Blocking Connexin-43 may improve diabetic retinopathy, AMD

Dr David S. Boyer sat down to discuss his presentation, “Inhibition of Connexin-43 for the Treatment of AMD and Diabetic Retinopathy,” at the Angiogenesis, Exudation and Degeneration Meeting, hosted by Bascom Palmer.

Dr Boyer is a partner and ophthalmologist at Retina Vitreous Associates Medical Group in addition to serving as an adjunct clinical professor of ophthalmology at USC.

Video transcript

Sheryl Stevenson: Dr Boyer, thank you so much for joining us. At this year's Angiogenesis meeting, you're giving a talk regarding the inhibition of Connexin-43 for a treatment of AMD and diabetic retinopathy. Could you take a few moments and kind of provide an overview of your talk for us?

Dr Boyer: Sure, thank you again for allowing me to present this. Xi lambda, which is the Connexin-43 locker, closes pathologically open Connexin-43 hemichannels and cell membranes and that inhibits the ATP release into the extracellular space, which activates the NLRP inflammasome process.

With the inflammasomes being activated, you start to get cytokine release inflammation vessels leak, oedema, ischemia, fibrosis, and it's a vicious cycle because this causes further inflammasome release and further ATP release. So if we can block this process, we can reduce the cytokine release and hopefully improve a variety of ocular conditions.

Xiflam, which is a drug, was developed 20 years ago by GSK for migraine; it was abandoned. It had two you know, novel properties. First of all, it inhibited pathologic opening of the Connexin-43 hemichannels, and it also crossed the blood brain retinal barrier. There are over 1000 subjects that were dosed in this study with concentrations ranging from 25, 40 and 80 milligrams, and the dosing was up to three months. In all concentrations, the drug was well-tolerated. So we have robust safety data concerning this drug.

There were a couple of proof-of-concept studies that were interesting. There's a Sprague Dawley rat that is born with diabetes and has a blood sugar level three times the normal range, and these animals actually show micro-aneurysms and macro-aneurysms, and have diabetic retinopathy.

In the group that was treated both the ERG as well as the OCT showed a marked improvement; the micro-aneurysms went away, and the ERG improve. So this is a proof of concept that in diabetes, if we can block Connexin-43 that we will hopefully get an improvement in the retinal vascular system.

Additional treatments have been performed for macular degeneration using a bright light model. And again, the treated group showed a marked improvement of retinal function and also in histopathology when they are treated with Xiflam. We also know that there are a lot of expression of Connexin-43 in the blood vessels in diabetic retinopathy and macular degeneration in human donor retinas.

So we are starting a phase two trial in diabetes: 130 patients, randomized, one-to-one, versus Xiflam versus placebo. We're looking both at the diabetic retinopathy severity as well as diabetic macular oedema. And the final analysis will be at six months, though there'll be an interim data safety monitoring at three months. And this has been run by the Diabetic Retinopathy Clinical Research Network, and we're hoping to start enrolling very quickly.

In addition, we are also looking at geographic atrophy, again, 130 patients being treated with a one-to-one relationship between Xiflam and placebo. And again, we're looking for decrease in growth and the decrease progression of other retinal lesions in a certain specified time points.

So in summary, this treatment may shift us from intravitreal injections to a once-a-day tablet. And since we have good safety data, we may go right ahead into clinical trials to restore normal biologic function of this this regulated inflammasome. And I'm hoping that the trials can start in the second quarter of this year.

Sheryl Stevenson: Excellent. We look forward to learning more about those trials. And how do you anticipate these results may help the clinician in day-to-day practice with their patients?

Dr Boyer: Well, we're hoping because it's, you know, systemic administration, we're hoping that we also will find that there'll be some renal improvement. Renal function goes very hand-in-hand basically with diabetic retinopathy. As renal function worsens, usually the retinopathy worsens, and some people believe you can even use this worsening as a guide to show that you'll be getting a worsening of the retinopathy.

So I think that it's, it's important to realize that, you know, our patients really have a hard time coming in, we can use this drug a little earlier in the cycle. They don't have to come in as often hopefully for evaluations, they don't have to receive the injection—which in many cases, you know, is well-tolerated and patients drive home. But in other cases, they have a day or day and a half that they're not feeling well that the eye is irritated, even with appropriate precautions after the injections are given. So I'm hoping that we start to see that we can start to have pills that will be able to help us and of course in addition when patients escape they will have the intravitreal injections, but hopefully they can be minimized.

Note: This transcript has been lightly edited for clarity.