird-bio-blazes-trail-for-lentiviral-vectors-at-back-to-back-fda-adcomm-meetings/
