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`AMD~ Americ.an
`Macular Degeneration Treatments
`
`Macular
`Degeneration
`Foundation
`
`Macular degeneration treatment breakthroughs inspire hope that someday we may
`see a cure to this disease. Promising treatments, described below, depend upon the
`stage of disease progression.
`
`The treatment for early dry AMD is generally nutritional therapy, with a healthy diet
`high in antioxidants to support the cells of the macula.
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`If AMD is further advanced but still dry, supplements are prescribed, to add higher
`quantities of certain vitamins and minerals which may increase healthy pigments
`and support cell structure.
`
`Until recently the only available treatment to seal leaking blood vessels associated
`with wet AMD was with a laser. The earliest treatment was Laser Photocoagulation.
`Between 1979 and 1994, the Macular Photocoagulation Study Group conducted a
`number of clinical trials that enrolled patients with CNV lesions (Choroidal
`Neovascularization) in one or both eyes. Each affected eye was randomly assigned to
`either laser treatment or observation. For eligible eyes with CNV in extrafoveal,
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`https://www.macular.org/treatments
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`Privacy • Terms
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`Novartis Exhibit 2258.001
`Regeneron v. Novartis, IPR2021-00816
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`juxtafoveal and subfoveal locations, laser treatment reduced the risk of severe visual
`loss.
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`Laser photocoagulation was followed by Photodynamic Therapy (PDT) with
`Visudyne™ (a drug injected intravenously and used to help direct the laser to the
`affected area). Visudyne™ therapy is a two-step procedure that can be performed in
`a doctor's office. First, Visudyne™ is injected intravenously into the patient's arm.
`The drug is then activated by shining non-thermal laser light into the patient's eye.
`Visudyne™ therapy involves the use of a specifically-designed laser that produces
`the low-level, non-thermal light required to activate the drug which results in a
`selective destruction of the unwanted leaking vessels. The procedure seals off
`leaking vessels while leaving healthy ones intact and is believed to be a major
`improvement over previous laser treatments. In one large clinical trial,
`photodynamic therapy with Visudyne™ photosensitizer delayed or prevented loss of
`vision during at least one year follow-up in patients with predominantly classic CNV
`lesions. Unfortunately I even the most successful treatments do not preclude
`reoccurrence, making multiple treatments likely. However, the rate of vision loss
`may be slowed down and some sight may be preserved. It is important to understand
`that this drug is not a cure. At best it preserves the status quo: It will not restore
`vision that has already been lost.
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`In sum, there are three major limitations of laser photocoagulation treatments.
`First, not more than 10-15% of CNV lesions are small enough and sufficiently
`delineated by fluorescent angiography to be eligible for laser treatment. Second,
`even if laser treatment is initially successful, there is at least 50% chance that
`leakage will recur during the next two years. Many such recurrences are amenable to
`additional treatment if detected early, which means that patients need careful
`monitoring after the first treatment. Finally I at least half of patients post-treatment
`with sufficiently well-circumscribed CNV lesions still have some leakage beneath
`the center of the fovea. Laser treatment leads to immediate reduction in central
`vision in these patients with leakages, but with sufficient follow-up, the extent of
`visual loss is less in laser treated eyes than in untreated eyes. Nevertheless, these
`existing laser therapies are limited in their effectiveness and may also lead to
`scarring of the macula and additional vision loss.
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`https://www.macular.org/treatments
`
`Privacy • Terms
`
`Novartis Exhibit 2258.002
`Regeneron v. Novartis, IPR2021-00816
`
`
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`Because of the limitations of laser treatment, researchers and physicians are in
`search of macular degeneration treatment breakthroughs, in order to maintain
`vision for a longer period of time without repeated laser use. They are also looking
`for new therapies which would be effective for all types of wet AMO.
`
`VEGF is an acronym for vascular endothelial growth factor. Currently, the most
`common and effective clinical treatment for wet Age-related Macular Degeneration
`is anti-VEGF therapy - which is periodic intravitreal (into the eye) injection of a
`chemical called an "anti-VEGF." In the normal life of the human body, VEGF is a
`healthy molecule which supports the growth of new blood vessels. In the case of
`macular health, though, VEGF is unhealthy. It promotes the growth of new, weak
`blood vessels in the choroid layer behind the retina, and those vessels leak blood,
`lipids, and serum into the retinal layers. The leakage (hemorrhaging) causes
`scarring in the retina and kills macular cells, including photoreceptor rods and
`cones.
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`An intraocular shot of an anti-VEGF drug inhibits the formation of new blood
`vessels behind the retina and may keep the retina free of leakage. An injection in the
`eye can be a disconcerting experience, and it may take several treatments to become
`accustomed to the procedure. However, the shot is usually not painful because the
`eye has been anesthetized. The procedure takes about fifteen minutes. Usually the
`appointment requires an hour. The effect lasts for a month or maybe more.
`
`Researchers report high rates of success with anti-VEGF injections, including
`receding blood vessels behind the retina, a far slower progression of the disease,
`and, in some cases, moderate gains made in vision. In some parts of the world, anti(cid:173)
`VEGF treatments have reduced the incidence of legal blindness by 50 percent.
`However, they have noted that injections of even small amounts of anti-VEGF drugs
`though research is inconclusive - have an effect on vascular function in
`could -
`the rest of the body. Strokes and hemorrhaging are two concerns, but because
`cardiovascular disease is already often associated with Age-related Macular
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`https://www.macular.org/treatments
`
`Privacy • Terms
`
`Novartis Exhibit 2258.003
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Degeneration, any data available to date about strokes or hemorrhaging has been
`difficult to interpret.
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`Several anti-VEGF drugs are being developed to inhibit VEGF by trapping it or
`preventing it from binding with elements which will stimulate growth. Chemically
`synthesized short strands of RNA (nucleic acid) called "aptamers» prevent the
`binding ofVEGF to its receptor. The various forms of anti-VEGF injections include
`ranibizumab (Lucentis, made by Genentech/Novartis), bevacizumab (off label
`Avastin from Genentech), and the recently Food and Drug Administration-approved
`aflibercept (Eylea/VEGF Trap-Eye from Regeneron/Bayer ). Each of these chemicals
`works in a different way to inhibit blood vessel growth.
`
`Side effects of intravetreal injections may include:
`
`• Serious eye infection that may include eye pain, light sensitivity, vision changes.
`• Increased eye pressure
`• Retinal detachment
`• Vitreous floaters
`
`Consult with your retinal specialist to make certain you understand what all the side
`effects might be.
`
`American Macular Degeneration Foundation
`P.O. Box515
`Northampton, MA 01061-0515
`413.268.7660 - Contact us
`1-888-MACULAR(l-888-622-8527)
`Privacy Policy
`https://www.macular.org/treatments
`
`Privacy • Tenns
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`Novartis Exhibit 2258.004
`Regeneron v. Novartis, IPR2021-00816
`
`
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`AMDF is a 501(c)(3) non-profit, publicly supported organization (Charity ID #04-3274007).
`Contributions are tax deductible to the extent allowed by law.
`
`https://www.macular.org/treatments
`
`Privacy • Tenns
`
`Novartis Exhibit 2258.005
`Regeneron v. Novartis, IPR2021-00816
`
`