May 23, 2024

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First gene therapy for cerebral adrenal leukodystrophy (CALD)!

Gene therapy for rare diseases! Bluebird Bio Skysona is about to be approved: the first gene therapy for the treatment of cerebral adrenal leukodystrophy (CALD)!


First gene therapy for cerebral adrenal leukodystrophy (CALD)!  Bluebird bio recently announced that the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has issued a positive review opinion recommending approval of Skysona (elivaldogene autotemcel, Lenti-D), which is a one-time gene therapy, In the treatment of patients under 18 years of age, with ABCD1 gene mutation, without HLA matching sibling hematopoietic stem cell (HSC) donor available, and early cerebral adrenoleukodystrophy (CALD).

In July 2018, EMA granted Skysona’s Priority Drug Designation (PRIME) for the treatment of CALD, and previously granted Orphan Drug Designation (ODD).

Now, CHMP’s opinions will be submitted to the European Commission (EC) for review, which usually makes a final review decision within the next 2 months. If approved, Skysona will become the first and only one-time gene therapy for CALD. CALD is a rare neurodegenerative disease that occurs in childhood, which can lead to progressive and irreversible neurological loss and death.

Richard Colvin, Chief Medical Officer of Bluebird Bio, said: “The goal of Skysona’s treatment is to stabilize disease progression in children with CALD without a matched sibling HSC donor to prevent further neurological decline and improve the survival rate of these young patients. This positive opinion of CHMP marks the first regulatory approval recommendation for any CALD gene therapy, bringing us closer to introducing a one-time, long-lasting treatment to the market that can stabilize neurological diseases while reducing allogeneic stem cells The risk of severe immune complications associated with transplantation (allo-HSCT) is the only treatment option for children with this devastating disease. Together with the ALD community and clinical researchers, we are all optimistic that there is a new hope It may be offered to CALD patients soon.”

First gene therapy for cerebral adrenal leukodystrophy (CALD)!

CALD (click on the picture to see a larger picture, the picture comes from the literature: DOI:10.3892/etm.2019.7804)


Adrenal leukodystrophy (ALD) is a rare X-linked metabolic disorder that mainly affects men; worldwide, it is estimated that one in every 21,000 male newborns is diagnosed with ALD. This disease is caused by mutations in the ABCD1 gene, which affects the production of adrenal leukodystrophin (ALDP) and subsequently leads to the toxic accumulation of very long chain fatty acids (VLCFA), mainly in the adrenal glands and white matter of the brain and spinal cord. About 40% of boys with ALD will develop CALD, which is the most severe form of ALD.

CALD is a progressive and irreversible neurodegenerative disease that involves the destruction of myelin sheath, which is the protective sheath of nerve cells in the brain responsible for thinking and muscle control. Symptoms of CALD usually occur in childhood (median age 7 years). Patients’ cognitive function and physical function decline rapidly and gradually. Without treatment, nearly half of patients will die within 5 years from the onset of symptoms.

Skysona is a one-time gene therapy that uses Lenti-D lentiviral vector (LVV) for in vitro transduction and adds a functional copy of the ABCD1 gene to the patient’s own hematopoietic stem cells (HSC). The addition of the functional ABCD1 gene can produce ALD protein in the patient’s body, which is believed to help the decomposition of VLCFA. The purpose of Skysona treatment is to stabilize the progression of CALD, thereby preserving neurological function as much as possible, including preserving motor function and communication skills. Importantly, with Skysona, there is no need to obtain a donor HSC from another person.

First gene therapy for cerebral adrenal leukodystrophy (CALD)!

Skysona treatment process (click on the picture to see a larger picture)


The positive review opinion of CHMP is based on the efficacy and safety data of Phase 2/3 Starbeam Study (ALD-02). All patients who have completed the ALD-102 study, as well as patients who will complete another phase 3 study (ALD-104), will be required to participate in the long-term follow-up study (LTF-304).

The primary efficacy endpoint of the pivotal ALD-102 study is survival for 2 years after treatment, no occurrence of any of the 6 major dysfunctions (MFD), and no second allogeneic hematopoietic stem cell transplantation (allo-HSCT) Or the proportion of patients who were given rescue cells and did not withdraw or lose follow-up within 2 years. Six MFDs are serious disabilities commonly found in CALD and are considered to have the most profound impact on the patient’s ability to live independently: loss of communication, cortical blindness, need for gastric feeding, general incontinence, wheelchair dependence, and complete loss of autonomous mobility.

So far, 32 patients have received Skysona treatment in the ALD-102 study. As of the last data cut-off date, 90% (27/30) of the patients reached the 24-month MFD-free survival endpoint. In addition, as mentioned earlier, 2 patients withdrew from the study based on the investigator’s judgment, and one patient experienced rapid disease progression early in the study, leading to multiple sclerosis and subsequent death.

In the ALD-102 study, the neurological function score (NFS) of 26/28 evaluable patients was maintained at ≤1 point until 24 months, and the NFS of 24 patients remained unchanged, indicating that the neurological function of most patients was maintained. All patients who completed the ALD-102 study participated in the long-term follow-up of the LTF-304 study. The median follow-up time was 38.59 months (minimum 13.4 months; maximum 82.7 months).

In this study, the safety/tolerability of treatment options (including mobilization/apheresis, conditioning and Skysona infusion) mainly reflected the known effects of mobilization/apheresis and conditioning. The adverse reactions of Skysona observed in clinical trials include viral cystitis, pancytopenia and vomiting.

In clinical studies (ALD-102/LTF-304 and ALD-104) in 51 patients who received Skysona treatment, no graft-versus-host disease (GVHD), graft failure or rejection, and transplant-related death (TRM) were reported , Replication active lentivirus. In addition, there have been no reports of lentiviral vector-mediated insertional mutations leading to tumorigenesis, including myelodysplasia, leukemia or lymphoma associated with Skysona. Nevertheless, there is still a theoretical risk of malignant tumors after Skysona treatment. Clonal expansion, which leads to clonal dominance without clinical evidence of malignancy, has been found in some patients treated with Skysona.



(source:internet, reference only)

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