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Lysosomal Disorders

Oncology

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Authors

Bakri Elsheikh, MBBS, FRCP, a professor of neurology at The Ohio State University Wexner Medical Center

The clinical neurophysiologist at Children’s National and the professor of neurology at The Ohio State University Wexner Medical Center discussed treatment considerations for patients already living with SMA.

Diana Bharucha-Goebel, MD, and Bakri Elsheikh, MBBS, FRCP, on Setting Realistic Goals for Long-Standing SMA

The clinical neurophysiologist at Children’s National and the professor of neurology at The Ohio State University Wexner Medical Center discussed treatment decisions in newly diagnosed SMA.

Diana Bharucha-Goebel, MD, and Bakri Elsheikh, MBBS, FRCP, on Considerations for Starting SMA Treatment

The clinical neurophysiologist at Children’s National and the professor of neurology at The Ohio State University Wexner Medical Center discussed the evolving SMA treatment landscape.

Diana Bharucha-Goebel, MD, and Bakri Elsheikh, MBBS, FRCP, on How New Therapies Are Changing SMA Care Guidelines

Patient use of the 2 FDA-approved gene therapy products for sickle cell disease (SCD), Vertex Pharmaceuticals' and CRISPR Therapeutics’ 

 (exa-cel; marketed as Casgevy) and bluebird bio’s 

 (lovo-cel; marketed as Lyfgenia), in the commercial setting has remained low.

Despite the approval of both gene therapy products by the FDA occurring simultaneously on December 8, 2023, only 4 patients have begun treatment with lovo-cel in the commercial setting, while 20 patients are reported to have begun treatment with exa-cel. Alongside the number for lovo-cel, bluebird also pointed out that this year 4 patients have started on elivaldogene autotemcel (Lenti-D, Skysona), its marketed gene therapy for cerebral adrenoleukodystrophy, and 19 patients have started on betibeglogene autotemcel (beti-cel, Zynteglo), its marketed gene therapy for transfusion dependent thalassemia (TDT). As such, bluebird bio has reported 23 total cell collections for SCD/TDT gene therapies lovo-cel and beti-cel. The company expects that patient uptake of the 3 aforementioned therapies will continue to increase, with 85 patient starts expected across the therapies by the end of the year.

“We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year,” Andrew Obenshain, MBA, the chief executive officer of bluebird bio, said in a statement.

 “We are further encouraged by the commitment to provide patient access across both commercial and government payers, most recently conveyed through multiple positive Medicaid decisions and the growing number of published coverage policies for Lyfgenia, and we expect approximately 85 patient starts across our portfolio this year.”

Notably, unlike lovo-cel, exa-cel is indicated for both SCD and TDT. Since Vertex has not clarified the breakdown of patients treated with exa-cel for each disease, direct comparison is difficult. The approval in TDT came slightly later, with 

“Vertex delivered another strong quarter of revenue growth coupled with outstanding execution across the business, and we are increasing our full year product revenue guidance,” Reshma Kewalramani, MD, the chief executive officer and president of Vertex, said in an August 1, 2024, statement.

 “Our focus for the second half of the year remains on commercial execution in cystic fibrosis and the global launch of Casgevy, readying for the upcoming potential launches of the vanzacaftor triple in cystic fibrosis and suzetrigine in acute pain, while rapidly advancing a robust pipeline that is poised to deliver value for patients and shareholders for the long term.”

Beyond gene therapy for SCD and TDT, uptake of 

hemophilia gene therapies has also been slow

. Although BioMarin’s valoctocogene roxaparvovec (val-rox, marketed as Roctavian) was approved in June 2023, the first patient outside of clinical trials 

 until December 2023, at the Center for Inherited Bleeding Disorders (CIBD) in California.

 Just this month, BioMarin announced that 

 with regard to val-rox, with the company now mainly focusing on distributing the gene therapy in the United States, Germany, and Italy, the 3 countries in which it has been approved for use by relevant regulatory authorities and is reimbursed.

 UniQure and CSL Behring’s hemophilia B gene therapy, etranacogene dezaparvovec (marketed as Hemgenix), which was 

, has also been slow to be embraced by patients.

“We haven't seen a lot of patients dosed yet,” Steven W. Pipe, MD, a professor of pediatric hematology/oncology at CS Mott Children’s Hospital, told 

 regarding Hemegenix earlier in 2024. “And I don't think that’s related to either the enthusiasm of the clinicians or the patients, but really just the mechanics of how to deliver this in the clinical space, as opposed to the research trials... We've seen that a lot of the hemophilia treatment center sites have got their components together, their infrastructure and personnel so that they can actually start delivering this in the commercial setting. And so, I'm really looking forward to seeing this making a difference in patients' lives in a real world setting.”

REFERENCES
1. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed August 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
2. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5885598
3. Vertex announces US FDA approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. Vertex Pharmaceuticals Incorporated. January 16, 2024. Accessed August 15, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
4. Vertex reports second quarter 2024 financial results. News release. Vertex Pharmaceuticals Incorporated. August 1, 2024. Accessed August 15, 2024. https://investors.vrtx.com/news-releases/news-release-details/vertex-reports-second-quarter-2024-financial-results
5. Center for Inherited Blood Disorders Administers Country's First Gene Therapy Infusion to Treat Hemophilia A. News release. Center for Inherited Blood Disorders. January 11, 2024. Accessed August 15, 2024. https://firstwordpharma.com/story/5817834?from=article
6. BioMarin Announces Updated Strategy for ROCTAVIAN® to Focus on U.S., Germany and Ital. News release. BioMarin Pharmaceutical Inc. August 5, 2024. Accessed August 15, 2024. https://investors.biomarin.com/news/news-details/2024/BioMarin-Announces-Updated-Strategy-for-ROCTAVIAN-to-Focus-on-U.S.-Germany-and-Italy/default.aspx
7. FDA approves first gene therapy to treat adults with hemophilia B. News release. FDA. November 22, 2022. Accessed August 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treat-adults-hemophilia-b

bluebird bio has reported 23 total cell collections for SCD and TDT gene therapies lovo-cel and beti-cel and Vertex Pharmaceuticals has reported approximately 20 cell collections for SCD/TDT gene therapy exa-cel.

Topic

Uptake of Nononcology Gene Therapy Remains Slow in Hematology

(arsa-cel, OTL-200; Orchard Therapeutics) is a gene-edited cell therapy designed to restore arylsulfatase A (ARSA) enzyme activity in children with presymptomatic (PS) late infantile (LI), PS early juvenile (EJ), or early symptomatic (ES) early juvenile (EJ) metachromatic leukodystrophy (MLD).

 arsa-cel under the name Lenmeldy to become the first gene therapy for children with MLD to be approved in the United States, following its approval in the European Union, UK, Iceland, Switzerland, Liechtenstein and Norway under the name Libmeldy.1 Orchard Therapeutics previously announced that the FDA had accepted the biologics license application with 

The FDA’s decision was based on data from patients treated with arsa-cel across 2 clinical trials (NCT01560182; NCT03392987) and additional patients treated in expanded access frameworks. These patients had follow-up times ranging from 0.64 years to 12.19 years (median, 6.76).

“Metachromatic leukodystrophy, is a really important unmet need in the pediatric community. So, this is a disease that's rare, it affects about one in 40,000 children. And up until recently, we have had no curative treatment option for this,” Madeleine Powys, MBBS, Staff Specialist, Blood Transplant and Cell Therapies, The Children's Hospital at Westmead, told 

. "Autologous hematopoietic stem cell gene therapy has offered really promising new hope for these patients.”

Madeleine Powys, MBBS, on Lessons Learned With Libmeldy

Arsa-cel is currently being evaluated in 6 participants enrolled in a phase 3 clinical trial (NCT04283227). The trial enrolled participants with documented biochemical and molecular diagnosis of MLD, including low ARSA activity and identification of 2 disease-causing ARSA alleles, with novel mutations analyzed and excluded as common polymorphisms, alongside specific genotype criteria. Symptomatic individuals must have onset between 7 and 17 years of age, or pre-symptomatic participants must be less than 17 years at treatment initiation and have a sibling with late-juvenile MLD variant, along with normal cognitive and motor function, with seizures or disease signs revealed by instrumental evaluations not being exclusionary if present alone, and compliance with contraceptive use requirements if applicable, with signed informed consent or assent provided by the participant or guardian.

The exclusion criteria for the study include documented HIV infection, malignant neoplasia except localized skin cancer or hereditary cancer syndrome unless successfully treated with no recurrence, myelodysplasia, acute myeloid leukemia, or serious hematological disorders, current enrollment in other interventional trials, prior allogeneic HSPC gene therapy or gene therapy, symptomatic herpes zoster unresponsive to treatment, active tuberculosis unless on antibiotic prophylaxis, acute or chronic stable Hepatitis B or positive Hepatitis C RNA test result unless specific conditions are met, end-organ dysfunction, severe infection not responsive to treatment, or other severe diseases deemed inappropriate for the study by the investigator. Additionally, testing for other transmissible infectious agents may be considered, and participants with elevated liver enzymes or bilirubin may be included after discussion and agreement with the medical monitor.

The study’s primary measures involve assessing the OTpbmsL-200 Arylsulfatase A (ARSA) activity levels in cerebrospinal fluid (CSF) and the neuronal metabolite ratio of N-acetyl-aspartate (NAA) to creatine (Cr) in white matter brain regions, both evaluated at 24 months post-treatment, with changes from baseline being monitored.

Secondary measures involve evaluating changes in ARSA activity levels in CSF and neuronal metabolite ratio in white matter brain regions, assessing ARSA levels in peripheral blood mononuclear cells (PBMCs) and specific subtypes, comparing neuronal metabolite ratios to baseline, siblings, or untreated controls, determining engraftment through lentiviral positivity in bone marrow progenitors and vector copy number in BM cells and PBMCs, assessing severity scale for brain MRI, neurocognitive function, full neurological clinical examination, gross motor function classification, nerve conduction velocity, Vineland Adaptive Behavior Scale, and monitoring conditioning regimen and non-conditioning-related adverse events up to 8 years post gene therapy, along with hematological reconstitution, infusion-related reactions, immune response, abnormal clonal proliferation, replication-competent lentivirus, and integration site analysis findings over time.

, held February 4-9, in San Diego, California, by Vera Gallo, MD, staff pediatrician, San Raffaele Telethon Institute for Gene Therapy. The data were from 5 patients with LJ MLD that had follow-up ranging from 3.2 to 21.3 months (median, 17.3). At the time of treatment, 3 patients had PS MLD and 2 had ES MLD. The group included a 2.7-year-old girl (PS), a 9.9-year-old boy (ES), a 15.2-year-old boy (PS), a 6.6-year-old girl (PS), and 10.9-year-old boy (ES) as of the December 2023 cutoff date.

"This represents of course, the proof of principle that gene therapy with ex- vivo lentiviral gene therapy into stem cells can correct a lysosomal storage disorder (LSD)... and could be applicable to other LSDS. So we're working on new diseases to bring this approach of enzyme correction also to other LSDs," investigator Alessandro Aiuti, MD, PhD, deputy director, clinical research, and head, Clinical Research Unit, San Raffaele Telethon Institute for gene therapy, and Group leader, Pathogenesis and therapy, primary immunodeficiencies unit, and full professor, Università Vita Salute San Raffaele, and chief of clinic, Pediatric Immunohematology Unit, San Raffaele, told 

Data from these participants showed that they all had normal hematological reconstitution and engraftment that was consistent with arsa-cel outcomes seen in patients with early-onset MLD who have been treated in other settings. Time to neutrophil engraftment ranged from 26 to 42 days (median, 33) posttreatment and time to platelet engraftment ranged from 25 to 46 days (median, 26) posttreatment. ARSA activity reached supranormal levels in the PBMCs and in CD15+ cells and increased to normal levels in the CSF in 3 patients for whom central nervous system pharmacodynamic efficacy measures were available.At 90 days after administration of arsa-cel transduced bone marrow progenitors made up between 23.81% to 81.25% of bone marrow progenitors. At this time point, the PBMCs showed a median vector copy number (VCN) of 0.49 copies/cell and the CD15+ cells showed a median VCN of 0.82 copies/cell.

In terms of safety, there were no serious adverse events (SAEs) deemed potentially related to arsa-cel. One nonserious AE deemed potentially related to the therapy, a case of erythematous rash, occurred in 1 patient. No SAEs deemed potentially related to the Busulfan conditioning regimen occurred; although cases of febrile neutropenia, cytopenia, and stomatitis were deemed to have potential relation to the regimen. An SAE of upper respiratory tract infection occurred in 1 patient. One patient with prolonged thrombocytopenia who had previously experienced treatment-failure with allogeneic transplant in the form of autologous reconstitution was administered thrombopoietin receptor agonist therapy for 5 months. No multilineage engraftment of transduced cells or malignancy occurred and there was no indication of clonal expansion or replication competent lentivirus.

1. FDA Approves First Gene Therapy for Children with Metachromatic Leukodystrophy. News release. Orchard Therapeutics. March 18, 2024. Accessed March 18, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-children-metachromatic-leukodystroph
2. Orchard Therapeutics announces acceptance of biologics license application for OTL-200 in MLD and receives priority review. News release. Orchard Therapeutics. September 18, 2023. Accessed September 18, 2023. https://ir.orchard-tx.com/news-releases/news-release-details/orchard-therapeutics-announces-acceptance-biologics-license
3. Fumagalli F, Calbi V, De Mattia F, et al. Long-term clinical outcomes of atidarsageneautotemcel (autologous hematopoietic stem cell gene therapy) preserves cognitive and motor development in early-onset metachromatic leukodystrophy with up to 12 years follow-up. Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #92
4. Gallo V, Calbi V, De Mattia F, et al. Lentiviral hematopoietic stem cell gene therapy (atidarsageneautotemcel) for late juvenile metachromatic leukodystrophy (MLD). Presented at: WORLDSymposium, held February 4-9, in San Diego, California. Poster #96

The gene-edited cell therapy has been approved as Lenmeldy by the FDA. 

Phase 3 Trial Seeks to Continue Supporting Arsa-Cel Gene Therapy for MLD 

, held February 3 to 7, 2025, in San Diego, California, data from clinical trials evaluating gene therapy products for the treatment of Fabry disease were among those presented. This included data from the ongoing phase 1/2 STAAR clinical trial (NCT04046224) evaluating isaralgagene civaparvove (ST-920), Sangamo Therapeutics’ investigational adeno-associated virus (AAV) vector-based gene therapy for Fabry disease, and data from a completed phase 1 clinical trials referred to as FACTS (NCT02800070). 

Following up on Fabry Disease Awareness Month, observed annually in the month of April, 

 got in touch with Aneal Khan MD, MSc, FCCMG, FRCPC, the president of MAGIC Clinic and CEO of Discovery DNA, to discuss gene therapy research in Fabry disease. Khan spoke about the data presented at WORLD

and about innovation in the field more generally. 

Can you give some background context about Fabry disease?

 Fabry disease is an X-linked genetic disease that affects both males and females. The main features include heart and kidney disease, stroke, and pain. These features can start in childhood, especially in males who can have early onset severe pain episodes, with silent progression of the organ disease and reduced life expectancy if untreated. There is no cure for Fabry disease. Current standard treatments include enzyme replacement therapy or oral chaperone therapy which needs to be taken at regular intervals for life.

Can you discuss the Fabry disease data presented at World

Data on gene therapies were presented. This includes outcomes of the Sangamo gene therapy trial and the FACTS gene therapy trial. These therapies are quite different in the sense that Sangamo is a trial using an AAV-like vector directly injected into the body (in vivo gene therapy). The FACTS trial takes stem cells from the body and administers a lentiviral vector outside the body into the stem cells and then injects the stem cells back into the patient (ex vivo gene therapy). Both types of gene therapy are in clinical trials.

How would you summarize the big-picture implications that doctors and the broader healthcare community should take away from this data?

The gene therapies offer the possibility of a once-in-life treatment by inserting a working copy of the 

 gene into the patient. These patients have been shown to make enough enzyme from the gene therapy to not be classified as enzyme-deficient. Studies are ongoing to see how well these therapies reduce the disease symptoms and organ involvement in patients with Fabry disease.

Have there been any challenges so far and/or have there been any areas of interest identified for further study?

Some patients have had mild inflammatory changes, such as liver inflammation, which has been temporary and [to my knowledge] no serious adverse events have been reported.

Do you have a main message you would like to share with the healthcare community for Fabry Disease Awareness Month in 2025?

When I started my career, there was no treatment for Fabry disease. Enzyme replacement therapy, which has been in place now for about 20 years, has really improved the outcomes for patients with Fabry disease. Oral therapies have made it easier to take the treatment rather than having an enzyme infusion. So, there is hope that one day a “one and done” therapy, like gene therapy, may offer patients with Fabry disease and easier way to live with Fabry disease and improve outcomes.

Is there anything not covered by the previous questions that you want to share?

Collecting data from studies takes time and a lot of dedication from the patients. The patients are essential in driving the technology forward and all of the patients I have had in clinical trials are involved to really help develop newer treatments that could be used in patients with those diseases in the future. While much has been reported about some gene therapy trials where there were negative outcomes, thousands of people with different diseases have now been treated in gene therapy trials safely and patients in this trial from Sangamo generally are healthy and continuing to do well.

This transcript has been edited for clarity.

The president of MAGIC Clinic and CEO of Discovery DNA discussed the implications of gene therapy data presented at the 2025 WORLDSymposium.

Aneal Khan, MD, MSc, FCCMG, FRCPC, on Evaluating Gene Therapy for Fabry Disease

The physician-scientists at CHOP discussed an n-of-1 clinical trial for a CRISPR gene-editing strategy.

Rebecca Ahrens-Nicklas, MD, PhD, and Kiran Musunuru, MD, PhD, MPH, ML, MRA, on Treating CPS1 Deficiency With Personalized Gene Editing

“Something worth emphasizing again is that this was a truly personalized therapy... This drug was made for one patient, this one kid with this very, very, bad urea cycle disorder, and it's tuned to his mutation to correct his mutation. As such, this drug is only for him. It won't actually work for anyone else because nobody else shares that particular mutation. It’s truly n-of-1...”

On May 15, 2025, Children’s Hospital of Philadelphia (CHOP), announced that it had successfully treated a child, named KJ, in an n-of-1 clinical trial for a personalized CRISPR-based gene editing therapy intended to treat KJ’s severe carbamoyl phosphate synthetase 1 (CPS1) deficiency.

 He received the therapy in February 2025 at between 6 and 7 months of age. The child’s case was detailed in newly published paper in 

 entitled “Patient-specific in vivo gene editing to treat a rare genetic disease” and a presentation at 

the American Society of Gene & Cell Therapy (ASGCT) 28th Annual Meeting

, held May 13 to 17, 2024, in New Orleans, LA.

 sat down with 2 of the paper’s authors, Kiran Musunuru, MD, PhD, a physician-scientist and Barry J. Gertz Professor for translational research in the Perelman School of Medicine at the University of Pennsylvania and CHOP and Rebecca Ahrens-Nicklas, MD, PhD, a physician-scientist and director of the Gene Therapy for Inherited Metabolic Disorders Frontier Program at CHOP, to discuss the news. Ahrens-Nicklas gave some background context about CPS1 deficiency, which is an ultra-rare, life-threatening urea cycle disorder. She explained the devastating nature of the disease, which causes toxic ammonia buildup in newborns, sometimes leading to death within days. The patient in this study had the most severe form, prompting efforts to create a targeted therapy.

Musunuru, drawing on his work in gene editing for cardiovascular disease, noted that the approach used for KJ adapted existing technology to correct the child’s specific genetic mutation. Using a one-time intravenous infusion, the therapy delivered a gene editor to liver cells, aiming to repair the faulty gene. Though still early, Ahrens-Nicklas and Musunuru noted that the child has tolerated the treatment well and shown initial signs of improvement, such as better protein tolerance. They emphasized that this is a single-patient case, so broader conclusions are premature, but the early success in safety and early efficacy indicators offer hope for expanding personalized gene therapies in the future.

Click here to view more coverage of the 2025 ASGCT Annual Meeting.

REFERENCES
1. World's first patient treated with personalized CRISPR gene editing therapy at Children’s Hospital of Philadelphia. News release. Children’s Hospital of Philadelphia. May 15, 2025. Accessed May 15, 2025.https://www.chop.edu/news/worlds-first-patient-treated-personalized-crispr-gene-editing-therapy-childrens-hospital
2. Musunuru K, Grandinette SA, Wang X, et al. Patient-specific in vivo gene editing to treat a rare genetic disease. The New England Journal of Medicine. May 15, 2025. Doi: 10.1056/NEJMoa2504747, LA.

Videos

Rebecca Ahrens-Nicklas, MD, PhD; and Kiran Musunuru, MD, PhD, MPH, ML, MRA, on Treating CPS1 Deficiency With Personalized Gene Editing

Spur Therapeutics’ SBT101, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat X-linked adrenoleukodystrophy (ALD), was deemed “generally well-tolerated" in new safety data from the ongoingphase 1/2 PROPEL clinical trial (NCT05394064).

The study results reported included 8 men with ages ranging from 19 to 36 years, 4 of whom had received a lower dose of SBT101 (1.0x10

 vg, cohort 1) and 4 of whom had received a higher dose of SBT101 (3.0x10

 vg, cohort 2). As of the April 21, 2025, data cut off, the most frequently reported treatment-emergent adverse events (TEAEs), defined as those with 3 or more events having occurred across all patients, were headache, muscular weakness, muscoskeletal stiffness, micturition urgency, interferon gamma assay positive, back pain, influenza, acne, asthenia, fatigue, insomnia, and paraesthesia.

In cohort 1, 3 patients (75%) experienced at least 1 serious TEAE, with 5 total serious TEAEs having occurred in this cohort. The serious TEAEs included gastroenteritis, pyelonephritis, muscular weakness, myelitis transverse, and aspiration. In cohort 2, only 1 patient (25%) experienced a single serious TEAE, a case of deep vein thrombosis, with the other patients in the cohort having not experienced any serious TEAEs.

Notably, 2 patients in the study experienced cerebral ALD conversion/progression. One of these patients, a 20-year-old patient dosed in cohort 1, showed gradual cerebral disease progression and systemic complications over the course of 10 months. The patient died at home, and his death was attributed to acute aspiration. An autopsy confirmed adrenomyeloneuropathy/cALD and the patient’s death was deemed unrelated to the gene therapy product. In another patient, aged 36 years, who was dosed in cohort 2, MRI findings at 18 months posttreatment suggested early cerebral involvement. This patient continues to be neurologically stable.

First author Marc Engelen, MD, PhD, a neurologist and clinical researcher at Amsterdam University Medical Centers, and colleagues noted that there were no clinically significant laboratory abnormalitiesobserved. Although, 2 patients in cohort 1 showed alanine transaminase levels more than 2 times greater than their baseline and 1 patient in cohort 2 showed creatinine levels more than 2 times greater than baseline.

“SBT101 was generally well-tolerated at both low and high dose levels evaluated...” Engelen and colleagues wrote in the poster.

 “Common TEAEs were mild to moderate and were consistent with common or expected events related to disease and immunosuppression used in the study. [There was] no clear dose-response relationship with regards to safety. Serious AEs were more frequent in the low dose cohort (3 of 4) compared to the high dose cohort (1 of 4)... Vector DNA shedding peaked early and cleared in blood and saliva within approximately 30 to 90 days. All urine samples were consistently below the lower limit of qualification.”

Notably, Spur Therapeutics previously operated under the name Freeline Therapeutics but made the change to its current name last year.

 Alongside this announcement, the company announced that it had purchased Swan Bio, a previously independent company that had been developing SBT101. At the time, Syncona, the founding shareholder for both original companies, contributed $50 million to the newly combined company.

“We see great promise across Spur’s broadened pipeline, with a highly differentiated lead clinical program backed by compelling data and a second potentially first-in-class clinical asset,” Chris Hollowood, the CEO of Syncona and the chairman of the board of directors of Spur, said in a June 2024 statement.

 “Building on its work, Spur has an exciting opportunity to become a leading gene therapy company developing one-time treatments for debilitating chronic diseases, potentially setting new standards of care and changing lives."

REFERENCES
1. Engelen M, Hayward L, Yin P, Foulds P. Initial safety results from the PROPEL trial evaluating SBT101 as a potential gene therapy for spinal cord disease in adult males with x-linked adrenoleukodystrophy. Presented at: at ASGCT 28th Annual Meeting, held May 13 to 17, 2024, in New Orleans, LA.
2. Spur Therapeutics (formerly freeline) announces new name and brand. News release. Syncona. June 17, 2024. Accessed May 15, 2025. https://www.synconaltd.com/news-insights/news/spur-therapeutics-formerly-freeline-announces-new-name-and-brand/

The new data were presented in a poster at the American Society of Gene and Cell Therapy’s 2025 meeting.

Spur Therapeutics’ Gene Therapy SBT101 Generally Well Tolerated in Phase 1 Trial for Adrenoleukodystrophy

An FDA Cellular, Tissue, and Gene Therapies Advisory Committee (AdComm) has voted against BrainStorm Cell Therapeutics’ debamestrocel (NurOwn), an investigational autologous mesenchymal stem cell (MSC) neurotrophic factor–secreting cell therapy product intended to treat amyotrophic lateral sclerosis (ALS), ahead of its Prescription Drug User Fee Act action date, which is slated for December 8, 2023.

 Notably, in the days leading up to the AdComm meeting, BrainStorm requested to change the indication targeted with NurOwn from “ALS” to “mild to moderate ALS”.

The committee overwhelmingly voted negatively, with 17 members voting no and 1 member voting yes to the question: “Do the data presented demonstrate substantial evidence of effectiveness for treatment of mild to moderate ALS?” One member abstained. In the public hearing portion of the AdComm, a number of patients, caregivers, and family members spoke in favor of approval based on their personal experiences with NurOwn.

“It's possible that this therapy has some benefit for some patients,” Lynn A. Raymond, MD, PhD, the director of the Djavad Mowafaghian Centre for Brain Health, said after voting no.

 “But we look at the total when we have to decide whether this goes forward to public market and there wasn't evidence for the whole group that this was effective and there was evidence to potentially suggest it was actually deleterious at least for those who are maybe more advanced with ALS, causing more deaths and causing more bulbar dysfunction. So for that reason, I vote no...”

BrainStorm’s argument in favor of approval of 

 largely focused on the potential impact of the floor effect on the results of the pivotal phase 3 clinical trial (NCT03280056) that evaluated the treatment against a placebo in patients with ALS, which did not meet any of its primary or key secondary end points. Regarding the floor effect, Brainstorm noted that in a prespecified subgroup of patients with less advanced disease, who had a score of at least 35 on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), a statistically significant difference in the change from baseline in ALSFRS-R was observed favoring the group of patients who received NurOwn compared with the group of patients who received a placebo.

 A posthoc sensitivity analysis of patients who had an ALSFFRS-R score of 26 or higher also found that participants treated with NurOwn progressed 2 points less on the ALSFRS-R scale on average compared with patients who received the placebo.

BrainStorm also included data from the phase 3 study 

 including neurofilament light (NfL) in its argument. After accounting for baseline disease covariates, treated participants had reduced NfL values from baseline to week 20 compared to placebo (

The FDA’s response focused mainly on the fact that the prespecified primary and key secondary end points were not met and that posthoc analyses, such as the analyses related to the floor effect that BrainStorm presented, are not sufficient to support approval on their own. The FDA emphasized that prespecification is the cornerstone of reliable evidence in clinical trials and that the results seen in the posthoc analysis are not reliable. An additional concern brought up was that more deaths occurred in the group of patients treated with NurOwn in the trial than in the placebo group. With regard to the NfL and other biomarker data from the trial, the FDA stated that the analysis did not support efficacy, as a greater NfL reduction was associated with worse outcomes in the modified intention to treat population and there was no clear association between changes in the levels of other biomarkers, including galectin-1, LAP (TGFβ-1), MCP-1, and VEGF, and measurements of clinical benefit. Further concerns noted by the FDA were the absent or incomplete critical manufacturing controls and lack of established product quality.

Overall, the FDA concluded that the available data do not support approval of NurOwn for either ALS or mild to moderate ALS indications. The agency suggested that the exploratory data regarding the floor effect may inform the basis of a new clinical trial aimed at demonstrating efficacy, if BrainStorm chooses to continue to pursue the product’s approval.

“I think it is very clear that I include data that no one else considers as real data...” Kathleen O’Sullivan-Fortin, Esq., the founder of ALD Connect, Inc., said while making the sole ‘yes’ vote.

 “I think there's no bigger risk than imminent certain deaths from ALS and these are unique and desperate circumstances that would require us to exercise flexibility. With everyone else here, I wish that the sponsor’s data was definitive and broad and fixed and helped and saved everyone, and it wasn't going to be that, but I still think there was a value.”

The meeting concluded with a discussion of potential design decisions for future clinical trials evaluating the therapy that could more effectively demonstrate efficacy. Some suggestions included accounting for the floor effect in prespecified analyses, using a different measure of efficacy than the ALSFRS-R in order to avoid the floor effect altogether, and developing an allogeneic version of the therapy in order to ensure more standardization of the product ultimately administered to patients.

“My suggestion to the sponsor would be to add a key secondary end point or quality of life measure that would capture the anecdotal improvements in daily activities and capture the testimonials of benefit [mentioned during the public hearing],” Wendy B. London, PhD, an associate professor of pediatrics at Boston Children’s Hospital/Dana-Farber Cancer Institute, who voted no, added during this portion.

1. 74th Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting. September 27, 2023. https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-september-27-2023-meeting-announcement
2. Brainstorm Cell Therapeutics announces FDA advisory committee meeting to review NurOwn® biologics license application scheduled for September 27, 2023. News release. BrainStorm Cell Therapeutics Inc. June 6, 2023. Accessed September27, 2023. https://ir.brainstorm-cell.com/2023-06-06-BrainStorm-Cell-Therapeutics-Announces-FDA-Advisory-Committee-Meeting-to-Review-NurOwn-R-Biologics-License-Application-Scheduled-for-September-27,-2023
3. BrainStorm Cell Therapeutics data show treatment with NurOwn significantly reduces NfL, a key biomarker of neurodegeneration. News release. BrainStorm Cell Therapeutics. July 7, 2023. Accessed September 27, 2023. https://prnmedia.prnewswire.com/news-releases/brainstorm-cell-therapeutics-data-show-treatment-with-nurown-significantly-reduces-nfl-a-key-biomarker-of-neurodegeneration-301871918.html

Committee members were overwhelmingly against the available data supporting NurOwn as an effective treatment for mild to moderate ALS, with 17 no votes, 1 yes vote, and 1 abstention. 

Bakri Elsheikh, MBBS, FRCP

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