ISTH0036 Shows Unexpected Anti-Fibrotic and Visual Benefits in Phase 2a Retinal Disease Trial
Key Insights
ISTH0036, an oligonucleotide antisense drug targeting TGF-β2 (search), demonstrated unexpected benefits in a 43-patient phase 2a BETTER study for neovascular AMD (search) and diabetic macular edema (search).
The drug not only prevented and reduced fibrosis but also showed anti-angiogenic properties and improved visual acuity in pre-treated patients who were already dry on anti-VEGF (search) therapy.
Researchers are now preparing for phase 2b trials with FDA discussions underway, planning separate studies for DME and neovascular AMD (search) with different endpoints and study designs.
A novel oligonucleotide antisense drug targeting transforming growth factor-beta 2 (TGF-β2 (search)) has shown promising and unexpected results in treating retinal fibrosis, according to findings from the recently completed phase 2a BETTER study. The drug, ISTH0036, demonstrated benefits beyond its intended anti-fibrotic effects, including anti-angiogenic properties and visual acuity improvements in patients with neovascular age-related macular degeneration (AMD) and diabetic macular edema (search) (DME).
Unexpected Clinical Benefits Emerge
The phase 2a trial enrolled 43 patients, including both pre-treated and treatment-naive individuals with neovascular AMD (search) and DME. According to Marion Munk, MD, PhD, who led the research, the results exceeded expectations in multiple ways.
"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," Munk explained. In pre-treated DME patients, the treatment produced further central retinal thickness reduction and additional fluid reduction compared to previous anti-VEGF (search) therapy alone.
Perhaps most surprising was the visual acuity improvement observed in pre-treated patients who entered the trial already dry from previous anti-VEGF (search) treatment. "The majority of patients remain dry on the one hand, and on the second, they gained additional vision," Munk noted. "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."
Mechanism of Action
The researchers attribute the unexpected visual benefits to ISTH0036's anti-epithelial-mesenchymal transformation (EMT) effect. By blocking TGF-β2 (search), the drug appears to reverse the process by which retinal pigment epithelial (RPE) cells transform into scar tissue.
"When you block TGF-β2 (search), 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," Munk explained. "This is how we think that this kind of visual acuity improvement works."
Addressing Unmet Medical Need
The prevention and regression of fibrosis represents a significant unmet need in retinal disease management. As Munk emphasized, "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."
The phase 1 trial had been conducted in patients undergoing trabeculectomy with a single injection of ISTH0036, providing limited insight into the drug's potential effects on retinal fibrosis and fluid dynamics in the current indication.
Phase 2b Development Plans
The research team is now advancing toward phase 2b trials, with regulatory discussions already underway. "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," Munk said.
The phase 2b program will include two separate studies: one for DME and another for neovascular AMD (search). The neovascular AMD trial will include both pre-treated and treatment-naive patients in a three-arm design combining non-inferiority and superiority assessments, with best corrected visual acuity as the primary endpoint.
For DME, the study will primarily focus on non-inferiority with central retinal thickness as the primary endpoint. The team continues to refine the study designs through ongoing discussions with key opinion leaders, the FDA, and other advisors while seeking investor funding for the trials.