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`BY EDIS
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`July 6, 2020
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`2001 M Street, NW Suite 600
`Washington, DC 20036
`+1 202 682 7000 tel
`+1 202 857 0940 fax
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`Robert T. Vlasis
`+1 (202) 682-7024
`robert.vlasis@weil.com
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`
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`The Honorable Lisa R. Barton
`Secretary to the Commission
`U.S. International Trade Commission
`500 E Street, SW, Room 112
`Washington, DC 20436
`
`
`Re: Certain Pre-filled Syringes for Intravitreal Injection and Components Thereof, DN 3460
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`Dear Secretary Barton:
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`Weil, Gotshal & Manges LLP hereby files the enclosed public interest statement on behalf of Szilárd
`Kiss, M.D. Weil, Gotshal & Manges LLP is representing Dr. Szilárd Kiss for the purposes of filing this
`statement.
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`Thank you for your attention to this matter.
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`Sincerely,
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`/s/ Robert T. Vlasis 1
`Robert T. Vlasis
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`Weil, Gotshal & Manges LLP, Counsel for Respondent Regeneron Pharmaceuticals, Inc.
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`Regeneron Exhibit 1086.001
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`UNITED STATES INTERNATIONAL TRADE COMMISSION
`WASHINGTON, D.C.
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`In the Matter of
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`CERTAIN PRE-FILLED SYRINGES FOR
`INTRAVITREAL INJECTION AND
`COMPONENTS THEREOF
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`Docket No. 3460
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`STATEMENT ON THE PUBLIC INTEREST BY SZILÁRD KISS, M.D.
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`Regeneron Exhibit 1086.002
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`My name is Szilárd Kiss, M.D., and I am an ophthalmologist, retinal specialist, and surgeon, and
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`the Associate Dean for Clinical Compliance and Associate Professor of Ophthalmology at Weill Cornell
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`Medical College. I received my B.A. in Biology from Columbia College in 1997 and my M.D. from
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`Columbia University in 2002. I was certified by the American Board of Ophthalmology in 2007. I have
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`over fifteen years of experience and am an expert in the treatment of ophthalmological diseases. My
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`clinical practice involves outpatient evaluation and management for complex vitreo-retinal pathologies
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`such as age-related macular degeneration, diabetic retinopathy, retinal vascular disorders, inherited retinal
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`degenerations, infectious and non-infectious uveitis, and inherited and acquired maculopathies.
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`I have been retained by Regeneron as an expert and key opinion leader, but this statement reflects
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`my independent views on the adverse impact of a remedy on my own practice and patients. Any remedy
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`would severely disrupt my practice, eliminate my ability to choose the best treatment for my patients, and
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`potentially force me to administer less effective and less safe treatments.
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`I.
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`OPHTHALMIC DISEASES THAT CAUSE VISION LOSS AND BLINDNESS
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`My practice involves the treatment of serious eye diseases involving the overproduction of a
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`naturally occurring protein in the body called vascular endothelial growth factor (“VEGF”). VEGF
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`triggers the formation of new blood vessels, but when cells secrete too much VEGF into the eye,
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`abnormal blood vessels can grow in the eye underneath the macula and retina. These abnormal blood
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`vessels can leak blood and other fluids, which blurs central vision and leads to blindness. VEGF diseases
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`include, among others, wet age-related macular degeneration (“wAMD”), diabetic retinopathy (“DR”),
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`diabetic macular edema (“DME”), and macular edema following retinal vein occlusion (“MEfRVO”).
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`wAMD is the most severe eye disease and is a leading cause of blindness among older
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`Americans. Patients with wAMD see the world as if looking through distorted lenses: straight lines may
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`appear bent, central vision may be reduced, brightness of colors may be dulled, and patients may see
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`haziness. Patients may also experience a well-defined blurry or blind spot in their central field of vision.
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`These patients thus face severe challenges with reading, writing, driving, or recognizing faces. The onset
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`of wAMD symptoms is abrupt—symptoms can develop in as little as one day. If left untreated, wAMD
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`1
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`Regeneron Exhibit 1086.003
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`may cause permanent vision loss within weeks or months. The debilitating effects of wAMD worsen over
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`time and can be irreversible, ultimately leading to permanent blindness.
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`DR is the most common diabetic eye disease and can lead to vision loss. DR occurs when too
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`much blood sugar damages the blood vessels in the retina. As a result, the retina does not receive enough
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`oxygen and nutrients, and blood vessels can leak blood and fluid into the retina. DME is a complication
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`of DR that can lead to further vision problems. DME occurs if the macula, the area of the retina at the
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`back of the eye responsible for sharp central vision, swells with fluid leaked from those damaged blood
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`vessels. Finally, MEfRVO occurs when fluid leaks into the macula as a result of a blocked blood vessel.
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`This condition leads to vision loss or blurring as the macula swells with the fluid.
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`II.
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`TREATMENT FOR SERIOUS EYE DISEASE
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`While there is currently no cure for wAMD, the advent of anti-VEGF therapies has made
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`remarkable strides in improving vision and easing the burden. Until recently, there were two main FDA-
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`approved anti-VEGF treatments for wAMD: LUCENTIS® (ranibizumab), approved in 2006, and
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`EYLEA® (aflibercept), approved in 2011. A third treatment, BEOVU® (brolucizumab) was approved on
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`October 8, 2019. EYLEA and LUCENTIS are also approved for the other eye diseases I described above,
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`and can be administered using a vial and syringe or a prefilled syringe “PFS.”
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`Anti-VEGF treatments are administered directly into the patient’s eye via syringe. This
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`administration is called an intravitreal injection, and it must be performed in a physician’s office. One
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`safety issue retinal specialists are concerned about with their patients receiving intravitreal injections of
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`anti-VEGF drugs is a very serious adverse effect called intraocular inflammation, or IOI. IOI involves
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`inflammation of the structures in the interior of the eye. IOI is an urgent medical condition, and it ranges
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`in severity, with severe cases capable of leading to blindness. Severe IOIs present a major concern for
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`retinal specialists and are a key consideration in selecting treatment; even small differences in occurrence
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`rates can be a critical factor in the product a physician chooses to prescribe.
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`An additional concern is that each injection can introduce foreign particles and microbes into the
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`eye. This can cause irritation or infection of the tissues or fluids of the eyeball (termed endophthalmitis
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`2
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`Regeneron Exhibit 1086.004
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`when encompassing the entire eye). Endophthalmitis can lead to blindness and loss of the eye itself.
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`III.
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`EYLEA PFS IS MY PREFERRED METHOD OF TREATMENT
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`I currently have approximately 500 patients who require anti-VEGF treatment. The most common
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`diagnosis which requires anti-VEGF is wAMD, followed by DR/DME, then branch and central vein
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`occlusion. Approximately 85% of my anti-VEGF injections are with EYLEA PFS, and the remainder are
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`with LUCENTIS PFS. We do not use BEOVU (as explained further below), and we do not use vial and
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`syringe because PFS requires fewer steps to administer, takes less time, and is more convenient. The vial,
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`for example, requires two needles. Because PFS requires fewer steps and less time than a vial and syringe,
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`using PFS allows me to treat more patients.
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`Given the number of patients that I and my staff treat on a daily basis, fewer steps with PFS also
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`translates to a clinically meaningful reduction in the rate of endophthalmitis.1 Endophthalmitis is one of
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`the most feared and devastating complications following an intravitreal injection, oftentimes leading to
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`severe, irreversible blindness in the affected eye. By reducing the number of steps in which the potential
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`for bacterial introduction can occur, PFS is currently the best method for injection of anti-VEGF therapy
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`into patients’ eyes. Switching back to older methods of drawing the drug up from a vial could expose
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`patients to additional, unnecessary risks.
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`As a practicing physician, I am in the best position to choose the method of treatment that is best
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`for my patients. For all of these reasons, I should not be forced to transition my patients from EYLEA
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`PFS back to the vial and syringe.
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`IV.
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`LUCENTIS IS LESS CONVENIENT AND LESS EFFECTIVE THAN EYLEA PFS
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`LUCENTIS is another anti-VEGF treatment, but I would be unable to convert all my patients
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`from EYLEA PFS to LUCENTIS PFS because the products are not interchangeable for insurance
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`approval purposes. Indeed, patients require prior authorization for these treatments (which can take
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`weeks), and an approval for one product cannot be transferred to another product.
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`1 Storey et al., The Impact of Prefilled Syringes on Endophthalmitis Following Intravitreal Injection of
`Ranibizumab, Am J Ophthalmol, 199:200-208 (Mar. 2019), https://pubmed.ncbi.nlm.nih.gov/30552891/.
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`3
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`Regeneron Exhibit 1086.005
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`Moreover, I should not be forced to convert my patients to LUCENTIS because it is less effective
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`than EYLEA for certain indications. For example, although EYLEA and LUCENTIS are both anti-VEGF
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`treatments, LUCENTIS has been shown to be significantly less effective in improving vision in diabetic
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`patients with the worst vision due to swelling of the retina.2 Diabetic patients make up a large portion of
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`my practice, and I only use ELYEA PFS for these patients. If forced to switch to LUCENTIS PFS, the
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`visual outcomes in these patients would suffer, even if LUCENTIS was administered as recommended.
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`LUCENTIS is also less convenient than EYLEA. For example, EYLEA is recommended for
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`intravitreal injection once a month for the first three months, and can thereafter be injected every two
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`months. LUCENTIS, by contrast, must be injected monthly. LUCENTIS therefore requires more frequent
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`injections—and thus, more frequent office visits—than EYLEA, which is inconvenient for patients and
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`puts them at higher risk of exposure to the coronavirus. Additional injections would also mean that the
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`patients would have a higher risk of contracting the eye infections I described above. My practice would
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`also have to store more product, but we only have so much storage capacity. This would be exacerbated
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`by the fact that EYLEA is available in one dosage strength across indications, whereas LUCENTIS
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`requires two dosage strengths.
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`In addition to these convenience and efficacy issues, I would be very reluctant to switch my
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`patients from EYLEA PFS to another anti-VEGF for no clinical reason. As I explained above, physicians
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`are in the best position to decide what treatment is best for their patients, and they should not be forced to
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`switch from a preferred treatment for a serious medical condition and in the midst of a global pandemic.
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`V.
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`BEOVU IS AN UNSAFE TREATMENT AND THUS NOT AN ACCEPTABLE
`SUBSTITUTE FOR EYLEA PFS
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`BEOVU is the third FDA-approved anti-VEGF treatment that is prescribed for wAMD only. But
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`earlier this year it was revealed that the clinical trials for BEOVU showed that the rate of IOI was five
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`times higher for BEOVU as compared to EYLEA. For example, on February 20, 2020, I personally
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`2 Wells et al., Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema, N Engl J Med,
`2015 Mar. 26;372(13):1193-203, https://www.nejm.org/doi/full/10.1056/NEJMoa1414264.
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`4
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`Regeneron Exhibit 1086.006
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`attended the Macula Society Annual Meeting in San Diego and attended a BEOVU safety presentation
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`given by Dr. Pravin Dugel, the lead investigator of certain BEOVU trials. Dr. Dugel spoke about
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`instances of severe inflammation and blinding conditions that were occurring with administration of
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`BEOVU. Dr. Dugel reported that patients treated with BEOVU had a higher incidence of retinal artery
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`occlusion (RAO) than had previously been reported. RAO describes the blockage of the retinal artery,
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`which slows or stops the blood flow to the retina, depriving retinal cells of oxygen and leading to
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`blindness if the blockage is severe enough. While there is no clinically proven treatment for RAO, any
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`therapy must be deployed within hours of symptoms to be potentially effective.
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`The effects in the patients treated with BEOVU with RAO, as reported by Dr. Dugel, were
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`severe—involving inflammation of the retinal artery—and most of them resulted in significant vision
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`loss. Dr. Dugel further explained that a significant number of patients treated with BEOVU experienced
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`both IOI and RAO—a condition that he referred to as “occlusive retinal vasculitis” or ORV. ORV occurs
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`when the inflammation in the eye is so severe that it causes inflammation of the retinal artery itself,
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`closing off the artery, blocking the passage of blood, and creating an RAO. ORV can result in irreversible
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`blindness when the retinal artery becomes completely blocked and oxygen cannot be delivered to the
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`retina. If such severe events were to occur in patients treated with BEOVU at the 1% rate listed on the
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`label for RAO, chances would be that several of my injection patients could go blind.
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`Suffice to say that neither me nor any of my colleagues use BEOVU anymore. In fact, in April of
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`this year, the EYLEA authorization for one of my patients had expired, and I did not have any EYLEA
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`samples to provide him. To avoid him having to return to my facility in the height of the pandemic, I gave
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`him the last BEOVU in our practice (which happened to be a sample). Sure enough, the patient had a bad
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`inflammatory reaction. BEOVU is thus not an acceptable substitute for EYLEA PFS.
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`VI.
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`CONCLUSION
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`I urge the Commission not to institute the requested investigation, or at a minimum, to develop a
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`full record on the adverse public health implications prior to issuing any relief.
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`5
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`Regeneron Exhibit 1086.007
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`Dated: July 6, 2020
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`Respectfully submitted,
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`/s/ Szilárd Kiss, MD
`Szilárd Kiss, MD
`Weill Cornell Medicine
`Associate Dean, Clinical Compliance
`Chair, General Faculty Council
`Chief, Retina Service
`Director, Clinical Research
`Director, Tele-Ophthalmology
`Associate Professor, Ophthalmology
`Associate Attending Physician
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`6
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`Regeneron Exhibit 1086.008
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`CERTIFICATE OF SERVICE
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`I hereby certify that a copy of the foregoing document STATEMENT ON THE PUBLIC
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`INTEREST BY SZILÁRD KISS, M.D. was served on July 6, 2020, as indicated, on the following:
`
`Via EDIS
`The Honorable Lisa R. Barton
`Secretary to the Commission
`U.S. International Trade Commission
`500 E Street, S.W., Room 112
`Washington, D.C. 20436
`
`Via Electronic Mail
`Margaret MacDonald
`Office of Unfair Import Investigations
`U.S. International Trade Commission
`500 E Street, S.W.
`Washington, D.C. 20436
`margaret.macdonald@usitc.gov
`
`Elizabeth J. Holland
`Linnea P. Cipriano
`Calvin E. Wingfield Jr.
`Goodwin Procter LLP
`The New York Times Building
`620 Eighth Avenue
`New York, NY 10018-1405
`Phone: (212) 813-8800
`Fax: (212) 355-3333
`eholland@goodwinlaw.com
`lcipriano@goodwinlaw.com
`cwingfield@goodwinlaw.com
`
`Mark G. Davis
`William G. James
`Patrick J. McCarthy
`Myomi T. Coad
`Goodwin Procter LLP
`1900 N St., N.W
`Washington, D.C. 20036-1612
`Phone: (202) 346-4000
`Fax: (202) 346-4444
`markdavis@goodwinlaw.com
`wjames@goodwinlaw.com
`pmccarthy@goodwinlaw.com
`mcoad@goodwinlaw.com
`
`
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`7
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`Regeneron Exhibit 1086.009
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`Joshua Weinger
`Goodwin Procter LLP
`100 Northern Avenue
`Boston, MA 02210
`Phone: (617) 570-1000
`Fax: (617) 523-1231
`jweinger@goodwinlaw.com
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`Counsel for Complainants Novartis Pharma AG, Novartis Pharmaceuticals Corporation, and Novartis
`Technology LLC
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`Respectfully Submitted,
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`/s/Lauren McDuffie
`Lauren McDuffie
`IP Paralegal
`Weil, Gotshal & Manges LLP
`2001 M Street, NW, Suite 600
`Washington, D.C. 20036
`lauren.mcduffie@weil.com
`202.682.7000
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`8
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`Regeneron Exhibit 1086.010
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