CGTLive's Pillars of Progress 2023: Top News in Ophthalmology

For all of 2023, the CGTLive^™ team was following along the clinical development of targeted and novel engineered approaches to the treatment of patients with various medical disorders. These efforts included holding in-depth conversations with experts in the clinical care of these individuals, as well as in cell and gene therapy development, culminating in our coverage of each step of progress that the most exciting cellular and genetic treatments have made along the pipeline.

From major data publications and presentations to FDA decisions and major medical meetings, the team spent all year bringing the latest information to the website's front page.

Among our areas of focus in 2023 has been ophthalmology. The major news items appeared among the top pieces our team produced—but sometimes smaller stories reach those heights as well because of their clinical impact, their inventive mechanisms, or otherwise. Whatever the reason for the attention these stories got, their place here helps provide an understanding of the themes in oncology over the course of 2023.

Here, we'll highlight some of the most-read content on CGTLive's ophthalmology page this year. Click the buttons to read further into these stories.

1. ABCA4 Retinopathy Gene Therapy Demonstrates Efficacy in Preclinical Study

• Intergalactic Therapeutics reports promising preclinical results for IG-002, a nonviral gene therapy targeting ABCA4-related retinopathies.
• IG-002 demonstrated sustained expression of the ABCA4 protein for 12 months in adult porcine retinas after a single subretinal administration.
• Intergalactic Therapeutics plans to conduct IND-enabling studies, with expectations for IG-002 to enter clinical trials in 2024, showcasing potential advancement in gene therapy.

March 27, 2023 — Intergalactic Therapeutics’ IG-002, an investigational nonviral gene therapy intended to treat retinopathies associated with mutations in the ABCA4 gene, demonstrated the ability to affect expression of the ABCA4 protein for 12 months in adult porcine retinas after a single subretinal administration. Intergalactic Therapeutics stated that it has plans to conduct IND-enabling studies, with the expectation that IG-002 could enter clinical trials in 2024. The company is also evaluating whether the C3DNA platform can be applied to other indications.

"We are highly encouraged by the promising and unprecedented findings from these preclinical studies. With these data, we have clearly demonstrated the feasibility of electro-transfer delivery of nonviral C3DNA expressing the full-length human ABCA4 gene to relevant cell types in the retina. We have also confirmed persistence of ABCA4 expression for at least 12 months in vivo in photoreceptors—the longest time point evaluated to date."

-José Lora, PhD, of Intergalactic Therapeutics

2. X-Linked Retinoschisis Gene Therapy Cleared for First-in-Human Trial

• Atsena Therapeutics receives FDA clearance for its gene therapy, ATSN-201, for evaluation in a phase 1/2 study in patients with X-linked retinoschisis (XLRS).
• ATSN-201 utilizes Atsena’s AAV.SPR spreading capsid technology, addressing limitations of intravitreally delivered AAVs and potentially providing a safer and more effective treatment for XLRS.
• Atsena plans to initiate the Lighthouse study, a dose-escalation trial, in mid-2023 for XLRS.

May 3, 2023 — The FDA has cleared Atsena Therapeutics’ investigational new drug application (IND) for the gene therapy ATSN-201 to be evaluated in the first-in-human, phase 1/2 Lighthouse study in patients with X-linked retinoschisis (XLRS). Atsena anticipates initiating the open-label, dose-escalation Lighthouse study in male patients aged 6 to 65 years with a clinical diagnosis of XLRS caused by pathogenic or likely pathogenic mutations in RS1 in mid-2023.

"AAV.SPR is well-suited for use in XLRS as it can drive therapeutic levels of gene expression in photoreceptors while avoiding the surgical risks of foveal detachment, which is important because XLRS patients have fragile retinas due to the presence of schisis lesions."

-Shannon Boye, PhD, of Atsena Therapeutics

3. Orchard Therapeutics' Gene Therapy OTL-203 Stabilizes or Improves Sensory Symptoms in Patients With MPS-IH

• Orchard Therapeutics announces positive results for OTL-203 gene therapy in a proof-of-concept study for mucopolysaccharidosis type I Hurler subtype (MPS-IH), showing improved or stabilized ocular and auditory symptoms in treated patients.
• In the study, 62.5% of patients demonstrated an improvement in corneal clouding, and 37.5% showed stabilization, with the absence of photophobia and associated symptoms post-treatment.
• The promising outcomes pave the way for a global registrational trial comparing OTL-203 to standard-of-care treatment, with enrollment activities expected to begin by the end of 2023.

November 2, 2023 — Orchard Therapeutics’ OTL-203, an investigational hematopoietic stem cell (HSC) gene therapy intended to treat the Hurler subtype of mucopolysaccharidosis type I (MPS-IH), has stabilized or improved some ocular and auditory symptoms among patients treated in a proof-of-concept study between July 2018 and December 2019.1 The new results, which build upon safety data previously reported, were announced at ESGCT 2023.

“These positive data presented at ESGCT add to the growing body of evidence underscoring the potential of a one-time HSC gene therapy to correct a range of disease manifestations not effectively addressed by the current standard of care."

- Leslie Meltzer, PhD, of Orchard Therapeutics.

4. Wet AMD Gene Therapy Trial Demonstrates Consistent Safety and Efficacy With New Manufacturing Process

• RGX-314, a gene therapy for wet AMD, consistently shows positive results and good tolerance.
• Patients treated with RGX-314, via NAVXpress or cell culture, exhibit similar outcomes.
• Encouraging wet AMD results prompt REGENXBIO to plan a 2024 biologics license application submission.

February 13, 2023 — REGENXBIO’s RGX-314, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat wet age-related macular degeneration (AMD), has demonstrated consistent results between product manufactured with the company’s new NAVXpress bioreactor platform process and product produced with an adherent cell culture process. RGX-314, which is being developed in collaboration with AbbVie, is delivered via REGENXBIO’s NAV AAV8 vector.

"The clinical profile of RGX-314 manufactured using the commercial-scale process is encouraging, as is the potential of a one-time therapy for the treatment of wet AMD."

Charles C. Wykoff MD, PhD, of Houston Methodist Hospital

5. Real World Data Confirm RPE65-IRD Gene Therapy Voretigene Neparvovec Efficacy in Improving Light Sensitivity

• Spark Therapeutics' Luxturna undergoes real-world efficacy verification in postmarketing studies, showing improvements in retinal function.
• Dr. Bart P. Leroy discusses the importance of real-world data for Luxturna, the first approved gene therapy.
• Postmarketing study in Belgium indicates no improvement in BCVA but significant gains in retinal function.

May 9, 2023 — Spark Therapeutics’ voretigene neparvovec (Luxturna) was originally approved by the FDA in December 2017 and by the European Medicines Agency (EMA) in 2018 for the treatment of inherited retinal dystrophy related to mutations in the RPE65 gene. Data from a recent postmarketing, real world study were presented in a poster at the Association for Research in Vision and Ophthalmology (ARVO) 2023 Annual Meeting, held April 23-27, 2023, in New Orleans, Louisiana, and evaluated the treatment in 10 Belgian patients.

"The essence of the results of our study showed that the BCVA indeed does not improve.... But with FST we saw a serious improvement of retinal function: mostly the rods, but certainly also the cones. And this translates, if you look at activities of daily living, into a patient being much more capable of navigating at lower light levels in daily life."

-Bart P. Leroy, MD, PhD, of Ghent University Hospital