Transformative Early and Patient-Centric Treatments for Retinal Diseases

Retinal diseases affected over 40 million people in 2020, a number that is expected to surge to over 70 million by 2040. These diseases — which include diabetic retinopathy, age-related macular degeneration (AMD), and diabetic macular edema (DME) — carry a significant burden that not only impacts a patient’s vision but their ability to work and their independence. While a number of therapies exist to treat these patients, they are typically invasive, adding to the burden on these patients, and, despite ongoing treatments including monthly intravitreal injections, vision outcomes also typically deteriorate over time. In addition, the current standard of care is not well suited to treating early stages of these diseases in the hope of stopping disease progression. As such, there is a critical unmet need to introduce therapies with novel mechanisms of action and more patient-centric delivery mechanisms to help patients receive longer-term benefits while reducing the burden of treatment. One company seeking to address this unmet need is OcuTerra Therapeutics, which, with their lead compound OTT166, is seeking to enable earlier and more patient-centric intervention for diabetic retinopathy.

From Fluorination to Ophthalmology

The genesis of OcuTerra Therapeutics reflects an interesting pivot in vision and focus. OcuTerra traces its origins to SciFluor Life Sciences, which was founded over a decade ago as a drug discovery company developing a best-in-class portfolio of therapeutics that strategically capitalized on the transformational power of a particular technique — fluorination. In this process, fluorine or fluorine-containing groups are strategically incorporated into drug molecules, changing the molecule’s physicochemical properties in a number of useful ways, with potential benefits in terms of increased half-life, improved safety and efficacy, tissue penetration, dosing, and patient compliance.

SciFluor emerged as a market leader among life sciences companies focused on selective fluorination, boasting a broad portfolio of differentiated therapies to treat a range of diseases, from pulmonary conditions to CNS disorders and retinal disease. However, one fluorinated drug candidate in that portfolio — now named OTT166 — demonstrated such promise that it initiated a tremendous internal change for the company.

OTT166 is a novel potent and selective small molecule integrin inhibitor developed for delivery as an eyedrop able to penetrate the barriers of the eye and to be accepted directly into the retina, SciFluor became OcuTerra Therapeutics, a clinical-stage drug development company focused on the treatment of ophthalmic diseases for which the progression of disease is not prevented or controlled by the current standard of care, according to OcuTerra’s Chief Executive Officer and President Kerrie Brady.

“There was an existing molecule that had very good activity against the target, which was a selective integrin inhibition. It was active orally for other indications, but it couldn’t be delivered by eyedrops to the retina at the back of the eye,” Brady says, explaining the origins of OTT166. That original molecule was developed by Merck as a candidate for the treatment of osteoporosis but not pursued further despite being relatively well-tolerated. However, after being tested for ophthalmologic use and modified by fluorine to create higher selectivity, increase its potency, and enable ocular delivery as an eyedrop formulation, OcuTerra was able to advance the molecule and in so doing transform the company and its mission. After OTT166 was optimized, it entered into Phase I clinical trials in patients with retinal disease. Following positive demonstration of OTT166’s safety and tolerability, as well as clear clinical evidence of biological activity, the company was able to raise $35 million in Series B financing, which cemented the pivot into a clinical-stage company focused on ophthalmic drug development.

Penetrating the Blood-Retinal Barrier

The critical differentiator for OTT166 — owing to that key addition of fluorine — is the molecule’s ability to treat the retina directly via an eyedrop, a notoriously difficult challenge. Drugs that are administered systemically, whether via oral solid dose or injectable, have traditionally faced a very literal barrier — enabling drugs to traverse the blood–retinal barrier has been a major challenge. The blood–retinal barrier, analogous to the blood–brain barrier, shields one of the most sensitive parts of the human anatomy from insult, but also makes drug delivery to the retina difficult. However, when administered in an eyedrop, OTT166 avoids the blood–retina barrier completely.

While OcuTerra imagines potentially broad applications for OTT166, the company is first focusing on non-proliferative diabetic retinopathy (NPDR), an early stage of diabetic retinopathy in which retinal blood vessels become weakened, leading to microaneurysms and swelling and typically progressing to proliferative diabetic retinopathy, which can result in severe vision loss and even blindness. The current standard of care for this condition includes monthly, invasive intravitreal injections, and/or destructive laser procedures, both of which considerably add to the burden faced by these patients.

OcuTerra hopes that the noninvasive, patient-centric delivery of OTT166 via eyedrops will slow progression of the disease or stop it entirely. “We have very compelling evidence and reason to believe that what we are working with here and what we’re taking into Phase II holds a lot of promise for a successful trial,” continues Brady. As diabetes is so prevalent and retinopathy is such a common development in diabetic patients over the course of their disease, the impact of OTT166 for maintaining healthy eyesight would be nearly unprecedented. Brady notes, “In working-age adults, diabetic retinopathy is the number one reason for vision loss.” As such, OTT166 presents a game-changing opportunity with the potential to change millions of lives.

Integrated Integrin Technology

Mechanistically, OTT166 achieves its therapeutic effect through selective inhibition of a subset of proteins called integrins — transmembrane protein receptors that enable cell-to-cell and cell-to–extracellular matrix adhesion that were recently linked to eye disorders. “There was starting to be some awareness about the role of integrins in angiogenesis and particularly the opportunity in ocular angiogenesis approaches,” Brady explains, lighting the spark that led to the molecule’s development.

There are actually 24 different integrins that function in the modulation of molecular signaling pathways associated with angiogenesis, including not only a range of retinal disorders, such as diabetic retinopathy, DME, and AMD, but also oncology. At present, OcuTerra is primarily interested in the RGD binding integrin receptors, which includes integrins αvβ3, αvβ6, and αvβ8, all of which have been implicated in the progression of retinal disease. This RGD sequence of integrins is the cell attachment site of many adhesive cellular surface proteins, the extracellular matrix, and blood. Over half of all integrin receptors recognize this motif in their adhesion protein ligands.

If there’s no activity, the integrins remain at rest, so to speak, but they work together when activated. Almost like a neighborhood watch, integrins sit on the outside of the cell surface and constantly monitor the environment of cell-to-cell interactions. “What‘s particularly interesting with αvβ3 integrin is that, when it’s stimulated, its actions are inside the cell, but it’s amplified and enhances the effects of growth factors that we know are the bad actors in angiogenesis — in particular, vascular endothelial growth factor — which is what you’re trying to knock out,” says Brady. “Inhibiting αvβ3 cuts signaling from multiple growth factors and modulates things going forward.”

In addition to VEGF, selective inhibition of αvβ3 has been shown to interfere with the signaling cascades of fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF), which are involved in angiogenesis and vascular leakage, while inhibition of αvβ6 and αvβ8 reduces fibrosis, a typical complication of retinal diseases.

Another added benefit of OTT166 is that the drug has demonstrated promising results even after cessation of treatment. “We saw a continuing benefit for another four weeks,” Brady explains. Though the team initially thought this result was attributable to a depot effect, it turned out to be even better. “We’re doing more than just blocking a receptor — we’re doing something to the whole system of interactions among these growth factors that takes a while to be reversed. We’ll see how that plays out as the development of selective integrin antagonists go forward, but, within the eyedrop delivery, if a patient forgets or occasionally misses a drop, it’s not as crucial as it might have been, because OTT166 delivers a longer-term effect.” This was a surprising development, especially for a small molecule delivered topically. Brady suggests that this benefit is likely more a result of hitting the right target than a characteristic of the OTT166 molecule itself.

While it’s hard to pinpoint how generalizable OTT166 may be for other ocular diseases involving angiogenesis, Brady emphasizes that OcuTerra Therapeutics has been very strategic on the molecule’s initial indication to ensure a clear alignment between patients need and the product profile. A noninvasive eyedrop therapy is an excellent match for early-stage NPDR patients, who currently represent a group with unmet medical needs but who are not well served by the current invasive standard of care.

However, Brady adds, “OTT166 also shows potential for the treatment of diabetic macular edema, which is a sight-threatening complication, in conjunction with intravitreal injections, and even with age-related macular degeneration. It may help improve response rates and further lengthen the intervals between needing to go to the clinic and get the injection.” Owing to the involvement of integrins in other indications associated with retinal angiogenesis, Brady suggests that there are many possibilities for OTT166 yet to be explored.

Phase II and Beyond

Brady notes that phase II trials of OTT166 are absolutely key to the company’s future direction. With funding secured, OcuTerra has developed its phase II protocol and is scheduled to being dosing patients in Q2 2022. Brady hopes to have the topline phase II readouts by early 2024, adding “We’ve got a host of activity occurring now to build the company out further. We have some other ideas for other indications and additional integrin products, but for now, our priority is getting this trial underway.”

A Powerhouse Team Leading a Company Built for the Future

Behind every successful company is a strong team, and the OcuTerra group is “small but mighty.” Brady is joined by Chief Medical Officer David J. Tanzer, M.D., an ophthalmologist with deep experience in clinical research on both drug and device development. “I think being an ophthalmologist, a clinician who has been in practice earlier in their career and seen these patients, who really understands at a much deeper level what the unmet need here is, is an extra motivation going forward,” Brady comments.

OcuTerra’s Chief Development Officer D. Scott Edwards, Ph.D., boasts an extensive background in big pharma R&D, particularly in small molecule therapeutics and medical imaging contrast agents, and is another holdover from the company’s first iteration. “He was one of the early team members in what was then SciFluor and was involved in actually creating the molecule and taking an active role in everything after that point — from the preclinical work to taking it into the clinic. He was there when they were doing the first-in-human study and he has quite a range of experience bringing that forward,” explains Brady.

Just joining the team in the role of Vice President of Clinical and Medical Affairs is Majid Anderesi, M.D., another ophthalmologist with many years of experience in ophthalmology drug development. The members of the leadership team average an impressive 30 years of industry experience.

In addition to having a strong team, the board of OcuTerra is as equally noteworthy. “Our Chairman of the Board (Vesper Healthcare CEO, president, and chairman) Brent Saunders joined just a year ago, and we’re the only ophthalmology company that he sits on the board of, given his broad experience — and that’s quite a coup for us. He believes in the promise of our molecule and our team to deliver on this.” All members of the board are also independent directors, focused on the company and its path forward. Two board members — William H. Koster and Robert Ruffolo — have 40 years of experience in Big Pharma overseeing drug development at the senior level and have had dozens of new molecular entities approved by the U.S. FDA on their watch.

A Bright Future in Ophthalmology

Making the leap to exclusively focus on ophthalmology has already proved rewarding. “There’s been a resurgence of interest in ophthalmology and new advances — that’s one of the areas where the first gene therapy was approved,” says Brady.

“I’ve worked in a number of different therapeutic areas in my career and I’ve really been struck by the vibrancy in ophthalmology. I haven’t seen it in other places. There’s amazing collaboration and interaction between academia, KOL clinicians, the eye care community, the companies, and even the FDA. All parties interact with each other and there’s an active dialogue which I think has helped a lot to move progress along. There’s a completely different culture,” she continues. “Perhaps it’s because there was a lot of collaboration around surgeons and surgical instruments and there has always been a strong surgical component to the history of ophthalmology — the drug component is relatively new.”

As for the future, Brady is expecting the best for OTT166. “I think in five years, we’ll be toward the end of the phase III program and moving forward from there,” she shares.

David Alvaro, Ph.D.

David is Scientific Editor in Chief of the Pharma’s Almanac content enterprise, responsible for directing and generating industry, scientific and research-based content, including client-owned strategic content, in addition to serving as Scientific Research Director for That's Nice. Before joining That’s Nice, David served as a scientific editor for the multidisciplinary scientific journal Annals of the New York Academy of Sciences. He received a B.A. in Biology from New York University in 1999 and a Ph.D. in Genetics and Development from Columbia University in 2008.