Nine speakers present results from preclinical and in-human clinical trials of interventions designed for patients with genetic diseases, neovascular age-related macular degeneration (nAMD), and geographic atrophy (GA).
Katarina Stingl, MD (Germany) began the programme presenting the safety and efficacy results from a phase 1b trial of intravitreal AAV2.NN-CNGA1 gene therapy for CNGA1 retinitis pigmentosa. The monocentric study included six patients divided into two dosing groups who received a unilateral injection. She reported there were no signs of efficacy in the low dose group, but a strong functional rod rescue in the treated eye and improvement in rod-tailored pupil campimetry was seen in the higher dose group. The intravitreal therapy showed an acceptable safety profile with possible intraocular inflammation that was well-controlled by oral steroid treatment.
Robert Henderson, MD (UK) presented 2-year results of the phase 1/2 study of TTX-381 gene therapy for CLN2 Batten disease-related retinopathy that demonstrated long-term safety and a disease-modifying effect on retinal degeneration after a one-time injection. He reported there was a rapid and durable dose-dependent increase in TPP1 expression to therapeutic levels based on analysis of aqueous samples and durable photoreceptor stabilisation or improvement was noted in five of five fully treated eyes during the available follow-up. Preliminary behavioural observation and functional vision score data also suggested stable visual function.
Gene therapy for nAMD was the subject of the next three presentations. Lejla Vajzovic, MD (United States) reported results from long-term (5-year) follow-up of participants in the phase 1/2a study investigating subretinal delivery of sura-vec gene therapy that aims to transduce RPE and photoreceptor cells with an anti-VEGF antibody fragment. The population consisted of 42 patients comprising five cohorts. All patients had responded previously to anti-VEGF therapy but required frequent injections.
The 5-year results showed no new safety signals related to the gene therapy or its administration. Cohorts 3 and 4 demonstrated stable to improved visual acuity, and, after receiving a single gene therapy injection, a >64% reduction in injection burden compared to their pre-enrollment history.
Dr. Vajzovic announced that two pivotal trials are currently ongoing that are investigating doses similar to those studied in cohorts 3 and 4 in the phase 1/2a study. Topline results from the pivotal trials are expected later this year.
Arshad Khanani, MD, MA (United States) reported first-time safety, tolerability, and efficacy results from a phase 1/2 study investigating single dose intravitreal SAR402663 for nAMD. The investigational agent is an adeno-associated virus gene therapy expressing soluble fms-like tyrosine kinase-1 (sFLT01), a VEGF receptor decoy that neutralizes VEGF signaling. The multicentre phase 1/2 study is a dose escalation and dose expansion study that investigated three doses. The medium dose is now being investigated in a phase 3 programme based on its demonstration of a positive benefit-risk profile with positive functional and anatomical results and a reduction in treatment burden such that >90% of subjects remained free from supplemental injections and 97% benefited with a reduction from their previous treatment burden. “The study is moving forward and as required by regulatory agencies, patients will be followed for five years,” Dr Khanani said.
Frank Holz, MD (Germany) presented results from 2 years of follow-up in PRISM, a phase 2b trial evaluating 4D-150 intravitreal gene therapy in a broad population of patients with mild to severe nAMD. 4D-150 delivers the transgene encoding the gene for the aflibercept protein and an inhibitory RNA sequence against VEGF-C. The data reported by Dr. Holz showed that after a single 4D-150 injection, average visual acuity and anatomic benefits were maintained with a consistent and durable treatment burden reduction through 2 years. The intravitreal gene therapy was also well-tolerated with no new safety or intraocular inflammation signals emerging during follow-up. Ongoing global phase 3 programmes are investigating the efficacy and safety of 4D-150.
Georges Weissgerber, MD (France) reported early results from a first in-human trial investigating PST-611, a non-viral ocular gene therapy using a naked plasmid expressing transferrin, for treatment of GA. He explained that iron dysregulation drives the pathogenesis of dry AMD and GA and that transferrin is a central gatekeeper of iron homeostasis. The results showed what Dr. Weissgerber described as “remarkable early signals of efficacy” that will be further investigated in a multiple dose phase 2a trial that is scheduled to begin soon. “We were stunned and very happily surprised by the improvements in structural biomarkers as well as reports of functional improvement and a consistent separation between the responding study eye and the untreated fellow eye,” he said.
Outcomes from 36 months of follow-up for 27 patients enrolled in the PRIMAvera pivotal trial investigating the now CE-marked PRIMA photovoltaic subretinal implant for patients with GA were presented by Mahi Muqit, MD, PhD (United Kingdom). The results showed durability of the implant’s significant benefit as measured by mean improvement in visual acuity of nearly 30 letters as compared to 25 letters at 12 months. Additionally, natural vision, measured without the PRIMA system, changed by only +0.04 logMAR, supporting the device’s long-term safety, he said.
Roger Goldberg, MD, MBA (United States) presented the topline efficacy and safety outcomes from LUGANO, a phase 3, randomised, double-masked study designed to evaluate the non-inferiority of EYP-1901, a bioerodible intravitreal vorolanib insert, administered every 6 months versus on-label aflibercept in both treatment-naïve and previously-treated patients with wet age-related macular degeneration. He reported that LUGANO missed the primary endpoint of change from baseline in best corrected visual acuity versus the control in the full analysis set, which was confounded by an asymmetric cohort. However, EYP-1901 was non-inferior to on-label aflibercept in a post hoc analysis excluding an asymmetric cohort of patients who had significant vision loss for causes unrelated to nAMD. LUGANO also demonstrated compelling outcomes in key secondary endpoints analysing treatment burden, supplement-free rates, safety with redosing, and anatomic control through Week 56 compared to on-label aflibercept. Topline results from LUCIA, an identically designed phase 3 programme, will be reported later this year.
The last presentation in the session given by Aiden Eblimit, PhD (United States) presented findings from preclinical studies investigating oral NLRP3 inflammasome inhibition as a treatment for GA. Dr Eblimit noted that as an oral modality, NLRP3 inflammasome inhibition could address several limitations of existing GA therapies that require intravitreal injection. He presented data showing that oral NLRP3 inhibition prevented lipofuscin accumulation, reduced AβO-driven retinal lesion formation, and preserved RPE integrity.
All sessions will be available on demand for registered attendees
