Opthea, a public company listed on the Australian Stock Exchange, is developing OPT-302, a novel therapy for wet age-related macular degeneration (AMD). The company’s lead compound targets two alternative members of the vascular endothelial growth factor (VEGF) family, VEGF-C and VEGF-D, through a “trap” mechanism.
Currently approved anti-VEGF treatments, Lucentis and EYLEA, target VEGF-A. Long-term single-agent therapy with VEGF-A inhibitors is associated with a sub-optimal response in both visual acuity and persistent retinal fluid. VEGF-C levels in the retina increase with AMD disease severity, and VEGF-C is up-regulated when VEGF-A is inhibited.
Megan Baldwin, CEO and managing director, explained that “VEGF-C and D are important mediators of neovascular function – they induce angiogenesis as well as vascular permeability, and can also mediate non-neovascular functions as well, such as inflammation. We’re developing OPT-302 as a combination therapy with the existing anti-VEGF-A agents in order to mediate a more complete blockade of this very important VEGF receptor family. But we’re also potentially complementary to other novel therapies that are currently in development as well.”
A Phase I/IIa trial is being conducted at 14 clinical sites in the US, with ongoing recruitment into the Phase IIa dose expansion cohort. In the 20-patient Phase I study, OPT-302 was administered in combination with Lucentis or as monotherapy, in difficult-to-treat sub-responsive patients plus some treatment-naive patients. OPT-302 was safe and well tolerated in this study, and 16 of 19 evaluable patients maintained or gained vision from baseline to week 12, with no patient losing more than 3 letters. Improved outcomes in patients that were sub-responsive to prior anti-VEGF-A therapy suggest incremental benefit of VEGF-C and VEGF-D inhibition. Opthea plans to advance OPT-302 combination therapy into a Phase IIb trial in 2017.
Megan Baldwin, PhD
Dr Megan Baldwin is CEO/Managing Director of Opthea Limited and has over 19 years of experience in preclinical and clinical development of therapies for cancer and eye diseases.
Megan Baldwin, PhD: Good afternoon, everyone, and thanks to the organizers for this opportunity to present Ophthea’s program, developing OPT-302 for the treatment of wet age-related macular degeneration. So Ophthea, Ltd. is a public company. We’re listed on the Australian Stock Exchange under the ticker symbol OPT. And we are developing a lead compound called OPT-302, which targets two alternative members of the vascular endothelial growth factor family, VEGF-C and VEGF-D. So VEGF-C and D are important mediators of neovascular functions. They induce angiogenesis as well as vascular permeability. They can also mediate non-neovascular functions as well, such as inflammation, all of which are very important for – very much hallmarks of wet AMD as well as other ocular diseases. We’re developing OPT-302 as a combination therapy with the existing anti-VEGF-A agents in order to mediate a more complete blockade of this very important VEGF receptor family. But we’re also potentially complimentary to other novel therapies that are currently in development as well. We have an ongoing phase 1-2a clinical study that’s being conducted under an IND in the United States. We are currently recruiting into the phase 2a dose expansion cohort and have recently reported top line data from our phase 1 clinical trial. So the development strategy for OPT-302 is to address the suboptimal responses associated with long term, single agent therapy with VEGF-A inhibitors, including the suboptimal improvements in visual acuity and the persistent retinal fluid which is observed after long term treatment with a VEGF-A inhibitor. Resistance to VEGF-A inhibitors may indeed be related to other family members. The family goes beyond just VEGF-A, and in fact VEGF-C and D share overlapping signaling pathways with VEGF-A, as well as signal through an independent pathway through a separate receptor. OPT-302 targets VEGF-C and VEGF-D through a trap mechanism. It potently blocks both, blocking to the receptors, and can also block the consequential upregulation of VEGF-C and D, which can occur when VEGF-A is inhibited. Used in combination with a VEGF-A inhibitor, we can more completely block the VEGF pathway, prevent these elevations in these alternative family members, and target an incomplete response to VEGF-A inhibition. This concept of VEGF-C upregulation when VEGF-A is inhibited is demonstrated here, with the aqueous levels of VEGF-C significantly elevated following 1 and 2 months of therapy with Avastin following intravitreal injection in wet AMD patients. The design of our phase 1 2A clinical trial is shown in this slide. You can see here that we’re conducting the trial in essentially two parts. The first is a phase 1 dose escalation study of 20 patients, in which OPT-302 is combined at 3 sequential dose levels in combination with Lucentis. And in that phase 1 trial we’ve also enrolled 5 patients to receive the monotherapy of the drug as well. The phase 2a clinical trial is currently still ongoing. We’re recruiting patients. That part of the study will recruit an additional 30 patients randomized to either monotherapy or the high dose combination cohort. The phase 1 clinical study recruited 20 patients, the majority of which presented with occult lesions; 17 of 20 presented with occult lesions, and we recruited one patient with a predominately classic lesion, and two patients with minimally classic lesions. Each patient in the study received three intravitreal injections of OPT-302, either alone or in combination with Lucentis over a 4-week period, with a week 12 follow up, one month after the third dose. The majority of our patients that were recruited in this clinical study were difficult to treat patients. They had received prior anti-VEGF-A therapy and had shown a sub-response to that therapy. And in addition, we recruited an additional 30% of patients that were treatment naïve. We successfully met the primary safety objective with this clinical study, as you can see here. We saw no drug related series adverse events, and no evidence of drug related immunogenicity. Overall, 16 out of 19 evaluable patients maintained or gained vision from baseline to week 12. No patient lost more than three letters in a study. Looking at the combination therapy across all patients enrolled that were treated with the combination, including both naïve and prior treated patients, we observed a mean visual acuity gain from baseline at week 12 of 8 letters overall, and a mean decrease in central subfield thickness from baseline to week 12 of 91 microns. Looking only at the naïve patients that we recruited and treated with the combination therapy, we recruited 4 patients in this phase 1 clinical study and observed a mean gain in visual acuity from baseline in those patients of 16.5 letters, together with a reduction in the central subfield thickness of 214 microns, which was a 42.7% reduction in the retinal thickness of these patients that were treatment naïve and treated with the combination. In our prior treated population, we had ten patients treated with the combination. The mean change in visual acuity at week 12 from baseline was 4 letters in this very difficult to treat patient population, and we saw a further reduction of 11% in the central retinal thickness of this prior treated patient population, many of whom had received extensive prior therapy, some up to 55 prior injections. In our monotherapy cohort, three of the five patients did not rescue therapy with Lucentis. Of the 2 patients that were rescued, they were rescued relatively early. At week 12, both had indeed continued to lose vision compared to baseline. So they indeed were very difficult to treat patients, and Lucentis therapy did not achieve any improvement in visual acuity in those patients. At week 12 in those patients that did not require rescue therapy, the mean visual acuity gain in those monotherapy patients was 3 letters from baseline. One patient experienced a 6 letter gain, and a mean increase in retinal thickness of 18 microns, which we believe is clinical stable. So just to finalize and summarize our program, we have a program which is a trap molecular targeting to alternative members of the VEGF pathway that a potential to address a large unmet medical need for wet AMD, given that the current treatments are only target VEGF-A. We’ve met our primary safety objective at the phase 1 study, and we’ve provided evidence of clinical activity from this 20 patient clinical study. Those patients that were treated with the combination showed mean visual acuity gains and retinal thickness improvements that were equal to or superior to historic 12-week data with Lucentis alone, despite having a very heavily pretreated patient population, and patients with a high proportion of occult lesions. In naïve patients, our data suggests that there is a meaningful additional VA gain and a reduction in CST over and above what we would expect with Lucentis alone. And we saw a stabilization in the monotherapy group. The totality of our data warrant advancing OPT-302 combination therapy into a phase 2b randomized, controlled trial, and the planning for that study is underway now, and we expect to initiate that in 2017. Right now we’re actively accruing into our dose expansion cohorts of the phase 2A clinical study. Thank you very much.