Dante J. Pieramici, MD

Intravitreal Therapy UBX1325 Proves Efficacy in DA and DME, with Dante Pieramici, MD

Clinical trials to date have indicated the favorable safety profile and long lasting efficacy of UBX1325 (foselutoclax), an intravitreal injection targeting cellular senescence, in slowing the progression of 

 Annual Scientific Meeting of the American Society of Retina Specialists

 in Long Beach, CA, came from 2 distinct phase 2 and 2b clinical trials, titled BEHOLD and ASPIRE, respectively. Investigators tested UBX1325, a novel senolytic small molecule inhibitor of anti-apoptotic protein BCL-xL, in limiting the impact of DME and DR.

Prior studies have indicated the efficacy of UBX1325 in treating 

neovascular age-related macular degeneration (nAMD)

. These trials indicated UBX1325’s ability to recover outer retinal function within 8 weeks of the trial’s start point. This prevents senescent cells from disrupting the blood-retinal barrier or increasing reactive oxygen production.

For enrollment in BEHOLD, patients were required to be ≥18 years old, have nonproliferative DR and DME, have center-involved DME with central subfield thickness (CST) ≥325 to 900 µm, and have best-corrected visual acuity (BCVA) in the study eye (most affected) of 70-30 ETDRS letters (equivalent to 20/40 to 20/250 on the Snellen chart). Patients were excluded if they had concurrent disease in the study eye or structural damage other than DME which could compromise BCVA or prevent improvement. Additionally, patients with significant media opacities like cataract were omitted.

The first step of the trials, BEHOLD, was a phase 2 proof-of-concept, double-masked, sham-controlled, multicenter trial. It enrolled 65 patients, all of whom received a single intravitreal dose of 10µg UBX1325. Pieramici and colleagues established a primary safety objective based on ocular and systemic treatment emergent adverse effects (TEAEs) through 48 weeks and a primary efficacy endpoint based on mean change from baseline in BCVA for UBX1325 versus sham at week 24. Follow-up assessments were conducted through week 48.

The ASPIRE trial, a phase 2b, multicenter trial, utilized aflibercept as an active comparator. A total of 52 subjects were included, receiving intravitreal injections of either 10µg UBX1325 or 2mg aflibercept. Patients were dosed every 8 weeks. The primary endpoint is change in BCVA from baseline to week 24, which will indicate noninferiority. Follow-up assessments will be conducted through week 36 to monitor the effect’s durability.

BEHOLD saw UBX1325 well tolerated with few TEAEs while substantially improving and maintaining BCVA. The difference between UBX1325 and sham in mean BCVA change to week 48 was +5.6 ETDRS letters (95% CI, -1.5 to 12.7). Patients in the UBX1325 arm also stabilized or improved central subfield thickness.

Investigators found that 53% of patients receiving UBX1325 did not require anti-VEGF rescue at any point, compared to 22% in the sham arm. Additionally, 30% of UBX1325-treated subjects showed 2-step improvements in diabetic retinopathy severity score (DRSS) at week 48.

 sat down with lead presenter Dante Pieramici, MD, California Retina Research Foundation to discuss the studies, their results, and the implications of this new genetic therapy for common ocular diseases. Pieramici discussed the relevance of cellular senescence and the reason this trial focused on this metric.

“Senescence is one of the hallmarks of aging,” Pieramici told 

. “But it also seems to play a role in retinal diseases such as diabetic retinopathy. There’s a lot of preclinical evidence in animal models that in models of retinopathy, cellular senescence occurs, the cells become senescent, they stop dividing. These are vascular cells, and they start producing secretory factors such as cytokines that can negatively impact the cells surrounding them.”

Pieramici also spoke to the potential next steps for UBX1325 and its uniqueness in the medical field.

“So, this is a very unique mechanism of action,” Pieramici said. “It’s actually going to help get rid of the cells that are sick, that are probably causing damage to the cells in their vicinity and then allowing replacement with more healthy cells. And so, I think it’s a completely different mechanism of action, but one that probably can be supplemented by using anti-VEGF agents as well.”

Editor's Note: Pieramici reports the following disclosures: NGM, Gemini, Neurotech, 4DMT, Oculus, Boehringer, and others.

Pieramici D, Sapieha P, Bhisitkul R, Mallinckrodt F, Klier S, et al. Senolytic Candidate UBX1325 for Diabetic Macular Edema: The BEHOLD Phase 2 and ASPIRE Phase 2b Trials. Abstract presented at the 43

 Annual Scientific Meeting of the American Society of Retina Specialists in Long Beach, CA, July 30-August 2, 2025.

Macha N, Yu M, Sapieha P, et al. Multifocal Electroretinography Changes after UBX1325 (Foselutoclax) Treatment in Neovascular Age-Related Macular Degeneration. J Clin Med. 2024;13(18):5540. Published 2024 Sep 19. doi:10.3390/jcm13185540

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Results from the BEHOLD and ASPIRE trials indicate the long lasting effects of UBX1325 in improving retinal function and structure. 

Intravitreal UBX1325 Shows Efficacy in Diabetic Retinopathy, DME, with Dante Pieramici, MD

Phase 2 LUNA Trial Results for Ixo-vec to Treat Neovascular AMD with Dante Pieramici, MD

2025 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting

, Dante Pieramici, MD, codirector of the California Retina Research Foundation and assistant clinical professor of ophthalmology at the Doheny Eye Center in Southern California, presented the results of the Phase 2 LUNA trial of ixoberogene Soroparvovec (Ixo-vec) intravitreal gene therapy for the treatment of 

neovascular age-related macular degeneration (AMD).

The trial aimed to validate the efficacy and safety of a single injection ixo-vec in extending dosage intervals. Participants were randomized across two Ixo-vec doses, one of 6E10 and one of 2E11 vg/eye, which were given along with multiple corticosteroid prophylactic regimens including oral prednisone +/- topical difluprednate +/- IVT dexamethasone.

“I think this is a big potential advantage,” Pieramici told 

. Currently we use intravitreal injections, and even despite the newer anti-VEGF agents, patients generally need to have injections every 4-8, 12-16 weeks. It’s relatively frequent intravitreal injections and if they miss an injection, life gets in the way, they get hospitalized or something, then they get vision loss, and it may not come back. I think Ixo-vec potentially offers, at least for most patients…a potential one shot therapy.”

The study’s primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline to week 52. Secondary endpoints included the proportion of patients remaining aflibercept injection free, number of supplemental aflibercept injections overall, and mean change in central subfield thickness (CST).

A total of 60 patients were enrolled with a mean age (standard deviation [SD]) of 76.6 +/- 7.8 years and a time since diagnosis of 3.0 +/- 2.9 years. These patients received 10.1 +/- 2.6 annualized anti-VEGF injections over the year leading up to receiving Ixo-vec. Baseline mean BCVA and CST were 72.3 (7.7) ETDRS letters and 350.6 (115.2) µm, respectively.

By week 52, investigators noted maintenance of BCVA and CST with a least squares mean change of -2.1 (6E10) and -1.8 (2E11) ETDRS letters and -10.2µm (6E10) and -21.9µm (2E11), respectively. 54% of 6E10 recipients and 69% of 2E11 recipients received no aflibercept injections. 75% (6E10) and 79% (2E11) needed ≤1 supplemental aflibercept injection, while 89% (6E10) and 90% (2E11) needed ≤2 supplemental injections.

After treatment, patients were surveyed about treatment preference. In total, 93% of patients preferred Ixo-vec over previous anti-VEGF therapy. Additionally, there were no serious treatment-related adverse events during the study. All adverse events related to Ixo-vec were mild or moderate.

Pieramici and colleagues indicated that the results of LUNA highlighted the safety, efficacy, and tolerability of Ixo-vec in maintaining visual and anatomic endpoints over 52 weeks, with more than 50% of patients requiring no additional therapy.

“I think it’s a very exciting time in gene therapy,” Pieramici said. “This is using it not to treat an inherited retinal disease, but using gene therapy as a biofactory approach as opposed to intravitreal injections. This, we’re hoping, is going to significantly reduce the treatment burden.”

Dante Pieramici, MD reports the following disclosures: Adverum, Eyepoint, Genentech, Inc., NGM Bio, Neurotech, Opthea, Perceive, Regeneron, Regenxbio, SMIR, Stealth, Unity: Code S (non-remunerative): None; Adverum, Gemini, Genentech, Inc., Iveric Bio, NGM Bio, Regeneron, Regenxbio: Code C (Consultant/Contractor): None; 4DMT, Adverum, Apellis, Chengdu Kanghong, Clearside, Eyepoint, F. Hoffmann-La Roche Ltd., Genentech, Inc., Iveric Bio, Jenssen, Kodiak Sciences, Novartis, Ocular Therapeutix, Ocurion, Opthea, Regeneron, Regenxbio, Resolute, Unity, Valo: Code F (Financial Support): None; Gemini: Code I (Personal Financial Interest): None

Ixoberogene Soroparvovec (Ixo-vec) Intravitreal Gene Therapy for Neovascular Age-Related Macular Degeneration: Phase 2 LUNA 52-Week Data

. Abstract presented at Association for Research in Vision and Ophthalmology in Salt Lake City, UT, from May 3 – May 8, 2025.

Ixo-vec, a potential one shot therapy for age-related macular degeneration has achieved noninferior results in maintaining best-corrected visual acuity and central subfield thickness.

Anti-VEGF for RVO: The Gold Standard

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John W Kitchens, MD, bookends the discussion by highlighting the landscape of branch vein occlusion (BRVO) treatment options. 

Anti-VEGF for RVO: The Gold Standard 

Faricimab for DME: Durability and Patient Outcomes

I'm sorry, but it seems there is no article text provided for me to summarize and extract key takeaways from. Could you please provide the text of the article

Dante J Pieramici, MD, shifts the conversation to diabetic macular edema (DME) and the promising drying and anatomical results from an open-label long-term extension trial. 

Dante J. Pieramici, MD

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