Diabetic Retinopathy
`What You Should Know
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`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`National Institutes of Health
`National Eye Institute
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`Mylan Exhibit 1044
`Mylan v. Regeneron, IPR2021-00880
`Page 1
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`Joining Petitioner: Apotex
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`What You Should Know
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`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`National Institutes of Health
`National Eye Institute
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`Mylan Exhibit 1044
`Mylan v. Regeneron, IPR2021-00880
`Page 1
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`Joining Petitioner: Apotex
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`The National Eye Institute (NEI) conducts and supports
`research that leads to sight-saving treatments and plays a
`key role in reducing visual impairment and blindness. NEI is
`part of the National Institutes of Health, an agency of the
`U.S. Department of Health and Human Services.
`
`For more information, contact—
`National Eye Institute
`National Institutes of Health
`2020 Vision Place
`Bethesda, MD 20892–3655
`Telephone: 301–496–5248
`Email: 2020@nei.nih.gov
`Website: www.nei.nih.gov
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`About Diabetic Retinopathy
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`Detection
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`Prevention and Treatment
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`What You Can Do
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`Current Research
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`Additional Resources
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`Contents
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`About Diabetic Retinopathy
`
`What is Diabetic Retinopathy?
`Diabetic retinopathy is a complication of diabetes and the
`leading cause of vision impairment and blindness among
`working-age adults. It occurs when diabetes damages the tiny
`blood vessels in the retina, which is the light-sensitive tissue
`at the back of the eye. Diabetic retinopathy may lead to
`diabetic macular edema (DME), which is a swelling in an area
`of the retina called the macula.
`
`Diabetic retinopathy involves damage to the retina,
`the light-sensitive tissue at the back of the eye.
`
`What causes diabetic retinopathy?
`Chronically high blood sugar from diabetes is associated with
`damage to the tiny blood vessels in the retina, leading to
`diabetic retinopathy. The retina detects light and converts it
`to signals sent through the optic nerve to the brain. Diabetic
`retinopathy can cause blood vessels in the retina to leak fluid
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`or hemorrhage (bleed), distorting vision. In its most advanced
`stage, new abnormal blood vessels proliferate (increase in
`number) on the surface of the retina, which can lead to
`scarring and cell loss in the retina.
`
`Diabetic retinopathy may progress through four stages:
`
`1. Mild nonproliferative retinopathy. Small areas of balloon-
`like swelling in the retina's tiny blood vessels, called
`microaneurysms, occur at this earliest stage of the disease.
`These microaneurysms may leak fluid into the retina.
`
`2. Moderate nonproliferative retinopathy. As the disease
`progresses, blood vessels that nourish the retina may swell
`and distort. They may also lose their ability to transport
`blood. Both conditions cause characteristic changes to the
`appearance of the retina and may contribute to DME.
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`3. Severe nonproliferative retinopathy. Many more blood
`vessels are blocked, depriving blood supply to areas of the
`retina. These areas secrete growth factors that signal the
`retina to grow new blood vessels.
`
`4. Proliferative diabetic retinopathy (PDR). At this advanced
`stage, growth factors secreted by the retina trigger the
`proliferation of new blood vessels, which grow along
`the inside surface of the retina and into the vitreous
`gel, the fluid that fills the eye. The new blood vessels
`are fragile, which makes them more likely to leak and
`bleed. Accompanying scar tissue can contract and cause
`retinal detachment—the pulling away of the retina from
`underlying tissue, like wallpaper peeling away from a wall.
`Retinal detachment can lead to permanent vision loss.
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`Detection
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`What is diabetic macular edema (DME)?
`DME is the build-up of fluid (edema) in a region of the retina
`called the macula. The macula is important for the sharp,
`straight-ahead vision that is used for reading, recognizing
`faces, and driving. DME is the most common cause of vision
`loss among people with diabetic retinopathy. About half
`of all people with diabetic retinopathy will develop DME.
`Although it is more likely to occur as diabetic retinopathy
`worsens, DME can happen at any stage of the disease.
`
`Who is at risk for diabetic retinopathy?
`People with all types of diabetes (type 1, type 2, and
`gestational) are at risk for diabetic retinopathy. Risk increases
`the longer a person has diabetes. Between 40 and 45 percent
`of Americans diagnosed with diabetes have some stage of
`diabetic retinopathy, although only about half are aware of
`it. Women who develop or have diabetes during pregnancy
`may have rapid onset or worsening of diabetic retinopathy.
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`Detection
`What are the symptoms of diabetic retinopathy and DME?
`The early stages of diabetic retinopathy usually have no
`symptoms. The disease often progresses unnoticed until it
`affects vision. Bleeding from abnormal retinal blood vessels
`can cause the appearance of "floating" spots. These spots
`sometimes clear on their own. But without prompt treatment,
`bleeding often recurs, increasing the risk of permanent vision
`loss. If DME occurs, it can cause blurred vision.
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`The same scene as viewed by a person normal vision (left) and
`with (center) advanced diabetic retinopathy. The floating spots
`are hemorrhages that require prompt treatment. DME (right)
`causes blurred vision.
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`How are diabetic retinopathy and DME detected?
`Diabetic retinopathy and DME are detected during a
`comprehensive dilated eye exam that includes:
`
`1. Visual acuity testing. This eye chart test measures a
`person’s ability to see at various distances.
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`2. Tonometry. This test measures pressure inside the eye.
`
`3. Pupil dilation. Drops placed on the eye’s surface dilate
`(widen) the pupil, allowing a physician to examine the
`retina and optic nerve.
`
`4. Optical coherence tomography (OCT). This technique
`is similar to ultrasound but uses light waves instead of
`sound waves to capture images of tissues inside the
`body. OCT provides detailed images of tissues that can be
`penetrated by light, such as the eye.
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`A comprehensive dilated eye exam allows the doctor to
`check the retina for:
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`Prevention and Treatment
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`1. Changes to blood vessels
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`2. Leaking blood vessels or warning signs of leaky blood
`vessels, such as fatty deposits
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`3. Swelling of the macula (DME)
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`4. Changes in the lens
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`5. Damage to nerve tissue
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`If DME or severe diabetic retinopathy is suspected, a
`fluorescein angiogram may be used to look for damaged or
`leaky blood vessels. In this test, a fluorescent dye is injected
`into the bloodstream, often into an arm vein. Pictures of the
`retinal blood vessels are taken as the dye reaches the eye.
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`Prevention and Treatment
`How can people with diabetes protect their vision?
`Vision lost to diabetic retinopathy is sometimes irreversible.
`However, early detection and treatment can reduce the risk
`of blindness by 95 percent. Because diabetic retinopathy
`often lacks early symptoms, people with diabetes should
`get a comprehensive dilated eye exam at least once a year.
`People with diabetic retinopathy may need eye exams more
`frequently. Women with diabetes who become pregnant
`should have a comprehensive dilated eye exam as soon as
`possible. Additional exams during pregnancy may be needed.
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`Studies such as the Diabetes Control and Complications
`Trial (DCCT) have shown that controlling diabetes slows
`the onset and worsening of diabetic retinopathy. DCCT
`study participants who kept their blood glucose level as
`close to normal as possible were significantly less likely than
`those without optimal glucose control to develop diabetic
`retinopathy, as well as kidney and nerve diseases. Other trials
`have shown that controlling elevated blood pressure and
`cholesterol can reduce the risk of vision loss among people
`with diabetes.
`
`Treatment for diabetic retinopathy is often delayed
`until it starts to progress to PDR, or when DME occurs.
`Comprehensive dilated eye exams are needed more
`frequently as diabetic retinopathy becomes more severe.
`People with severe nonproliferative diabetic retinopathy have
`a high risk of developing PDR and may need a comprehensive
`dilated eye exam as often as every 2 to 4 months.
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`How is DME treated?
`DME can be treated with several therapies that may be used
`alone or in combination.
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`Anti-VEGF Injection Therapy. Anti-VEGF drugs are injected
`into the vitreous gel to block a protein called vascular
`endothelial growth factor (VEGF), which can stimulate
`abnormal blood vessels to grow and leak fluid. Blocking
`VEGF can reverse abnormal blood vessel growth and
`decrease fluid in the retina. Available anti-VEGF drugs
`include Avastin (bevacizumab), Lucentis (ranibizumab), and
`Eylea (aflibercept). Lucentis and Eylea are approved by the
`U.S. Food and Drug Administration (FDA) for treating DME.
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`Prevention and Treatment
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`Avastin was approved by the FDA to treat cancer, but is
`commonly used to treat eye conditions, including DME.
`
`The NEI-sponsored Diabetic Retinopathy Clinical Research
`Network compared Avastin, Lucentis, and Eylea in a clinical
`trial. The study found all three drugs to be safe and
`effective for treating most people with DME. Patients who
`started the trial with 20/40 or better vision experienced
`similar improvements in vision no matter which of the three
`drugs they were given. However, patients who started the
`trial with 20/50 or worse vision had greater improvements
`in vision with Eylea.
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`Most people require monthly anti-VEGF injections for the
`first six months of treatment. Thereafter, injections are
`needed less often: typically three to four during the second
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`The retina of a person with diabetic retinopathy and
`DME, before (left) and after anti-VEGF treatment
`(right). The large white circle is the optic nerve. The
`bright yellow spots are fatty deposits. Note that they
`have mostly cleared after treatment.
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`six months of treatment, about four during the second
`year of treatment, two in the third year, one in the fourth
`year, and none in the fifth year. Dilated eye exams may be
`needed less often as the disease stabilizes.
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`Avastin, Lucentis, and Eylea vary in cost and in how often
`they need to be injected, so patients may wish to discuss
`these issues with an ophthalmologist.
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`Focal/grid macular laser surgery. In focal/grid macular laser
`surgery, a few to hundreds of small laser burns are made to
`leaking blood vessels in areas of edema near the center of
`the macula. Laser burns for DME slow the leakage of fluid,
`reducing swelling in the retina. The procedure is usually
`completed in one session, but some people may need more
`than one treatment. Focal/grid laser is sometimes applied
`before anti-VEGF injections, sometimes on the same day or
`a few days after an anti-VEGF injection, and sometimes only
`when DME fails to improve adequately after six months of
`anti-VEGF therapy.
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`Corticosteroids. Corticosteroids, either injected or
`implanted into the eye, may be used alone or in
`combination with other drugs or laser surgery to treat DME.
`The Ozurdex (dexamethasone) implant is for short-term use,
`while the Iluvien (fluocinolone acetonide) implant is longer
`lasting. Both are biodegradable and release a sustained
`dose of corticosteroids to suppress DME. Corticosteroid use
`in the eye increases the risk of cataract and glaucoma. DME
`patients who use corticosteroids should be monitored for
`increased pressure in the eye and glaucoma.
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`Prevention and Treatment
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`How is proliferative diabetic retinopathy (PDR) treated?
`For decades, PDR has been treated with scatter laser surgery,
`sometimes called panretinal laser surgery or panretinal
`photocoagulation. Treatment involves making 1,000 to 2,000
`tiny laser burns in areas of the retina away from the macula.
`These laser burns are intended to cause abnormal blood
`vessels to shrink. Although treatment can be completed in
`one session, two or more sessions are sometimes required.
`While it can preserve central vision, scatter laser surgery may
`cause some loss of side (peripheral), color, and night vision.
`Scatter laser surgery works best before new, fragile blood
`vessels have started to bleed. Recent studies have shown
`that anti-VEGF treatment not only is effective for treating
`DME, but is also effective for slowing progression of diabetic
`retinopathy, including PDR, so anti-VEGF is increasingly used
`as a first-line treatment for PDR.
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`What is a vitrectomy?
`A vitrectomy is the surgical removal of the vitreous gel in
`the center of the eye. The procedure is used to treat severe
`bleeding into the vitreous, and is performed under local or
`general anesthesia. Ports (temporary water-tight openings)
`are placed in the eye to allow the surgeon to insert and
`remove instruments, such as a tiny light or a small vacuum
`called a vitrector. A clear salt solution is gently pumped into
`the eye through one of the ports to maintain eye pressure
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`during surgery and to replace the removed vitreous. The
`same instruments used during vitrectomy also may be used
`to remove scar tissue or to repair a detached retina.
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`Vitrectomy may be performed as an outpatient procedure
`or as an inpatient procedure, usually requiring a single
`overnight stay in the hospital. After treatment, the eye
`may be covered with a patch for days to weeks and may be
`red and sore. Drops may be applied to the eye to reduce
`inflammation and the risk of infection. If both eyes require
`vitrectomy, the second eye usually will be treated after the
`first eye has recovered.
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`What You Can Do
`What should I ask my eye care professional?
`You can protect yourself against vision loss by working in
`partnership with your eye care professional. Ask questions
`and get the information you need to take care of yourself
`and your family.
`
`What are some questions to ask?
`About my eye disease or disorder…
`• What is my diagnosis?
`• What caused my condition?
`• Can my condition be treated?
`• How will this condition affect my vision now and in
`the future?
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`What You Can Do
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`• Should I watch for any particular symptoms and notify
`you if they occur?
`• Should I make any lifestyle changes?
`
`About my treatment…
`• What is the treatment for my condition?
`• When will the treatment start and how long will it last?
`• What are the benefits of this treatment and how
`successful is it?
`• What are the risks and side effects associated with this
`treatment?
`• Are there foods, drugs, or activities I should avoid while
`I'm on this treatment?
`• If my treatment includes taking medicine, what should I
`do if I miss a dose?
`• Are other treatments available?
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`About my tests…
`• What kinds of tests will I have?
`• What can I expect to find out from these tests?
`• When will I know the results?
`• Do I have to do anything special to prepare for any of
`the tests?
`• Do these tests have any side effects or risks?
`• Will I need more tests later?
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`What if treatment doesn’t improve vision?
`An eye care professional can help locate and make referrals
`to low vision and rehabilitation services and suggest devices
`that may help make the most of remaining vision. Many
`community organizations and agencies offer information
`about low vision counseling, training, and other special
`services for people with visual impairment. A nearby school
`of medicine or optometry also may provide low vision and
`rehabilitation services.
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`What research is being done?
`The NEI is conducting and supporting research that seeks
`better ways to detect, treat, and prevent vision loss in
`people with diabetes. This research is being conducted in
`labs and clinical centers across the country.
`
`For example, the Diabetic Retinopathy Clinical Research
`Network (DRCR.net) conducts large multi-center trials to
`test new therapies for diabetic eye disease, and to compare
`different therapies. The network formed in 2002 and
`comprises more than 350 physicians practicing at more than
`140 clinical sites across the country. Many of the sites are
`private practice eye clinics, enabling the network to quickly
`bring innovative treatments from research into community
`practice.
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`NEI-funded scientists are also seeking ways to detect
`diabetic retinopathy at earlier stages. For example,
`researchers are harnessing a technology called adaptive
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`Additional Resources
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`optics (AO) to improve imaging techniques such as OCT.
`AO was developed by astronomers seeking to improve the
`resolution of their telescopes by filtering out distortions in
`the atmosphere. In the clinic, diagnostic devices that use
`AO may improve the detection of subtle changes in retinal
`tissue and blood vessels.
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`Where can I get more information?
`For more information about diabetic retinopathy,
`you may wish to contact:
`
`American Academy of Ophthalmology
`P.O. Box 7424
`San Francisco, CA 94120–7424
`415–561–8500
`www.aao.org
`www.eyecareamerica.org (Online Referral)
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`American Diabetes Association
`1701 North Beauregard Street
`Alexandria, VA 22311
`1–800–342–2383 (National Headquarters)
`703–549–1500
`1–888–342–2383 (Washington DC Office)
`Email: askada@diabetes.org
`www.diabetes.org
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`American Foundation for the Blind
`2 Penn Plaza, Suite 1102
`New York, NY 10121
`1–800–232–5463
`212–502–7600
`E-mail: afbinfo@afb.net
`www.afb.org
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`American Optometric Association
`243 North Lindbergh Boulevard, Floor 1
`St. Louis, MO 63141–7851
`314–991–4100
`Toll-free (800) 365-2219
`www.aoa.org
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`Council of Citizens with Low Vision International
`2200 Wilson Blvd. Suite 650
`Arlington, VA 22201
`1–800–733–2258
`Email: president@cclvi.org
`www.cclvi.org
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`Juvenile Diabetes Research Foundation International
`26 Broadway
`New York, NY 10004
`1–800–553–CURE (2873)
`(212) 785-9500
`Fax: (212) 785-9595
`Email: info@jdrf.org
`www.jdrf.org
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`Mylan v. Regeneron, IPR2021-00880
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`Additional Resources
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`National Eye Institute
`National Institutes of Health
`2020 Vision Place
`Bethesda, MD 20892–3655
`301–496–5248
`Email: 2020@nei.nih.gov
`www.nei.nih.gov
`
`National Institute of Diabetes and Digestive and Kidney
`Diseases Clearinghouses Publications Catalog
`5 Information Way
`Bethesda, MD 20892–3568
`1–800–860–8747
`TTY: 1-866-569-1162
`Fax: 301-634-0716
`Email: catalog@niddk.nih.gov
`www.niddk.nih.gov
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`Prevent Blindness
`211 West Wacker Drive, Suite 1700
`Chicago, IL 60606
`1–800–331–2020
`Email: info@preventblindness.org
`www.preventblindness.org
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`U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
`National Institutes of Health
`National Eye Institute
`Revised 9/15
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