Supplement to
`
`RT Retina Today
`NRMD
`
`New Retina MD
`
`September 2017
`
`Treatment Paradigms in AMD
`Management: Assessing
`Consistent Long-Term Dosing
`
`W. Lloyd Clark, MD,
`moderator
`David Brown, MD, FAG
`David Eichenbaum, MD
`Peter K. Kaiser, MD
`
`-
`
`
`
`EXHIBIT
`
`12
`
`A CME provided by Evolve Medical Education LLC and distributed
`with New Retina MD and Retina Today.
`Supported by an unrestricted educational grant from.
`Regeneron Pharmaceuticals Inc
`
`BROWN
`April 26, 2022
`
`medical education
`
`'I
`ii',, evolve
`
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`Mylan v. Regeneron, IPR2021-00880
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`

`Treatment Paradigms in AMD Management. Assessing Consistent Long-Term Dosing
`
`Release Dace. September 2017
`Expiration Date: September 2018
`
`CONTENT SOURCE
`This continuing medical education (CME) activity captures
`content from roundtable discussion held in June of 2017.
`
`TARGET AUDIENCE
`This certified CME activity is designed for retina specialists
`and general ophthalmologists involved in the management of
`patients with retinal disease.
`
`LEARNING OBJECTIVES
`Upon completion of this activity, the participant should be
`able to:
`• Understand the most recent monotherapy and combination
`therapy clinical study evidence using available anti-VEGF
`therapies for common retinal diseases, including AMD.
`• Discuss the ocular and systemic effects of anti-VCGF
`therapies and how to educate patients on appropriate
`expectations.
`• Develop plans to initiate treatment for conditions such as
`AMD using anti-VEGF agents, as well as better understand
`when to change therapeutic strategies.
`
`ACCREDITATION STATEMENT
`This activity has been planned and implemented in
`accordance with the accreditation requirements and policies of
`the Accreditation Council for Continuing Medical Education
`(ACCME) through the joint providership of Evolve Medical
`Education LLC, Retina Today and New Retina MD.
`
`AMA CREDIT DESIGNATION STATEMENT
`Evolve Medical Education LLC designates this enduring
`material for a maximum of 1 AMA PRA Category I Credit.'
`Physicians should claim only the credit commensurate with the
`extent of their participation in the activity.
`
`TO OBTAIN AMA PRA CATEGORY 1 CREDIT(S)TM
`To obtain AMA PRA Category I Credit' for this activity, you
`must read the activity in its entirety and complete the Post Test/
`Activity Evaluation Form, which consists of a series of multiple
`choice questions. To answer these questions online and receive
`real-time results, please visit evolvemeded.com and click "Online
`Courses." Upon completing the activity and achieving a pass-
`ing score of 70% on this self-assessment test, you may print out
`a CME credit letter awarding 1 AMA PRA Category I Credit,"
`Alternatively, please complete the Post Test/Activity Evaluation
`Forms and mail or fax to Evolve Medical Education LLC; P0 Box
`358, Pine Brook, NJ 07058; Fax (610) 771-4443. The estimated
`time to complete this activity is one (1) hour.
`
`2 SUPPLEMENT TO RETINA TODAY/NEW RETINA MO I SEPTEMBER 2017
`
`FACULTY CREDENTIALS
`W. Lloyd Clark, MD, Moderator
`Palmetto Retina Center
`University of South Carolina School of Medicine
`Columbia, SC
`
`INT
`
`David Brown, MD, FACS
`Director of the Greater Houston Retina Research
`Center
`Clinical professor of ophthalmology
`Baylor College of Medicine
`Houston, TX
`
`2
`
`David Eichenbaum, MD
`Private practice at Retina Vitreous Associates of Florida
`in Tampa Bay
`Clinical assistant professor of ophthalmology at the
`University of South Florida
`Tampa, FL
`
`Peter K. Kaiser, MD
`Professor of ophthalmology, Cleveland Clinic Lerner
`College of Medicine
`Staff surgeon, vitreoretinal department at the Cole Eye
`Institute Cleveland Clinic
`Cleveland, OH
`
`GRANTOR STATEMENT
`This continuing medical education activity is supported
`through an unrestricted educational grant from Regeneron
`Pharmaceuticals, Inc.
`
`DISCLOSURE POLICY
`It is the policy of Evolve Medical Education LLC that faculty
`and other individuals who are in the position to control the
`content of this activity disclose any real or apparent conflict
`of interests relating to the topics of this educational activity.
`Evolve Medical Education LLC has full policies in place that
`will identify and resolve all conflicts of interest prior to this
`educational activity.
`
`The following faculty members have the following financial
`relationships with commercial interests:
`
`W. Lloyd Clark, MD, has had a financial agreement or
`affiliation during the past year with the following commercial
`interests in the form of Consultant/Advisory Board/Speaker's
`Bureau: Bayer Pharmaceuticals; Genentech,Inc; Ohr
`
`Mylan Exhibit 1093
`Mylan v. Regeneron, IPR2021-00880
`Page 2
`
`

`

`Pharmaceutical, Inc.; Regeneron Pharmaceuticals, Inc.; and
`Santen Pharmaceutical Co., Ltd. Grant/Research Support:
`Allergan, Inc.; Genentech, Inc.; and Regeneron Pharmaceuticals,
`Inc.
`
`David Brown, MD, FACS, has had a financial agreement or
`affiliation during the past year with the following commercial
`interests in the form of Consultant/Advisory Board/Speaker's
`Bureau: Alcon; Allergan Plc; Bayer Pharmaceuticals; Genentech,
`Inc.; Novartis AG; Regeneron Pharmaceuticals, Inc.; and
`ThromboGenics NV.
`
`David Eichenbaum, MD, has had a financial agreement or
`affiliation during the past year with the following commercial
`interests in the form of Consultant/Advisory Board/Speaker's
`Bureau: Alimera Sciences, Inc.; Allergan, Plc; Genentech, Inc.;
`and Ophthotech Corporation; and Regeneron Pharmaceuticals,
`Inc.; Grant/Research Support; Alcon; Allergan Plc; Opthotech
`Corporation; and River Vision Development Corp. Stock/
`Shareholder. Hemera Biosciences Inc., and USRetina.
`
`Peter K. Kaiser, MD, has had a financial agreement or
`affiliation during the past year with the following commercial
`interests in the form of Consultant/Advisory Board/Speaker's
`Bureau: Aerpio Therapeutics; Alcon, Allegro Ophthalmics,
`LLC; Allergan, Plc; Bayer Pharmaceuticals; Biogen, Inc.; Digisight,
`Kanghong Neurtch Ohr Pharmaceutical, Inc.; Ophthotech
`
`Regeneron Pharmaceuticals, Inc.; and Santen Pharmaceutical Co.,
`Ltd. Thrombogenics Shire. Stock/Shareholder. Ohr Pharmaceutical.
`
`EDITORIAL SUPPORT DISCLOSURE
`Cheryl Cavanaugh, MS. Director of Operations, Evolve Medical
`Education LLC and Michelle Dalton, Writer, have no real or appar-
`ent conflicts of interest to report. Rishi P. Singh, MD, Peer Reviewer,
`has had a financial agreement or affiliation during the past year
`with the following commercial interests in the form of Consultant/
`Advisory Board/Speaker's Bureau: Alcon; Allergan Plc; Carl Zeiss
`Meditec; Genentech, Inc; Optos; Regeneron Pharmaceuticals, Inc;
`and Shire Plc Grant/Research Support; Alcon; Apellis Pharmaceuticals;
`Genentech, Inc; and Regeneron Pharmaceuticals, Inc.
`
`OFF-LABEL STATEMENT
`This educational activity may contain discussion of published
`and/or investigational uses of agents that are not indicated by
`the FDA. The opinions expressed in the educational activity are
`those of the faculty. Please refer to the official prescribing infor-
`mation for each product for discussion of approved indications,
`contraindications, and warnings.
`
`DISCLAIMER
`The views and opinions expressed in this educational activ-
`ity are those of the faculty and do not necessarily represent the
`views of Evolve Medical Education LLC, Retina Today, New Retina
`MD, or Regeneron Pharmaceuticals, Inc.
`
`Go to evolverneded.coni/online-courses/ to view the online version
`of this supplement.
`
`I! ,!, evolve
`
`medical education
`
`,EPTEMBFR2Oi7i :ir , i-kF
`
`.RiiiNA
`
`.:)8- Ni
`
`MI 3
`
`Mylan Exhibit 1093
`Mylan v. Regeneron, IPR2021-00880
`Page 3
`
`

`

`Treatment Paradigms in AMD Management
`
`Treatment Paradigms in AMD
`Management: Assessing Consistent
`Long-Term Dosing
`
`Age-related macular degeneration (AMD) is a chronic, progressive disease. It is a leading cause of blindness in developed
`countries, 74 with an overall global prevalence of 8.69%. AMD is most prevalent in patients older than 60 years, with
`incidence rates expected to increase as the population ages—approximately 228 million people will be diagnosed with AMD
`in 2040. 5 There is no cure, but in today's world, AMD can be managed through medical intervention via intravitreal anti-
`VEGP injections in a fixed, pro re nata (PR N) or treat-and-extend dosing regimen. This roundtable gathered retina specialist
`experts to discuss the pros and cons of these treatment options and the data supporting them, long-term outcomes and
`vision loss with current treatment options, and the clinical pearls we can learn from pivotal studies. It also tackles the cause
`and treatment of geographic atrophy.
`
`- W. Lloyd Clark, MD, moderator
`
`COMPARING AMD TREATMENT REGIMENS VS REAL-
`WORLD OUTCOMES
`W. Lloyd Clark, MD: When examining the long-term treatment
`strategies, outcomes, and expectations of anti-VEGF therapy for
`AMD, three dosing strategies surface: gold standard monthly
`treatments, PRN, and treat-and-extend. The seminal papers
`supporting monthly AMD anti-VEGI therapy - MARINA,
`ANCHOR, and VIEW 1/VIEW t10 -
`provided us with pivotal
`information regarding the clinical viability of monthly treatment.
`What are the positive and negatives to monthly therapy, and what
`data support this regimen?
`
`David Brown, MD, FACS: Everyone agrees the best treat-
`ment available is monthly therapy if the patient has the time to
`devote to it. The data is strong. ANCHOR and MARINA both
`examined ranibizumab as a monthly treatment; for the first time,
`patients with wet AMD were able to show visual improvement
`In ANCHOR (n = 423), patients were randomized to monthly
`ranibizumab at 0.3 mg or 0.5 mg plus sham verteporfin therapy or
`monthly sham injections plus active verteporfin therapy.' Primary
`endpoint was loss of fewer than -15 letters from baseline visual
`acuity (VA) at 1 year.
`The results were staggering. A total of 35.7% of patients treated
`with ranibizumab 0.3 mg and 40.3% of patients treated with ranibi-
`zumab 0.5 mg showed VA gains of +15 letters or more.6 in con-
`trast, patients treated with active verteporfin therapy actually lost
`an average of -9.5 letters during the same timeframe.
`MARINA randomized patients (n = 716) to monthly ranibi-
`zumab intravitreal injections (either 0.3 mg or 0.5 mg) or sham
`
`injections.6 Like ANCHOR, the primary endpoint was loss of fewer
`than -15 letters from baseline at 1 year. The results from MARINA
`were similar to ANCHOR: VA improved by +15 or more letters in
`24.8% of patients in the 0.3 mg ranibizumab group and in 33.8% of
`patients in the 0.5 mg ranibizumab group, compared with 5% of
`patients of the sham-injection group.6
`Monthly therapy is also safe; patients will not experience recur-
`rent fluid or recurrent hemorrhage.
`So why do we do anything else, but monthly anti-VEGF injec-
`tions for AMD patients? Unfortunately, the real world gets in the
`way, and patients miss appointments. The average patient gets
`sick, breaks a hip, and cannot have a family member take off work
`every month to bring them to our clinics.
`Now, VIEW 1 and VIEW 2 illustrated that we can extend that
`monthly treatment to every 2 months with aflibercept with simi-
`lar results as monthly ranibizumab therapy. These parallel studies
`randomized patients to intravitreal aflibercept at 0.5 mg monthly,
`2 mg monthly, or 2 mg every 2 months after three initial monthly
`doses or ranibizumab 0.5 mg monthly.'° All aflibercept groups
`were noninferior and, on average, clinically equivalent to monthly
`ranibizumab, demonstrating that an every 2-month regimen with
`aflibercept is an effective treatment strategy for most patients with
`wet AMD.
`The problem is patients want the least amount of treatments
`possible, and every 2 months is still too frequent for many patients.
`That is why in my practice, and I think most of the country, we use
`treat-and-extend. We treat until dry, we extend until the patient
`has evidence of active exudation, and then we back off and treat at
`an interval that avoids recurrent leakage.
`
`4 A IPPt-MI N
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`41 [INA (L'A
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`W RE F I N M I SEPTEMBF A 2017
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`Page 4
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`Assessing Consistent Long-Term Dosing
`
`The TREX-AMD trial validated this as a treatment approach by
`comparing treat-and-extend to monthly ranibizuniab.1' Treat-
`and-extend is not quite as effective as monthly anti-VEGF therapy,
`but it was very close with minimal exposure to risk. At 24 months,
`patients in the monthly ranibizumab group gained +10.5 letters,
`while patients in the treat-and-extend cohort gained i-8.7 letters.11
`No patient on ranibizumab lost more than -2 letters, but five treat-
`and-extend patients lost at least -15 letters. We know the treat-
`and-extend strategy is not perfect but it is the treatment schedule
`most patients can comply with, and it is the compromise they are
`willing to make.
`
`Peter K. Kaiser, MD: There is no question fixed monthly or
`every other month in the case of aflibercept injections is the gold
`standard and offers the best visual outcomes. We have seen this
`in numerous head-to-head studies, including CATT, IVAN, and
`SUSTAIN.' 2"5 This treatment regimen, however, is not sustainable.
`CATT was a randomized clinical study (n = 1,185) that set out
`to answer two questions: are bevacizumab and ranibizumab
`clinically equivalent, and does PRN dosing yield the same visual
`outcomes as monthly injections? In the 1,107 patients who were
`followed during year?, ranibizumab and bevacizumab had simi-
`lar VA gains over a 2-year period, with both drugs resulting in a
`mean +0.5 line gain compared to PRN. More patients in the PRN
`groups lost more than -3 lines of vision and had persistent reti-
`nal fluid than those in the monthly groups. Plus, switching from
`monthly to PRN resulted in a greater mean decrease in vision
`during year 2 (-2.2 letters).' 2
`IVAN (n = 610), a study from the United Kingdom, also com-
`pared bevacizumab and ranibizumab on a monthly or PRN dosing
`schedule. At 1 year, the comparison of VA between bevacizumab
`and ranibizumab was inconclusive because bevacizumab did
`not meet the prespecified noninferiority criteria of -3.5 letters.
`Continuous monthly treatment however, led to smaller choroidal
`neovascular (CNV) lesions, less fluorescein leakage, and less fluid on
`the OCT,"
`SUSTAIN (n = 513) examined ranibizumab only, comparing
`the safety and efficacy of monthly injections to a PRN dosing in
`treatment-naive patients. Patients were given three initial monthly
`injections of ranibizumab 0.5 mg and evaluated monthly. Patients
`were retreated if more than -s letters were lost.' 4
`The results were not too surprising given the other data. Safety
`was comparable to the favorable tolerability profile of ranibizumab
`illustrated in previous studies. VA was at the highest point after the
`first three monthly injections, decreased slightly under PRN during
`the next? to 3 months, and was then sustained throughout the
`treatment period. 14
`What we should be taking from all these studies is that it does
`not really matter what anti-VEGE drug you are using in terms of
`safety and efficacy. What matters is the dosing schedule. Fixed
`monthly dosing always performed better. The problem is that
`monthly anti-VEGF therapy is an unsustainable treatment regimen,
`especially as we get further and further out from baseline. To me,
`PRN is not an option; it essentially equates to extend and neglect.
`
`'Tome, PRN is not an option; it essentially
`equates to extend and neglect,"
`
`—Peter K. Kaiser, MD
`
`In my opinion, the next best thing is a treat-and-extend regimen.
`LUCAS showed that treat-and-extend can have good visual
`outcomes. 36 This study randomized 441 patients to either bevaci-
`zumab 1.25 mg or ranibizumab 0.5 mg on a treat-and-extend pro-
`tocol. Injections were given every 4 weeks until the patient became
`dry. The treatment then was extended by 2-week intervals for a
`maximum of 12 weeks until recurrence. After recurrence, the treat-
`ment interval was shortened by 2 weeks at a time. Bevacizumab
`was equivalent to ranibizumab, with +7.4 and +6.6 letters gained,
`respectively.
`A treat-and-extend treatment regimen offers us the ability to be
`proactive with our treatment and avoid the recurrences that you
`wait for with a PRN regimen. So, to me, treat-and-extend is the best
`treatment for wet AMD, given the compliance issues with monthly
`injections.
`
`David Eichenbaum, MD: According to the 2016 Preferences
`and Trends Survey from the American Society of Retina Specialists,
`about 70% of all US retina specialists default to treat-and-extend
`for wet AMD, and only 5% recommend monthly treatment. 17 It
`is not difficult to see why. When I am treating new patients and
`discussing anti-angiogenic injections with them, the first thing
`question patients ask is, "How many of these do I need?," followed
`by, "When do I have to come back?" What patients immediately
`think about is less frequent injections. They want fewer visits. Their
`family wants them to come in less. That is what we are up against
`as clinicians.
`When I explain to the patient that I will attempt to give them
`fewer injections over time, I am alluding to treat-and-extend, even
`though I know the data is not as strong as monthly treatment. Like
`Dr. Brown, I treat until dry, then I slowly extend until the eye tells
`me it cannot extend any further. I will then pull back and generally
`leave that interval in place for a long time.
`
`SEPTEMBER 2O1?L!JPP : If,
`
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`
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`Mylan v. Regeneron, IPR2021-00880
`Page 5
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`

`

`Treatment Paradigms in AMD Management
`
`Making a Case for Treat-and-Extend
`
`Case study supplied by David Eicheribaum, MD
`
`In this case, a 77-year-old Caucasian male presented in
`May 2016 with vision of 20/63 in the right eye. The initial
`spectral-domain optical coherence tomography (OCT) scan
`showed a central foveal thickness of 361 microns. Based on
`his OCT and early/late indocyanine green images (Figures
`1-3), I recommended treatment. We discussed commercially
`available agents for treatment of neovascular macular
`degeneration and the patient requested aflibercept. We
`
`began monthly injections of aflibercept, and he continues on
`aflibercept throughout this case report, In November 2016,
`he returned following extension to weeks from the last
`aflibercept injection. At the time, his vision was 20/50+2, and
`on OCT the central foveal thickness had reduced substantially
`to 294 microns (Figure 4). I, again, gave a treatment and
`recommended a 6-week interval) and I then continued
`extending by one week at each subsequent visit. At his last
`visit in August 2017, he was S weeks post-injection. His vision
`was 20/40+2, and OCT showed a central foveal thickness
`of 309 microns, but with re-accumulation of subretinal
`fluid adjacent to the shallow 'ED (Figure 5). Despite the
`improvement in vision, the recurrence of subretinal fluid
`and increase in foveal thickness are consistent with recurrent
`choroidal neovascular activity, and I contracted the treatment
`interval to 7 weeks. If the vision is maintained, and the fluid
`regresses, I plan to continue the patient at a 7-week interval. If
`the fluid persists or accumulates further, I plan to reduce the
`treatment interval again to 6 weeks,
`
`IRACC WMT HIT(It1n fl
`
`Figure 4. Patient's vision is 20/50+2 with a central foveal thickness
`of 294 microns in November 2016-
`
`Figures 1-3. Patient's vision is 20/63 with a central foveal thickness
`of 361 microns in May 2016.
`
`Figure S. Patient's vision is 20/40+2 with a central foveal thickness
`of 309 microns in August 2017.
`
`6 uPr'tFMNJ It) III -IlNA F(['Aq/NFvRFIlNA M SEPTEMBER 20I /
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`Assessing Consistent Long-Term Dosing
`
`Dr. Clark: Is there a role for PRN therapy today? Is there a clinical
`scenario where it still makes sense and can be provided effectively?
`
`Dr. Brown: In about 10% of my patients, three injections will
`shut down their choroidal neovascularization (CNV), and they
`do not need another one. If a patient totally dries out with three
`shots, I am willing to move to PRN. I am waiting for the patient to
`recur. If a patient gets to 10 weeks without recurrence, he or she
`is one of the lucky 10%. But the fact is, 90% of my patients recur
`at 6, 8, or 10 weeks, and then move to treat-and-extend for the
`rest of their life, Treat-and-extend does not mean testing an upper
`treat-and-extend interval forever. it is about finding the fixed-dose
`regimen that controls their disease; 90% of patients live with that
`interval and preserve their vision- The other 10% continually nego-
`tiate to extend their treat-and-extend interval. I tell these patients
`they can negotiate with their disease, but they will lose vision.
`
`Dr. Kaiser: I think PRN is useful in patients who need a limited
`number of injections, such as vasculopaths who may have had a
`stroke or in patients who have macular atrophy encroaching on
`the center of the fovea. In these situations, I try to limit the num-
`ber of injections. One could argue that you are limiting the number
`of injections in the later years when using treat-and-extend, but I
`try to limit the injections even further in these patients.
`
`Dr. Clark: Many of our colleagues in community practice still
`use PRN today. I do not because I find that PRN therapy typically
`leads to undertreatment and to increased disease activity for a long
`period of time. That is one of the main drivers of long-term vision
`loss in AMD.
`
`Dr. Kaiser: Part of the problem is that when people talk
`about PRN, they are not talking about the PRN regimen tested
`in clinical studies. PRN did well in studies because patients were
`seen monthly. In real life, they are being seen on increasingly
`longer intervals between PRN visits, which may result in a
`significant bleed or leakage that cannot be corrected with
`additional injections. Thus, if you are going to use PRN, you truly
`need to see the patient monthly.
`
`Dr. Eichenbaum: I agree—you do have to see the patient
`monthly for years to achieve the good results seen in clinical
`trials with true PRN therapy. If you do not see the patient
`monthly, you wind up with progressive retinal neglect. There is
`also the "PRN-and-extend" concept, which is really rooted in no
`randomized controlled trial evidence. You wind up with very
`few injections, and you probably get results similar to SAILOR, 18
`which are pretty dismal.
`SAILOR included two cohorts totaling 4,300 patients. Patients
`in cohort 1 were randomly assigned to ranibizumab 0.3 mg (n =
`1,169) or 0.5 mg (n = 1,209) for three monthly loading doses. Dose
`groups were stratified by AMD treatment history, either treatment-
`naive or previously treated. Patients in cohort 1 were retreated on
`the basis of optical coherence tomography (OCT) or VA criteria.
`
`'Treat-and-extend does not mean testing an
`upper treat-and-extend interval forever. It is
`about finding the fixed-dose regimen that
`controls their disease..."
`
`—David Brown, MD, FACS
`
`Patients in cohort 2 (n = 1,922) received an initial dose of ranibi-
`zumab 0.5 mg and were retreated at physician discretion. The
`average number of ranibizumab injections was 4.9 for cohort 1 and
`3.6 for cohort 2. At 1 year, cohort 1 treatment-naive patients had
`gained an average of +0.5 (0.3 mg group) and +2.3 (0.5 mg group)
`letters. Previously treated patients had gained +1.7 (0.3 mg group)
`and +2.3 (0.5 mg group) letters. 18
`
`DETERMINING TREAT-AND-EXTEND INTERVALS AND PED
`TREATMENT
`Dr. Clark: How long do you extend treat-and-extend intervals?
`What are you looking for, and what is your response when you see
`recurrences?
`
`Dr. Eichenbaum: I individualize the treatment and stick to the
`available data as best as I can. I am a 2-week extender, which is
`in line with treat-and-extend studies such as LUCAS. 16 A differ-
`ence in my recommended extension intervals is that I will often
`extend a patient from maybe 4 weeks to 6 weeks, but then leave
`the patient at 6 weeks for a few cycles before the next extension.
`I am concerned about disease activity when I see subretinal fluid
`on the OCT or subretinal hemorrhage on a dilated funduscopic
`exam. I will return to the the interval when that fluid was dry or to
`the interval at which there was no hemorrhage. For example, if a
`patient went from 6 weeks to 8 weeks, and there is fluid at 8 weeks,
`I will pull them back to 6 or 7 weeks, shoot another scan, and leave
`them there for at least three or four cycles. After several months,
`we can discuss extension again, at which point I would try? to
`weeks. Often, the patients are pushing for more extension through-
`out this process.
`
`SEPTEMBER 2017 1 ..'1
`
`LMI+I
`
`RETINA
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`Treatment Paradigms in AMD Management
`
`blindness. On a population basis, it is like saying that no one in the
`United States should ever fly in an airplane because Dan Martin
`read about an airplane crash.
`
`Dr. Eichenbaum: I tend to inject more now than I did when I
`started practice 10 years ago. I push hard on subretinal fluid and
`subretinal blood, but I do not push hard specifically on fibrovas-
`cular PEDs. I agree that we are probably not causing geographic
`atrophy (GA) in flat retinas, but I do worry about inciting atrophy
`by flattening out a big PED.
`
`Dr. Brown: I think a bigger problem with fibrovascular PEDs is
`letting them fluctuate in size. Think of it like an elastic balloon that
`is repeatedly inflating and deflating This action is likely to result in
`a tear in the balloon, Once the PED is stable, I would rather keep
`the patient at their interval and not extend further.
`
`Dr. Kaiser: When you have a fibrovascular PED, what concerns
`me most is seeing the CNV on the undersurface of the RPE on
`the OCT. By definition, this is a type 1 CNV, but I worry about
`rapidly flattening the PED if the CNV is right underneath the RPE
`surface. This can lead to RPE tears, Therefore, I try to be a little
`less aggressive in terms of rapidity, which is detailed in a paper we
`wrote in 2010 in Retina.20'21
`
`Dr. Clark: How do you measure PED height in your clinical
`practice? Do you measure them manually or is this more of a sub-
`jective gestalt?
`
`Dr. Eichenbaum: I do not measure them manually. It is more of
`a gestalt for me.
`
`Dr. Kaiser: I do not think the average retina specialist needs
`to measure PED height. In HARBOR, we were very precise at our
`reading center about how the PEDs were
`but I think
`in clinical practice really what you are trying to see is change over
`time, not precise measurements. What is important is the ability
`to look at the PED sequentially over time to make sure that it is
`decreasing in size. If the PED is enlarging or a new PED is forming I
`consider that fluid just like I would any fluid above the RPE. But, I
`do not think you have to take out the calipers and measure it.
`
`LONG-TERM TREATMENT FACTORS IMPACTING VISION
`LOSS
`Dr. Clark: With long-term data from the CATT trial, we now
`see data emerging that demonstrates loss of the vision gains out
`to 4, 5, and 6 years.' 5 Similar findings have been seen in other
`loosely-structured, longer term follow-up protocols, such as
`SAILOR and SEVEN-UP. 22 One-third of patients in SEVEN-UP had
`visual declines of -15 letters or more 7 years post-ranibizumab
`therapy in the ANCHOR or MARINA trials, In particular, CATT
`illustrated three main causes of this: recurrent disease activity,
`geographic atrophy, and sub-retinal fibrosis. Is this a big problem
`in your practice?
`
`It is important to remember that treating a patient
`
`every 2 weeks, or even every 4 weeks, is not realistic
`
`in the real-world environment because life gets in
`
`the way, and patients miss appointments."
`
`-
`
`David Eichenbaum, MD
`
`Dr. Clark: That sounds a lot like the TREX-AMD study." Does
`anyone else do this?
`
`Dr. Brown: Usually, but with the exception of new subreti-
`nal pigment epithelium (sub-RPE) fluid. That indicates a leakage
`from new CNV activity, which needs a more aggressive treatment
`approach. I use the same treatment strategy for new sub-RPE fluid
`as was used in the CATT trials, 12 but I do not chase it if it does not
`go away. If a fibrovascular pigment epithelial detachment (PED)
`pops up with an increased dosing extension, however, I have found
`it will respond and regress if you treat it more aggressively and
`tighten the dosing interval.
`
`Dr. Eichenbaum: I am sometimes nervous about completely
`flattening out subfoveal fibrovascular PEDs because of the de
`novo atrophy data from HARBOR. 19 Post hoc analysis found
`that although the presence of PED was a retreatment criteria in
`HARBOR, patients with complete resolution of PED did not neces-
`sarily see an additional vision benefit and were more likely to dem-
`onstrate macular atrophy at month 24. Therefore, my primary goal
`with PEDs is not to purposefully flatten them out because there
`are reasonable post hoc data that doing so increases the risk of de
`novo atrophy at the site of that lesion.
`
`Dr. Brown: There is certainly controversy in that. To me, fluid is
`bad and activity is bad, and I want to get rid of it. I am more in the
`favor of overtreating than undertreatirig. There is no convincing
`evidence on the atrophy scare, and I am not going to undertreat
`patients based on a hypothesis that has no solid data behind it. We
`have concrete data that undertreatment leads to vision loss and
`
`8 1 OPP' I MFN IC'RtiINA I1JA1/NK\'hi IIN,'M:,lSEprI2MBERO1/
`
`Mylan Exhibit 1093
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`Page 8
`
`

`

`Utility of Fluorescein
`and OCT Angiography in
`Real-World Practice
`
`Dr. Clark: We use fluorescein angiography (FA) to identify
`CNV membranes, but can it be used to predict outcomes or
`how patients will respond to treatment?
`
`Dr. Eichenbaum: I use liquid angiography less than I used
`to. I do get a traditional FA on all new wet AMD patients. I
`think that the angiographic findings have some predictive
`value for injection burden, anatomic response, and visual
`response. I do not talk to individual patients about my pre-
`dictions for their lesions based on the angiographic findings
`because they are variable each patient responds differently.
`A true type-2, well-defined classic lesion that is clear on
`angiography, however, is likely to respond faster and require
`less overall burden of care than a large, poorly defined, pre-
`dominantly occult lesion. Obviously there is no hard-and-fast
`rule, and I do not think we can depend on the pr-treatment
`angiogram to give us a sensitive and specific predictor of
`response. But, it can inform our own "internal monologue" in
`each case.
`
`Dr. Clark How are you using OCT angiography for diagno-
`sis and for any predictors of a treatment response?
`
`Dr. Kaiser. We have not learned enough from OCT angiog-
`raphy to determine the imaging biomarkers that would allow
`us to make outcome predictions. It is too new. Similar to Dr.
`Eichenbaum, I still get an IA at baseline. I think it is an impor-
`tant tool in predicting how often a patient will need treat-
`ment, and there is some predictive value in knowing if it is a
`type 1, 2, or 3 lesion. As OCT angiography improves, however,
`we will use fluorescein angiography less and less in the future.
`
`Dr. Clark Would anyone repeat the angiogram after baseline?
`
`Dr. Kaiser. It is rare for me to repeat the angiogram after
`baseline. I may consider repeating it in a nonresponder or a
`patient who isn't responding like I expected. Usually at that
`point, however, an ICG angiogram would give me more infor-
`mation than a fluorescein angiogram.
`
`Dr. Brown: I think there is a selection bias of patients who go
`into trials. Many patients who go into trials are underinsured and
`enroll because they can get better care in the trial than they can
`with their own insurance. They enroll on a trial like CATT or VIEW
`1 or VIEW 2, which gives them monthly therapy for the duration
`
`Assessing Consistent Long-Term Dosing
`
`of the study, and the patient does very well. But, when the trial is
`over, the patient goes back to being underinsured and undertreat-
`ed and they regress.
`CATT was a 2-year study funded by the National Eye Institute
`(NEI). If we are going to get a view of real-world outcomes long
`term, NEI needs to fund a trial for S to? years and see how patients
`do compared to these other studies that were only funded for 2
`years. Many of my patients with good insurance who s