Ocular Therapeutix: Intravitreal Depot Technology for Retinal Drug Delivery

Ocular Therapeutix has built a portfolio of products around its proprietary hydrogel technology. ReSure Sealant is FDA approved for sealing clear corneal incisions following cataract surgery, Dextenza (dexamethasone intracanalicular depot) is in Phase III for ocular allergy and post-surgical pain, and a sustained-release travoprost depot is entering Phase III for glaucoma. The same proprietary hydrogel technology has been licensed to other companies across multiple specialties, with millions of patients treated.

At the OIS@ASRS Retina Company Showcase, Jonathan Talamo, MD, chief medical officer, reviewed the company’s intravitreal depot technology for retinal diseases. These depots are delivered through fine needle injection (25–27 gauge) and hydrate on contact with fluid, forming compact geometries to avoid impact on vision. The depots are designed to carry a six-month payload of drug that elutes with nearly zero order kinetics. The depots hydrolyze and absorb without removal after six to seven months.

“Immunotolerance has been a challenge for all intravitreal sustained drug delivery programs over many years,” said Dr. Talamo. The Ocular Therapeutix hydrogel materials are highly biocompatible, with low histopathology scores in rabbit models suggesting little or no inflammation.

Ocular Therapeutix is pursuing preclinical development of both large-molecule protein therapeutics and small-molecule drugs. Large-molecule development is focused on a bevacizumb (Avastin) loaded coil, which has been shown to suppress vascular leakage in a rabbit model for three months, compared with less than six weeks for an Avastin injection. Small-molecule efforts have been focused on a tyrosine kinase inhibitor (TKI) that has been approved for systemic use. Attempts to administer topical or systemic TKIs for wet age-related macular degeneration (AMD) have been limited by bioavailability and off-target effects. Preclinical testing has shown that the company’s intravitreal depot may provide effective local and sustained delivery of TKIs.


Jonathan Talamo

Jonathan Talamo, MD

Jonathan Talamo, MD, joined Ocular Therapeutix in 2016, bringing more than 25 years of experience as an ophthalmologist, innovator, and clinical investigator.

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Jonathan Talamo, MD: These are our forward looking statements. As many of you in the room know, Ocular Therapeutix brings deep expertise to its development of proprietary hydrogel technology for sustained drug release, in part through our experience commercializing ReSure Sealant. But what you may not know is that this same proprietary hydrogel technology has been licensed to many other companies across medicine in orthopedics, neurosurgery, cardiology, to treat millions of patients. So there’s deep experience across a number of different organ systems. We have multiple controlled release assets in clinical development, and I’m going to focus on our intravitreal depot technology today. But we also have a sustained release dexamethasone and Travoprost insert programs that work through intracanalicular placement. And we hope to see approval in the near term future of our dexamethasone delivery device for anterior segment diseases. Our intravitreal depots are delivered through small gauge, fine needle injections and hydrate on contact with fluid to form compact geometries, designed to avoid optical impact. In the case of our large molecule protease, this is a coil, and for small molecule tirase and kinase inhibitor, a thin, straight fiber. Each contains a six-month payload of drug designed to elute using close to zero order kinetics over time. And then these hydrolyze and absorb without removal after 6 to 7 months. They’re very biocompatible. I’ll show you some of that information today, and the strong IP backing provides good commercial potential for further development. Our intravitreal depot program we’ve named OTXIV, and this really has two components: the large molecule protein therapeutic program, and small molecule efforts, which are focused right now on approved tirase and kinase inhibitor for systemic use. And I’ll share our preclinical data for each with you. The video on your right is our current generation hydrogel coil depot, and you can see it rapidly folds upon itself after exiting a needle to form a compact configuration in the vitreous. The smooth and hydrophilic surface is very biocompatible, and we think is contributing to its good immuno-tolerance characteristics. The angiograms on your right are an example of a bevacizumab loaded coil implant, inhibiting vascular leakage in a rabbit VEGF challenge model. The graph on your left shown in blue is the performance in terms of leaking inhibition of the bevacizumab coil over 3-months’ time, in contrast to a conventional Avastin single dose injection in red and a blank hydrogel coil in black, which as you can see, did not inhibit any leakage. We’ve looked at several high molecular weight protein release – protein compounds in terms of their release kinetics over time in vitro, and you can see those graphed in blue here, releasing drug steadily over 4 to 5 months. The red plots at the bottom of the graph are the high molecular weight species, and those would be indicative of aggregation or inactivation and stability of these compounds. And really, there was very minimal in the way of high molecular weight products, suggesting high stability in the hydrogel. And this was confirmed by ELISA analysis at 4 to 6 months. I want to switch gears for a minute or two now and talk about our small molecule, TKI program. As many of you know, attempts to administer these compounds intravitreally have been limited by their low solubility and short half-lives. There have been a number of attempts, previous and ongoing to administer topical and systemic TKI’s for wet AMD, but as yet there have been no approvals. And these are difficult approaches because for topical, bioavailability is limited, and for systemic administration, off target effects of these drug classes can be an issue. We at Ocular Therapeutix think the solution is both local and sustained delivery, and hence our intravitreal depot program. These two panels are angiogram examples of a DLAAA rabbit model of continuous vascular leakage. The panels on your left show what you would expect from a single Avastin injection, which is recurrence of leakage by two months, whereas on the right, and you can see it in the shadow of the TKI implant, over the optic nerve there is continued suppression at eight weeks. And in the more common rabbit VEGF challenge model, we’ve demonstrated this effect, suppression of leakage, out to six months. Immunotolerance has been a challenge for all intravitreal sustained drug delivery programs over many year’s duration, and we continue to evaluate our product in this regard. But we are encouraged by what we’re seeing. The HNE sections here on your left are from a rabbit, a vitreous placement of a blank hydrogel coil at 4 months. And as you can see, there’s no inflammatory reaction associated. In this cohort of animals, we scored this inflammation, and as you can see, the mean scores were very low, a fraction of 1 on a zero to 5 scale with a tight standard deviation. So in closing, we’re encouraged by our progress to date with our preclinical programs for large molecule protein and small molecule TKI delivery. We hope to partner with a manufacturer of an existing approved anti-VEGF drug in the near future for our large molecule protein program, and hope to have some details of that soon. For small molecules, we are continuing internal development and, given the shorter time course for small molecules, hope to be in human clinical trials within the next year or so. Thanks for your attention.