Shifting the Paradigm
Clinicians who manage patients with diabetic retinopathy (DR) are familiar with the unmet need associated with the insidious, progressive, and chronic eye disease: Despite the viability of interventions for more advanced stages and macular edema, there is uncertainty about the best injection treatment paradigm for patients with moderate to severe nonproliferative DR (NPDR).1
A role for anti-VEGF therapy seems rational: Periodic intravitreal injections have been demonstrated to reduce the risk of progression and improve DR severity, as well as reduce the risk of vision-threatening complications, including center-involved diabetic macular edema (DME).2,3 VEGF blockade effectively inhibits abnormal blood vessel growth and exudation and may reverse DME, the two most common causes of vision loss in DR.4 However, anti-VEGF therapy may not provide a significant benefit in 20% or more of eyes with NPDR.5 As well, a lifetime commitment that may be unsustainable or undesirable for many patients introduces the potential for serious injection-related complications (e.g., endophthalmitis, retinal detachment, sustained elevation of IOP) and is associated with uncertain benefit for long-term visual acuity.3,6
OcuTerra Therapeutics is developing a topical drug candidate, OTT166, which is designed to address these issues. A small molecule selective integrin inhibitor that is designed to disrupt the signaling cascade induced by multiple growth-factor-binding interactions involved in DR pathophysiology, OTT166 has demonstrated in preclinical and Phase 1 studies an ability to penetrate effectively through anterior ocular tissues (i.e., conjunctiva and sclera) to the retina at predicted therapeutic levels, thereby offering a potential noninvasive treatment opportunity for earlier active management.
In short, what OTT166 ultimately offers is the potential to shift DR treatment from a defensive, watch-and-wait posture to one in which treatment is proactive, thus allowing patients greater control over their outcomes.
“What we aim to do with OTT166 is to bring a noninvasive treatment option to DR patients that can allow earlier intervention when the eyecare professional deems it’s appropriate, so patients can take ownership of their treatment, hopefully obviating or reducing the need for more invasive treatments,” said David J. Tanzer, MD, Chief Medical Officer, OcuTerra.
Why Integrins?
Integrins have garnered significant interest as a high-value biological target due to their pivotal role in numerous signaling pathways. The integrin receptor family is organized into four classes on the basis of their structural similarities and ligand recognition patterns.7 Most relevant to DR (and other retinal disorders, including neovascular age-related macular degeneration) is the family of RGD-binding (arginine, glycine and aspartate) integrins, as they interact with other transmembrane receptors to amplify growth factor signaling intracellularly, including VEGF, PDGF, βFGF, and TGF-βR. In preclinical testing, OTT166 demonstrated an ability to block three crucial RGD-binding integrins: avβ3, avβ6, and avβ8, which are integral in modulating inflammation, vascular leakage, angiogenesis, and fibrosis associated with DR.8
“This molecule has potential to impact multiple aspects of DR pathology by inhibiting the integrin transmembrane receptor, which in turn could block or at least dampen the effects of other growth factors interacting with their respective transmembrane receptors,” explained Carl D. Regillo, MD, Chief of the Retina Service at Wills Eye Hospital, Philadelphia.
OTT166 is designed with purposeful engineering for topical delivery. Through fluorination and other physiochemical alterations, OTT166 has high lipophilicity and membrane permeability.8 Topical administration resulted in predicted therapeutic doses reaching the retina in preclinical studies (Figure 1).
“The molecular modification is really key,” Dr. Regillo said, “because that increases its potential bioavailability. Even if a compound has activity in vitro, the compound must reach the target tissue in patients to have the desired clinical activity.”
The Value Proposition
The risk of progression in DR is significant, with about 43.5% of untreated eyes with moderate or worse NPDR overall, and 68% with severe NPDR, developing center-involving DME or proliferative DR at 2 years.3 Despite approval of intravitreal anti-VEGF injections for DR without DME, the inherent limitations of its use in real-world clinical practice means that management of these patients is often reduced to watchful waiting and encouraging glycemic control, with prompt intervention upon evidence of progression (see Sidebar).9 The fundamental value proposition of a topical therapy that has the potential to stop the signaling of multiple growth factors in DR, including VEGF, PDGF, βFGF, and TGF-βR, is that it could change treatment from “watching and waiting” to proactive management and be a potentially acceptable alternative to intravitreal injections.
“We’re in search of a simpler, easier, safer way to prevent DR progression and complications that threaten vision,” Dr. Regillo said. “It could be in the form of an oral therapy, but an eye drop likely would be easier for patients to use, not subject to risks associated with injections or systemic exposure, and convenient.”
Update on Development
OTT166 has completed a phase 1b study that enrolled 40 eyes with DME secondary to DR in which patients were randomized to two dose groups, each treated twice daily for 28 days followed by 28 days of observation. The study met its primary endpoint, demonstrating safety and tolerability, with no reports of serious drug-related adverse events and no evidence of corneal toxicity. As well, the study drug demonstrated evidence of biological activity (Figure 2). On the basis of preclinical and Phase 1 study success, OcuTerra expects to begin a Phase 2 clinical trial later in 2022. The study aims to enroll ~200 patients with moderately severe to severe NPDR and mild proliferative DR (Diabetic Retinopathy Severity Scores 47, 53, and 61), randomized to a low-dose or high-dose OTT166 treatment group or vehicle control. The primary endpoint is the percentage of patients achieving two or more step improvements in Diabetic Retinopathy Severity Score. Secondary endpoints include prevention of progression to vision-threatening complications, delay time to intravitreal injection and/or panretinal photocoagulation, and a variety of exploratory imaging endpoints. Dr. Regillo will serve as the principal investigator of the study.
“For us, the next key is executing with excellence the Phase 2 study to assess the safety and efficacy of OTT166,” explained Kerrie Brady, BPharm, MS, MBA, Chief Executive Officer & President, OcuTerra. “Working closely with our advisors, we’ve prepared a robust protocol to generate appropriate data on important clinical endpoints that also will provide us with novel imaging endpoints. In order to do that, we’ve developed the team, we’ve secured the financing, and we’re ready to go forward with this program.”
Toward a Wider Range of Options for Nonproliferative Diabetic Retinopathy: The Patient Perspective
The world is facing an explosion in the prevalence of diabetic retinopathy (DR) over the next few decades. Current epidemiologic projections suggest that the number of Americans living with DR will double from around 7.7 million to 14.6 million by 2050, with even greater increases expected in certain ethnic populations.1 Meanwhile, about half of American adults either have prediabetes or diabetes,2 and about 8% to 13% of patients with prediabetes have retinopathy.3
The complex nature of managing patients with diabetes is already readily apparent in clinical practice. According to A. Paul Chous, MA, OD, FAAO, an optometrist specializing in patient care for individuals with diabetes and a nationally renowned diabetes educator, monitoring and treatment of diabetes and its complications is highly patient-specific, which places stress on providers and patients.
Dr. Chous explained, “These are patients already stressed about other diabetes complications, and they are really in search of solutions that will help preserve or save their vision.”
“Among the patients with worsening disease in the PANORAMA Trial, a lot of these patients had A1C in the sixes, which would seem to be protective. But study results showed that current blood glucose control wasn’t protective against progression to proliferative DR, anterior segment neovascularization, or center-involved diabetic macular edema (DME) in subjects with moderately severe or severe nonproliferative DR (NPDR) without center-involved DME at baseline; the horse is already out of the barn,” Dr. Chous said. “Good glycemic control is only effective against the most severe retinal disease when disease severity is absent or minimal, and a majority of patients don’t achieve excellent control within the first 5-10 years after diagnosis of their diabetes when ‘metabolic memory’—demonstrated in every major diabetes trial—is so important,” Dr. Chous added.
In this regard, a safe and effective topical treatment available for use in eyes with NPDR would be extremely meaningful, even beyond the potential to interrupt the progressive pathology.
“It would relieve a significant source of patient stress because it would give them something proactive they can do in addition to trying to achieve better blood glucose control,” Dr. Chous said.
1. National Eye Institute. Diabetic Retinopathy Data and Statistics. Available at: https://www.nei.nih.gov/learn-about-eye-health/outreach-campaigns-and-resources/eye-health-data-and-statistics/diabetic-retinopathy-data-and-statistics#:~:text=Projections%20for%20diabetic%20retinopathy%20(2010,1.2%20million%20to%205.3%20million. Accessed March 30, 2022.
2. The Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey. The Centers for Disease Control and Prevention. Accessed: April 1, 2022. Available at: https://www.cdc.gov/nchs/nhanes/index.htm
3. Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med. 2007;24(2):137-144.
4. Beck RW, Connor CG, Mullen DM, et al. The fallacy of average: how using HbA1c alone to assess glycemic control can be misleading. Diabetes Care. 2017;40(8):994-999.
1. ASRS. 2021 PAT Survey. ASRS. Available at: https://www.asrs.org/asrs-community/pat-survey. Accessed: April 18, 2022.
2. Brown DM, Wykoff CC, Boyer D, et al. Evaluation of intravitreal aflibercept for the treatment of severe nonproliferative diabetic retinopathy: results from the PANORAMA randomized clinical trial. JAMA Ophthalmol. 2021;139(9):946-955.
3. Maturi RK, Glassman AR, Josic K, et al; DRCR Retina Network. Effect of intravitreous anti-vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of diabetic retinopathy: the Protocol W randomized clinical trial. JAMA Ophthalmol. 2021;139(7):701-712.
4. Crawford TN, Alfaro DV 3rd, Kerrison JB, Jablon EP. Diabetic retinopathy and angiogenesis. Curr Diabetes Rev. 2009;5(1):8-13.
5. Wykoff CC, Eichenbaum DA, Roth DB, et al. Ranibizumab induces regression of diabetic retinopathy in most patients at high risk of progression to proliferative diabetic retinopathy. Ophthalmol Retina. 2018;2(10):997-1009.
6. Lim JI. Intravitreal aflibercept injection for nonproliferative diabetic retinopathy: year 2 results from the PANORAMA study. Invest Ophthalmol Vis Sci. 2020;61(7):1381-1381.
7. Van Hove I, Hu TT, Beets K, et al. Targeting RGD-binding integrins as an integrative therapy for diabetic retinopathy and neovascular age-related macular degeneration. Prog Retin Eye Res. Published online March 26, 2021.
8. Askew BC, Furuya T, Edwards DS. Ocular distribution and pharmacodynamics of SF0166, a topically administered αvβ3 integrin antagonist, for the treatment of retinal diseases. J Pharmacol Exp Ther. 2018;366(2):244-250.
9. Hahn P. ASRS Preferences and Trends Membership Survey. Presented at: American Society of Retina Specialists, 2021; Chicago, IL.
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