Skysona Gene Therapy Approved in EU for Early CALD


Bluebird Bio plans to submit its biologics license application in the US by mid 2021.

Elivaldogene autotemcel (Lenti-D, Skysona; bluebird bio) has been approved in the European Union for pediatric patients with early cerebral adrenoleukodystrophy (CALD) with an ABCD1 mutation and no matched sibling donors.1

The gene therapy uses patients’ blood stem cells, altered to express the missing copy of ABCD1. One-time administration of the treatment was shown to improve survival outcomes and preserve neurologic function across pivotal and long-term studies, with nearly 7 years of follow-up demonstrating a durable response.

“Skysona is the first and only one-time gene therapy approved in the EU for patients with CALD, a devastating neurodegenerative disease, and we are immensely grateful to all who have brought us to this milestone, from the patients and their loved ones, to all study investigators, regulators, the ALD community and of course, the extended bluebird family,” said Andrew Obenshain, president, severe genetic diseases, Bluebird Bio, in a statement. 

Skysona, with its functional copy of the ABCD1 gene, allows the production of the ALD protein (ALDP), which is thought to facilitate the breakdown of VLCFAs. The one-time treatment is designed to have a life-long effect and stop the progression of CALD.

READ MORE: Long-Term Data Show No MFDs for Eli-Cel in CALD

Data from the phase 2/3 Starbeam study (ALD-102) supported the approval of Skysona, as well as data from the ongoing ALD-104 study. In ALD-102, 90% (n = 27) of participants met the 24-month Major Functional Disabilities (MFD)-free survival end point. Two patients withdrew at investigator discretion and 1 experienced rapid disease progression early in the study, resulting in MFDs and death. ALD-104 is approaching enrollment completion in the US. Patients from both ALD-102 and ALD-104 have also been asked to participate in a long-term follow up study, LTF-304.

LTF-304 has so far demonstrated a durable effect, with 96.3% (n = 26) maintaining their MFD-free status through the last follow-up. Median follow-up duration was 3.2 years (38.6 months; min, 13.4 months; max, 82.7 months) and 14 patients reached at least 5 years of follow-up.

The FDA has granted Skysona orphan drug designation, rare pediatric disease designation, and breakthrough therapy designation for the treatment of CALD. Biologics license application submission is expected by mid 2021.

“Bluebird Bio was founded with the mission of developing a therapy to recode CALD on the genetic level, and today’s announcement represents over twenty years of research and development that has laid the groundwork for future gene therapies to be possible,” Obenshain added.

Adverse events (AEs) included known effects of mobilization/apheresis and conditioning, as well as cystitis viral, pancytopenia, and vomiting. No graft-versus-host disease, graft failure or rejection, transplant-related mortality, or replication competent lentivirus have been reported in any clinical studies. Clonal expansion resulting in clonal predominance was detected in some treated patients. The company states that there is a potential risk of hematologic malignancy after Skysona treatment, although there have been no reports of such to date.

Bluebird's gene therapy studies that use the BB305 vector were halted in February 2021 after the diagnosis of acute myeloid leukemia (AML) in a patient who received bb1111 around 6 years ago in a phase 1/2 study. Another Suspected Unexpected Serious Adverse Reaction (SUSAR) of myelodysplastic syndrome (MDS) was also reported.

Halted studies included the phase 1/2 HGB-206 and phase 3 HGB210 trials for LentiGlobin for sickle cell disease (SCD) as well as the phase 3 Northstar-2 (HGB-207) and Northstar-3 (HGB-212) studies of betibeglogene autotemcel (Zynteglo) for patients with transfusion-dependent β-thalassemia (TDT). The FDA lifted the holds in June 2021 following the demonstration that B305 was not associated with cancer in patients enrolled in clinical trials for SCD.2

1. bluebird bio receives EC approval for SKYSONA™ (elivaldogene autotemcel, Lenti-D™) gene therapy for patients less than 18 years of age with early cerebral adrenoleukodystrophy (CALD) without matched sibling donor. News release. bluebird bio. July 21, 2021.
2. bluebird bio announces the lifting of FDA clinical hold for sickle cell disease and β-Thalassemia studies. News release. bluebird bio. June 7, 2021.
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