VANCOUVER -- An investigational gene therapy offered clinical benefit in patients with childhood cerebral adrenoleukodystrophy (CCALD) and was well tolerated, according to researchers here.
In an ongoing phase II/III study done in 17 patients, 94% of the male patients had stabilization of their neurological function scores and stabilization on imaging at 6 months, while three patients have completed 2 years of follow-up after treatment with Lenti-D, reported , of Massachusetts General Hospital (MGH) in Boston, and colleagues.
Action Points
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- An investigational gene therapy offered clinical benefit in patients with childhood cerebral adrenoleukodystrophy (CCALD) and was well tolerated.
- Note that CCALD is a neurodegenerative disease caused by deficiency of the ALD protein (ALDP) encoded by ABCD1, and involves a progressive destruction of myelin.
There were no deaths, no failures of the autologous blood cell grafts transfected with the missing ABCD1 gene that characterize the disease, and no reported graft-versus-host disease, he said in a presentation at the American Academy of Neurology annual meeting.
CCALD -- depicted in the 1992 film -- is a neurodegenerative disease caused by deficiency of the ALD protein (ALDP) encoded by ABCD1. The disease involves a progressive destruction of myelin, the protective sheath of the nerve cells in the brain that are responsible for thinking and muscle control. It primarily affects young boys.
Eichler said that the disease affects about one in 21,000 boys, but added that he suspected that, as testing for the disorder increases, the incidence might fall to one in 12,000. About 30% to 40% of these children have cerebral forms of the disease.
Clinical progression can be halted with allogeneic hematopoietic stem cell transplantation (HSC), and outcomes are best in those few patients with an HLA-matched sibling donor.
Lenti-D is an investigational gene therapy, consisting of autologous HSCs transduced with a lentiviral vector encoding ABCD1 cDNA, designed to restore functional ALDP production, the authors explained.
"We think this is an important milestone in treating cerebral adrenoleukodystrophy," Eichler said of the results to 乌鸦传媒.
"Lenti-D gene therapy may offer an alternative to allogeneic bone marrow transplant, particularly for patients with no matched-sibling donor," he explained. "This is a devastating disorder of childhood, affecting boys who are developing normally and develop this inflammatory demyelization. Currently the only treatment out there is allogeneic bone marrow transplant that can halt the progression of early-stage disease. However, this causes a lot of morbidity and mortality. We have come up with an alternative approach. Instead of using allogeneic bone marrow, we use autologous bone marrow cells that have been transfected with the lentivirus."
In the Starbeam Study, enrolled patients (age range 4-13 years) had CCALD with gadolinium enhancement on MRI, Loes score 0.5-9.0, Neurological Function Score (NFS) ≤1, and no matched-sibling donor. Treatment consisted of HSC harvest by apheresis, myeloablative conditioning with busulfan and cyclophosphamide, and one intravenous dose of Lenti-D.
The primary efficacy endpoint was the proportion of patients with no major functional disabilities at 24 months, with follow-up planned for at least 15 years. Eichler reported interim results.
Specifically, all patients remained free of major functional disabilities post-treatment with Lenti-D.
In addition, NFS stabilized in 16 of 17 patients, and was defined as changes of less than three points and an absolute score of ≤4 on the NFS scale. Also, 14 of 17 patients had a stable Loes Score, defined as a change of 5 points or less or an absolute Loes Score of ≤9.
Sixteen of 17 had resolution of gadolinium enhancement by month 6. Re-emergence of diffuse contrast enhancement was seen in five patients at month 12. Of those five patients, the two with at least 18 months of follow-up showed resolution of gadolinium enhancement at month 18.
All patients demonstrated successful engraftment of neutrophils and platelets, as well as polyclonal reconstitution without clonal dominance. ALDP expression in leukocytes was observed in all patients at latest follow-up.
Eichler said there was one possible drug-related serious adverse event -- grade 3 viral cystitis -- and one possible drug-related adverse event (grade 1 tachycardia). However, both resolved with standard measures.
He noted that the safety profile of Lenti-D treatment appeared consistent with myeloablative chemotherapy.
"This is truly groundbreaking work," said, also of MGH and vice-chair of the scientific committee of the AAN. "This is a fatal disorder that affects boys predominantly. Boys begin to show signs of disease at age 6; by age 9 they are incapacitated and by age 16 they have died."
Even though bone marrow transplant has been attempted in these children, the mortality risk with that procedure is about 10%, so "there really is no option but to try something [else]." Rost, who was not involved in the study, told 乌鸦传媒. "This ex-vivo gene therapy is trying something that could bring about a cure."
She called the results from this preliminary study "hopeful," for clinicians, patients, and their families.
Disclosures
The study is sponsored by bluebird bio, Cambridge, Mass.
Rost has disclosed relevant relationships with Genzyme Corporation.
Eichler disclosed relevant relationships with Third Rock Ventures, Alexion, Retrophin, bluebird bio, and Vertex Pharmaceuticals.
Primary Source
American Academy of Neurology
Source Reference: Eichler L et al, "Interim results from a phase 2/3 study of the efficacy and safety of ex vivo gene therapy with lentiviral vector (Lenti-D) for childhood cerebral adrenoleukodystrophy" AAN 2016; Abstract PL2.002.