Angiogenesis 2024: Interim results from the first in-human Phase 2 RIPPLE-1 trial of a dexamethasone implant for DME and RVO

Baruch Kuppermann, MD, PhD, sat down with Ophthalmology Times to discuss the interim results from the first in-human Phase 2 RIPPLE-1 Trial of a dexamethasone implant for diabetic macular edema and retinal vein occlusion at the virtual Angiogenesis, Exudation, and Degeneration 2024 meeting. He shares some of the highlights here with Group Editorial Director Sheryl Stevenson.

Video Transcript

Editor's note - This transcript has been edited for clarity.

Sheryl Stevenson: We are joined today by Dr. Baruch Kuppermann, who is among the faculty at this year's Angiogenesis meeting. Welcome to you. We're really excited to learn more about the interim results from the first in-human phase 2 RIPPLE-1 trial. Can you tell us about that?

Baruch Kuppermann, MD, PhD: Sure, thanks for having me. And again, happy to participate in the Angiogenesis meeting. Still looking forward to it someday being live again but again reporting here from the Gavin Herbert Eye Institute behind me at University of California, Irvine.

What's exciting about this technology or this study is that it's a new technology. So this is another way to deliver dexamethasone. So this is a study that was conducted at two different doses of a drug delivery product containing dexamethasone, in patients with retinal vein occlusion and diabetic macular edema.

But of particular interest is the focus on the technology. What's unique about it [is] it's an injectable, biodegradable drug delivery system lasting between 6 and 9 months. What's unique about it is that there's no polymers, there's no other excipients, it is pure prodrug. So it's a dexamethasone prodrug with a linker, a chemical linker—not an excipient, not a polymer—that so that the entire implant is drug essentially. And the drug creates first order linear pharmacokinetics...as the implant disappears, the drug is disappearing with it.

So many other drug delivery systems that are polymer based elute the drug and again there's some erosion of polymer along the way, of course, but then when the drug is all gone, there's still a residual skeleton of polymer that takes another few months to dissolve. And so the mantra in design of those types of products is that you'd like to have the polymer implant be gone no longer than it took to elute all the drugs, so 2x. This is different.

When the implant is gone, the drug has been fully dissolved in the eye. There may still be residual drug in the eye, but there's no longer any polymer [or] anything else. So it's a very nice 1:1 ratio. And again, it's being looked at right now with dexamethasone, but what's interesting about this linker technology to create a prodrug is it depends on the chemical moieties and the compound, but depending on those chemical moieties that have to have certain end groups, which I discussed in my presentation, you can create different sort of form factors. It can be microspheres, it can be rods, it can be mesh. Also, different types of drugs are looking at tyrosine kinase inhibitors or possibility complement inhibition has been looked at as well.

So what's both exciting about it is the drug delivery of the dexamethasone with a durability of 6 to 9 months with full degradation of the product, but also the fact that it can be used in other sorts of technologies as other sorts of drugs as well. It's not suitable at the current time for the complex biologics that we inject. Very few companies are capable of doing that. But it's a unique prodrug based drug delivery technology with no excipients and no polymers at all in this. The results show a benefit with a dramatic reduction in supplemental need of injection of supplemental agents over a 6 to 9 month period of time. The diabetic patients with high dose had the best effect. The retinal vein occlusion had comparable effects in low dose and high dose, again 70 and 140 micrograms are these doses—very low doses for 6 to 9 months of dexamethasone.

And again, it looks promising and we don't yet have the full results. I'll be presenting the results to date. We hope to have the study fully completed by the end of 2024. But amongst the messaging is this technology is a particular interest. It's unique in that it's biodegradable without any polymers or excipients.

Stevenson: That's fascinating research. What might be a next step then in this process depending on the results?

Kuppermann: It depends on the results. They're interested in exploring this further. By the way, I should mention Ripple Therapeutics...why this study is called the RIPPLE-1 study...is based in Toronto. They also have a bimatoprost for the front of the eye for glaucoma that has a similar [where] you would inject that intracamerally in the anterior chamber and have a prolonged delivery of glaucoma agents, in this case, bimatoprost. They're interested in exploring other compounds as well.

The dexamethasone product is interesting. It does cause cataract and glaucoma similar to other steroid products so they're interested in both this but also developing other ones, particularly TKIs [tyrosine kinase inhibitors] and the complement inhibition to see if they could be fit into this platform because those are products that could use extended delivery. This is a nice way to do it via this...linker technology. It's an interesting modality that we're still understanding the full array of things that could be used with it but quite unique.