What supported Lucentis’s most recent approval?


Genentech announced on April 17, 2017 that Lucentis had been approved in the United States for the treatment of all types of diabetic retinopathy (DR), expanding on the previous product approval granted in February 2015 for the treatment of DR patients with coexisting diabetic macular edema (DME), and making it the first pharmacotherapy approved for DR in the absence of DME. Nontraditionally, this most-recent approval was based on results from the Protocol S trial1 conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net), a network that is funded by the National Eye Institute (NEI), which is itself a part of the National Institutes of Health (NIH); Genentech is reported as a collaborator on the trial. While Lucentis 0.3 mg was the dose initially approved for DR in patients with DME, and continues to be the dose approved for the expanded DR label, the Protocol S trial only included the Lucentis 0.5 mg dose, which is approved for all other indications. Additionally, Lucentis’s approval includes all patients with DR, even though the population in the Protocol S trial was largely reserved to patients with proliferative DR (PDR), the most advanced type of DR. According to Lucentis’s updated label, just over one-quarter of DR patients without DME experienced at least a three-step improvement in the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Score (ETDRS-DRSS), a measure of DR severity, while approximately 38% had at least a two-step improvement. No efficacy results are reported in the label compared with panretinal photocoagulation (PRP), the standard of care for PDR for several decades, which was used as the active comparator in the Protocol S trial.


How are DR patients currently being managed in the United States?


Primary market research conducted by Decision Resources Group suggests that the management of DR patients who do not have coexisting DME varies by disease severity—patients with less severe forms of DR (i.e., mild or moderate nonproliferative DR [NPDR]) are often treated with systemic control only, while PRP is the first-line treatment for patients with PDR. Patients with severe NPDR, a more advanced stage of DR, are often managed with systemic control only or some type of ophthalmic medical intervention (e.g., PRP). Indeed, our data indicate that, even after publication of the Protocol S trial results in November 2015, only a minority of patients with severe NPDR or PDR were treated with intravitreal (IVT) anti-vascular endothelial growth factor (VEGF) agents, such as Lucentis. This treatment approach is instead largely reserved for DR patients with coexisting DME, with IVT pharmacotherapy being the treatment of choice for patients with center-involved DME. Retinal specialists’ reluctance to treat DR patients who do not have coexisting DME with IVT anti-VEGF agents is driven largely by the perceived burden to patients, caregivers, and physicians of such treatment due to the frequent, up to monthly, dosing required with these therapies, as well as the potential for a lack of patient compliance and subsequent disease worsening. IVT injections also carry some safety risks, such as a risk of endophthalmitis, which physicians understandably want to minimize for their patients. Additionally, the expected cost of treating DR patients without DME with Eylea or Lucentis is a substantial obstacle to use, particularly given that, until now, these agents were not approved for this indication, with patients likely being subject to high out-of-pocket costs.


How is Lucentis’s expanded labeling likely to impact future treatment of DR?


Even with Lucentis’s label including the treatment of all DR patients, we expect that, in the absence of concomitant DME, Lucentis, as well as other anti-VEGF agents, will largely be reserved for patients with the most advanced form of DR (i.e., PDR). Although retinal specialists may appreciate an additional treatment option being approved—and likely reimbursed—for DR patients, Lucentis’s recommended dosing of one injection per month for the treatment of DR could be a barrier to use given that patients often need only one (or a few) PRP treatments. In addition, two year results from Protocol S demonstrated that Lucentis 0.5 mg was noninferior to PRP on mean change in visual acuity at two years, the primary endpoint in the trial, among the trial population (i.e., including the ~23% of patients with baseline center-involved DME with vision impairment). However, it should be noted that Lucentis demonstrated some significant advantages in the Protocol S trial compared with PRP, such as reduced peripheral visual field sensitivity loss, reduced need for vitrectomy, and, among patient without center-involved DME and vision impairment at baseline, a reduced probability of developing this condition. It is possible that these results may encourage some retinal specialists to prescribe Lucentis to their PDR patients without DME, although we do not expect this approval to be a substantial driver of future Lucentis sales in the United States. Interestingly, Regeneron is currently conducting the Phase III PANORAMA trial in the United States evaluating the efficacy of Eylea in improving moderately severe to severe NPDR (among patients who do not have DME threatening the center of the macula) using two undisclosed dosing regimens; we expect at least one of these regimens will involve less frequent dosing than Lucentis’s recommended monthly dosing schedule. Topline results from this trial are expected early next year, suggesting that, if Eylea demonstrates efficacy in this patient population, Lucentis would have more than one year of a first-to-market advantage over Eylea for DR exclusive of DME.


For more information related to the current treatment of DR and DME patients in the United States and Europe, please refer to the Diabetic Macular Edema/Diabetic Retinopathy | Current Treatment US and Diabetic Macular Edema/Diabetic Retinopathy | Current Treatment EU5 reports, respectively. For a more in-depth analysis of dynamics in the DR/DME market, please see our market assessment in Diabetic Macular Edema/Diabetic Retinopathy | Disease Landscape and Forecast | G7.


  1. Writing Committee for the Diabetic Retinopathy Clinical Research Network, et al. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2015;314:2137-2146.

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