For this month's Retina Minute, I have the pleasure of interviewing my dear friend, Arshad Khanani, who is Clinical Professor at the University of Nevada, Reno School of Medicine and Managing Partner, Director of Clinical Research, Director of Fellowship at Sierra Eye Associates.

Recently at Clinical Trials at the Summit (CTS) 2025, Dr. Khanani, you presented some incredibly interesting data at the first-time results session. Can you explain it to our readers?

Thanks, Dr. Singer. I was honored to present the data on PER-001, which is a novel, long-acting endothelin antagonist administered as a bio-erodible intravitreal implant for the treatment of retinal ischemia. We have data on glaucoma as well as diabetic retinopathy, and I shared the data from Perfuse Therapeutics’ phase 2a glaucoma and diabetic retinopathy trials at CTS.

How was the study designed and what did you find?

I will start with the pathway. First, endothelin is a validated pathway of human vascular disease. Endothelin-1 is upregulated in glaucoma, diabetic retinopathy, and AMD, and it is the most potent vasoconstrictor in the body. It is the key driver of vascular pathology driving ischemia, inflammation, retinal ganglion cell apoptosis, neovascularization, vascular leak, and fibrosis. With PER-001, we are trying to block this pathway.

PER-001 is designed to be a q 6-month implant. Its composition is similar to the dexamethasone implant, which you have pioneered, and it is the first-in-class endothelin antagonist for ocular diseases.

The diabetic retinopathy study is a phase 2a, 6-month, randomized, controlled study. It involves 27 patients with moderate-to-severe nonproliferative diabetic retinopathy (diabetic retinopathy serverity score [DRSS] range 47 to 53) who were divided into 3 groups: low dose PER-001, high dose PER-001, and sham. The primary endpoint was safety and tolerability, and the exploratory endpoints included functional (contrast sensitivity and visual field vision) and structural outcomes which were measured using ultrawidefield imaging.

PER-001 was safe and well tolerated. There were no serious drug-related ocular or systemic adverse events, best corrected visual acuity (BCVA) remained stable, and there were no changes in intraocular pressure (IOP). DRSS was mostly stable and comparable across all groups. The key finding in this study is what was observed in the low luminance contrast sensitivity testing. Patients with moderate-to-severe diabetic retinopathy have deficits in their low-luminance contrast sensitivity which gets worse as time progresses, especially at night. Many patients complain of difficulty in night driving. In this study, we saw that patients treated with PER-001 had an improvement in their low-luminance contrast sensitivity compared to the control group. Furthermore, this study found that the PER-001 treated groups were better than the control group by 3 decibels, which is equivalent to 15 letters or 3 lines on ETDRS testing.

This is the first time we have seen a functional improvement in diabetic retinopathy, and contrast sensitivity is an approvable endpoint based on the FDA regulatory guidance.

At baseline, patients in the low-dose and control groups had visual field deficits while the high-dose group was normal. In this study we saw an improvement in visual field in the low-dose group while the control remained unchanged. As noted, in the high-dose group, the visual field was already normal at baseline; therefore, there was no room to improve, and this group’s visual field remained unchanged during the study. Regarding structure, on ultrawidefield fluorescein angiography, we saw improvement in ischemia, leakage, and number of microaneurysms in the PER-001 treated groups compared to control. These functional and structural benefits were observed after just 1 injection over a 6-month study, so it will be exciting to see what we will happen in a longer trial.

As I mentioned, PER-001 has been studied in glaucoma as well. In the phase 2a glaucoma study, we saw that PER-001 improved optic nerve blood flow and retinal nerve fiber layer/structure with visual functional benefits; specifically, visual field improvement, which we have also never seen before in glaucoma.

Fascinating. It sounds like the low dose seemed to do a better job in terms of controlling the visual field in the DR study. Is that what the company is thinking about going forward in the next study?

The data I mentioned for the low-dose group was for the visual field testing, where the low dose patients were abnormal at baseline. In contrast, the high-dose visual field was normal at baseline and left little room for measurable improvement. Importantly, both PER-001 doses demonstrated benefit compared to control for other outcomes (structural measures and contrast sensitivity) where the baseline was abnormal. At this stage, it has not been decided whether it will be 1 or 2 doses in the next study—that will be based on the regulatory feedback—but clearly, we are seeing a benefit that we have not seen before in our patients with diabetic retinopathy. Phase 2b/3 trials are planned in glaucoma as well as diabetic retinopathy. Dry AMD could also be interesting in future studies. We know there is a component of ischemia there as well, and we may be able to help those patients where there is a big unmet need, especially with intermediate AMD. So that will be something else to explore in the near future.

Given the fact that PER-001 is an implant, how long does the drug stick around? We have seen many different implant studies with TKIs in which some drugs stay around longer than the implant, while some implants stay around longer than the drug. How does that work with this delivery system?

This implant technology is similar to the dexamethasone implant in terms of delivery. The PER-001 implant is specifically designed to release the drug at the same rate as the implant erodes, so the implant and drug are both gone by 6 months.

Are there any significant differences from the injectors we have used before? What size is the needle?

The injector is a 25 gauge preloaded needle, and the implant is 4 mm. I do not expect that giving multiple implants over a longer term of study would be a problem because it is PLGA and it dissolves.

Where do you see PER-001 fitting into your armamentarium?

Our patients with diabetic retinopathy continue to progress. Even with anti-VEGF, we are not seeing improvement for ischemia and, more importantly, we are not seeing a functional benefit, but here we are able to go in the opposite direction by perfusing the retinal tissue, which is the primary cause of the problem in patients with diabetic retinopathy. I think this is exciting, and if the program does well and PER-001 becomes an option, then I think twice a year injections to preserve or improve function will be meaningful.

Dr. Khanani, this is fascinating. Given that we do not currently have anything that really changes ischemia, and given the fact this potentially could be a twice a year injection, it might be even more amenable to our patients with earlier stage diabetic retinopathy.

Thanks for having me, Dr. Singer. It is always a pleasure to speak with you.

Arshad M. Khanani, MD, MA, FASRS is Clinical professor at the University of Nevada, Reno School of Medicine, and Managing partner, Director of Clinical Research, Director of Fellowship at Sierra Eye Associates.

Michael A. Singer, MD is a board-certified vitreoretinal specialist and director of clinical research at Medical Center Ophthalmology Associates in San Antonio, TX. He is currently the clinical professor of ophthalmology at the University of Texas Health Science Center in San Antonio.

 This editorial content was supported via unrestricted sponsorship.