Topical Therapy – Empowering Patients to Administer Treatment at Home

Introduction

A new study published this month in JAMA Ophthalmology estimated that just under 10 million people in the United States are living with diabetic retinopathy (DR), and 1.84 million of those people have VTDR1 – vision-threatening diabetic retinopathy – that would necessitate active, invasive treatment.

The current strategy for treating patients with newly diagnosed DR is “watch and wait” – patients are advised to manage their glucose intake to help minimize exacerbation of disease and the progression of their DR is monitored, but at present there is no way to predict who will progress to the more advanced stages of disease. Because of the invasive nature of the current therapeutic options – laser photocoagulation and intravitreal injection of therapeutics – as well as potential adverse side effects, the risks may not outweigh the benefits during the earlier stages of disease, and they are only used once a vision-threatening development has occurred2. It is well established (and not surprising) that many people have an aversion to invasive therapies, often opting to let disease symptoms progress rather than go through with treatments; however, when you consider that the number of DR patients with vision-threatening disease doubled between 2004 and 20211, and is estimated to increase from 37.3 million to 56.3 million by 20303, this underscores the need for prompt action in developing alternative therapeutic modalities.

The problem of non-compliance with current therapeutic options 

The increasing prevalence of DR is linked to rising prevalence of diabetes4,5, which has now reached epidemic proportions in countries across the globe. At present, approximately 366 million people live with diabetes worldwide, and the numbers are increasing6. As DR is a progressive disease, the fact that better access to improved treatments is allowing patients to live longer is also increasing the number of patients who go on to develop vision-threatening retinopathies7. In diabetic patients up to 24 years old, more than 10% have DR; that figure increases to nearly 20% in patients aged 25 to 39 years, and 25% in patients over 401.

Intravitreal injection of anti-VEGF has shown great effectiveness in the treatment of DR, in part because it allows for the direct delivery of therapeutic agents to the retina. However, in order to be effective, regular, repeated injections are needed, which pose a serious treatment burden and increase the risk of complications. Further, studies evaluating early anti-VEGF treatment for DR have not demonstrated a functional benefit in preventing progression of DR over a four-year timespan and, as such, the risk/benefit to this treatment for DR oftentimes does not support active, invasive therapy2.

Treatment non-compliance is a significant factor in the observed disparity between real-world effectiveness and randomized clinical trials of anti-VEGF treatment; the reasons for non-compliance are multifactorial, but some of the major driving factors are logistical concerns such as taking time off work or finding a care giver to transport the patient to and from the clinic, and anxiety around the procedure itself. One study found that up to 30% of patients reported that fear of eye injections was a factor in avoiding treatment8.

Whatever the reasons leading to non-compliance, one study showed that as many as 95% of patients did not properly adhere to their regimens of intravitreal injection therapy, compared with around 10% non-compliance in a clinical trial setting8. Studies have demonstrated a clear link between a reduced adherence to the treatment regimen and poorer outcomes – including worsening and progression of disease9 – suggesting that non-invasive therapeutic options which encourage higher compliance could have a significant positive impact on the growing epidemic of diabetic retinopathy.

Development of eye drop based therapeutics 

Development of eye drop based therapeutics could potentially address these concerns by enabling patients to self-administer medication at home on a regular basis and starting treatment as soon as disease is diagnosed to improve retinal health and prevent disease progression. Earlier active treatment could possibly reduce or eliminate the need for intravitreal injection, laser photocoagulation, or both.

With all these obvious benefits, why are there still no approved eye drop based treatments for DR? One major factor is also the reason why intravitreal injection has been so successful – the physiology of the eye makes it difficult for topical or externally delivered therapeutics to access the retina. Our previous article covered some of the challenges in developing an effective eye drop therapeutic, and the strategies that OcuTerra has used in the development of OTT166, our novel selective integrin inhibitor designed to be delivered by eye drop, at home by the patient. OTT166 is currently under evaluation in the Phase 2 DR:EAM study to assess its safety and efficacy in the treatment of DR and to determine optimum dosing regimens for planned Phase 3 trials. Previous clinical trials have demonstrated unequivocal safety and clear evidence of biological activity and, if approved, OTT166 has the potential to empower patents with an early, non-invasive treatment option that could be used immediately upon diagnosis, rather than waiting for disease to progress.

Patients themselves have expressed an overwhelmingly positive view about the idea of a self-administered eye drop alternative to intravitreal injections, when speaking with OcuTerra10. In their own words:

“I have a lot of fatigue. So going in takes a lot out of me, and it's usually like a whole thing and then I have to rest the next day. So the eyedrops definitely would still be an easier option for me.”

“If that's just something I put next to my pill box and do it as I'm going to sleep? That's the least invasive. Not just physically, but also generally to my life.”

And as one person nicely summed up: “Obviously that would be preferable to having needles stuck in your eyes.”

References 

  1. Lundeen EA, Burke-Conte Z, Rein DB, et al. Prevalence of Diabetic Retinopathy in the US in 2021 [published online ahead of print, 2023 Jun 15]. JAMA Ophthalmol. 2023;10.1001/jamaophthalmol.2023.2289. doi:10.1001/jamaophthalmol.2023.2289

  2. Maturi RK, Glassman AR, Josic K, et al. Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy [published correction appears in JAMA. 2023 Mar 28;329(12):1034]. JAMA. 2023;329(5):376-385. doi:10.1001/jama.2022.25029 

  3. Zheng Y, He M, Congdon N. The worldwide epidemic of diabetic retinopathy. Indian J Ophthalmol. 2012;60(5):428-431. doi:10.4103/0301-4738.100542 

  4. Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004;122(4):552-563. doi:10.1001/archopht.122.4.552    

  5. Yang W, Lu J, Weng J, et al. Prevalence of diabetes among men and women in China. N Engl J Med. 2010;362(12):1090-1101. doi:10.1056/NEJMoa0908292

  6. IDF Diabetes Atlas. 5th ed. Brussels, Belgium: International Diabetes Federation; 2011. International Diabetes Federation.

  7. Nishimura R, LaPorte RE, Dorman JS, Tajima N, Becker D, Orchard TJ. Mortality trends in type 1 diabetes. The Allegheny County (Pennsylvania) Registry 1965-1999. Diabetes Care. 2001;24:823–7.

  8. Okada M, Mitchell P, Finger RP, et al. Nonadherence or Nonpersistence to Intravitreal Injection Therapy for Neovascular Age-Related Macular Degeneration: A Mixed-Methods Systematic Review. Ophthalmology. 2021;128(2):234-247. doi:10.1016/j.ophtha.2020.07.060

  9. Holz FG, Tadayoni R, Beatty S, et al. Key drivers of visual acuity gains in neovascular age-related macular degeneration in real life: findings from the AURA study. Br J Ophthalmol. 2016;100(12):1623-1628. doi:10.1136/bjophthalmol-2015-308166

  10. Horonjeff J, Stoltzfus L, Hernandez V. The Diabetic Retinopathy Patient Experience: 3 Focus group discussions, and one interview about the challenges and opportunities of the Diabetic Retinopathy patient journey. Internal report Facilitated by Savvy Cooperative in cooperation with OcuTerra. 2022

Brad Good