Most ophthalmologists are aware that Aerie Pharmaceuticals is developing Rho-kinase and norepinephrine transporter inhibitors (Rhopressa, or netarsudil) for the treatment of glaucoma, and that the company plans on filing its first NDA by the end of the quarter. Another product combines Rhopressa with leading glaucoma prostaglandin treatment latanoprost; that treatment is in phase 3 development.
But Aerie is just as interested in the posterior segment, said Casey C. Kopczynski, PhD, chief scientific officer.
“AR-13154 is a topical Rho-kinase inhibitor that also inhibits the kinases PDGF receptor and Janus kinase (JAK). The combination of these activities allows AR-13154 to address multiple different disease processes that underlie AMD, as well as diabetic retinopathy. Because of this, we think it has great potential as both a standalone therapy as well as an injunctive therapy to current anti-VEGF treatments,” he said.
Rhokinase has been shown in preclinical models to address “all three of the main drivers of disease: angiogenesis, inflammation, and fibrosis,” Dr. Kopczynski said. “This contrasts with the current anti-vascular endothelial growth factor therapies that are primarily anti-angiogenic.”
AR-13154 should be able to inhibit not only Rho-kinase, but also protein kinase C, PDGF receptor, and JAK. In a preclinical model of a laser-induced choroidal neovascularization (CNV) model, AR-13154 as a stand-alone therapy “was very effective at reducing lesion size in this model, and was numerically more effective that the positive control with Eylea [aflibercept, Regeneron].”
Aerie is also evaluating 0.06% AR-13154 as monotherapy and in conjunction with Eylea in an oxygen-induced mouse model of proliferative diabetic retinopathy (PDR), and early results show “the combination was substantially more effective than either of the two monotherapies alone,” Dr. Kopczynski noted.
With efficacy of the compound in both a monotherapy and adjunctive therapy established, Aerie is concentrating on drug delivery. Ideally, the company would like to deliver the treatment in a bioerodable implant that would only need to be injected every three to six months, said Dr. Kopczynski.
Preclinical proof of concept for long-term efficacy within the next six months is expected, and Aerie will begin its IND studies in the first quarter of 2017, he added.
Casey C. Kopczynski, PhD has served as our Chief Scientific Officer since co-founding our company in 2005. From 2002 to 2005, he was the Managing Partner at Biotech Initiative, LLC, a consulting practice dedicated to emerging biotech companies.
Casey C. Kopczynski: At Aerie we’re developing new therapies that target the root causes of vision loss in glaucoma and retinal disease. Our lead compound for glaucoma is Rhopressa, which lowers IOP by inhibiting rho kinase and norepinepherine transporter. We expect to file and NDA for Rhopressa by the end of this quarter. We have another product, Roclatan, which is a combination product of Rhopressa and latanoprost that’s currently in phase 3 development. Today I want to focus on our efforts in retinal disease, and specifically our lead compound for the treatment of age related macular degeneration and diabetic retinopathy, AR 13154. AR 13154 is a rho kinase inhibitor that also inhibits the kinase’s PDGF receptor and Janus kinase. The combination of these activities allows AR 13154 to address multiple different disease processes that underlie AMD and diabetic retinopathy. And because of this, we think it has great potential as both a stand-alone therapy as well as an adjunctive therapy to current anti-VEGF treatments. Rho kinase is actually an interesting new target for the treatment of AMD and diabetic retinopathy. In preclinical models, it has been shown to address all three of the main drivers of disease: angiogenesis, inflammation, and fibrosis. And this obviously contrasts with the anti-VEGF therapies that are focused primarily on treating angiogenesis and vascular leakage, and perhaps because of that, over time there appears to be a significant proportion of patients who progress on anti-VEGF therapy. So it’s possible that a highly selective inhibitor of rho kinase alone would be sufficient to address these main drivers of disease. However, in practice, multi-kinase inhibitors tend to be more effective, and particularly if one selects that kinases to have complimentary activity to one another. So we went to our library of 3000 different rho kinase inhibitors, and we selected 182 compounds representing different structural classes and activities, and we screened them against all available human kinases. Our goal was to identify molecules that inhibited not only rho kinase, but inhibited other kinases known to be important for angiogenesis, inflammation or fibrosis. And this screening is what identified AR 13154. It inhibits rho kinase, protein kinase C, PDGF receptor, and Janus kinase. Now PDGF receptor is obviously of interest because anti-PDGF molecules have been shown not only preclinically to inhibit angiogenesis and vascular leakage; the Fovista product in the clinic now has shown promise in phase 2 clinical studies as well. Protein kinase C is also an interesting target for reducing vascular leakage, and that’s supported by preclinical models of diabetes. Janus kinase is an interesting target for reducing inflammation based on the ability to reduce leukocyte adhesion. And PDGF inhibition also appears to have some anti-fibrotic activity. So we’ve tested AR 13154 as a monotherapy in a preclinical model of wet AMD, which is the laser induced CNV model. And we found that as a standalone therapy, it was very effective at reducing lesion size in this model, and in this study actually was numerically more effective than the positive control Eylea. We then wanted to test whether AR 13154 with its multiple different targets could be effective in combination with anti-VEGF therapy. And so we combined AR 13154 with Eylea in a model of – in an OIR model of retinal angiogenesis. And we found that that combination was actually substantially more effective than either of the two monotherapies alone. So with these experiments, we’ve demonstrated that AR 13154 is effective both as a standalone therapy and can be used adjunctively to anti-VEGF. Now that we’ve established efficacy, we’re focusing on delivery of AR 13154 to the back of the eye. Our objective is to deliver it as a bio erodible implant that will need to be injected once every 3 to 6 months. We expect to establish preclinical proof of concept for long term efficacy within the next 6 months, and to begin our IND enabling tox and CMC studies in the first quarter of 2017. So in summary, AR 13154 is a first in class, multi-kinase inhibitor that addresses some of the limitations of current AMD and diabetic retinopathy therapies. By targeting multiple disease processes, it has the potential to provide better longer term outcomes for patients. Through its unique mechanisms of actions, it can be used either as an adjunct to current anti-VEGF therapy, or we expect will provide efficacy as a standalone product. And with our planned dosing regimen of intravitreal injection every 3 to 6 months, we believe AR 13154 could reduce risk as well as treatment burden for both patients and physicians. Thank you.