UNITED STATES INTERNATIONAL TRADE COMMISSION
`WASHINGTON, D.C.
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`BEFORE THE HONORABLE CLARK S. CHENEY
`ADMINISTRATIVE LAW JUDGE
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` Inv. No. 337-TA-1207
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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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`OPENING EXPERT REPORT OF SZILÁRD KISS, M.D.
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`Regeneron Exhibit 1245.001
`Regeneron v. Novartis
`IPR2021-00816
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`these patients from experiencing permanent blindness, and irreversible vision loss in other
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`patients, the ITC should not exclude EYLEA PFS, or else exempt existing patients from the
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`remedy and delay its effective date as long as possible.
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`VII. OTHER TREATMENTS, IF AVAILABLE, ARE LESS EFFECTIVE, INFERIOR,
`AND IN SOME CASES, UNSAFE
`A.
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`LUCENTIS Is Less Effective Than and Inferior to EYLEA PFS
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`47.
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`Assuming an exclusion order is granted against EYLEA PFS and LUCENTIS is
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`available in enough supply as an anti-VEGF treatment option, I believe LUCENTIS is less
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`effective than, and inferior to, EYLEA PFS.39
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`48.
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`First, the EYLEA and LUCENTIS molecules are not the same. Given its structure
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`as a recombinant fusion protein, EYLEA is more likely to bind VEGF targets more tightly than
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`LUCENTIS, which is an antibody fragment, and not able to deliver as strong of a VEGF
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`inhibition.40 The EYLEA molecule is also much larger than LUCENTIS, so it does not clear out
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`of the eye as quickly.41 EYLEA also binds the placental growth factor, another useful secondary
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`molecule that can help treat wAMD and DR, which LUCENTIS does not do.42
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`49.
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`LUCENTIS is also less effective than EYLEA for certain indications. See, e.g.,
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`REGITC00376350; REGITC00377221. For example, although EYLEA and LUCENTIS are
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`both anti-VEGF treatments, LUCENTIS has been shown to be significantly less effective in
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`39 The 2019 Preferences and Trends (PAT) Membership Survey, conducted by the American Society of Retinal
`Specialists, also showed nearly 80 percent of retinal specialists would use EYLEA to treat new-onset wet AMD, if
`AVASTIN, LUCENTIS and EYLEA cost the same. See, Stone TW, Hahn P, eds. ASRS 2019 Preferences and
`Trends Membership Survey. Chicago, IL. American Society of Retina Specialists; 2019 at slide 5.
`40 Tschulakow A, Christner S, Julien S, Ludinsky M, van der Giet M, Schraermeyer U. Effects of a single
`intravitreal injection of aflibercept and ranibizumab on glomeruli of monkeys. PLoS One. 2014;9(11):e113701.
`Published 2014 Nov 21. doi:10.1371/journal.pone.0113701
`41 Raj Sharma, Yog; Tripathy, Koushik; Venkatesh, Pradeep; Gogia, Varun (2015): Aflibercept – How does it
`compare with other Anti-VEGF Drugs?. figshare. Journal contribution.
`https://doi.org/10.6084/m9.figshare.1373843.v2
`42 Nguyen QD, De Falco S, Behar-Cohen F, Lam WC, Li X, Reichhart N, Ricci F, Pluim J, Li WW. Placental
`growth factor and its potential role in diabetic retinopathy and other ocular neovascular diseases. Acta Ophthalmol.
`2018 Feb;96(1):e1-e9. doi: 10.1111/aos.13325. Epub 2016 Nov 22. PMID: 27874278; PMCID: PMC5811779.
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`19
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`Regeneron Exhibit 1245.002
`Regeneron v. Novartis
`IPR2021-00816
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`improving vision in diabetic patients with the worst vision due to swelling of the retina.43,44
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`Diabetic patients make up a large portion of my practice, and I only use ELYEA PFS for these
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`patients. If forced to switch to LUCENTIS PFS, the visual outcomes in these patients would
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`suffer, even if LUCENTIS was administered as recommended. The difference in effectiveness
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`can mean the difference in being able to obtain a driver’s license and functioning at work.
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`50.
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`LUCENTIS is inferior to EYLEA for the additional reason that it must be dosed
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`more frequently. Indeed, EYLEA is recommended for intravitreal injection once a month for the
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`first three months for wAMD, once a month for the first five months for DME and DR, and can
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`thereafter be injected every two months for wAMD, DME and DR.45 See REGITC00143489.
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`LUCENTIS, by contrast, must be injected monthly for all its approved indications. See
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`NOVITC(CH)00165856. Regeneron clinical studies showed that EYLEA administered every
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`two months was clinically equivalent to LUCENTIS dosed monthly.46,47 Given the burden and
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`risk associated with intravitreal injections, virtually any retinal specialist would agree that fewer
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`injections into the eye is preferred whenever possible.
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`43 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.
`44 Steinle, Nathan C. “Lessons from DRCR.net Protocol T.” Retina Specialist, 5 Mar. 2015, www.retina-
`specialist.com/article/lessons-from-drcrnet-protocol-t.
`45 MEfRVO is recommended to be dosed monthly.
`46 Raj Sharma, Yog; Tripathy, Koushik; Venkatesh, Pradeep; Gogia, Varun (2015): Aflibercept – How does it
`compare with other Anti-VEGF Drugs?. figshare. Journal contribution.
`https://doi.org/10.6084/m9.figshare.1373843.v2
`47 A March 2020 publication I authored found that in the 2014-2016 time period, some physicians were underdosing
`patients and as a result there was no difference in dosing frequencies between EYLEA and LUCENTIS in those
`patients. NOVITC(US)00388317. The paper found that the underdosing was a cause for concern that may result in
`suboptimal vision outcomes. Id. at 317, 326. Since this time period, retinal physicians have recognized the
`underdosing concern. See, Stone TW, Hahn P, eds. ASRS 2019 Preferences and Trends Membership Survey.
`Chicago, IL. American Society of Retina Specialists; 2019 at slide 7.
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`20
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`Regeneron Exhibit 1245.003
`Regeneron v. Novartis
`IPR2021-00816
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`51.
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`In particular, additional injections mean that patients would have a higher risk of
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`contracting a serious intraocular infection from foreign particles being introduced into the eye.
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`REGITC00377092; REGITC00377077; REGITC00378064; REGITC00863006.
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` Obviously, the
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`fewer injections associated with EYLEA as compared to LUCENTIS necessarily translates to a
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`lower risk of such infections and endophthalmitis.
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`52. More frequent injections can also mean more out-of-pocket costs for the patient.
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` More frequent injections are especially problematic for
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`patients who require assistance in going to a physician’s office, especially in areas where the
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`nearest retinal specialist is far from the patient’s home.
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`53. More frequent office visits would also translate to more clinician time, meaning
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`that the clinician would see fewer individual patients. My practice would also have to store more
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`product, but we only have so much storage capacity. This would be exacerbated by the fact that
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`EYLEA is available in one dosage strength across indications, whereas LUCENTIS requires two
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`dosage strengths.
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`roughly 30% of my patients due to their insurance requirements. In particular, the insurance
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` Additional office visits would also be needed for
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`21
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`Regeneron Exhibit 1245.004
`Regeneron v. Novartis
`IPR2021-00816
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`requirements for certain of my patients require an initial office visit for a clinical evaluation to
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`obtain insurance authorization. A second office visit would then be required for the injection.
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`Thus, for these patients, transitioning to LUCENTIS would require an additional office visit and
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`a delay from their last EYLEA injection.
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`54. Moreover, given that LUCENTIS requires more frequent injections, Genentech,
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`which manufactures and sells LUCENTIS in the US, would have to significantly increase
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`production of the drug substance if LUCENTIS were to replace the less-frequently injected
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`EYLEA.
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`55.
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`In addition to the above concerns, I would be very reluctant to switch my patients
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`from EYLEA PFS to another anti-VEGF for no clinically valid reason. Physicians are in the best
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`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, especially in the midst of a
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`global pandemic.
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`B.
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`22
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`Regeneron Exhibit 1245.005
`Regeneron v. Novartis
`IPR2021-00816
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`106.
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`I may use documents and/or materials to help me explain my opinions. I may
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`also prepare and use graphics, images, photographs, video recordings, animations, and other
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`presentation aids to help me explain my opinions.
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`Dated: January 22, 2021
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`Respectfully submitted,
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`__________________________
`Szilárd Kiss, MD
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` 42
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`Regeneron Exhibit 1245.006
`Regeneron v. Novartis
`IPR2021-00816
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