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Lysosomal Disorders

Oncology

1rem

Authors

The medical oncologists at Washington University School of Medicine in St. Louis discussed surprising findings from their retrospective study. 

Alice Zhou, MD, PhD, and Omar Butt, MD, PhD, on Surprising Associations With Neurotoxicity and Neurofilament Light 

The medical oncologists at Washington University School of Medicine in St. Louis discussed background to their research on associations between neurofilament light and neurotoxicity. 

Alice Zhou, MD, PhD, and Omar Butt, MD, PhD, on Investigating Associations With CAR T Toxicities 

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 

The European Commission (EC) has granted marketing authorization to obecabtagene autoleucel (Aucatzyl; Autolus), also known as obe-cel, a CD19-directed genetically modified autologous T-cell immunotherapy, for the treatment of individuals 26 years or older with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL).

The therapy was approved based on findings of the pivotal phase 1b/2 FELIX clinical trial (NCT04404660), which evaluated the therapy in adult patients with R/R B-ALL. Results from FELIX were published in the 

 in November of last year and showed a complete response (CR) with incomplete hematological recovery (CRi) rate of 76.6% for patients in the pivotal cohort (n = 94) who were treated with obe-cel. Furthermore, it was reported that the median duration of response in the study for all patients who received obe-cel was 21.2 months and that the median event-free survival (EFS) was 11.9 months. The estimated 6-month EFS rate constituted 65.4%, and the estimated 12-month EFS rate was found to be 49.5%.

With regard to safety, cases of cytokine release syndrome (CRS) occurred in 68.5% of patients (87 of 127). CRS cases assessed as grade 3 or higher occurred in 2.4% of patients (3 of 127). Cases of immune effector cell–associated neurotoxicity syndrome (ICANS) were reported in 22.8% of patients (29 of 127), and grade 3 or higher ICANS cases were reported in 7% of patients (9 of 127). The most common nonlaboratory adverse events assessed as grade 3 or higher included infections (unspecified pathogen infections occurred in 32% of patients), febrile neutropenia (24%), and bacterial infectious disorders (11%).

“We believe Aucatzyl represents an important new treatment option for physicians treating adult patients [with] R/R B-ALL,” Christian Itin, PhD, CEO of Autolus, said in a statement.

 “With the EU [European Union] marketing authorization, we are now evaluating market entry opportunities in EU countries.”

The EC’s approval applies to the 27 member states of the EU as well as Iceland, Norway, and Liechtenstein. Notably, obe-cel has been approved in the United States 

 The FDA’s approved indication differs slightly from the EC’s. In the United States, the therapy is approved for adults with R/R B-ALL without the stipulation that the patients must be 26 years or older. The agency's total recommended dose of obe-cel is 410 × 10

 CD19 chimeric antigen receptor (CAR)–positive viable T cells, preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy and administered as split-dose infusion on day 1 and day 10 (± 2 days) of treatment, based on bone marrow blast assessment. Risk evaluation and mitigation strategies were not required by the agency at the time of approval. Obe-cel has also previously been approved in the United Kingdom by the Medicines and Healthcare products Regulatory Agency.

Obe-cel incorporates a novel fast off-rate CD19-binding domain intended to shorten the time that it takes for CAR T cells to bind to leukemia cells, which may simultaneously decrease the number of cytokines secreted and reduce the rate of T-cell exhaustion.

, the lead investigator of the FELIX study and associate professor of haematology at the University College London Cancer Institute, about obe-cel in June 2023.

“We know that other products on the market for adult ALL have got significant toxicity profiles, and that's actually really difficult for us physicians to manage and particularly difficult for the patients and their families,” Roddie told 

. “It makes it difficult to anticipate or imagine a clinical world where we can give these comfortably as outpatient therapies, which is obviously where [we want to go]; we want to be able to improve the patient experience, quality of life, etc. And so I think that's where obe-cel comes into this because the toxicity profile is so much less difficult for patients to tolerate—even patients with lots and lots of disease—and I think that's its biggest selling point. From the perspective of just safely navigating patients through this therapy, it’s much more straightforward.”

REFERENCES
1. Autolus Therapeutics’ CAR T therapy AUCATZYL (obecabtagene autoleucel) granted European Marketing Authorization for adult patients (age 26 and older) with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL). News release. Autolus Therapeutics plc. July 21, 2025. Accessed July 24, 2025. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-car-t-therapy-aucatzylr-obecabtagene
2. FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed July 24, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute
3. Autolus Therapeutics announces FDA approval of AUCATZYL (obecabtagene autoleucel – obe-cel) for adults with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). News release. Autolus Therapeutics plc. November 8, 2024. Accessed July 24, 2025. https://autolus.gcs-web.com/news-releases/news-release-details/autolus-therapeutics-announces-fda-approval-aucatzylr
4. Roddie C, Sandhu KS, Tholouli E, et al. Safety and efficacy ofobecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): top line results of the pivotal FELIX study. Abstract presented at: 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL. Abstract 7000.

The therapy was approved based on findings of the pivotal phase 1b/2 FELIX clinical trial.

European Commission Approves Obe-Cel for Adults With R/R B-Cell Precursor Acute Lymphoblastic Leukemia

This video originally appeared on our sister site,

The professor in the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope discussed unanswered questions with regard to DLBCL treatment sequencing.

Alexey Danilov, MD, PhD, on CAR-T and Bispecific Antibody Sequencing for DLBCL

"In terms of sequencing, there is now an emerging question of whether we should be using bispecifics or CAR T-cells first. Some of this will be driven by logistical issues, some will be driven by whether there is easy accessibility to a tertiary care center that can [administer] CAR T-cell therapy, and some will be driven by patient comorbidities, cost, and other factors."

A number of important considerations exist for sequencing of treatment in patients with diffuse large B-cell lymphoma (DLBCL), as do unanswered questions. In an interview with 

®, Alexey Danilov, MD, PhD, the Marianne and Gerhard Pinkus Professor of Early Clinical Therapeutics, medical director of the Early Phase Therapeutics Program for the Systems Clinical Trials Office, codirector of the Toni Stephenson Lymphoma Center, and a professor in the Division of Lymphoma in the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California, discussed these topics.

the publication of a consensus manuscript

 looking at therapeutic developments and unmet needs in mantle cell lymphoma, DLBCL, and chronic lymphocytic leukemia.

Danilov pointed out that because multiple highly active therapies, including chimeric antigen receptor (CAR) T-cell therapies, bispecific antibodies, and CD19-directed agents, are now available, optimizing the sequencing of treatment in patients with relapsed/refractory DLBCL has become complex. Whether bispecific antibodies should be administered prior to CAR T-cell therapy or vice versa is now a question of central importance. Danilov stressed that decisions regarding sequencing will likely be affected by a number of factors, such as logistical constraints related to CAR T-cell therapy administration, nearness to specialized treatment centers, comorbidities, and cost factors.

Emerging data suggest bidirectional efficacy between these modalities. Bispecific antibodies, which predominantly target CD20, appear to retain activity following disease progression on CAR T-cell therapy. Conversely, some patients with DLBCL who experience disease progression on bispecific antibodies may still respond to CAR T-cell therapy, contingent upon continued antigen expression. This has important implications for sequencing choices, particularly as bispecific antibodies become more integrated into earlier lines of therapy.

Danilov noted that CAR T-cell therapies have already displaced autologous stem cell transplantation in certain clinical scenarios, such as in patients with primary refractory disease or those who experience relapse within 12 months of frontline chemoimmunotherapy. However, in later lines of therapy, data are growing in support of both CAR T-cell therapy and bispecific antibodies. As a result, optimal sequencing remains undefined, and future comparative and real-world evidence will be critical in shaping the future standard of care.

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Canonical

Alexey Danilov, MD, PhD, on CAR T and Bispecific Antibody Sequencing for DLBCL

Ocugen has dosed the first patient in its phase 2/3 GARDian3 clinical trial (NCT05956626) evaluating OCU410ST (AAV5-hRORA), a novel modifier gene therapy candidate, for the treatment of Stargardt disease (ABCA4-associated retinopathies).

The trial marks a critical step forward in Ocugen’s strategy to bring a onetime therapy to patients with inherited retinal degenerative conditions.

“Dosing the first patient is an especially significant milestone and brings us closer to our goal of addressing the unmet medical need that exists for all patients [with] Stargardt [disease]: 100,000 in the US and Europe and 1 million worldwide,” Shankar Musunuri, PhD, chairman, CEO, and cofounder of Ocugen, said in a statement.

The phase 2/3 GARDian3 study follows positive findings from the phase 1 GARDian trial, which showed a 48% slower lesion growth at 12-month follow-up in treated eyes compared with untreated eyes. Treated eyes also demonstrated a statistically significant (P = .031) and clinically meaningful improvement of nearly 2 lines in best corrected visual acuity (BCVA).

“Initiating dosing in this pivotal phase 2/3 study is an important advancement for Ocugen and more importantly for the Stargardt community,” Huma Qamar, MD, MPH, chief medical officer of Ocugen, added to the statement.

“The adaptive design of this trial, including a masked interim analysis at 8 months on 24 subjects, enables us to efficiently evaluate early signals of efficacy and safety while optimizing study conduct.”

The phase 2/3 trial will enroll 51 participants with Stargardt disease. Thirty-four participants will receive a onetime subretinal injection of OCU410ST (200 μL at a concentration of 1.5 × 10¹¹ vector genomes/mL) in the worse-seeing eye, and 17 will serve as untreated controls. The primary end point is reduction in atrophic lesion size, with secondary end points including BCVA and low-luminance visual acuity. Ocugen plans to use 1-year follow-up data to support a biologics license application (BLA), targeted for 2027.

“Treating the first patient with this novel gene therapy in the GARDian3 trial is a proud and hopeful moment for our team and for families affected by Stargardt disease,” Victor H. Gonzalez, MD, principal investigator at Valley Retina Institute in McAllen, Texas, added to the statement.

“The encouraging phase 1 results give us confidence that OCU410ST could meaningfully slow disease progression and help preserve vision. This trial brings us closer to the possibility of a onetime gene therapy that could transform patients’ quality of life for years to come.”

To date, OCU410ST has shown a favorable safety and tolerability profile, with no serious adverse events or adverse events of special interest, such as ischemic optic neuropathy, vasculitis, intraocular inflammation, endophthalmitis, or choroidal neovascularization.

OCU410ST is Ocugen’s second late-stage clinical program and part of its broader modifier gene therapy platform, which uses adeno-associated virus vectors to deliver the 

gene. The candidate targets multiple pathogenic pathways implicated in Stargardt disease, including oxidative stress, lipofuscin accumulation, inflammation, and complement dysregulation. RORA encodes a nuclear hormone receptor that regulates gene expression via hormone response elements and interacts with proteins involved in organ development and differentiation, functions that may be impaired in Stargardt disease. It may also play a role in circadian rhythm regulation, which may also contribute to its role in retinal homeostasis.

This platform reflects a gene-agnostic strategy that aims to provide durable, broad-spectrum benefit for inherited retinal diseases.

 “Progressing our second modifier gene therapy candidate into a registration clinical trial is a pivotal step in potentially providing a onetime therapy for life,” Musunuri said.

 Stargardt disease, the most common form of inherited macular degeneration, is characterized by progressive loss of central vision, typically beginning in childhood or adolescence. Current management options are limited, with no approved therapies available to alter disease progression. Ocugen aims to file 3 BLAs over the next 3 years, with OCU410ST positioned as a leading candidate to address an area of significant unmet need in retinal degenerative disease. 

REFERENCES 
1. Ocugen, Inc. announces first patient dosed in phase 2/3 GARDian3 pivotal confirmatory trial for OCU410st—novel modifier gene therapy candidate for Stargardt disease. News release. July 18, 2025. Accessed July 23, 2025. https://ir.ocugen.com/news-releases/news-release-details/ocugen-inc-announces-first-patient-dosed-phase-23-gardian3 
2. RORA RAR related orphan receptor A [ 

 (human) ]. National Library of Medicine. Updated July 6, 2025. Accessed July 23, 2025. https://www.ncbi.nlm.nih.gov/gene/6095

Ocugen initiates pivotal confirmatory trial for OCU410ST, its second modifier gene therapy candidate, in patients with Stargardt disease.

First Patient Dosed in Phase 2/3 GARDian3 Trial of OCU410ST for Stargardt Disease

The senior director at Regeneron discussed the company’s receptor-driven approach to AAV targeting, leveraging antibody engineering to enhance tissue specificity and reduce off-target effects.

Sven Moller-Tank, PhD, on Regeneron’s Precision Approach to AAV Targeting

“We are going after a particular receptor and then engineering our capsids to target that receptor. I think that's a unique approach. We're one of the first, I think, to successfully show that this can work in vivo.”

® spoke with Sven Moller-Tank, PhD, a senior director at Regeneron, at 

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

, held May 13 to 17, 2025, in New Orleans, Lousiana. He detailed how the company is advancing a receptor-driven strategy to improve gene therapy targeting, one grounded in antibody expertise rather than random library screening. His team is developing antibody/adeno-associated virus (AAV) fusion platforms to precisely direct gene therapy payloads to specific tissues, including skeletal muscle, the central nervous system (CNS), and peripheral nervous system. This could build on Regeneron’s efforts in genetic medicine, where the company is applying cross-disciplinary efforts to develop new therapeutic candidates.

Moller-Tank noted that while others in the field are retroactively identifying receptor interactions post hoc, Regeneron’s method starts with the receptor in mind. This enables more predictable biodistribution and may reduce immune complications, such as off-target effects or preexisting immunity. At the meeting, he discussed platforms designed to target the transferrin receptor for CNS delivery, CACNG1 for skeletal muscle, and p75 for peripheral neurons. His team is also refining capsid-antibody constructs for both covalent and bispecific formats, with new preclinical findings in nonhuman primates validating these constructs, particularly in skeletal muscle and CNS models.

This in vivo success marks a turning point in the field’s evolution toward not targeting the liver and mitigating off-target toxicities. Regeneron’s efforts also extend beyond AAV, with early progress applying this targeted delivery system to siRNA, lipid nanoparticles, and other modalities. As these platforms advance, they may change how therapies are delivered across different treatment types. With gene therapy’s challenges more visible than ever, Moller-Tank believes this precision-first approach may help unlock its full potential.

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

Omar H. Butt, MD, PhD

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