ABCD1

Data show SBT101 effectively delivered a functional copy of the ABCD1 gene to spinal cord tissues with resultant protein expression, addressing the underlying cause of disease and improving function in preclinical models Highlighted in peer-reviewed journal Molecular Therapy Methods & Clinical Development, these data supported the advancement of SBT101 into a Phase 1/2 clinical trial Expect to report updated safety data from the ongoing trial in first half of 2025 LONDON, Oct. 31, 2024 (GLOBE NEWSWIRE) -- Spur Therapeutics today announced the publication of preclinical proof-of-concept data for SBT101, its potential first-in-class gene therapy program for the treatment of adrenomyeloneuropathy (AMN), in Molecular Therapy Methods & Clinical Development. AMN is a rare and devastating neurodegenerative disease caused by a mutation in the ABCD1 gene and characterized by progressive muscle weakness and sensory loss, leading to impaired mobility, increased risk of falls, incontinence and debilitating pain. “People living with AMN currently have no treatment options to slow or alter the progression of this devastating disease, and gene therapy presents the opportunity to address the disease at its root cause,” said Pamela Foulds, M.D., Chief Medical Officer at Spur. “These data demonstrate SBT101’s potential to halt disease progression by delivering a functioning ABCD1 gene to generate the adrenoleukodystrophy protein (ALDP) lacking in AMN. We are currently advancing SBT101 in a Phase 1/2 trial with the aim of developing a life-changing gene therapy for people with AMN.” The studies highlighted in the publication, titled “An in vitro and in vivo efficacy evaluation of a novel gene therapy candidate (SBT101) in mouse models of adrenomyeloneuropathy and in NHPs,” supported SBT101’s advancement into the PROPEL study1. Key findings from the studies include: Favorable safety and tolerability, with no treatment-related mortality or clinical signs observed in non-human primates (NHPs).Successful delivery of the ABCD1 gene to target tissues in the spinal cord in mouse models of the disease and NHPs.Increased ALDP protein production in the target tissues, resulting in reductions in the harmful buildup of substrates caused by the deficiency of the ABCD1 gene in AMN.Significant improvement or prevention of loss in grip strength, an established metric for assessing muscle strength, were seen in double knockout mouse models. “These studies validate SBT101’s potential to be a first-in-class gene therapy for AMN, which could change the lives of thousands of people with this progressive and debilitating disease,” said Florian Eichler, M.D., Director of Leukodystrophy Service at Massachusetts General Hospital, a co-author of the publication. “These data demonstrate the ability of SBT101 to target the underlying disease mechanism of AMN and provide positive indications of preclinical efficacy.” Spur expects to complete dosing in the Phase 1/2 PROPEL study of SBT101 early next year and report initial safety data from the high-dose cohort in the first half of 2025. More information about the trial can be found at ClinicalTrials.gov. About Spur Therapeutics Spur Therapeutics is a clinical-stage biotechnology company focused on developing life-changing gene therapies for debilitating chronic conditions. By optimizing every component of its product candidates, Spur aims to unlock the true potential of gene therapy to realize outsized clinical results. Spur is advancing a breakthrough gene therapy candidate for Gaucher disease and a potential first-in-class gene therapy candidate for adrenomyeloneuropathy, as well as a research strategy to move gene therapy into more prevalent diseases, including forms of Parkinson’s, dementia, and cardiovascular disease. Expanding our impact, and advancing the practice of genetic medicine. Toward life-changing therapies, and brighter futures. Toward More™ For more information, visit www.spurtherapeutics.com or connect with Spur on LinkedIn and X. Investor Contact Naomi Aokinaomi.aoki@spurtherapeutics.com+ 1 617 283 4298 Media ContactCarolyn Noyescarolyn.noyes@spurtherapeutics.com+1 617 780 2182 1 Spur Therapeutics acquired SwanBio Therapeutics in 2024, adding SBT101 to its pipeline.

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.

iStock, Love Employee The pediatric patients, with a rare neurodegenerative disease, were treated with bluebird bio’s Skysona to slow the progression of neurologic dysfunction. Six patients developed myelodysplastic syndrome and one patient developed acute myeloid leukemia. Seven children treated with bluebird bio ’s gene therapy Skysona for cerebral adrenoleukodystrophy, a rare and progressive neurodegenerative disease, developed blood cancers, according to a study published Wednesday in The New England Journal of Medicine . Six of the seven cases of hematological malignancies were diagnosed as myelodysplastic syndrome (MDS), arising between 14 and 92 months after Skysona treatment. The other patient was diagnosed with acute myeloid leukemia (AML) at 57 months. Six patients were subsequently treated with stem cell transplantation, which led to one death due to graft-versus-host disease. The single AML patient remains alive and has shown good response to the transplant. According to the researchers, the emergent blood cancers are linked with clonal vector insertions in cancer-related genes, and with the accumulation of somatic mutations in certain sites of interest, including in the KRAS, WT1 and CDKN2A genes. Skysona is a gene therapy that works by delivering functional copies of the ABCD1 gene into patients’ hematopoietic stem cells, which promotes the production of mature monocytes that can express functional ALDP proteins. ALDP plays an important role in the breakdown of very long chain fatty acids. In September 2022, the FDA granted Skysona accelerated approval to the slow the progression neurologic dysfunction in boys four to 17 years of age with cerebral adrenoleukodystrophy (CALD), a rare and neurodegenerative disorder caused by a dysfunctional ABCD1 gene and which leads to severe functional decline. In the Phase II/III Starbeam trial, which formed the basis of its regulatory win, Skysona demonstrated strong major functional disability-free survival over 24 months. In terms of safety, Starbeam detected cases of nausea, vomiting and febrile neutropenia, among other mild toxicities. Adverse events of grade 3 or 4 included lymphopenia, thrombocytopenia and hypokalemia. Skysona’s label carries a boxed warning for hematologic malignancies, including “life-threatening cases” of MDS. These complications appear to be the result of the Skysona lentiviral vector that becomes integrated in proto-oncogenes—similar to what had been documented in the NEJM study. The concerns about secondary blood cancers are not new. In August 2021, about a year before Skysona’s approval, the FDA hit its development program with a clinical hold after one patient developed MDS following treatment. In an advisory committee meeting in June 2022, however, a panel of external experts unanimously backed bluebird, agreeing that Skysona’s benefits outweigh its risks. Wednesday’s study results come less than a month after news broke that patients had finally started receiving infusions of another bluebird gene therapy, Lyfgenia, for sickle cell disease. It is not yet clear whether the new safety signals will have far-reaching implications for bluebird’s portfolio.