Diabetic eye disease: The urgent need for early, non-invasive treatments

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Dr Catherine Beech, CEO at Exonate and Dr Pete Adamson, CSO at Breye Therapeutics discuss the need for better therapies to treat diabetic retinal disease and current progress in the field.

Diabetic retinal disease, termed diabetic retinopathy (DR), is a significant risk factor for people with Type I or II diabetes, and one that increases with time as patients experience repeated and continued issues with glycaemic control. Up to half of all patients with type II diabetes will develop a form of DR after 20 years, with approximately 27% of diabetes patients presenting with evident retinopathy at any one time1. Despite affecting such a large subset of diabetic patients, treatment options are limited to repeated, invasive intravitreal injections to the eye. To address this issue and improve patient wellbeing, there is a clear demand for the development of non-invasive therapies that can be administered earlier in disease progression.

Diabetic retinopathy – current treatments

The journey for patients with DR is one of increasing severity and loss of vision. The early stages – termed non-proliferative DR (NPDR) – can be observed on fundoscopy examination, and although not regarded as vision threatening, presents enhanced risk of transition to the vision-threatening, proliferative form of the disease (PDR) as severity increases. NPDR is measured using a composite score called the Diabetic Retinopathy Severity Score (DRSS). Specific numerical values (steps) denote the severity of NPDR, with 47-53 describing the moderately severe disease. PDR is associated with retinal structural damage and, in some cases, irreversible sight loss. One of several other events associated with NPDR is the emergence of centre-involved diabetic macular edema (ci-DME), a similarly vision threatening condition that can arise independently of the transition to PDR.

Presently, the ophthalmology community takes a ‘watch and wait’ approach to NPDR, waiting for patients to develop a vision threating event (VTE), such as ci-DME or PDR, normally predicated by a loss of visual acuity, before beginning treatment with regular intravitreal injections of vascular endothelial growth factor (VEGF) neutralising agents. The argument for this treatment delay is that NPDR is a quiescent disease, however, significant numbers of patients still progress to the later, more serious stages of disease. Disease progression is dependent on the severity of NPDR, although patients with severe NPDR are at 50% risk of progression to PDR within a year2. Within the clinical community, there is significant support for a novel approach enabling earlier intervention, to prevent or even reverse, the progression of NPDR. 

One pivotal Phase III study (PANORAMA), for Eylea (Aflibercept) met the FDA criteria of a meaningful clinical effect size, reversing NPDR by two-step changes in diabetic retinopathy severity score (DRSS) score and reducing the overall risk of progression to PDR by half. It also had a notable impact on overall of progression to VTEs, and is now approved for the treatment of NPDR. The PANORAMA study demonstrates that the progression of NPDR can be halted and reversed, and moreore importantly that such a reversal of NPDR leads to an absolute reduction in VTE progression. 

Despite these data, Eylea is not being used for the treatment of NPDR, perhaps due to the cost and the invasive nature of the treatment, which is via injections to the eye. The reluctance to treat moderate to severe NPDR may be overcome by the development of non-invasive treatments, which can be used earlier and would also have the added benefit of treating both eyes concurrently. 

Developing novel treatment strategies

Given the central role of VEGF in many of the pathological processes in DR and associated VTEs, it is no surprise that novel non-invasive therapies have focussed on targeting this core mechanism. Approaches using existing compounds, reformulated as topical eye drops to target VEGF-mediated signalling pathways, such as Bayer’s Regorafenib3, GSK’s Pazopanib4, and PanOptica’s PAN-90806 have been trialled, but have failed to show equivalent efficacy to intravitreal approaches. These agents may have limitations in exposing the retina to the therapeutic – which is not measurable in clinical studies. 

Retinal exposure is being addressed by the approach taken by Exonate. The company is developing a Serine/Arginine Rich Protein Kinase (SRPK-1) inhibitor which controls the splicing of VEGF mRNA, specifically increasing the potentially protective, anti-angiogenic VEGF-b isoform, at the expense of the pathogenic, pro-angiogenic VEGF-a isoform. The VEGF-a isoform is a key driver of disease progression, causing new growth of leaky blood vessels within the eye. Selective targeting would enable the therapy to treat the disease whilst not impacting the natural processes of VEGF. Early studies in mild NPDR/DME subjects have shown promising results, particularly on vascular leakage. Retinal penetration was co-optimised along with both target potency and selectivity, and there are plans to study this approach in more severe DR/DME. 

Other approaches, not specifically targeting VEGF, using topically applied steroid (Oculis, OCS-01) or integrin inhibitors (OcuTerra) continue in development, but have yet to start pivotal studies. Diabetic retinopathy (DR) is ultimately a disease of the retinal vasculature, which can be affected by therapeutics restricted to the plasma compartment, e.g orally administered compounds. Early development has focussed on mechanisms to control VEGF and inflammatory pathways, such as Occuphire (APX-3330), although companies such as Kalvista are addressing other mechanisms including the kallikrein system. However, little progress has been reported or studies have yielded disappointing outcomes, relative to intravitreally administered comparators. 

The use of oral agents also offers the opportunity to address other key mechanisms in DR pathophysiology, specifically capillary breakdown and vascular endothelial cell death. Capillary breakdown leads to retinal non-perfusion, regional hypoxia and the associated production of VEGF. Marketed anti-VEGF therapeutics effectively neutralise retinal VEGF levels and reduce both vascular leak and consequential oedema, resulting in a temporary improvement in vision, but do nothing to address the underlying pathology – capillary drop-out5. As such the vicious cycle of capillary drop-out, retinal non-perfusion, hypoxia and VEGF production continues, ensuring that there is ongoing disease progression which has a negative impact on neuroretinal function. 

Danegaptide, a small orally dosed molecule, has been noted to prevent capillary drop-out and retinal cell apoptosis. Currently in a Phase Ib/IIa study, it is believed to stabilise GAP-junction activity through regulation of connexin-43. This approach has been shown to reduce retinal vascular leakage with similar efficacy to intravitreal anti-VEGF agents. InfammX are also developing Xiflam, another connexin-43 targeting molecule aimed at modulating the functions of hemichannels in DR/DME and are currently conducting clinical studies.

A look to the future

As the global population ages and obesity levels rise, so does the prevalence of diabetes and associated eye complications. DR is the main cause of vision loss in the working age population, often occurring in both eyes and progressing to blindness. In 2019 there were >14.2 million diagnosed cases of diabetic retinopathy in the nine major pharmaceutical markets, expected to grow to >17.7 million by 2029, according to GlobalData. Early diagnosis is key to monitor and treat earlier stage DR, with some countries already establishing screening programmes to identify patients and offer support and treatment at an earlier stage. 

It has already been illustrated that NPDR is a modifiable disease, with a strong correlation with progression to VTEs, following the US approval of Eylea. These elements and supports the development of new approaches and mechanisms to better treat DR, beyond just neutralising excessive VEGF. To be widely adopted, there is an urgent need to develop non-invasive therapies that will improve patient welfare as well as compliance, and preserve vision long-term. This need is even more acute when considered in a global context, where in many regions intravitreal injections are not available and the disease remains entirely untreated.

As a global community we need to improve how we manage and care for patients with NPDR and ultimately halt and reverse the underlying microvascular complications of diabetes. After 20 years of successfully treating the later stage manifestations of the disease, the time has come to treat both eyes at earlier stages of disease and reduce the risk of progression to VTEs and irreversible vision loss.

DDW Volume 25 – Issue 2, Spring 2024

References:

  1. Thomas RL, Halim S, Gurudas S, et al. IDF Diabetes Atlas: A review of studies utilising retinal photography on the global prevalence of diabetes related retinopathy between 2015 and 2018. Diabetes Res Clin Pract. 2019;157:107840.
  2. Staurenghi G, Feltgen N, Arnold JJ, et al; VIVID-DME and VISTA-DME study investigators. Impact of baseline Diabetic Retinopathy Severity Scale scores on visual outcomes in the VIVID-DME and VISTA-DME studies. Br J Ophthalmol. 2018;102(7):954-958.
  3. Joussen AM, Wolf S, Kaiser PK, et al. The Developing Regorafenib Eye drops for neovascular Age-related Macular degeneration (DREAM) study: an open-label phase II trial. Br J Clin Pharmacol. 2019;85(2):347-355.
  4. Danis R, McLaughlin MM, Tolentino M, et al; Pazopanib Eye Drops Study Group. Pazopanib eye drops: a randomised trial in neovascular age-related macular degeneration. Br J Ophthalmol. 2014;98(2):172-8.
  5. Alagorie AR, Velaga S, Nittala MG, et al. Effect of Aflibercept on Diabetic Retinopathy Severity and Visual Function in the RECOVERY Study for Proliferative Diabetic Retinopathy. Ophthalmol Retina. 2021;5(5):409-419.

About the authors

Catherine BeechCatherine Beech is co-founder and CEO of Exonate, leading the company’s commercial and corporate development. Beech has over 25 years of biotech and pharmaceutical industry experience. She started her medical career in the NHS, followed by 12 years with multinational pharmaceutical companies both in the USA and Europe. 

 

Pete AdamsonPete Adamson is CSO at Breye Therapeutics. Prior to Breye, Adamson was VP and Global Head of the Retinal Disease Area Stronghold at Janssen, where he was in part responsible for gene-therapy programs directed at X-linked Retinitis Pigmentosa (XLRP), achromatopsia, and other monogenic retinal diseases, as well as leading the acquisition of AAV2-sCD59 for geographic atrophy age-related macular degeneration.

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