What Are the Opportunities and Challenges to Drug Development for Diabetic Retinopathy?

Contributor(s)s : Emma McFadden, PhD - Director, CNS and Ophthalmology | Himanshu Jain, M.S. Pharm - Lead Analyst, CNS & Ophthalmology Disorders | Ruchita Kumar, PhD - Lead Analyst, CNS & Ophthalmology Disorders

Publish date: 11 Dec, 2018

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Diabetic retinopathy (DR) occurs as a consequence of diabetes and is the leading cause of visual impairment and blindness among the working-age population.1 With the prevalent DR population expected to grow over the next decade and the limited options available to treat DR, commercial opportunity for the development of efficacious and safe pharmacotherapies to treat DR is sizeable, although such development is not without challenges.

What is the current treatment landscape for diabetic retinopathy without diabetic macular edema?

The treatment of DR is dependent on the severity of the disease, with DR classified into nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).2 NPDR is a slowly progressing less-severe stage of the disease, which can be mild, moderate, or severe, whereas PDR is a rapidly progressing late-stage that threatens a patient’s vision. All patients with DR can also develop vision-threatening diabetic macular edema (DME), although this complication is more common in the advanced stages of DR. DME also typically necessitates treatment, making disease management more complex. Indeed, when edema involves the center of the macular, intravitreal (IVT) pharmacotherapies, such as vascular endothelial growth factor (VEGF) inhibitors, are usually administered to restore vision. However, in the absence of this macular edema, which represents the majority of DR patients, drug treatment is currently uncommon. Patients with mild to moderate NPDR without DME are typically managed with systemic control only, while panretinal photocoagulation (PRP) has been the standard of care (SOC) for patients with PDR for several decades. Some patients with severe NPDR without DME are also treated with PRP but more often these patients are managed with systemic control and close observation.

What drives drug-development opportunities in diabetic retinopathy without diabetic macular edema?

  • Large and growing prevalent population: With the growing diabetic population and population ageing, DRG estimates that the prevalent DR population will grow to 20 million over the next ten years in the G7.3
  • Limitations of current treatment options: Although PRP reduces the risk of severe vision loss in PDR patients and causes regression of the disease, the treatment is associated with side effects, such as peripheral vision loss, which drives a need for alternative treatment options.4 Additionally, because the risk of vision impairment increases as the disease progresses from NPDR to PDR, there is a need for therapies that can arrest or reduce the rate of disease progression early in the course of DR.
  • Established regulatory pathway and increasing evidence of the benefit of pharmacologic treatment: With Roche/Genentech’s Lucentis 0.3 mg becoming the first pharmacotherapy approved for the treatment of DR without DME in the United States in 2017,5 the regulatory pathway for approval of a drug for this indication was established. Lucentis’s label was expanded to include all DR patients based on results from the DRCR.net Protocol S trial in PDR patients. The American Academy of Ophthalmology’s Preferred Practice Pattern in DR now recommends anti-VEGF treatment as an alternative to PRP for some PDR patients and notes that Lucentis could be considered for severe NPDR patients where PRP would otherwise be an option.2 Indeed, evidence is growing on the potential utility of VEGF inhibitors in the treatment of DR patients without DME and the anticipated approval of Regeneron’s Eylea in the United States in 2019 and Novartis’s Lucentis 0.5 mg in Europe in 2020 for DR is expected to further strengthen the position of these agents in the treatment of DR without DME.6

What are the challenges to drug development in diabetic retinopathy without diabetic macular edema?

  • Lack of routine screening of DR and less-than optimal diagnosis rates for DR: According to the American Academy of Ophthalmology, only ~60% of diabetics in the United States undergo screenings for DR each year.2 Interviewed experts in most of the major markets highlight that lack of routine, effective screening programs for DR is a substantial concern,6 which prevents timely diagnosis and contributes to a lower than-optimal diagnosis rate in prevalent DR patients. Given that a majority of patients with DR do not experience any symptoms and remain undiagnosed until the disease has advanced to PDR or to DME, this could limit the eligible treatment pool for pharmacotherapies to treat DR without DME.
  • Competition from laser photocoagulation: Although PRP is associated with some side effects, it typically only requires one or a few procedures, whereas long-term follow-up is needed with Lucentis in DR without DME.4 Moreover, five-year results from the Protocol S study do not indicate a substantial efficacy advantage for Lucentis over PRP in PDR patients over the long term,6 which raises questions around the efficacy benefit of using a VEGF inhibitor in these patients. The anticipated high cost associated with the VEGF inhibitors, especially compared with PRP, could also limit their use, particularly in countries with cost-sensitive markets.
  • Resistance by patients and ophthalmologists to frequent IVT delivery: Because DR patients without DME may not always experience vision loss, frequent invasive administration of an IVT pharmacotherapy may not be considered feasible or attractive by ophthalmologists or patients, as indicated by DRG primary research, in part due to safety and tolerability concerns.3 Indeed, the burden of repeated follow-up visits with anti-VEGF agents could be a challenge for the largely working-age DR population, thus limiting the commercial potential of IVT-administered agents in DR. Self-administered therapies with proven efficacy and safety would likely be a preferred option by DR patients without DME, including for patients with early stages of DR.

What is the market outlook for diabetic retinopathy without diabetic macular edema?

Shifting the treatment paradigm for DR patients without DME to VEGF inhibitors will be an uphill task for multiple reasons, including the need for frequent IVT administrations and follow-up visits, the high cost associated with approved VEGF inhibitors, and the lack of a major efficacy benefit over PRP. The performance of these drugs in this patient segment hinges on the degree of acceptance by ophthalmologists, patients, payers, and health authorities. However, we currently expect that expanded labeling of VEGF inhibitors for DR without DME and increasing evidence of the benefit of these agents will establish a drug-treated population for DR without DME over the next decade.5 Nevertheless, opportunity will remain for the development of additional drugs to treat DR without DME, especially for efficacious and safe agents with non-IVT routes of administration. Although such agents are in early-phase development, some have the advantage of treating both eyes simultaneously, which is an attractive feature because DR frequently occurs in both eyes.

Contact us today to learn how to access DRG’s diabetic retinopathy and diabetic macular edema research and reports: 


  1. National Eye Institute, Facts About Diabetic Eye Disease, accessed December 6, 2018.


  1. American Academy of Ophthalmology, DR Preferred Practice Pattern. December 2017 (https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2017).
  2. Decision Resources Group. Diabetic Retinopathy | Epidemiology | Mature Markets Data. January 2018.
  3. Zhao Y, Singh RP. The role of anti-vascular endothelial growth factor (anti-VEGF) in the management of proliferative diabetic retinopathy. Drugs Context. 2018;7:212532.Genentech, press release, April 27, 2017.
  4. Decision Resources Group. Diabetic Retinopathy/Diabetic Macular Edema | Disease Landscape & Forecast | G7 (update publishing in December 2018).
  5. Gross JG, et al. Five-year outcomes of panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA Ophthalmol. 2018;136:1138-1148.

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