On April 17, 2017, the United States Food and Drug Administration (FDA) granted approval to the injectable drug Lucentis (generic name ranibizumab) for the treatment of proliferative diabetic retinopathy (PDR), a serious vision-related complication of diabetes.
Previously, the FDA approved Lucentis for the treatment of diabetic macular edema (DME), a buildup of fluid in the macula, the center of the retina. Thus, with this latest treatment advance and FDA approval, physicians can use Lucentis to manage diabetic retinopathy in people with or without diabetic macular edema.
Important Background On this Research from The Journal of the American Medical Association
Results from an important clinical trial revealed that the injectable drug Lucentis is highly effective in treating proliferative diabetic retinopathy, a serious vision-related complication of diabetes.
The research, titled Panretinal Photocoagulation [i.e., laser treatment] vs Intravitreous Ranibizumab [i.e., Lucentis injection] for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial, was published online as an open-source article in the November 13, 2015 edition of The Journal of the American Medical Association and was timed to coincide with a presentation by the study authors at the 2015 Annual Meeting of the American Academy of Ophthalmology. The authors are the members of the Writing Committee for the Diabetic Retinopathy Clinical Research Network.
The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a collaborative research group that supports the identification, design, and implementation of multi-center clinical research studies focused on diabetes-related eye and retinal disorders, including diabetic retinopathy and diabetic macular edema. The DRCR.net was formed in September 2002 and currently includes over 115 participating sites with over 400 physicians throughout the United States. It is funded by the National Eye Institute (NEI).
“These findings,” said Dr. Paul Sieving, Director of the National Eye Institute (NEI), “provide crucial evidence for a safe and effective alternative to laser therapy against proliferative diabetic retinopathy.” The clinical trial was funded by NEI, which described Lucentis as the first major advance in therapy for proliferative diabetic retinopathy in nearly 40 years. Although longer-term follow-up will be needed, Lucentis may provide a reasonable treatment alternative, at least through two years, for persons with proliferative diabetic retinopathy.
About Diabetic Eye Disease and Diabetic Retinopathy
Although people with diabetes are more likely to develop cataracts at a younger age and are twice as likely to develop glaucoma as people who do not have diabetes, the primary vision problem caused by diabetes is diabetic retinopathy, the leading cause of new cases of blindness and low vision in adults aged 20-65:
- “Retinopathy” is a general term that describes damage to the retina.
- The retina is a thin, light-sensitive tissue that lines the inside surface of the eye. Nerve cells in the retina convert incoming light into electrical impulses. These electrical impulses are carried by the optic nerve to the brain, which interprets them as visual images.
- Diabetic retinopathy occurs when there is damage to the small blood vessels that nourish tissue and nerve cells in the retina.
- “Proliferative” is a general term that means to grow or increase at a rapid rate by producing new tissue or cells. When the term “proliferative” is used in relation to diabetic retinopathy, it describes the growth, or proliferation, of abnormal new blood vessels in the retina. “Non-proliferative” indicates that this process is not yet occurring.
- Proliferative diabetic retinopathy affects approximately 1 in 20 individuals with the disease.
Four Stages of Diabetic Retinopathy
According to the National Eye Institute, diabetic retinopathy has four stages:
- Mild non-proliferative retinopathy: At this early stage, small areas of balloon-like swelling occur in the retina’s tiny blood vessels.
- Moderate non-proliferative retinopathy: As the disease progresses, some blood vessels that nourish the retina become blocked.
- Severe non-proliferative retinopathy: Many more blood vessels become blocked, which disrupts the blood supply that nourishes the retina. The damaged retina then signals the body to produce new blood vessels.
- Proliferative retinopathy: At this advanced stage, signals sent by the retina trigger the development of new blood vessels that grow (or proliferate) in the retina and the vitreous, which is a transparent gel that fills the interior of the eye. Because these new blood vessels are abnormal, they can rupture and bleed, causing hemorrhages in the retina or vitreous. Scar tissue can develop and can tug at the retina, causing further damage or even retinal detachment.
In addition, fluid can leak into the macula, the small sensitive area in the center of the retina that provides detail vision. This fluid can cause macular edema (or swelling), which can occur at any stage of diabetic retinopathy, although it is more likely to occur as the disease progresses.
Lucentis: An Anti-Angiogenic Drug to Treat Retinal Bleeding
Angiogenesis is a term used to describe the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. Sometimes, however, excessive and abnormal blood vessel development can occur in diseases such as cancer (tumor growth) and retinal disease.
Substances that stop the growth of these excessive blood vessels are called anti-angiogenic (anti=against; angio=vessel; genic=development), and anti-neovascular (anti=against; neo=new; vascular=blood vessels).
The focus of current anti-angiogenic drug treatments for retinal disease is to reduce the level of a particular protein (vascular endothelial growth factor, or VEGF) that stimulates abnormal blood vessel growth in the retina and macula; thus, these drugs are classified as anti-VEGF treatments and are administered by injection directly into the eye after the surface has been numbed.
At present, these anti-VEGF drugs (Lucentis, Avastin, and Eylea) require monthly injections or a pro re nata [meaning “as needed”] (PRN) regimen, with monthly controls and injections for recurrent or persistent blood vessel growth and retinal bleeding.
More about Lucentis and Diabetic Retinopathy Research
Excerpted from Lucentis proves effective against proliferative diabetic retinopathy, via Science Codex:
A clinical trial among more than 300 patients has found that the drug ranibizumab (Lucentis) is highly effective in treating proliferative diabetic retinopathy (PDR), a complication of diabetes that can severely damage eyesight. The results demonstrate the first major therapy advance for the condition in nearly 40 years.
The trial compared Lucentis injections with a type of laser therapy called panretinal photocoagulation, which has remained the gold standard for PDR since the mid-1970s. Although laser therapy preserves central vision, it can damage night and side vision, so researchers have sought therapies that lack these side effects.
“Patients who received Lucentis showed a little bit better central vision, much less loss of their side vision, and substantially less risk for surgery than patients who received laser treatment,” said Lloyd Paul Aiello, M.D., Ph.D., director of the Beetham Eye Institute at Joslin Diabetes Center and Professor of Ophthalmology at Harvard Medical School. “These findings will change the available treatment options for patients with PDR.”
The DRCR.net enrolled 305 participants (394 eyes) with PDR in one or both eyes at 55 clinical sites across the country. Eyes were assigned randomly to treatment with Lucentis or laser. About half of the eyes assigned to the laser group required more than one round of laser treatment. In the other group, Lucentis was injected into the eye once per month for three consecutive months, and then as needed until the disease resolved or stabilized.
Because Lucentis is commonly injected to treat diabetic macular edema (DME) – a build-up of fluid in the center of the retina – the study permitted the use of Lucentis for DME in the laser group, if necessary. Slightly more than half (53 percent) of eyes in the laser group received Lucentis injections to treat DME. About 6 percent of eyes in the Lucentis group received laser therapy, mostly for issues other than DME.
At two years, vision in the Lucentis group improved by an average of about half a line on an eye chart, compared with virtually no change in the laser group. Participants treated with laser generally lost substantial peripheral vision, but those given injections did not. Additionally, the need for vitrectomy surgery was lower in the Lucentis group (8 of 191 eyes) than in the laser group (30 of 203 eyes).
Overall, the drug’s benefits are particularly clear for people with both PDR and DME. “We know that this drug will help treat both conditions at the same time, so this is an especially appealing treatment alternative for these patients,” Dr. Aiello noted.
The study also suggested that Lucentis may help prevent DME. Among people without this condition at the start of the study, only 9 percent of Lucentis-treated eyes developed it, compared with 28 percent in the laser group. Scientists will follow up on that result as the DRCR.net continues to track patients for a total of five years.
More about the Study from The Journal of the American Medical Association
Excerpted from the article abstract, with the full article available online:
Importance: Panretinal photocoagulation (PRP) is the standard treatment for reducing severe visual loss from proliferative diabetic retinopathy. However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME).
Objective: To evaluate the non-inferiority of intravitreous ranibizumab [i.e., Lucentis injections] compared with [laser] for visual acuity outcomes in patients with proliferative diabetic retinopathy.
Design, Setting, and Participants: Randomized clinical trial conducted at 55 US sites among 305 adults with proliferative diabetic retinopathy enrolled between February and December 2012 (mean age, 52 years; 44% female; 52% white). Both eyes were enrolled for 89 participants (1 eye to each study group), with a total of 394 study eyes. The final 2-year visit was completed in January 2015.
Interventions: Individual eyes were randomly assigned to receive PRP treatment, completed in 1 to 3 visits (n=203 eyes), or [Lucentis], 0.5 mg, by intravitreous [i.e., within the eye] injection at baseline and as frequently as every 4 weeks based on a structured re-treatment protocol (n=191 eyes). Eyes in both treatment groups could receive [Lucentis] for DME.
Main Outcomes and Measures: The primary outcome was mean visual acuity change at 2 years (5-letter non-inferiority margin; intention-to-treat analysis). Secondary outcomes included visual acuity area under the curve, peripheral visual field loss, vitrectomy, DME development, and retinal neovascularization.
Results: Mean visual acuity letter improvement at 2 years was +2.8 in the [Lucentis] group vs +0.2 in the PRP group. The mean treatment group difference in visual acuity area under the curve over 2 years was +4.2. Mean peripheral visual field sensitivity loss was worse, vitrectomy was more frequent, and DME development was more frequent in the [laser] group vs the [Lucentis] group, respectively. Eyes without active or regressed neovascularization at 2 years were not significantly different. One eye in the [Lucentis] group developed endophthalmitis [i.e., an inflammation of the eye, usually caused by infection]. No significant differences between groups in rates of major cardiovascular events were identified.
Conclusions and Relevance: Among eyes with proliferative diabetic retinopathy, treatment with [Lucentis] resulted in visual acuity that was non-inferior to (not worse than) [laser] treatment at 2 years. Although longer-term follow-up is needed, [Lucentis] may be a reasonable treatment alternative, at least through 2 years, for patients with proliferative diabetic retinopathy.