ISTH0036 shows promise in treating retinal diseases

Marion Munk, MD, PhD, talked with Modern Retina® during the 2025 European Society of Retina Specialists (EURETINA) about a promising phase 2a clinical study of ISTH0036, an oligonucleotide antisense drug targeting TGF-β2.

Developed to address fibrosis in neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME), the drug showed unexpected benefits, including reduced fibrosis, anti-angiogenic properties, and improved visual acuity.

The research team is now preparing for phase 2b trials, seeking US Food and Drug Administration (FDA) approval and investor funding to further investigate this potentially groundbreaking treatment for retinal diseases.

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

Marion Munk, MD, PhD:

I'm very excited about this project. We just finalized the phase 2a study. It was called the BETTER study. It's actually a study looking at a new compound. It's called ISTH0036. It's an oligonucleotide antisense against TGF-β2. The target here is really to prevent, and now we've seen also reduced fibrosis in patients with neovascular AMD, but also in patients with diabetic macular edema. We included pre-treated as well as treatment-naive patients, and we treated them with ISTH0036.

What we saw over the course of the trial is that these patients, so the drug not only prevented and reduced fibrosis, we also saw that it has an anti-angiogenic property, so it was also drying the retina, and also in pre-treated DME patients, we saw further central retinal thickness reduction and further fluid reduction in patients previously treated with anti-VEGF when compared to our drug.

So we had very, very interesting findings here, and especially the prevention and regression of fibrosis is something, which is really of significant need in our patient population, because we know over the long term, this is the reason why patients lose vision, and even if the patients are stable and are not active at all, they develop fibrosis, and this will lead to long-term visual acuity decrease. In order to have something which is preventative for this would be very beneficial.

Our phase 1 trial was actually in patients undergoing trabeculectomy, and it was just 1 single individual injection of ISTH0036, and so we had no experience in like humans, what it will do to the fibrosis development and also how, whether it would have an anti-drying effect. Actually, we have never expected the results we've seen.

So first, we've seen in pre-treated patients who entered the trial dry and were continued on our drug. So the majority of patients remain dry on the one hand, and on the second, they gained additional vision. So this is something which you're not expecting when you have patients on anti-VEGF because once they are dry, you're not expecting that the visual acuity improves anymore. So you only try to prevent that the patient loses vision, while in this case is we really saw a visual acuity benefit in all these pretreated patients, which we didn't expect. We think it's due to the anti-EMT effect. So blocking TGF-β2 also blocks EMT. So the epithelial-mesenchymal tranformation, and this is usually a process. So what is happening is that a pigment epithelial cells, which is is a mesenchymal cells, epithelial cell, I'm sorry, transforms slowly into a mesenchymal cell. So becoming a scar tissue. When you block TTGF-β2, you can reverse this. So kind of this RPE cell can go back to its initial way and also to its initial way of functioning. This is how we think that this kind of visual acuity improvement works. So this was one thing we didn't expect.

The second thing we didn't expect that we saw drying effect beyond the anti-VEGF effect. We saw this in the pre-treated DME patients where patients still had residual fluid, but as soon as they were started on our drug, the patient dried out. So this was also something which was very encouraging and great to see. So this was a small phase 2a trial. So we had like 43 patients included and enrolled.

And now, of course, we are going into the phase 2b trial. So we are currently designing the trial. We are talking with the FDA. We are preparing everything, the packaging, to the FDA and to the EMA in order to get ready for a phase 2b, and of course, we are talking to potential investors in order to help us fund the phase 2b trial.

We will do 2 trials: 1 in DME and also one in neovascular AMD. In neovascular AMD, we will include pre-treated as well as treatment-naive patients. In DME, similarly to a certain extent. In neovascular AMD, we will probably have a non-inferiority and superiority study all-in-one, so we will have 3 arms, and 1 arm will be compared in a non-inferior fashion, and the other 1 will be a combination arm which will kind of target the superiority way. In diabetic macular edema, we will have a primarily non-inferiority study with the primary endpoint being central retinal thickness. In In neovascular AMD, it will be best correct visual acuity.

But I can't tell more because, you know, it's still in process, and we are still talking to all the other key opinion leaders, to the FDA, and to other advisors in order to get the best study design possible.